WO2026030464A1

WO2026030464A1 - Dosage regimen for reducing cytokine release syndrome (crs) with anti-fcrh5/anti-cd3 bispecific antibodies in multiple myeloma therapy

Info

Publication number: WO2026030464A1
Application number: PCT/US2025/039903
Authority: WO
Inventors: Chihunt WONG; James Niall COOPER; Rin NAKAMURA; Divya Anthony SAMINENI; Teiko SUMIYOSHI; Monica Etelina SUSILO
Original assignee: Genentech Inc
Current assignee: Genentech Inc
Priority date: 2024-07-30
Filing date: 2025-07-30
Publication date: 2026-02-05
Anticipated expiration: 2027-01-30

Abstract

The disclosure provides methods of dosing for the treatment of cancers, such as multiple myelomas, with anti-fragment crystallizable receptor-like 5 (FcRH5)/anti-cluster of differentiation 3 (CDS) bispecific antibodies (e.g., cevostamab).

Description

DOSAGE REGIMEN FOR REDUCING CYTOKINE RELEASE SYNDROME (CRS) WITH ANTI-FCRH5/ANTI-CD3 BISPECIFIC ANTIBODIES IN MULTIPLE MYELOMA THERAPY

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Patent Application Serial No. 63/677,374, filed on July 30, 2024, and U.S. Patent Application Serial No. 63/727,146, filed on December 2, 2024, the disclosures of which are incorporated herein by reference in their entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on July 30, 2025, is named “50474-360W03_Sequence_Listing_7_30_25” and is 41 ,595 bytes in size.

TECHNICAL FIELD

The present disclosure relates to the treatment of cancers, such as B cell proliferative disorders. More specifically, the disclosure concerns the specific treatment of human patients having multiple myeloma (MM) using anti-fragment crystallizable receptor-like 5 (FcRH5)/anti-cluster of differentiation 3 (CD3) bispecific antibodies (e.g., cevostamab).

BACKGROUND

Cancer remains one of the most deadly threats to human health. In the U.S., cancer affects more than 1 .7 million new patients each year and is the second leading cause of death after heart disease, accounting for approximately one in four deaths.

Hematologic cancers, in particular, are the second leading cause of cancer-related deaths. Hematologic cancers include multiple myeloma (MM), a neoplasm characterized by the proliferation and accumulation of malignant plasma cells. Worldwide, approximately 1 10,000 people are diagnosed with MM annually. MM remains incurable despite advances in treatment, with an estimated median survival of 8-10 years for standard-risk myeloma and 2-3 years for high-risk disease, despite receipt of an autologous stem-cell transplant. Despite the significant improvement in patient’s survival over the past 20 years, only 10-15% of patients achieve or exceed expected survival compared with the matched general population. Increased survival has been achieved with the introduction of proteasome inhibitors, immunomodulatory drugs (IMiDs), and monoclonal antibodies. Nevertheless, most patients (if not all) eventually relapse, and the outcome of patients with MM after they become refractory, or ineligible to receive a current treatment (e.g., a proteasome inhibitor or an I Mi D) , is quite poor, with survival less than 1 year. Therefore, relapsed or refractory (R/R) MM, in particular, continues to constitute a significant unmet medical need, and novel therapeutic agents are needed. For such patients, alternative or secondary treatment modalities, such as bispecific antibody-based immunotherapies, may be particularly efficacious. However, the administration of such bispecific-based immunotherapies may cause unwanted side effects, such as cytokine release syndrome (CRS) and other adverse events (AEs). There is an unmet need in the field not only for the development of efficacious therapeutic bispecific antibodies (e.g., anti-FcRH5/anti-CD3 bispecific antibodies), but also safe and tolerable methods of dosing in order to achieve a more favorable benefit-risk profile.

SUMMARY

In one aspect, the disclosure provides a method of reducing the likelihood of cytokine release syndrome (CRS) in a subject (e.g., a human subject) having multiple myeloma (MM) (e.g., relapsed or refractory (R/R) MM), wherein the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D2 is greater than the C1 D1 , and the C1 D3 is greater than the C1 D2, and wherein each dose less than the therapeutically effective amount of cevostamab.

In another aspect, the disclosure provides a method of reducing the CRS in a subject (e.g., a human subject) having MM (e.g., R/R MM) and being administered an effective amount of cevostamab, wherein, prior to a first administration to the subject of the effective amount of cevostamab, the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg (e.g., 1 .2 mg or 3.3 mg), and the C1 D3 is between about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg).

In another aspect, the disclosure provides a method of reducing the likelihood of CRS in a subject (e.g., a human subject) having MM (e.g., R/R MM) and being administered an effective amount of cevostamab, wherein, prior to a fist administration to the subject of the effective amount of cevostamab, the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; and the C1 D3 is about 3.6 mg.

In another aspect, the disclosure features a method of reducing the likelihood of CRS in a subject (e.g., a human subject) having MM (e.g., R/R MM) and being administered an effective amount of cevostamab, wherein, prior to a first administration to the subject of the effective amount of cevostamab, the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 3.3 mg; and the C1 D3 is about 7.2 mg.

In yet another aspect, the disclosure provides a method of limiting median peak IL-6 levels in a population of human subjects having MM (e.g., R/R MM) to be administered a therapeutically effective amount of cevostamab, .wherein the method comprises administering to each subject (e.g., a human subject) in the population prior to administration of the therapeutically effective amount of cevostamab a dosing regimen comprising a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D2 is greater than the C1 D1 , and the C1 D3 is greater than the C1 D2, and wherein each dose less than the therapeutically effective amount of cevostamab. In yet another aspect, the disclosure provides a method of achieving a median peak IL-6 level of less than about 30 pg/mL in a population of subjects having MM (e.g., R/R MM) and being administered an effective amount of cevostamab, the method comprising administering to a subject (e.g., a human subject) in the population, prior to being administered the effective amount of cevostamab, a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg, and the C1 D3 is between about 3.6 mg to about 7.2 mg.

In yet another aspect, the disclosure provides a method of limiting peak IL-6 level to less than about 30 pg/mL in a human subject having MM and being administered an effective amount of cevostamab, the method comprising administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3, the C1 D2 is between about 1 mg to about 2.9 mg, and the C1 D3 is between about 3 mg to about 5.9 mg.

In some embodiments of the foregoing aspect, the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; and the C1 D3 is about 3.6 mg.

In some embodiments, the median peak IL-6 level is about 18 pg/mL following administration of the effective amount of cevostamab.

In yet another aspect, the disclosure provides a method of achieving a peak IL-6 level of less than about 30 pg/mL in a subject (e.g. a human subject) having MM (e.g., R/R MM) and being administered an effective amount of cevostamab, the method comprising administering to the subject, prior to being administered the effective amount of cevostamab, a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3, the C1 D2 is between about 1 .2 mg to about 3.3 mg, and the C1 D3 is between about 3.6 mg to about 7.2 mg.

In some embodiments, the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; and the C1 D3 is about 3.6 mg.

In some embodiments, the peak IL-6 level is about 18 pg/mL following administration of cevostamab.

In yet another aspect, the disclosure provides a method of reducing the likelihood of the occurrence of CRS events in a subject (e.g., a human subject) being treated for MM (e.g., R/R MM) with a target dose of cevostamab, the method comprising administering to the subject, prior to a first administration of the target dose to the subject, a dosing regimen comprising a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D2 is greater than the C1 D1 , and the C1 D3 is greater than the C1 D2, and wherein each dose less than the therapeutically effective amount of cevostamab.

In yet another aspect, the disclosure provides a method of reducing the occurrence of CRS events in a subject (e.g., a human subject) being treated for MM (e.g., R/R MM) with a target dose of cevostamab, the method comprising administering to the subject, prior to a first administration of the target dose to the subject, a dosing regimen comprising a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D2 is greater than the C1 D1 , and the C1 D3 is greater than the C1 D2, and wherein each dose less than the therapeutically effective amount of cevostamab.

In yet another aspect, the disclosure provides a method of reducing the occurrence of CRS events in a subject (e.g., a human subject) being treated for MM (e.g., R/R MM) with a target dose of cevostamab, the method comprising administering to the subject, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.03 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg, and the C1 D3 is between about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg).

In another aspect, the disclosure provides a method of reducing the occurrence of CRS events in a subject (e.g., a human subject) being treated for MM (e.g., R/R MM) with a target dose of cevostamab, the method comprising administering to the subject, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), (i) a first dose (C1 D1 ) of about 0.3 mg, (ii) a second dose (C1 D2) of about 1 .2 mg, and (iii) a third dose (C1 D3) of about 3.6 mg of cevostamab.

In another aspect, the disclosure provides a method of reducing the occurrence of CRS events in a subject (e.g., a human subject) being treated for MM (e.g., R/R MM) with a target dose of cevostamab, the method comprising administering to the subject, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), (i) a first dose (C1 D1 ) of about 0.3 mg, (ii) a second dose (C1 D2) of about 3.3 mg, and (ii) a third dose (C1 D3) of about 7.2 mg of cevostamab.

In some embodiments of the foregoing aspect, the method reduces the occurrence of CRS events in a subject as compared to a subject who, prior to a first administration of a target dose, received two or fewer step-up/priming doses (e.g., received no step-up doses, only a C1 D1 , or only a C1 D1 and C1 D2).

In some embodiments, the C1 is 21 days in length, and: (i) the C1 D1 is administered on Day 1 of the C1 ; (ii) the C1 D2 is administered on Day 2, Day 3, or Day 4 of the C1 ; and (iii) the C1 D3 is administered on Day 8 of the C1 .

In some embodiments, the target dose is greater than the C1 D3. In some embodiments the target dose is between about 20 mg to about 252 mg (e.g., about 160 mg).

In some embodiments of the foregoing aspects, the method further comprises administering to the subject an additional dose of cevostamab, wherein the additional dose of cevostamab is greater than the C1 D3. In some embodiments, the additional dose of cevostamab is administered during the C1 as a fourth dose (C1 D4) of cevostamab, wherein the C1 D4 is an effective amount of cevostamab. In some embodiments, the C1 D4 is between about 20 mg to about 252 mg (e.g., about 160 mg). In some embodiments, the C1 D4 is an effective amount of cevostamab and is administered after the C1 D3.

In another aspect, the disclosure provides a method of treating MM (e.g., R/R MM) in a subject (e.g., a human subject), wherein the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3) and a target dose of cevostamab.

In another aspect, the disclosure provides a method of treating MM (e.g., R/R MM) in a subject (e.g., a human subject), wherein the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3) and a target dose of cevostamab, wherein the target dose of cevostamab is a therapeutically effective amount of cevostamab and C1 D1 , C1 D2, and C1 D3 are less than therapeutically effective amount of cevostamab.

In another aspect, the disclosure provides a method of treating MM (e.g., R/R MM) in a subject (e.g., a human subject), wherein the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3) and a target dose of cevostamab, wherein the target dose of cevostamab is an effective amount of cevostamab, the C1 D1 , C1 D2, and C1 D3 are less than the effective amount of cevostamab, the C1 D1 is less than C1 D2, and C1 D2 is less than C1 D3.

In another aspect, the disclosure provides a method of treating a subject (e.g., a human subject) having MM (e.g., R/R MM), wherein the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, wherein C1 D4 is a therapeutically effective amount of cevostamab, and wherein C1 D1 is less than C1 D2, which is less than C1 D3, which is less than C1 D4.

In another aspect, the disclosure provides a method of treating a subject (e.g., a human subject) having a MM (e.g., a R/R MM), wherein the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, wherein the C1 D1 is about 0.3 mg, the C1 D2 is about 1 .2 mg to about 3.3 mg (e.g., 1 .2 mg or 3.3 mg) , the C1 D3 is about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg), and the C1 D4 is between about 20 mg to about 252 mg (e.g., about 160 mg).

In some embodiments, the C1 D4 is an effective amount of cevostamab. In some embodiments, the C1 D4 is about 160 mg.

In some embodiments, the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; and the C1 D3 is about 3.6 mg. In some embodiments, the C1 D1 is about 0.3 mg; the C1 D2 is about 3.3 mg; and the C1 D3 is about 7.2 mg.

In another aspect, the disclosure provides a method of treating a subject (e.g., a human subject) having MM (e.g., R/R MM), wherein the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; the C1 D3 is about 3.6 mg; and the C1 D4 is about 160 mg.

In another aspect, the disclosure provides a method of treating a subject (e.g., a human subject) having MM (e.g., R/R MM), wherein the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, the C1 D1 is about 0.3 mg; the C1 D2 is about 3.3 mg; the C1 D3 is about 7.2 mg; and the C1 D4 is about 160 mg. In some embodiments of any one of the foregoing aspects, the length of the C1 is 21 days. In some embodiments, the method comprises administering to the subject: (a) the C1 D1 on or about Day 1 of the C1 ; (b) the C1 D2 on or about Day 2, Day 3, or Day 4 of the C1 ; and (c) the C1 D3 on or about Day 8 of the C1 .

In some embodiments of the foregoing aspects, the method comprises administering to the subject the C1 D4 on or about Day 9, Day 10, or Day 1 1 of the C1 .

In some embodiments, the method comprises administering to the subject the C1 D4 about 1 day, 2 days, or 3 days after the C1 D3 of the C1 (e.g., after the resolution of a CRS event, if any, that may have occurred after administration of the C1 D3).

In some embodiments of any one of the foregoing aspects, the dosing regimen further comprises a second dosing cycle (C2) comprising a single dose (C2D1 ) of cevostamab, wherein the C2D1 is an effective amount of cevostamab that is equal to or greater than the last administered dose of cevostamab and is between about 20 mg to about 252 mg (e.g., about 160 mg). In some embodiments, the C2D1 is about 160 mg. In some embodiments, the length of the C2 is 21 days. In some embodiments, the method comprises administering to the subject the C2D1 on Day 1 of the C2.

In some embodiments, the dosing regimen further comprises one or more additional dosing cycles. In some embodiments, the dosing regimen comprises one to 15 additional dosing cycles. In some embodiments, the length of each of the one or more additional dosing cycles is 21 days. In some embodiments, each of the one or more additional dosing cycles comprises a single effective dose of cevostamab. In some embodiments, the method comprises administering to the subject the single dose of cevostamab on Day 1 of the one or more additional dosing cycles. In some embodiments, the single dose is between about 20 mg to about 252 mg (e.g., about 160 mg). In some embodiments, the single dose is about 160 mg.

In some embodiments, a median peak IL-6 level in a population of subjects treated according to the method does not exceed 80 pg/mL (e.g., does not exceed 80 pg/mL, 79 pg/mL, 78 pg/mL, 77 pg/mL, 76 pg/mL, 75 pg/mL, 74 pg/mL, 73 pg/mL, 72 pg/mL, 71 pg/mL, 70 pg/mL, 69 pg/mL, 68 pg/mL, 67 pg/mL, 66 pg/mL, 65 pg/mL, 64 pg/mL, 63 pg/mL, 62 pg/mL, 61 pg/mL, 60 pg/mL, 59 pg/mL, 58 pg/mL,

57 pg/mL, 56 pg/mL, 55 pg/mL, 54 pg/mL, 53 pg/mL, 52 pg/mL, 51 pg/mL, 50 pg/mL, 49 pg/mL, 48 pg/mL, 47 pg/mL, 46 pg/mL, 45 pg/mL, 44 pg/mL, 43 pg/mL, 42 pg/mL, 41 pg/mL, or 40 pg/mL, 39 pg/mL,

38 pg/mL, 37 pg/mL, 36 pg/mL, 35 pg/mL, 34 pg/mL, 33 pg/mL, 32 pg/mL, 31 pg/mL, or 30 pg/mL) between the C1 D1 and the C1 D2. In some embodiments, the median peak IL-6 level in a population of subjects treated according to the method does not exceed 30 pg/mL (e.g., does not exceed 30 pg/mL, 29 pg/mL, 28 pg/mL, 27 pg/mL, 26 pg/mL, 25 pg/mL, 24 pg/mL, 23 pg/mL, 22 pg/mL, 21 pg/mL, 20 pg/mL, 19 pg/mL, 18 pg/mL, 17 pg/mL, 16 pg/mL, 15 pg/mL, 14 pg/mL, 13 pg/mL, 12 pg/mL, 1 1 pg/mL, 10 pg/mL, 9 pg/mL, 8 pg/mL, 7 pg/mL, 6 pg/mL, 5 pg/mL, 4 pg/mL, 3 pg/mL, 2 pg/mL, or 1 pg/mL) between the C1 D1 and the C1 D2.

In some embodiments, a median peak IL-6 level in a population of subjects treated according to the method does not exceed 80 pg/mL (e.g., does not exceed 80 pg/mL, 79 pg/mL, 78 pg/mL, 77 pg/mL, 76 pg/mL, 75 pg/mL, 74 pg/mL, 73 pg/mL, 72 pg/mL, 71 pg/mL, 70 pg/mL, 69 pg/mL, 68 pg/mL, 67 pg/mL, 66 pg/mL, 65 pg/mL, 64 pg/mL, 63 pg/mL, 62 pg/mL, 61 pg/mL, 60 pg/mL, 59 pg/mL, 58 pg/mL, 57 pg/mL, 56 pg/mL, 55 pg/mL, 54 pg/mL, 53 pg/mL, 52 pg/mL, 51 pg/mL, 50 pg/mL, 49 pg/mL, 48 pg/mL, 47 pg/mL, 46 pg/mL, 45 pg/mL, 44 pg/mL, 43 pg/mL, 42 pg/mL, 41 pg/mL, or 40 pg/mL, 39 pg/mL, 38 pg/mL, 37 pg/mL, 36 pg/mL, 35 pg/mL, 34 pg/mL, 33 pg/mL, 32 pg/mL, 31 pg/mL, or 30 pg/mL) between the C1 D2 and the C1 D3. In some embodiments, the median peak IL-6 level in a population of subjects treated according to the method does not exceed 30 pg/mL (e.g., does not exceed 30 pg/mL, 29 pg/mL, 28 pg/mL, 27 pg/mL, 26 pg/mL, 25 pg/mL, 24 pg/mL, 23 pg/mL, 22 pg/mL, 21 pg/mL, 20 pg/mL, 19 pg/mL, 18 pg/mL, 17 pg/mL, 16 pg/mL, 15 pg/mL, 14 pg/mL, 13 pg/mL, 12 pg/mL, 11 pg/mL, 10 pg/mL, 9 pg/mL, 8 pg/mL, 7 pg/mL, 6 pg/mL, 5 pg/mL, 4 pg/mL, 3 pg/mL, 2 pg/mL, or 1 pg/mL) between the C1 D2 and the C1 D3.

In some embodiments, the method further comprises administering to the subject a fourth dose (C1 D4) of cevostamab during the C1 , wherein the C1 D4 is between about 20 mg to about 252 mg (e.g., 160 mg), and wherein the median peak IL-6 level in a population of subjects treated according to the method does not exceed 30 pg/mL (e.g., does not exceed 30 pg/mL, 29 pg/mL, 28 pg/mL, 27 pg/mL, 26 pg/mL, 25 pg/mL, 24 pg/mL, 23 pg/mL, 22 pg/mL, 21 pg/mL, 20 pg/mL, 19 pg/mL, 18 pg/mL, 17 pg/mL, 16 pg/mL, 15 pg/mL, 14 pg/mL, 13 pg/mL, 12 pg/mL, 11 pg/mL, 10 pg/mL, 9 pg/mL, 8 pg/mL, 7 pg/mL, 6 pg/mL, 5 pg/mL, 4 pg/mL, 3 pg/mL, 2 pg/mL, or 1 pg/mL) between the C1 D3 and the C1 D4.

In some embodiments, a median peak IL-6 level in a population of subjects treated according to the method does not exceed 30 pg/mL (e.g., does not exceed 30 pg/mL, 29 pg/mL, 28 pg/mL, 27 pg/mL, 26 pg/mL, 25 pg/mL, 24 pg/mL, 23 pg/mL, 22 pg/mL, 21 pg/mL, 20 pg/mL, 19 pg/mL, 18 pg/mL, 17 pg/mL, 16 pg/mL, 15 pg/mL, 14 pg/mL, 13 pg/mL, 12 pg/mL, 11 pg/mL, 10 pg/mL, 9 pg/mL, 8 pg/mL, 7 pg/mL, 6 pg/mL, 5 pg/mL, 4 pg/mL, 3 pg/mL, 2 pg/mL, or 1 pg/mL) between the C1 D3 and the C1 D4.

In some embodiments, a peak IL-6 level in the subject does not exceed 80 pg/mL (e.g., does not exceed 80 pg/mL, 79 pg/mL, 78 pg/mL, 77 pg/mL, 76 pg/mL, 75 pg/mL, 74 pg/mL, 73 pg/mL, 72 pg/mL, 71 pg/mL, 70 pg/mL, 69 pg/mL, 68 pg/mL, 67 pg/mL, 66 pg/mL, 65 pg/mL, 64 pg/mL, 63 pg/mL, 62 pg/mL, 61 pg/mL, 60 pg/mL, 59 pg/mL, 58 pg/mL, 57 pg/mL, 56 pg/mL, 55 pg/mL, 54 pg/mL, 53 pg/mL, 52 pg/mL, 51 pg/mL, 50 pg/mL, 49 pg/mL, 48 pg/mL, 47 pg/mL, 46 pg/mL, 45 pg/mL, 44 pg/mL, 43 pg/mL, 42 pg/mL, 41 pg/mL, or 40 pg/mL, 39 pg/mL, 38 pg/mL, 37 pg/mL, 36 pg/mL, 35 pg/mL, 34 pg/mL, 33 pg/mL, 32 pg/mL, 31 pg/mL, or 30 pg/mL) between the C1 D1 and the C1 D2. In some embodiments, the peak IL-6 level in the subject does not exceed 30 pg/mL (e.g., does not exceed 30 pg/mL, 29 pg/mL, 28 pg/mL, 27 pg/mL, 26 pg/mL, 25 pg/mL, 24 pg/mL, 23 pg/mL, 22 pg/mL, 21 pg/mL, 20 pg/mL, 19 pg/mL, 18 pg/mL, 17 pg/mL, 16 pg/mL, 15 pg/mL, 14 pg/mL, 13 pg/mL, 12 pg/mL, 11 pg/mL, 10 pg/mL, 9 pg/mL, 8 pg/mL, 7 pg/mL, 6 pg/mL, 5 pg/mL, 4 pg/mL, 3 pg/mL, 2 pg/mL, or 1 pg/mL) between the C1 D1 and the C1 D2.

In some embodiments, a peak IL-6 level in the subject does not exceed 80 pg/mL (e.g., does not exceed 80 pg/mL, 79 pg/mL, 78 pg/mL, 77 pg/mL, 76 pg/mL, 75 pg/mL, 74 pg/mL, 73 pg/mL, 72 pg/mL, 71 pg/mL, 70 pg/mL, 69 pg/mL, 68 pg/mL, 67 pg/mL, 66 pg/mL, 65 pg/mL, 64 pg/mL, 63 pg/mL, 62 pg/mL, 61 pg/mL, 60 pg/mL, 59 pg/mL, 58 pg/mL, 57 pg/mL, 56 pg/mL, 55 pg/mL, 54 pg/mL, 53 pg/mL, 52 pg/mL, 51 pg/mL, 50 pg/mL, 49 pg/mL, 48 pg/mL, 47 pg/mL, 46 pg/mL, 45 pg/mL, 44 pg/mL, 43 pg/mL, 42 pg/mL, 41 pg/mL, or 40 pg/mL, 39 pg/mL, 38 pg/mL, 37 pg/mL, 36 pg/mL, 35 pg/mL, 34 pg/mL, 33 pg/mL, 32 pg/mL, 31 pg/mL, or 30 pg/mL) between the C1 D2 and the C1 D3. In some embodiments, the peak IL-6 level in the subject does not exceed 30 pg/mL (e.g., does not exceed 30 pg/mL, 29 pg/mL, 28 pg/mL, 27 pg/mL, 26 pg/mL, 25 pg/mL, 24 pg/mL, 23 pg/mL, 22 pg/mL, 21 pg/mL, 20 pg/mL, 19 pg/mL, 18 pg/mL, 17 pg/mL, 16 pg/mL, 15 pg/mL, 14 pg/mL, 13 pg/mL, 12 pg/mL, 11 pg/mL, 10 pg/mL, 9 pg/mL, 8 pg/mL, 7 pg/mL, 6 pg/mL, 5 pg/mL, 4 pg/mL, 3 pg/mL, 2 pg/mL, or 1 pg/mL) between the C1 D2 and the C1 D3.

In some embodiments, a peak IL-6 level in the subject does not exceed 30 pg/mL (e.g., does not exceed 30 pg/mL, 29 pg/mL, 28 pg/mL, 27 pg/mL, 26 pg/mL, 25 pg/mL, 24 pg/mL, 23 pg/mL, 22 pg/mL, 21 pg/mL, 20 pg/mL, 19 pg/mL, 18 pg/mL, 17 pg/mL, 16 pg/mL, 15 pg/mL, 14 pg/mL, 13 pg/mL, 12 pg/mL, 11 pg/mL, 10 pg/mL, 9 pg/mL, 8 pg/mL, 7 pg/mL, 6 pg/mL, 5 pg/mL, 4 pg/mL, 3 pg/mL, 2 pg/mL, or 1 pg/mL) between the C1 D3 and the C1 D4.

In some embodiments, the method further comprises administering to the subject a fourth dose (C1 D4) of cevostamab during the C1 , wherein the C1 D4 is between about 20 mg to about 252 mg, and wherein the peak IL-6 level in the subject does not exceed 30 pg/mL (e.g., does not exceed 30 pg/mL, 29 pg/mL, 28 pg/mL, 27 pg/mL, 26 pg/mL, 25 pg/mL, 24 pg/mL, 23 pg/mL, 22 pg/mL, 21 pg/mL, 20 pg/mL, 19 pg/mL, 18 pg/mL, 17 pg/mL, 16 pg/mL, 15 pg/mL, 14 pg/mL, 13 pg/mL, 12 pg/mL, 11 pg/mL, 10 pg/mL, 9 pg/mL, 8 pg/mL, 7 pg/mL, 6 pg/mL, 5 pg/mL, 4 pg/mL, 3 pg/mL, 2 pg/mL, or 1 pg/mL) between the C1 D3 and the C1 D4.

In some embodiments of the foregoing aspects, the method further comprises administering to the subject a fourth dose (C1 D4) of cevostamab during the C1 , wherein the C1 D4 is between about 20 mg to about 252 mg, and wherein the peak IL-6 level in the subject does not exceed 30 pg/mL (e.g., does not exceed 30 pg/mL, 29 pg/mL, 28 pg/mL, 27 pg/mL, 26 pg/mL, 25 pg/mL, 24 pg/mL, 23 pg/mL, 22 pg/mL, 21 pg/mL, 20 pg/mL, 19 pg/mL, 18 pg/mL, 17 pg/mL, 16 pg/mL, 15 pg/mL, 14 pg/mL, 13 pg/mL, 12 pg/mL, 11 pg/mL, 10 pg/mL, 9 pg/mL, 8 pg/mL, 7 pg/mL, 6 pg/mL, 5 pg/mL, 4 pg/mL, 3 pg/mL, 2 pg/mL, or 1 pg/mL) between the C1 D3 and the C1 D4.

In some embodiments of any one of the foregoing aspects, a peak level of CD8+ T cell activation in the subject in the C1 occurs between administration of the C1 D1 and the C1 D2.

In some embodiments of any one of the foregoing aspects, a peak level of CD8+ T cell activation in the subject in the C1 occurs between administration of the C1 D2 and the C1 D3.

In some embodiments, a peak level of CD8+ T cell activation in the subject in the C1 occurs between administration of the C1 D3 and the C1 D4.ln some embodiments, the peak level of CD8+ T cell activation in the subject in the C1 within 24 hours after administration of cevostamab.

In some embodiments of any one of the foregoing aspects, the method further comprises evaluating CRS after administration of at least one of the C1 D1 , the C1 D2, and/or the C1 D3. In some embodiments, the method further comprises evaluating CRS after each of the C1 D1 , the C1 D2, and the C1 D3. In some embodiments, after administration of at least one of the C1 D1 , the C1 D2, and/or the C1 D3 (i) no CRS event has occurred, or (ii) CRS signs and symptoms from the previous dose have resolved, and the subject is administered the next dose of cevostamab. In some embodiments, the subject is not administered the next dose of cevostamab unless (i) no CRS event has occurred from administration of at least one of the C1 D1 , the C1 D2, and/or the C1 D3, or (ii) CRS signs and symptoms have resolved after administration of at least one of the C1 D1 , the C1 D2, and/or the C1 D3. In some embodiments, the subject is administered the next dose of cevostamab no earlier than 20 hours from administration of the previous dose.

In some embodiments of any one of the foregoing aspects, the method further comprises measuring CRS after the C1 D1 , the C1 D2, and/or the C1 D3. In some embodiments, the method further comprises measuring CRS after the C1 D1 , the C1 D2, and the C1 D3. In some embodiments, (i) there is no CRS or (ii) CRS signs and symptoms from the previous dose have resolved, and the subject is administered the next dose of cevostamab. In some embodiments, the subject is administered the next dose of cevostamab no earlier than 20 hours from administration of the previous dose.

In some embodiments, the method reduces the likelihood of the subject experiencing a CRS event. In some embodiments, the method reduces the likelihood of the subject experiencing Grade >1 CRS. In some embodiments, the method reduces the likelihood of the subject experiencing Grade >2 CRS. In some embodiments, the method reduces the likelihood of the subject experiencing Grade >3 CRS.

In some embodiments, the likelihood of the subject experiencing Grade 1 CRS after the C1 D1 is less than 10% (e.g., less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1 %, e.g. 0%). In some embodiments, the likelihood of the subject experiencing Grade 1 CRS after the C1 D2 is less than 25% (e.g., less than 25%, less than 24%, less than 23%, less than 22%, less than 21 %, less than 20%, less than 19%, less than 18%, less than 17%, less than 16%, less than 15%, less than 14%, less than 13%, less than 12%, less than 1 1 %, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1 %, e.g. 0%). In some embodiments, the likelihood of the subject experiencing Grade 1 CRS after the C1 D3 is less than 15% (e.g., less than 15%, less than 14%, less than 13%, less than 12%, less than 1 1 %, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1 %, e.g. 0%).

In some embodiments, the likelihood of the subject experiencing Grade 2 CRS after the C1 D1 is less than 10% (e.g., less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1 %, e.g. 0%). In some embodiments, the likelihood of the subject experiencing Grade 2 CRS after the C1 D2 is less than 25% (e.g., less than 25%, less than 24%, less than 23%, less than 22%, less than 21 %, less than 20%, less than 19%, less than 18%, less than 17%, less than 16%, less than 15%, less than 14%, less than 13%, less than 12%, less than 1 1 %, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1 %, e.g. 0%). In some embodiments, the likelihood of the subject experiencing Grade 2 CRS after the C1 D3 is less than 15% (e.g., less than 15%, less than 14%, less than 13%, less than 12%, less than 1 1 %, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1 %, e.g. 0%).

In some embodiments, the likelihood of the subject experiencing at least one Grade 1 or Grade 2 CRS event after the first administration of the C1 D4 is less than 65% (e.g., less than 65%, less than 64%, less than 63%, less than 62%, less than 61 %, less than 60%, less than 59%, or less than 58%).

In some embodiments of any one of the foregoing aspects, the dosing regimen results in a CRS event in less than about 90% (e.g., less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, or less than about 60%) of a population of subjects having MM (e.g., R/R MM). In some embodiments, the dosing regimen results in the CRS event in about 58% to about 90% (e.g., about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81 %, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, or about 90%) of the population of subjects having MM (e.g., R/R MM). In some embodiments, the dosing regimen results in the CRS event in about 58% to about 68% (e.g., about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, or about 68%) of the population of subjects having MM (e.g., R/R MM). In some embodiments, the dosing regimen results in the CRS event in about 63% of the population of subjects having MM (e.g., R/R MM).

In some embodiments of any one of the foregoing aspects, the dosing regimen results in a grade >2 CRS event in less than about 50% of a population of subjects having MM (e.g., R/R MM). In some embodiments, the dosing regimen results in the grade >2 CRS event in about 10% to about 25% (e.g., about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25%) of the population of subjects having MM (e.g., R/R MM). In some embodiments, the dosing regimen results in the grade >2 CRS event in about 17% (e.g., 16%, 17%, or 18%) of the population of subjects having MM (e.g., R/R MM).

In some embodiments of any one of the foregoing aspects, the dosing regimen results in a grade >3 CRS event in less than about 10% of a population of subjects having MM (e.g., R/R MM). In some embodiments, the dosing regimen results in the grade >3 CRS event in about 0% to about 5% (e.g., about 0%, about 1%, about 2%, about 3%, about 4%, or about 5%) of the population of subjects having MM (e.g., R/R MM). In some embodiments, the dosing regimen does not result in any grade >3 CRS event in the population of subjects having MM (e.g., R/R MM).

In some embodiments of any one of the foregoing aspects, cevostamab is administered to the subject as a monotherapy. In some embodiments of any one of the foregoing aspects, cevostamab is administered to the subject as a combination therapy. In some embodiments, cevostamab is administered to the subject concurrently with one or more additional therapeutic agents. In some embodiments, cevostamab is administered to the subject before one or more additional therapeutic agents.

In some embodiments, cevostamab is administered to the subject prior to the administration of one or more additional therapeutic agents. In some embodiments, cevostamab is administered to the subject subsequent to the administration of one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents comprise an effective amount of tocilizumab. In some embodiments, tocilizumab is administered to the subject by intravenous infusion.

In some embodiments: (a) the subject weighs > 100 kg, and tocilizumab is administered to the subject at a dose of 800 mg; (b) the subject weighs > 30 kg and < 100 kg, and tocilizumab is administered to the subject at a dose of 8 mg/kg; or (c) the subject weighs < 30 kg, and tocilizumab is administered to the subject at a dose of 12 mg/kg. In some embodiments, 1 to 2 doses of tocilizumab are administered to the subject if the subject experiences no CRS event. In some embodiments, 4 to 5 doses of tocilizumab are administered to the subject if the subject experiences a Grade 1 CRS event. In some embodiments, 4 doses of tocilizumab are administered to the subject if the subject experiences a Grade 2 CRS event.

In some embodiments, tocilizumab is administered to the subject about 2 hours before administration of cevostamab.

In some embodiments of any one of the foregoing aspects and embodiments, cevostamab is administered to the subject by intravenous infusion. In some embodiments, cevostamab is administered to the subject subcutaneously. In some embodiments, the subject has a CRS event, and treatment with cevostamab is suspended as a result of the CRS event. In some embodiments, the subject has a CRS event, and the method further comprises treating the symptoms of the CRS event while suspending treatment with cevostamab. In some embodiments, the method further comprises administering to the subject an effective amount of tocilizumab to treat the CRS event. In some embodiments, the effective amount is 800 mg if the subject weighs > 100 kg, 8 mg/kg if the subject weighs > 30 kg and < 100 kg, and 12 mg/kg if the subject weighs < 30 kg.

In some embodiments of any one of the foregoing aspects, the subject has received prior treatment for MM. the prior treatment for MM is selected from one or more of a proteasome inhibitor, an IMiD, an anti-CD38 therapeutic agent, an anti-SLAMF7 therapeutic agent, a nuclear export inhibitor, a histone deacetylase (HDAC) inhibitor, an autologous stem cell transplant (ASCT), a bispecific antibody, an antibody-drug conjugate (ADC), a CAR-T cell therapy, and a BCMA-directed therapy

In some embodiments the subject has received a standard of care treatment for MM prior to being administered the C1 D1 . In some embodiments the subject has received prior treatment for MM selected from one or more of a proteasome inhibitor, an immunomodulatory drug (IMiD), and an anti- CD38 therapeutic agent. In some embodiments, the subject has relapsed or become refractory to the standard of care treatment for MM.

In some embodiments of any one of the foregoing aspects, the subject has received at least three prior lines of treatment for the MM. In some embodiments, the subject has received at least four prior lines of treatment for the MM. In some embodiments, the subject has received at least five prior lines of treatment for the MM. In some embodiments, the subject has received at least six prior lines of treatment for the MM. In some embodiments, the subject has received at least seven prior lines of treatment for the MM. In some embodiments, the subject has received at least eight prior lines of treatment for the MM. In some embodiments, the subject has received at least nine prior lines of treatment for the MM. In some embodiments, the subject has received at least ten prior lines of treatment for the MM.

In some embodiments of any one of the foregoing aspects and embodiments, the MM is relapsed or refractory (R/R) MM. drug (IMiD), and an anti-cluster of differentiation 38 (CD38) monoclonal antibody (mAb).

In another aspect, the disclosure provides a method of treating a subject (e.g., a human subject) having R/R MM, wherein the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 of C1 ; the C1 D2 is about

1 .2 mg and is administered on Day 2, Day 3, or Day 4 of C1 ; the C1 D3 is about 3.6 mg and is administered on Day 8 of C1 ; and the C1 D4 is an effective amount of cevostamab and is administered on Day 9, Day 10, or Day 11 of C1 .

In another aspect, the disclosure provides a method of treating a subject (e.g., a human subject) having R/R MM, wherein the method comprises administering to the subject an effective amount of cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 1 .2 mg and is administered on Day 2, Day 3, or Day 4; the C1 D3 is about 3.6 mg and is administered on Day 8; and the C1 D4 is about 160 mg and is administered on Day 9, Day 10, or Day 11 .

In another aspect, the disclosure provides a method of treating a subject (e.g., a human subject) having R/R MM, wherein the method comprises administering to the subject an effective amount of cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 3.3 mg and is administered on Day 2, Day 3, or Day 4; the C1 D3 is about

7.2 mg and is administered on Day 8; and the C1 D4 is about 160 mg and is administered on Day 9, Day 10, or Day 11 .

In another aspect, the disclosure provides a method of reducing the likelihood of CRS in a subject (e.g., a human subject) being treated for R/R MM with a target dose of cevostamab in at least a first dosing cycle (C1 ) of 21 days, wherein prior to administration of the target dose of cevostamab, the C1 further comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 1 .2 mg and is administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 3.6 mg and is administered on Day 8.

In another aspect, the disclosure provides a method of reducing the likelihood of CRS in a subject (e.g., a human subject) having R/R MM and being administered an effective amount of cevostamab, wherein, prior to a first administration to the subject of the effective amount of cevostamab, the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 1 .2 mg and is administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 3.6 mg and is administered on Day 8.

In another aspect, the disclosure provides a method of reducing the likelihood of CRS in a subject (e.g., a human subject) having R/R MM and being administered an effective amount of cevostamab, wherein, prior to a first administration to the subject of the effective amount of cevostamab, the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 3.3 mg and is administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 7.2 mg and is administered on Day 8.

In another aspect, the disclosure provides a method of achieving a median peak IL-6 level of less than about 30 pg/mL (e.g., less than about 30 pg/mL, 29 pg/mL, 28 pg/mL, 27 pg/mL, 26 pg/mL, 25 pg/mL, 24 pg/mL, 23 pg/mL, 22 pg/mL, 21 pg/mL, 20 pg/mL, 19 pg/mL, 18 pg/mL, 17 pg/mL, 16 pg/mL, 15 pg/mL, 14 pg/mL, 13 pg/mL, 12 pg/mL, 11 pg/mL, 10 pg/mL, 9 pg/mL, 8 pg/mL, 7 pg/mL, 6 pg/mL, 5 pg/mL, 4 pg/mL, 3 pg/mL, 2 pg/mL, or 1 pg/mL) in a population of subjects (e.g., human subjects) having R/R MM and being administered an effective amount of cevostamab, the method comprising administering to a subject (e.g., a human subject) in the population, prior to being administered the effective amount of cevostamab, a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 1 .2 mg and is administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 3.6 mg and is administered on Day 8.

In yet another aspect, the disclosure provides a method of treating a subject (e.g., a human subject) having R/R MM, wherein the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 3.3 mg and is administered on Day 2, Day 3, or Day 4; the C1 D3 is about 160 mg and is administered on Day 8, and wherein tocilizumab is administered to the subject about 2 hours prior to administering the first dose of cevostamab.

In another aspect, the disclosure provides a method of treating a subject (e.g., a human subject) having R/R MM, wherein the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3), wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 3.3 mg and is administered on Day 4; and the C1 D3 is about 160 mg and is administered on Day 8.

In some embodiments of any one of the preceding aspects, the dosing regimen further comprises a second dosing cycle (C2) comprising a single dose (C2D1 ) of cevostamab, wherein the length of the C2 is 21 days, and wherein the C2D1 is about 160 mg and is administered to the subject on Day 1 of the second dosing cycle. In some embodiments, the dosing regimen comprises one or more additional dosing cycles, wherein the length of each of the one or more additional dosing cycles is 21 days, wherein each of the one or more additional dosing cycles comprises a single 160 mg dose of cevostamab, and wherein the single 160 mg dose of cevostamab is administered to the subject on Day 1 of each of the one or more additional dosing cycles.

In another aspect, the disclosure provides a method of reducing the occurrence of CRS events in a subject (e.g., a human subject) being treated for R/R MM with a target dose of cevostamab, the method comprising administering to the subject, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 1 .2 mg and is administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 3.6 mg and is administered on Day 8, wherein the length of the C1 is 21 days.

In another aspect, the disclosure provides a method of reducing the occurrence of CRS events in a subject (e.g., a human subject) being treated for R/R MM with a target dose of cevostamab, the method comprising administering to the subject, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 3.3 mg and is administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 7.2 mg and is administered on Day 8, wherein the length of the C1 is 21 days

In another aspect, the disclosure provides a method of reducing the occurrence of CRS events in a subject (e.g., a human subject) being treated for R/R MM with a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ), (ii) a second dose (TS-C1 D2), and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering such target dose to a first plurality of such subjects results in a reduction in the number of subjects experiencing a CRS event after first administration of the target dose, as compared to a second plurality of such subjects administered such target dose after administration of a first dose (DS-C1 D1 ) and a second dose (DS- C1 D2), with no third dose (DS-C1 D3), and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS- C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

In some embodiments of the foregoing aspect, administering such target dose to the first plurality of such subjects results in at least a 10% reduction (e.g., at least a 10% reduction, at least an 1 1 % reduction, at least a 12% reduction, at least a 13% reduction, at least a 14% reduction, or at least a 15% reduction) in the number of subjects experiencing a CRS event after first administration of the target dose. In some embodiments, administering such target dose to the first plurality of such subjects results in a 15% reduction in the number of subjects experiencing a CRS event after first administration of the target dose.

In yet another aspect, the disclosure provides a method of reducing the occurrence of CRS events in a subject (e.g., a human subject) being treated for R/R MM with a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ), (ii) a second dose (TS-C1 D2), and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering such target dose to a first plurality of such subjects results in at least a 10% reduction (e.g., at least a 10% reduction, at least an 1 1 % reduction, at least a 12% reduction, at least a 13% reduction, or at least a 14% reduction) in the number of subjects experiencing a CRS event during the C1 , as compared to a second plurality of such subjects administered such target dose after administration of a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), with no third dose (DS-C1 D3), and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 . In some embodiments, wherein administering such target dose to the first plurality of such subjects results in a 14% reduction in the number of subjects experiencing a CRS event during the C1 . In another aspect, the disclosure provides a method of reducing the occurrence of CRS events in a subject (e.g., a human subject) being treated for R/R MM with a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering cevostamab in the C1 to a first plurality of such human subjects results in at least a 30% reduction in the number of CRS events experienced by each subject during the C1 , as compared to a second plurality of human patients administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose (DS-C1 D3) of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

In some embodiments of the foregoing aspect, administering such target dose to the first plurality of such subjects results in at least a 10% reduction (e.g., at least a 10% reduction, at least an 11% reduction, at least a 12% reduction, or at least a 13% reduction) in the number of subjects experiencing a CRS event during the C1 . In some embodiments, administering such target dose to the first plurality of such subjects results in a 14% reduction in the number of subjects experiencing a CRS event during the C1.

In yet another aspect, the disclosure provides a method of reducing the occurrence of CRS events in a subject being treated for MM (e.g., R/R MM) at a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of CRS events experienced by each subject during the C1 , as compared to a second plurality of subjects administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose (DS-C1 D3) of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 . In some embodiments, administering cevostamab in the C1 to the first plurality of such subjects results in at least a 30% reduction in the number of CRS events experienced by each subject during the C1 .

In yet another aspect, the disclosure provides a method of reducing the occurrence of CRS events in a subject (e.g., a human subject) being treated for MM (e.g., R/R MM) at a target dose of cevostamab, wherein, prior to first administration of the target dose to the subject in a first treatment cycle (C1 ), the subject is administered cevostamab at (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3), wherein administering cevostamab in the first treatment cycle to a first plurality of such human subjects results in a reduction in the number of subjects requiring tocilizumab treatment for CRS during first treatment cycle, as compared to a second plurality of human subjects administered a target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose (DS-C1 D3) of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 . In some embodiments of the foregoing aspect, administering cevostamab in the C1 to the first plurality of such subjects results in at least a 10% reduction in the number of subjects requiring tocilizumab treatment for CRS during the C1 .

In yet another aspect, the disclosure provides a method of pre-treating a subject (e.g., a human subject) for receiving a target dose of cevostamab, wherein the method comprises administering to the subject (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D2 is greater than the C1 D1 , and the C1 D3 is greater than the C1 D2, wherein the risk of CRS events in the subject, after administration of the C1 D1 , C1 D2, and C1 D3 to the subject, is at a level that is safe for the subject to receive the target dose of cevostamab.

In some embodiments of the foregoing aspect, following administration of the C1 D1 , C1 D2, and C1 D3 to the subject, the subject achieves a peak IL-6 level of less than about 80 pg/mL (e.g., less than 80 pg/mL, 79 pg/mL, 78 pg/mL, 77 pg/mL, 76 pg/mL, 75 pg/mL, 74 pg/mL, 73 pg/mL, 72 pg/mL, 71 pg/mL, 70 pg/mL, 69 pg/mL, 68 pg/mL, 67 pg/mL, 66 pg/mL, 65 pg/mL, 64 pg/mL, 63 pg/mL, 62 pg/mL,

61 pg/mL, 60 pg/mL, 59 pg/mL, 58 pg/mL, 57 pg/mL, 56 pg/mL, 55 pg/mL, 54 pg/mL, 53 pg/mL, 52 pg/mL, 51 pg/mL, 50 pg/mL, 49 pg/mL, 48 pg/mL, 47 pg/mL, 46 pg/mL, 45 pg/mL, 44 pg/mL, 43 pg/mL,

42 pg/mL, 41 pg/mL, or 40 pg/mL, 39 pg/mL, 38 pg/mL, 37 pg/mL, 36 pg/mL, 35 pg/mL, 34 pg/mL, 33 pg/mL, 32 pg/mL, 31 pg/mL, or 30 pg/mL), thereby indicating that the risk of CRS events in the subject is at a level that is safe for the subject to receive the target dose of cevostamab. In some embodiments, the subject achieves a peak IL-6 level of less than about 30 pg/mL (e.g., less than about 30 pg/mL, 29 pg/mL, 28 pg/mL, 27 pg/mL, 26 pg/mL, 25 pg/mL, 24 pg/mL, 23 pg/mL, 22 pg/mL, 21 pg/mL, 20 pg/mL, 19 pg/mL, 18 pg/mL, 17 pg/mL, 16 pg/mL, 15 pg/mL, 14 pg/mL, 13 pg/mL, 12 pg/mL, 11 pg/mL, 10 pg/mL, 9 pg/mL, 8 pg/mL, 7 pg/mL, 6 pg/mL, 5 pg/mL, 4 pg/mL, 3 pg/mL, 2 pg/mL, or 1 pg/mL) prior to the administration of the target dose of cevostamab. In some embodiments, the method further comprises administering to the pre-treated subject a target dose of cevostamab.

In yet another aspect, the disclosure provides a method of reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS- C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering cevostamab in the C1 to a first plurality of such human subjects results in a reduction in the number of CRS events experienced by each subject during the C1 , as compared to a second plurality of subjects administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose (DS-C1 D3) of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .In some embodiments of the foregoing aspect, administering cevostamab in the C1 to the first plurality of such subjects results in at least a 25% reduction in the number of CRS events experienced by each subject during the C1 .

In yet another aspect, the disclosure provides a method of reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS- C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering cevostamab in the C1 to a first plurality of such subjects results in an increase in the number of subjects experiencing no CRS event during the C1 , as compared to a second plurality of subjects administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose (DS-C1 D3) of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

In some embodiments of the foregoing aspect, administering cevostamab in the C1 to the first plurality of such subjects results in at least a 50% increase in the number of subjects experiencing no CRS event during the C1 .

In yet another aspect, the disclosure provides a method of reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS- C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of subjects experiencing at least two CRS events during the C1 , as compared to a second plurality of subjects administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose (DS-C1 D3) of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

In some embodiments of the foregoing aspect, administering cevostamab in the C1 to the first plurality of such subjects results in at least a 50% reduction in the number of subjects experiencing at least two CRS events during the C1 .

In some embodiments of any one of the foregoing aspects, the subject is a human subject.

In yet another aspect, the disclosure features a method of reducing the likelihood of cytokine release syndrome (CRS) in a subject (e.g., a human subject) having multiple myeloma (MM), wherein the method comprises administering to the subject a bispecific antibody that binds to Fc receptor-like 5 (FcRH5) and cluster of differentiation 3 (CD3) (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the first dosing cycle (C1 ) comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the bispecific antibody, wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., about 0.01 mg to about 0.1 mg, about 0.1 mg to about 0.5 mg, about 0.25 mg to about 0.75 mg, about 0.5 mg to about 0.9 mg, or about 0.2 mg to about 0.4 mg, e.g., about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, or about 0.9 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., about 1 mg to about 1 .5 mg, about 1 mg to about 2 mg, about 1 mg to about 2.9 mg, about 1 mg to about 3.4 mg, about 1 .1 mg to about 1 .3 mg, about 1 .2 mg to about 3.3 mg, about 1 .5 mg to about 4 mg, about 2 mg to about 3 mg, about 2 mg to about 4.5 mg, about 2.5 mg to about 5 mg, about 3 mg to about 4 mg, about 3 mg to about 5 mg, about 3.5 mg to about 5.9 mg, about 3.2 mg to about 3.4 mg, or about 3.5 mg to about 3.7 mg, e.g., about 1 mg, about 1 .1 mg, about 1 .2 mg, about 1 .3 mg, about 1 .4 mg, about 1 .5 mg, about 1 .6 mg, about 1 .7 mg, about 1 .8 mg, about 1 .9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about

4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, or about 5.9 mg), and the C1 D3 is between about 3 mg to about 19.9 mg (e.g., about 3 mg to about 10 mg, about 3 mg to about 7.5 mg, about 3 mg to about 5 mg, about 3 mg to about 4 mg, about 3.5 mg to about 3.7 mg, about 3.5 mg to about 7 mg, about 3.6 mg to about 7.2 mg, about 5 mg to about 7 mg, about 5 mg to about 10 mg, about 5 mg to about 15 mg, about 6 mg to about 19.9 mg, about 6.5 mg to about 10 mg, about 7 mg to about 15 mg, about 7.1 mg to about 7.3 mg, about 10 mg to about 15 mg, about 12 mg to about 17 mg, or about 15 mg to about 19.9 mg, e.g., about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about

9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, about 10 mg, about 10.1 mg, about

10.2 mg, about 10.3 mg, about 10.4 mg, about 10.5 mg, about 10.6 mg, about 10.7 mg, about 10.8 mg, about 10.9 mg, about 11 mg, about 11.1 mg, about 11 .2 mg, about 11 .3 mg, about 11 .4 mg, about 11 .5 mg, about 11 .6 mg, about 11 .7 mg, about 11 .8 mg, about 11 .9 mg, about 12 mg, about 12.1 mg, about

12.2 mg, about 12.3 mg, about 12.4 mg, about 12.5 mg, about 12.6 mg, about 12.7 mg, about 12.8 mg, about 12.9 mg, about 13 mg, about 13.1 mg, about 13.2 mg, about 13.3 mg, about 13.4 mg, about 13.5 mg, about 13.6 mg, about 13.7 mg, about 13.8 mg, about 13.9 mg, about 14 mg, about 14.1 mg, about

14.2 mg, about 14.3 mg, about 14.4 mg, about 14.5 mg, about 14.6 mg, about 14.7 mg, about 14.8 mg, about 14.9 mg, about 15 mg, about 15.1 mg, about 15.2 mg, about 15.3 mg, about 15.4 mg, about 15.5 mg, about 15.6 mg, about 15.7 mg, about 15.8 mg, about 15.9 mg, about 16 mg, about 16.1 mg, about

16.2 mg, about 16.3 mg, about 16.4 mg, about 16.5 mg, about 16.6 mg, about 16.7 mg, about 16.8 mg, about 16.9 mg, about 17 mg, about 17.1 mg, about 17.2 mg, about 17.3 mg, about 17.4 mg, about 17.5 mg, about 17.6 mg, about 17.7 mg, about 17.8 mg, about 17.9 mg, about 18 mg, about 18.1 mg, about

18.2 mg, about 18.3 mg, about 18.4 mg, about 18.5 mg, about 18.6 mg, about 18.7 mg, about 18.8 mg, about 18.9 mg, about 19 mg, about 19.1 mg, about 19.2 mg, about 19.3 mg, about 19.4 mg, about 19.5 mg, about 19.6 mg, about 19.7 mg, about 19.8 mg, or about 19.9 mg) and is greater than the C1 D2.

In another aspect, the disclosure features a method of achieving a median peak IL-6 level of less than about 30 pg/mL (e.g., about 10 pg/mL, about 11 pg/mL, about 12 pg/mL, about 13 pg/mL, about 14 pg/mL, about 15 pg/mL, about 16 pg/mL, about 17 pg/mL, about 18 pg/mL, about 19 pg/mL, about 20 pg/mL, about 21 pg/mL, about 22 pg/mL, about 23 pg/mL, about 24 pg/mL, about 25 pg/mL, about 26 pg/mL, about 27 pg/mL, about 28 pg/mL, about 29 pg/mL, or about 30 pg/mL) in a population of subjects (e.g., human subjects) having MM following administration of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab), wherein the method comprises administering to a subject in the population the bispecific antibody in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the first dosing cycle (C1 ) comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the bispecific antibody, wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., about 0.01 mg to about 0.1 mg, about 0.1 mg to about 0.5 mg, about 0.25 mg to about 0.75 mg, about 0.5 mg to about 0.9 mg, or about 0.2 mg to about 0.4 mg, e.g., about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, or about 0.9 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., about 1 mg to about 1 .5 mg, about 1 mg to about 2 mg, about 1 mg to about 2.9 mg, about 1 mg to about 3.4 mg, about 1 .1 mg to about 1 .3 mg, about 1 .2 mg to about 3.3 mg, about 1 .5 mg to about 4 mg, about 2 mg to about 3 mg, about 2 mg to about 4.5 mg, about 2.5 mg to about 5 mg, about 3 mg to about 4 mg, about 3 mg to about 5 mg, about 3.5 mg to about 5.9 mg, about 3.2 mg to about 3.4 mg, or about 3.5 mg to about 3.7 mg, e.g., about 1 mg, about 1 .1 mg, about 1 .2 mg, about 1 .3 mg, about 1 .4 mg, about 1 .5 mg, about 1 .6 mg, about

I .7 mg, about 1 .8 mg, about 1 .9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, or about 5.9 mg), and the C1 D3 is between about 3 mg to about 19.9 mg (e.g., about 3 mg to about 10 mg, about 3 mg to about 7.5 mg, about 3 mg to about 5 mg, about 3 mg to about 4 mg, about 3.5 mg to about 3.7 mg, about 3.5 mg to about 7 mg, about 3.6 mg to about 7.2 mg, about 5 mg to about 7 mg, about 5 mg to about 10 mg, about 5 mg to about 15 mg, about 6 mg to about 19.9 mg, about 6.5 mg to about 10 mg, about 7 mg to about 15 mg, about 7.1 mg to about 7.3 mg, about 10 mg to about 15 mg, about 12 mg to about 17 mg, or about 15 mg to about 19.9 mg, e.g., about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, about 10 mg, about 10.1 mg, about 10.2 mg, about 10.3 mg, about 10.4 mg, about 10.5 mg, about 10.6 mg, about 10.7 mg, about 10.8 mg, about 10.9 mg, about 1 1 mg, about 1 1 .1 mg, about

I I .2 mg, about 1 1 .3 mg, about 1 1 .4 mg, about 1 1 .5 mg, about 1 1 .6 mg, about 1 1 .7 mg, about 1 1 .8 mg, about 1 1 .9 mg, about 12 mg, about 12.1 mg, about 12.2 mg, about 12.3 mg, about 12.4 mg, about 12.5 mg, about 12.6 mg, about 12.7 mg, about 12.8 mg, about 12.9 mg, about 13 mg, about 13.1 mg, about 13.2 mg, about 13.3 mg, about 13.4 mg, about 13.5 mg, about 13.6 mg, about 13.7 mg, about 13.8 mg, about 13.9 mg, about 14 mg, about 14.1 mg, about 14.2 mg, about 14.3 mg, about 14.4 mg, about 14.5 mg, about 14.6 mg, about 14.7 mg, about 14.8 mg, about 14.9 mg, about 15 mg, about 15.1 mg, about

15.2 mg, about 15.3 mg, about 15.4 mg, about 15.5 mg, about 15.6 mg, about 15.7 mg, about 15.8 mg, about 15.9 mg, about 16 mg, about 16.1 mg, about 16.2 mg, about 16.3 mg, about 16.4 mg, about 16.5 mg, about 16.6 mg, about 16.7 mg, about 16.8 mg, about 16.9 mg, about 17 mg, about 17.1 mg, about

17.2 mg, about 17.3 mg, about 17.4 mg, about 17.5 mg, about 17.6 mg, about 17.7 mg, about 17.8 mg, about 17.9 mg, about 18 mg, about 18.1 mg, about 18.2 mg, about 18.3 mg, about 18.4 mg, about 18.5 mg, about 18.6 mg, about 18.7 mg, about 18.8 mg, about 18.9 mg, about 19 mg, about 19.1 mg, about

19.2 mg, about 19.3 mg, about 19.4 mg, about 19.5 mg, about 19.6 mg, about 19.7 mg, about 19.8 mg, or about 19.9 mg).

In some embodiments, the median peak IL-6 level is about 10 pg/mL to about 80 pg/mL (e.g., about 10 pg/mL, about 1 1 pg/mL, about 12 pg/mL, about 13 pg/mL, about 14 pg/mL, about 15 pg/mL, about 16 pg/mL, about 17 pg/mL, about 18 pg/mL, about 19 pg/mL, about 20 pg/mL, about 21 pg/mL, about 22 pg/mL, about 23 pg/mL, about 24 pg/mL, about 25 pg/mL, about 26 pg/mL, about 27 pg/mL, about 28 pg/mL, about 29 pg/mL, about 30 pg/mL, about 31 pg/mL, about 32 pg/mL, about 33 pg/mL, about 34 pg/mL, about 35 pg/mL, about 36 pg/mL, about 37 pg/mL, about 38 pg/mL, about 39 pg/mL, about 40 pg/mL, about 41 pg/mL, about 42 pg/mL, about 43 pg/mL, about 44 pg/mL, about 45 pg/mL, about 46 pg/mL, about 47 pg/mL, about 48 pg/mL, about 49 pg/mL, about 50 pg/mL, about 51 pg/mL, about 52 pg/mL, about 53 pg/mL, about 54 pg/mL, about 55 pg/mL, about 56 pg/mL, about 57 pg/mL, about 58 pg/mL, about 59 pg/mL, about 60 pg/mL, about 61 pg/mL, about 62 pg/mL, about 63 pg/mL, about 64 pg/mL, about 65 pg/mL, about 66 pg/mL, about 67 pg/mL, about 68 pg/mL, about 69 pg/mL, about 70 pg/mL, about 71 pg/mL, about 72 pg/mL, about 73 pg/mL, about 74 pg/mL, about 75 pg/mL, about 76 pg/mL, about 77 pg/mL, about 78 pg/mL, about 79 pg/mL, or about 80 pg/mL) following administration of the bispecific antibody. In some embodiments, the median peak IL-6 level is about 80 pg/mL following administration of the bispecific antibody. In some embodiments, the median peak IL-6 level is about 30 pg/mL following administration of the bispecific antibody. In some embodiments, the median peak IL-6 level is about 18 pg/mL following administration of the bispecific antibody.

In some embodiments, the median peak IL-6 level is measured in blood samples obtained from the population of subjects (e.g., human subjects). In some embodiments, the blood samples are peripheral blood samples.

In some embodiments, the method further comprises administering to the subject (e.g., human subjects) an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is greater than the C1 D3. In some embodiments, the additional dose of the bispecific antibody that is greater than the C1 D3 is a target dose of the bispecific antibody. In some embodiments, the additional dose of the bispecific antibody is administered during the first dosing cycle (C1 ) as a fourth dose (C1 D4) of the bispecific antibody and is between about 20 mg to about 252 mg (e.g., about 30 mg to about 252 mg, about 40 mg to about 252 mg, about 60 mg to about 252 mg, about 80 mg to about 252 mg, about 100 mg to about 200 mg, about 140 mg to about 180 mg, about 150 mg to about 170 mg, about 132 mg to about 160 mg, about 70 mg to about 105 mg, or about 100 mg to about 180 mg, e.g., about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, or about 252 mg). In some embodiments, the C1 D4 of the bispecific antibody is a target dose of the bispecific antibody.

In another aspect, the disclosure features a method of treating a subject (e.g., a human subject) having MM, wherein the method comprises administering to the subject an effective amount of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the first dosing cycle (C1 ) comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of the bispecific antibody, wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., about 0.01 mg to about 0.1 mg, about 0.1 mg to about 0.5 mg, about 0.25 mg to about 0.75 mg, about 0.5 mg to about 0.9 mg, or about 0.2 mg to about 0.4 mg, e.g., about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, or about 0.9 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., about 1 mg to about 1 .5 mg, about 1 mg to about 2 mg, about 1 mg to about 2.9 mg, about 1 mg to about 3.4 mg, about 1 .1 mg to about 1 .3 mg, about 1 .2 mg to about

3.3 mg, about 1 .5 mg to about 4 mg, about 2 mg to about 3 mg, about 2 mg to about 4.5 mg, about 2.5 mg to about 5 mg, about 3 mg to about 4 mg, about 3 mg to about 5 mg, about 3.5 mg to about 5.9 mg, about 3.2 mg to about 3.4 mg, or about 3.5 mg to about 3.7 mg, e.g., about 1 mg, about 1 .1 mg, about 1 .2 mg, about 1 .3 mg, about 1 .4 mg, about 1 .5 mg, about 1 .6 mg, about 1 .7 mg, about 1 .8 mg, about 1 .9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about

2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about

5.6 mg, about 5.7 mg, about 5.8 mg, or about 5.9 mg), the C1 D3 is between about 3 mg to about 19.9 mg

(e.g., about 3 mg to about 10 mg, about 3 mg to about 7.5 mg, about 3 mg to about 5 mg, about 3 mg to about 4 mg, about 3.5 mg to about 3.7 mg, about 3.5 mg to about 7 mg, about 3.6 mg to about 7.2 mg, about 5 mg to about 7 mg, about 5 mg to about 10 mg, about 5 mg to about 15 mg, about 6 mg to about

19.9 mg, about 6.5 mg to about 10 mg, about 7 mg to about 15 mg, about 7.1 mg to about 7.3 mg, about 10 mg to about 15 mg, about 12 mg to about 17 mg, or about 15 mg to about 19.9 mg, e.g., about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about

4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, about 10 mg, about 10.1 mg, about 10.2 mg, about 10.3 mg, about 10.4 mg, about 10.5 mg, about 10.6 mg, about 10.7 mg, about 10.8 mg, about 10.9 mg, about 11 mg, about 11 .1 mg, about 11 .2 mg, about 11 .3 mg, about 11 .4 mg, about

11 .5 mg, about 11 .6 mg, about 11 .7 mg, about 11 .8 mg, about 11 .9 mg, about 12 mg, about 12.1 mg, about 12.2 mg, about 12.3 mg, about 12.4 mg, about 12.5 mg, about 12.6 mg, about 12.7 mg, about 12.8 mg, about 12.9 mg, about 13 mg, about 13.1 mg, about 13.2 mg, about 13.3 mg, about 13.4 mg, about

13.5 mg, about 13.6 mg, about 13.7 mg, about 13.8 mg, about 13.9 mg, about 14 mg, about 14.1 mg, about 14.2 mg, about 14.3 mg, about 14.4 mg, about 14.5 mg, about 14.6 mg, about 14.7 mg, about 14.8 mg, about 14.9 mg, about 15 mg, about 15.1 mg, about 15.2 mg, about 15.3 mg, about 15.4 mg, about

15.5 mg, about 15.6 mg, about 15.7 mg, about 15.8 mg, about 15.9 mg, about 16 mg, about 16.1 mg, about 16.2 mg, about 16.3 mg, about 16.4 mg, about 16.5 mg, about 16.6 mg, about 16.7 mg, about 16.8 mg, about 16.9 mg, about 17 mg, about 17.1 mg, about 17.2 mg, about 17.3 mg, about 17.4 mg, about

17.5 mg, about 17.6 mg, about 17.7 mg, about 17.8 mg, about 17.9 mg, about 18 mg, about 18.1 mg, about 18.2 mg, about 18.3 mg, about 18.4 mg, about 18.5 mg, about 18.6 mg, about 18.7 mg, about 18.8 mg, about 18.9 mg, about 19 mg, about 19.1 mg, about 19.2 mg, about 19.3 mg, about 19.4 mg, about

19.5 mg, about 19.6 mg, about 19.7 mg, about 19.8 mg, or about 19.9 mg) and is greater than the C1 D2, and the C1 D4 is between about 20 mg to about 252 mg (e.g., about 30 mg to about 252 mg, about 40 mg to about 252 mg, about 60 mg to about 252 mg, about 80 mg to about 252 mg, about 100 mg to about 200 mg, about 140 mg to about 180 mg, about 150 mg to about 170 mg, about 132 mg to about 160 mg, about 70 mg to about 105 mg, or about 100 mg to about 180 mg, e.g., about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about

105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 131 mg, about

132 mg, about 133 mg, about 134 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about

155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about

190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about

225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, or about 252 mg). In some embodiments, the C1 D4 of the bispecific antibody is a target dose of the bispecific antibody.

In some embodiments, the C1 D4 is between about 132 mg to about 160 mg. In some embodiments, the C1 D4 is about 160 mg. In some embodiments, the C1 D4 of the bispecific antibody is a target dose of the bispecific antibody.

In some embodiments, the C1 D1 is between about 0.1 mg to about 0.6 mg (e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, or about 0.6 mg); the C1 D2 is between about 1 mg to about 5 mg (e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg); and the C1 D3 is between about 3 mg to about 10 mg (e.g., about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg) and is greater than the C1 D2. In some embodiments, the C1 D1 is about 0.3 mg; the C1 D2 is between about 1 mg to about 2.9 mg (e.g., about 1 mg, about 1 .1 mg, about 1 .2 mg, about 1 .3 mg, about 1 .4 mg, about 1 .5 mg, about 1 .6 mg, about 1 .7 mg, about 1 .8 mg, about 1 .9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about

2.6 mg, about 2.7 mg, about 2.8 mg, or about 2.9 mg); and the C1 D3 is between about 3 mg to about 5.9 mg.

In some embodiments, the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; and the C1 D3 is about 3.6 mg. In some embodiments, the C1 D1 is about 0.3 mg; the C1 D2 is between about 3 mg to about 5 mg (e.g., about 3 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about

4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, or about 5 mg); and the C1 D3 is between about 6 mg to about 10 mg (e.g., about 6 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about

7.7 mg, about 7.8 mg, about 7.9 mg, about 8 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, or about 10 mg). In some embodiments, the C1 D1 is about 0.3 mg; the C1 D2 is about 3.3 mg; and the C1 D3 is about 7.2 mg.

In another aspect, the disclosure features a method of treating a subject (e.g., a human subject) having MM, wherein the method comprises administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the first dosing cycle (C1 ) comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of the bispecific antibody, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; the C1 D3 is about 3.6 mg; and the C1 D4 is about 160 mg. In some embodiments, the C1 D4 of the bispecific antibody is a target dose of the bispecific antibody.

In another aspect, the disclosure features method of treating a subject (e.g., a human subject) having MM, wherein the method comprises administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the first dosing cycle (C1 ) comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of the bispecific antibody, the C1 D1 is about 0.3 mg; the C1 D2 is about

3.3 mg; the C1 D3 is about 7.2 mg; and the C1 D4 is about 160 mg. In some embodiments, the C1 D4 of the bispecific antibody is a target dose of the bispecific antibody.

In one aspect, the disclosure features a method of reducing the likelihood of CRS in a subject (e.g., a human subject) having MM, wherein the method comprises administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the first dosing cycle (C1 ) comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the bispecific antibody, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; and the C1 D3 is about 3.6 mg.

In another aspect, the disclosure features a method of reducing the likelihood of CRS in a subject (e.g., a human subject) having MM, wherein the method comprises administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the first dosing cycle (C1 ) comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the bispecific antibody, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 3.3 mg; and the C1 D3 is about 7.2 mg.

In one aspect, the disclosure features a method of achieving a median peak IL-6 level of about 30 pg/mL in a population of subjects (e.g., human subjects) having MM following administration of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab), wherein the method comprises administering to a subject in the population the bispecific antibody in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the first dosing cycle (C1 ) comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the bispecific antibody, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; and the C1 D3 is about 3.6 mg.

In some embodiments, the length of the first dosing cycle (C1 ) is 21 days. In some embodiments, the method comprises administering to the subject: (a) the C1 D1 on or about Day 1 of the first dosing cycle (C1 ); (b) the C1 D2 on or about Day 2, Day 3, or Day 4 of the first dosing cycle; and (c) the C1 D3 on or about Day 8 of the first dosing cycle.

In some embodiments, the length of the first dosing cycle (C1 ) is 21 days, and the method comprises administering to the subject the C1 D4 on or about Day 9, Day 10, or Day 11 of the first dosing cycle (C1 ).

In some embodiments, the length of the first dosing cycle (C1 ) is 21 days, and the method comprises administering to the subject the C1 D4 about 1 day, 2 days, or 3 days after the C1 D3 of the first dosing cycle (C1 ).

In some embodiments, the C1 D4 of the bispecific antibody is a target dose of the bispecific antibody.

In one aspect, the disclosure features a method of treating a subject (e.g., a human subject) having MM, wherein the method comprises administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the first dosing cycle (C1 ) is 21 days, wherein the first dosing cycle (C1 ) comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the bispecific antibody, and wherein: (a) the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., about 0.01 mg to about 0.1 mg, about 0.1 mg to about 0.5 mg, about 0.25 mg to about 0.75 mg, about 0.5 mg to about 0.9 mg, or about 0.2 mg to about 0.4 mg, e.g., about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, or about 0.9 mg) and is administered to the subject on or about Day 1 of the first dosing cycle (C1 ); (b) the C1 D2 is between about 1 mg to about 5.9 mg (e.g., about 1 mg to about 1 .5 mg, about 1 mg to about 2 mg, about 1 mg to about 2.9 mg, about 1 mg to about 3.4 mg, about 1 .1 mg to about 1 .3 mg, about 1 .2 mg to about 3.3 mg, about 1 .5 mg to about 4 mg, about 2 mg to about 3 mg, about 2 mg to about 4.5 mg, about 2.5 mg to about 5 mg, about 3 mg to about 4 mg, about 3 mg to about 5 mg, about 3.5 mg to about 5.9 mg, about 3.2 mg to about 3.4 mg, or about 3.5 mg to about 3.7 mg, e.g., about 1 mg, about 1 .1 mg, about 1 .2 mg, about 1 .3 mg, about 1 .4 mg, about 1 .5 mg, about 1 .6 mg, about 1 .7 mg, about 1 .8 mg, about 1 .9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, or about 5.9 mg) and is administered to the subject on or about Day 2, Day 3, or Day 4 of the first dosing cycle (C1 ); and (c) the C1 D3 is between about 100 mg to about 180 mg and is administered to the subject on or about Day 8 of the first dosing cycle (C1 ).

In some embodiments, the C1 D1 is between about 0.1 mg to about 0.6 mg; the C1 D2 is between about 1 mg to about 5 mg; and the C1 D3 is between about 132 mg to about 160 mg.

In another aspect, the disclosure features a method of treating a subject (e.g., a human subject) having MM, wherein the method comprises administering to the subject an effective amount of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle (C1 ) comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the bispecific antibody, and wherein: (a) the C1 D1 is about 0.3 mg and is administered to the subject on or about Day 1 of the first dosing cycle (C1 ); (b) the C1 D2 is about 3.3 mg and is administered to the subject on or about Day 2, Day 3, or Day 4 of the first dosing cycle (C1 ); and (c) the C1 D3 is about 160 mg and is administered to the subject on or about Day 8 of the first dosing cycle (C1 ).

In some embodiments, the method further comprises administering to the subject (e.g., a human subject) an effective amount of tocilizumab about 2 hours prior to administering the first dose of the bispecific antibody. In some embodiments, the subject weighs > 100 kg, and tocilizumab is administered to the subject at a dose of 800 mg. In some embodiments, the subject weighs > 30 kg and < 100 kg, and tocilizumab is administered to the subject at a dose of 8 mg/kg. In some embodiments, the subject weighs < 30 kg, and tocilizumab is administered to the subject at a dose of 12 mg/kg.

In some embodiments, the dosing regimen further comprises a second dosing cycle comprising a single dose (C2D1 ) of the bispecific antibody, wherein the C2D1 is equal to or greater than the last administered dose of the bispecific antibody and is between about 100 mg to about 180 mg. In some embodiments, the C2D1 is between about 132 mg to about 160 mg. In some embodiments, the C2D1 is about 160 mg.

In some embodiments, the length of the second dosing cycle is 21 days. In some embodiments, the method comprises administering to the subject (e.g., a human subject) the C2D1 on Day 1 of the second dosing cycle. In some embodiments, the dosing regimen comprises one or more additional dosing cycles. In some embodiments, the dosing regimen comprises one to 15 additional dosing cycles. In some embodiments, the length of each of the one or more additional dosing cycles is 21 days. In some embodiments, each of the one or more additional dosing cycles comprises a single dose of the bispecific antibody. In some embodiments, the method comprises administering to the subject the single dose of the bispecific antibody on Day 1 of the one or more additional dosing cycles. In some embodiments, the single dose is between about 100 mg to about 180 mg. In some embodiments, the single dose is between about 132 mg to about 160 mg. In some embodiments, the single dose is about 160 mg. In some embodiments, a median peak IL-6 level in a population of subjects (e.g., human subjects) treated according to the method does not exceed 80 pg/mL between the C1 D1 and the C1 D2. In some embodiments, the median peak IL-6 level in a population of subjects treated according to the method does not exceed 30 pg/mL between the C1 D1 and the C1 D2.

In some embodiments, a median peak IL-6 level in a population of subjects (e.g., human subjects) treated according to the method does not exceed 80 pg/mL between the C1 D2 and the C1 D3. In some embodiments, the median peak IL-6 level in a population of subjects treated according to the method does not exceed 30 pg/mL between the C1 D2 and the C1 D3.

In some embodiments, a median peak IL-6 level in a population of subjects treated according to the method does not exceed 30 pg/mL between the C1 D3 and the C1 D4. In some embodiments, the C1 D4 of the bispecific antibody is a target dose of the bispecific antibody.

In some embodiments, the IL-6 level is measured in a blood sample. In some embodiments, the blood sample is a peripheral blood sample.

In some embodiments, a peak level of CD8+ T cell activation in the subject (e.g., a human subject) in the first dosing cycle occurs between administration of the C1 D1 and the C1 D2. In some embodiments, a peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs between administration of the C1 D2 and the C1 D3. In some embodiments, a peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs between administration of the C1 D3 and the C1 D4. In some embodiments, the peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs within 24 hours after administration of the bispecific antibody.

In some embodiments, the bispecific antibody (e.g., cevostamab) comprises an anti-FcRH5 arm comprising a first binding domain comprising the following six hypervariable regions (HVRs): (a) an HVR- H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO:3); (d) an HVR-L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6); and an anti-CD3 arm comprising a second binding domain comprising the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) an HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) an HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11 ); (d) an HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) an HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) an HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

In some embodiments, the bispecific antibody comprises an anti-FcRH5 arm comprising a first binding domain comprising a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% (e.g., 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the bispecific antibody comprises an anti-FcRH5 arm comprising a first binding domain comprising a light chain variable (VL) domain comprising an amino acid sequence having at least 95% (e.g., 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO: 8. In some embodiments the binding domain comprises a VH domain comprising an amino acid sequence having at least 95% (e.g., 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO: 7 and a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO: 7 and a VL domain comprising an amino acid sequence of SEQ ID NO: 8.

In some embodiments, the bispecific antibody comprises an anti-CD3 arm comprising a second binding domain comprising a VH domain comprising an amino acid sequence having at least 95% (e.g., 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO: 15. In some embodiments the bispecific antibody comprises an anti-CD3 arm comprising a second binding domain comprising a VL domain comprising an amino acid sequence having at least 95% (e.g., 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO: 16. In some embodiments, the second binding arm comprises a VH domain comprising an amino acid sequence having at least 95% (e.g., 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO: 15 and a VL domain comprising an amino acid sequence having at least 95% (e.g., 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO: 16. In some embodiments, the second binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and a VL domain comprising an amino acid sequence of SEQ ID NO: 16.

In some embodiments, the bispecific antibody comprises an aglycosylation site mutation. In some embodiments, the aglycosylation site mutation reduces effector function of the bispecific antibody. In some embodiments, the aglycosylation site mutation is a substitution mutation. In some embodiments, the bispecific antibody comprises a substitution mutation in the Fc region that reduces effector function.

In some embodiments, the bispecific antibody is a monoclonal antibody. In some embodiments, the bispecific antibody is a humanized antibody. In some embodiments, the bispecific antibody is a chimeric antibody. In some embodiments, the bispecific antibody is a full-length antibody. In some embodiments, the bispecific antibody is an IgG antibody. In some embodiments, wherein the IgG antibody is an IgG 1 antibody.

In some embodiments, the bispecific antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH1 _?) domain, a first CH2 (CH2j) domain, a first CH3 (CH3y) domain, a second CH1 (CH1₂) domain, second CH2 (CH2₂) domain, and a second CH3 (CH3₂) domain. In some embodiments, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some embodiments, the CH3y and CH3₂ domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH3y domain is positionable in the cavity or protuberance, respectively, in the CH3₂ domain. In some embodiments, the CH3j and CH3₂ domains meet at an interface between the protuberance and cavity. In some embodiments, the CH2j and CH2₂ domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2j domain is positionable in the cavity or protuberance, respectively, in the CH2₂ domain. In some embodiments, the CH2j and CH2₂ domains meet at an interface between said protuberance and cavity. In some embodiments, the anti- FcRH5 arm comprises the protuberance and the anti-CD3 arm comprises the cavity. In some embodiments, a CH3 domain of the anti-FcRH5 arm comprises a protuberance comprising a T366W amino acid substitution mutation (EU numbering) and a CH3 domain of the anti-CD3 arm comprises a cavity comprising T366S, L368A, and Y407V amino acid substitution mutations (EU numbering).

In some embodiments, the bispecific antibody comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1 ) and a light chain polypeptide (L1 ) and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), and wherein: (a) H1 comprises the amino acid sequence of SEQ ID NO: 35; (b) L1 comprises the amino acid sequence of SEQ ID NO: 36; (c) H2 comprises the amino acid sequence of SEQ ID NO: 37; and (d) L2 comprises the amino acid sequence of SEQ ID NO: 38.

In some embodiments, the bispecific antibody is cevostamab.

In some embodiments, the bispecific antibody is an antibody fragment that binds FcRH5 and CD3. In some embodiments, the antibody fragment is selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments.

In some embodiments, the dosing regimen results in a CRS event in less than about 90% of a population of subjects (e.g., human subjects) having MM. In some embodiments, the dosing regimen results in a CRS event in less than about 68% of a population of subjects having MM. In some embodiments, the dosing regimen results in the CRS event in about 58% to about 90% (e.g., about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, or about 90%) of the population of subjects having MM.

In some embodiments, the dosing regimen results in the CRS event in about 58% to about 68% (e.g., about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, or about 68%) of the population of subjects (e.g., human subjects) having MM.

In some embodiments, the dosing regimen results in the CRS event in about 63% of the population of subjects (e.g., human subjects) having MM.

In some embodiments, the dosing regimen results in a grade >2 CRS event in less than about 50% of a population of subjects (e.g., human subjects) having MM. In some embodiments, the dosing regimen results in a grade >2 CRS event in less than about 25% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, or about 24%) of a population of subjects having a MM. In some embodiments, the dosing regimen results in the grade >2 CRS event in about 10% to about 50% (e.g., about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50%) of the population of subjects having MM.

In some embodiments, the dosing regimen results in the grade >2 CRS event in about 17% of the population of subjects (e.g., human subjects) having MM.

In some embodiments, the dosing regimen results in a grade >3 CRS event in less than about 10% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about6%, about 7%, about 8%, about 9%, or about 10%) of a population of subjects (e.g., human subjects) having MM. In some embodiments, the dosing regimen results in the grade >3 CRS event in about 0% to about 5% (e.g., about 0%, about 1%, about 2%, about 3%, about 4%, or about 5%) of the population of subjects having MM.

In some embodiments, the dosing regimen does not result in any grade >3 CRS event in the population of subjects having MM.

In some embodiments, the bispecific antibody is administered to the subject as a monotherapy.

In some embodiments, the bispecific antibody is administered to the subject as a combination therapy. In some embodiments, the bispecific antibody is administered to the subject concurrently with one or more additional therapeutic agents. In some embodiments, the bispecific antibody is administered to the subject prior to the administration of one or more additional therapeutic agents. In some embodiments, the bispecific antibody is administered to the subject subsequent to the administration of one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents comprise an effective amount of tocilizumab. In some embodiments, tocilizumab is administered to the subject by intravenous infusion. In some embodiments, the subject weighs > 100 kg, and tocilizumab is administered to the subject at a dose of 800 mg. In some embodiments, the subject weighs > 30 kg and < 100 kg, and tocilizumab is administered to the subject at a dose of 8 mg/kg. In other embodiments, the subject weighs < 30 kg, and tocilizumab is administered to the subject at a dose of 12 mg/kg. In some embodiments, tocilizumab is administered to the subject 2 hours before administration of the bispecific antibody. In some embodiments, the one or more additional therapeutic agents comprise an effective amount of pomalidomide, daratumumab, and/or a B-cell maturation antigen (BCMA)-directed therapy.

In some embodiments, the bispecific antibody is administered to the subject by intravenous infusion.

In some embodiments, the bispecific antibody is administered to the subject subcutaneously.

In some embodiments, the subject has a CRS event, and the method further comprises treating the symptoms of the CRS event while suspending treatment with the bispecific antibody. In some embodiments, the method further comprises administering to the subject an effective amount of tocilizumab to treat the CRS event. In some embodiments, tocilizumab is administered intravenously to the subject as a single dose of about 8 mg/kg. In some embodiments, the CRS event does not resolve or worsens within 24 hours of treating the symptoms of the CRS event, and the method further comprises administering to the subject one or more additional doses of tocilizumab to manage the CRS event. In some embodiments, the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 8 mg/kg. In some embodiments, the one or more additional therapeutic agents comprises an effective amount of a corticosteroid. In some embodiments, the corticosteroid is administered intravenously to the subject. In some embodiments, the corticosteroid is methylprednisolone. In some embodiments, methylprednisolone is administered at a dose of about 80 mg. In some embodiments, the corticosteroid is dexamethasone. In some embodiments, dexamethasone is administered at a dose of about 20 mg.

In some embodiments, the one or more additional therapeutic agents comprise an effective amount of acetaminophen or paracetamol. In some embodiments, acetaminophen or paracetamol is administered at a dose of between about 500 mg to about 1000 mg (e.g., about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg). In some embodiments, acetaminophen or paracetamol is administered orally to the subject.

In some embodiments, the one or more additional therapeutic agents comprise an effective amount of diphenhydramine. In some embodiments, diphenhydramine is administered at a dose of between about 25 mg to about 50 mg (e.g., about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, or about 50 mg). In some embodiments, diphenhydramine is administered orally to the subject.

In some embodiments, the MM is relapsed or refractory (R/R) MM. In some embodiments, the individual has received at least three prior lines of treatment for the MM. In some embodiments, the individual has received at least four prior lines of treatment for the MM. In some embodiments, the individual has been exposed to a prior treatment comprising a proteasome inhibitor, an IMiD, and/or an anti-CD38 therapeutic agent. In some embodiments, the proteasome inhibitor is bortezomib, carfilzomib, or ixazomib. In some embodiments, the IMiD is thalidomide, lenalidomide, or pomalidomide. In some embodiments, the anti-CD38 therapeutic agent is an anti-CD38 antibody. In some embodiments, the anti- CD38 antibody is daratumumab, MOR202, or isatuximab. In some embodiments, the anti-CD38 antibody is daratumumab.

In some embodiments, the individual has been exposed to a prior treatment comprising an anti- SLAMF7 therapeutic agent, a nuclear export inhibitor, a histone deacetylase (HDAC) inhibitor, an autologous stem cell transplant (ASCT), a bispecific antibody, an antibody-drug conjugate (ADC), a CAR- T cell therapy, or a BCMA-directed therapy. In some embodiments, the anti-SLAMF7 therapeutic agent is an anti-SLAMF7 antibody. In some embodiments, the anti-SLAMF7 antibody is elotuzumab. In some embodiments, the nuclear export inhibitor is selinexor. In some embodiments, the HDAC inhibitor is panobinostat. In some embodiments, the BCMA-directed therapy is an antibody-drug conjugate targeting BCMA.

In another aspect, the disclosure features a method of treating a subject having R/R MM, wherein the method comprises administering to the subject an effective amount of cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the first dosing cycle (C1 ) is 21 days, wherein the first dosing cycle (C1 ) comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of the bispecific antibody, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 of C1 ; the C1 D2 is about 1 .2 mg and is administered on Day 2, Day 3, or Day 4 of C1 ; the C1 D3 is about 3.6 mg and is administered on Day 8; and the C1 D4 is the effective amount of cevostamab and is administered on Day 9, Day 10, or Day 1 1 of C1 . In some embodiments, the C1 D4 is about 160 mg.

In another aspect, the disclosure features a method of treating a subject having R/R MM, wherein the method comprises administering to the subject an effective amount of cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the first dosing cycle (C1 ) is 21 days, wherein the first dosing cycle (C1 ) comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of the bispecific antibody, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 of C1 ; the C1 D2 is about 3.3 mg and is administered on Day 2, Day 3, or Day 4 of C1 ; the C1 D3 is about 7.2 mg and is administered on Day 8 of C1 ; and the C1 D4 is the effective amount of cevostamab and is administered on Day 9, Day 10, or Day 1 1 . In some embodiments, the C1 D4 is about 160 mg.

In another aspect, the disclosure features a method of reducing the likelihood of CRS in a subject having R/R MM, wherein the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the first dosing cycle (C1 ) is 21 days, wherein the first dosing cycle (C1 ) comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the bispecific antibody, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 of C1 ; the C1 D2 is about 1 .2 mg and is administered on Day 2, Day 3, or Day 4 of C1 ; and the C1 D3 is about 3.6 mg and is administered on Day 8 of C1 .

In another aspect, the disclosure features a method of reducing the likelihood of CRS in a subject having R/R MM, wherein the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the first dosing cycle (C1 ) is 21 days, wherein the first dosing cycle (C1 ) comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the bispecific antibody, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 3.3 mg and is administered on Day 2, Day 3, or Day 4; and the C1 D3 is about

7.2 mg and is administered on Day 8.

In another aspect, the disclosure features a method of achieving a median peak IL-6 level of less than about 30 pg/mL (e.g., about 10pg/mL, about 1 1 pg/mL, about 12pg/mL, about 13pg/mL, about 14pg/mL, about 15pg/mL, about 16pg/mL, about 17pg/mL, about 18pg/mL, about 19pg/mL, about 20pg/mL, about 21 pg/mL, about 22pg/mL, about 23pg/mL, about 24pg/mL, about 25pg/mL, about 26pg/mL, about 27pg/mL, about 28pg/mL, about 25pg/mL, about 26pg/mL, about 27pg/mL, about 28pg/mL, or about 29pg/mL) in a population of subjects having R/R MM, wherein the method comprises administering to a subject in the population cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the first dosing cycle (C1 ) is 21 days, wherein the first dosing cycle (C1 ) comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the bispecific antibody, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about

1 .2 mg and is administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 3.6 mg and is administered on Day 8.

In another aspect, the disclosure features a method of treating a subject having R/R MM, wherein the method comprises administering to each subject an effective amount of cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the first dosing cycle (C1 ) is 21 days, wherein the first dosing cycle (C1 ) comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the bispecific antibody, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 3.3 mg and is administered on Day 2, Day 3, or Day 4; the C1 D3 is about 160 mg and is administered on Day 8, and wherein an effective amount of tocilizumab is administered to the subject about 2 hours prior to administering the first dose of cevostamab.

In another aspect, the disclosure features a method of treating a subject having R/R MM, wherein the method comprises administering to the subject an effective amount of cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the first dosing cycle (C1 ) is 21 days, wherein the first dosing cycle (C1 ) comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3), wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 3.3 mg and is administered on Day 4; and the C1 D3 is about 160 mg and is administered on Day 8.

In some embodiments of any of the foregoing aspects, the dosing regimen further comprises a second dosing cycle (C2) comprising a single dose (C2D1 ) of cevostamab, wherein the length of the C2 is 21 days, and wherein the C2D1 is an effective amount of cevostamab and is administered to the subject on Day 1 of the second dosing cycle. In some embodiments, the dosing regimen further comprises one or more additional dosing cycles, wherein the length of each of the one or more additional dosing cycles is 21 days, wherein each of the one or more additional dosing cycles comprises a single dose of the effective amount of cevostamab administered to the subject on Day 1 of each of the one or more additional dosing cycles.

In another aspect, the disclosure features a method of reducing the occurrence of CRS events in a subject being treated for R/R MM with a target dose of cevostamab, the method comprising administering to the subject, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 1 .2 mg and is administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 3.6 mg and is administered on Day 8, wherein the length of the C1 is 21 days.

In another aspect, the disclosure features a method of reducing the occurrence of CRS events in a subject being treated for R/R MM with a target dose of cevostamab, the method comprising administering to the subject, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 3.3 mg and is administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 7.2 mg and is administered on Day 8, wherein the length of the C1 is 21 days.

In another aspect, the disclosure features a method of reducing the occurrence of CRS events in a subject being treated for R/R MM with a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ), (ii) a second dose (TS- C1 D2), and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering such target dose to a first plurality of such subjects results in a reduction in the number of subjects experiencing a CRS event after first administration of the target dose, as compared to a second plurality of such subjects (e.g., human subjects) being treated for R/R MM with a target dose of cevostamab and administered such target dose after administration of a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), with no third dose (DS- C1 D3)of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 . In some embodiments, administering such target dose to the first plurality of such subjects results in at least a 10% reduction in the number of subjects experiencing a CRS event after first administration of the target dose. In some embodiments, administering such target dose to the first plurality of such subjects results in a 15% reduction in the number of subjects experiencing a CRS event after first administration of the target dose.

In another aspect, the disclosure features a method of reducing the occurrence of CRS events in a subject being treated for R/R MM with a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ), (ii) a second dose (TS- C1 D2), and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering such target dose to a first plurality of such subjects results in a reduction in the number of subjects experiencing a CRS event during the C1 , as compared to a second plurality of subjects (e.g., human subjects) being treated for R/R MM with a target dose of cevostamab and administered such target dose after administration of a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), with no third dose of cevostamab, and wherein the TS- D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 . In some embodiments, administering such target dose to the first plurality of such subjects results in at least a 10% reduction in the number of subjects experiencing a CRS event during the C1 . In some embodiments, administering such target dose to the first plurality of such subjects results in a 14% reduction in the number of subjects experiencing a CRS event during the C1 .

In another aspect, the disclosure features a method of reducing the occurrence of CRS events in a subject being treated for R/R MM at an target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS- C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of CRS events experienced by each subject during the C1 , as compared to a second plurality of subjects administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose (DS-C1 D3) of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 . In some embodiments, administering cevostamab in the C1 to the first plurality of such subjects results in at least a 30% reduction in the number of CRS events experienced by each subject during the C1 .

In another aspect, the disclosure features a method of reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein, prior to first administration of the target dose to the subject in a first treatment cycle (C1 ), the subject is administered cevostamab at (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3), wherein administering cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of subjects requiring tocilizumab treatment for CRS during the C1 , as compared to a second plurality of subjects being treated for MM and administered a target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose (DS-C1 D3) of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , and the TS-C1 D3 is greater than the TS-C1 D2, and the DS- C1 D2 is greater than the DS-C1 D1 . In some embodiments, administering cevostamab in the C1 to the first plurality of such subjects results in at least a 10% reduction in the number of subjects requiring tocilizumab treatment for CRS during the C1 .

In another aspect, the disclosure features a method of pre-treating a subject for receiving a target dose of cevostamab, wherein the method comprises administering to the subject (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D2 is greater than the C1 D1 , and the C1 D3 is greater than the C1 D2, wherein the risk of CRS events in the subject, after administration of the C1 D1 , C1 D2, and C1 D3 to the subject, is at a level that is safe for the subject to receive the target dose of cevostamab. In some embodiments following administration of the C1 D1 , C1 D2, and C1 D3 to the subject, the subject achieves a peak IL-6 level of less than about 80 pg/mL, thereby indicating that the risk of CRS events in the subject is at a level that is safe for the subject to receive the target dose of cevostamab. In some embodiments, the subject achieves a peak IL-6 level of less than about 30 pg/mL prior to the administration of the target dose of cevostamab. In some embodiments, the method further comprises administering to the pre-treated subject a target dose of cevostamab.

In another aspect, the disclosure features a method of reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering cevostamab in the C1 to a first plurality of such human subjects results in a reduction in the number of CRS events experienced by each subject during the C1 , as compared to a second plurality of subjects being treated for R/R MM and administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose (DS-C1 D3) of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 . In some embodiments, administering cevostamab in the C1 to the first plurality of such subjects results in at least a 25% reduction in the number of CRS events experienced by each subject during the C1 .

In another aspect, the disclosure features a method of reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering cevostamab in the C1 to a first plurality of such subjects results in an increase in the number of subjects experiencing no CRS event during the C1 , as compared to a second plurality of subjects being treated for R/R MM and administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose (DS- C1 D3) of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 . In some embodiments, administering cevostamab in the C1 to the first plurality of such subjects results in at least a 50% increase in the number of subjects experiencing no CRS event during the C1 .

In another aspect, the disclosure features a method of reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of subjects experiencing Grade >2 CRS events during the C1 , as compared to a second plurality of subjects being treated for R/R MM and administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose (DS-C1 D3) of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 . In some embodiments, administering cevostamab in the C1 to the first plurality of such subjects results in at least a 35% reduction in the number of subjects experiencing Grade >2 CRS events during the C1 .

In another aspect, the disclosure features a method of reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of subjects experiencing at least two CRS events during the C1 , as compared to a second plurality of subjects being treated for R/R MM and administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose (DS-C1 D3) of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 . In some embodiments, administering cevostamab in the C1 to the first plurality of such subjects results in at least a 50% reduction in the number of subjects experiencing at least two CRS events during the C1 .

In some embodiments of any of the foregoing aspects, the subject is a human subject.

In another aspect, the disclosure provides cevostamab for use in a method of reducing the likelihood of CRS in a subject (e.g., a human subject) having MM (e.g., R/R MM) and being administered an effective amount of cevostamab, wherein, prior to a first administration to the subject of an effective amount of cevostamab, cevostamab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg, and the C1 D3 is between about 3.6 mg to about 7.2 mg.

In another aspect, the disclosure provides cevostamab for use in a method of reducing the likelihood of CRS in a subject (e.g., a human subject) having MM (e.g., R/R MM) and being administered an effective amount of cevostamab, wherein, prior to a first administration to the subject of the effective amount of cevostamab, cevostamab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; and the C1 D3 is about 3.6 mg.

In another aspect, the disclosure provides cevostamab for use in a method of reducing the likelihood of CRS in a subject (e.g., a human subject) having MM (e.g., R/R MM) and being administered an effective amount of cevostamab, wherein, prior to a first administration to the subject of the effective amount of cevostamab, cevostamab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 3.3 mg; and the C1 D3 is about 7.2 mg.

In yet another aspect, the disclosure provides cevostamab for use in a method of achieving a median peak IL-6 level of less than about 30 pg/mL in a population of subjects having a MM (e.g., a R/R MM) and being administered an effective amount of cevostamab, wherein, prior to the subject being administered the effective amount of cevostamab, cevostamab is to be administered to a subject in the population a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg, and the C1 D3 is between about 3.6 mg to about 7.2 mg.

In yet another aspect, the disclosure provides cevostamab for use in a method of achieving a peak IL-6 level of less than about 30 pg/mL in a subject (e.g., a human subject) having a MM (e.g., a R/R MM) and being administered an effective amount of cevostamab, wherein prior to the subject being administered the effective amount of cevostamab, cevostamab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3, the C1 D2 is between about 1 .2 mg to about 3.3 mg, and the C1 D3 is between about 3.6 mg to about 7.2 mg.

In yet another aspect, the disclosure provides cevostamab for use in a method of treating a subject (e.g., a human subject) having MM (e.g., R/R MM), wherein an effective amount of cevostamab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, wherein the C1 D1 is about 0.3 mg, the C1 D2 is about 1 .2 mg to about 3.3 mg (e.g., about 1 .2 mg or about 3.3 mg), the C1 D3 is about 3.6 mg to about 7.2 mg (e.g., about 3.6 mg or about 7.2 mg), and the C1 D4 is between about 20 mg to about 252 mg (e.g., about 160 mg).

In another aspect, the disclosure provides cevostamab for use in a method of treating a subject (e.g., a human subject) having MM (e.g., R/R MM), wherein an effective amount of cevostamab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; the C1 D3 is about 3.6 mg; and the C1 D4 is about 160 mg.

In another aspect, the disclosure provides cevostamab for use in a method of treating a subject (e.g., a human subject) having MM (e.g., R/R MM), wherein an effective amount of cevostamab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, the C1 D1 is about 0.3 mg; the C1 D2 is about 3.3 mg; the C1 D3 is about 7.2 mg; and the C1 D4 is about 160 mg.

In yet another aspect, the disclosure provides cevostamab for use in a method of treating a subject (e.g., a human subject) having an R/R MM, an effective amount of cevostamab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, wherein the C1 D1 is about 0.3 mg and is to be administered on Day 1 of C1 ; the C1 D2 is about 1 .2 mg and is to be administered on Day 2, Day 3, or Day 4 of C1 ; the C1 D3 is about 3.6 mg and is to be administered on Day 8 of C1 ; and the C1 D4 is the effective amount of cevostamab and is to be administered on Day 9, Day 10, or Day 11 of C1 .

In another aspect, the disclosure provides cevostamab for use in a method of treating a subject (e.g., a human subject) having an R/R MM, wherein an effective amount of cevostamab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, wherein the C1 D1 is about 0.3 mg and is to be administered on Day 1 ; the C1 D2 is about 3.3 mg and is to be administered on Day 2, Day 3, or Day 4; the C1 D3 is about 7.2 mg and is to be administered on Day 8; and the C1 D4 is the effective amount of cevostamab and is to be administered on Day 9, Day 10, or Day 11 .

In another aspect, the disclosure provides cevostamab for use in a method reducing the likelihood of CRS in a subject having an R/R MM and being administered an effective amount of cevostamab, wherein, prior to a first administration to the subject of the effective amount of cevostamab, cevostamab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is to be administered on Day 1 ; the C1 D2 is about 1 .2 mg and is to be administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 3.6 mg and is to be administered on Day 8.

In another aspect, the disclosure provides cevostamab for use in a method of achieving a median peak IL-6 level of less than about 30 pg/mL in a population of subjects having an R/R MM and being administered an effective amount of cevostamab, wherein prior to being administered the effective amount of cevostamab, each subject in the population is to be administered a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is to be administered on Day 1 ; the C1 D2 is about 1 .2 mg and is to be administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 3.6 mg and is to be administered on Day 8.

In another aspect, the disclosure provides cevostamab for use in a method of treating a subject having an R/R MM, wherein an effective amount of cevostamab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is to be administered on Day 1 ; the C1 D2 is about 1 .2 mg and is to be administered on Day 2, Day 3, or Day 4; the C1 D3 is about 3.6 mg and is to be administered on Day 8, and wherein an effective amount of tocilizumab is to be administered to the subject about 2 hours prior to administration of the first dose of cevostamab.

In another aspect, the disclosure provides cevostamab for use in a method of treating a subject having an R/R MM, wherein an effective amount of cevostamab is to be administered to the subject in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3), wherein the C1 D1 is about 0.3 mg and is to be administered on Day 1 ; the C1 D2 is about 3.3 mg and is to be administered on Day 4; and the C1 D3 is about 160 mg and is to be administered on Day 8.

In another aspect, the disclosure provides cevostamab for use in a method of reducing the occurrence of CRS events in a subject being treated for an R/R MM with a target dose of cevostamab, wherein prior to a first administration of the target dose to the subject, cevostamab is to be administered to the subject in a dosing regimen comprising a first dosing cycle (C1 ) comprising (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is to be administered on Day 1 ; the C1 D2 is about 1 .2 mg and is to be administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 3.6 mg and is to be administered on Day 8, wherein the length of the C1 is 21 days.

In another aspect, the disclosure provides cevostamab for use in a method of reducing the occurrence of CRS events in a subject being treated for a R/R MM with a target dose of cevostamab, wherein prior to a first administration of the target dose to the subject, cevostamab is to be administered to the subject in a dosing regimen comprising a first dosing cycle (C1 ) comprising (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is to be administered on Day 1 ; the C1 D2 is about 3.3 mg and is to be administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 7.2 mg and is to be administered on Day 8, wherein the length of the C1 is 21 days.

In another aspect, the disclosure provides cevostamab for use in a method of reducing the occurrence of CRS events in a subject being treated for R/R MM with a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject, cevostamab is to be administered to the subject in a dosing regimen comprising a first dosing cycle (C1 ) comprising (i) a first dose (TS- C1 D1 ), (ii) a second dose (TS-C1 D2), and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering such target dose to a first plurality of such subjects results in a reduction in the number of subjects experiencing a CRS event after first administration of the target dose, as compared to a second plurality of subjects (e.g., human subjects) being treated for R/R MM with a target dose of cevostamab and administered such target dose after administration of a first dose (DS-C1 D1 ) and a second dose (DS- C1 D2), with no third dose of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

In another aspect, the disclosure provides cevostamab for use in a method of reducing the occurrence of CRS events in a subject being treated for MM at an target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject, cevostamab is to be administered to the subject in a dosing regimen comprising a first dosing cycle (C1 ) comprising (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administration of cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of CRS events experienced by each subject during the C1 , as compared to a second plurality of subjects administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

In another aspect, the disclosure provides cevostamab for use in a method of reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein, prior to first administration of the target dose to the subject, cevostamab is to be administered to the subject in a first treatment cycle (C1 ) comprising (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS- C1 D2); and (iii) a third dose (TS-C1 D3), wherein administration of cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of subjects requiring tocilizumab treatment for CRS during the C1 , as compared to a second plurality of subjects being treated for MM and administered a target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , and the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

In another aspect, the disclosure features cevostamab for use in a method of pre-treating a subject for receiving a target dose of cevostamab, wherein cevostamab is to be administered to the subject as (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D2 is greater than the C1 D1 , and the C1 D3 is greater than the C1 D2, wherein the risk of CRS events in the subject, after administration of the C1 D1 , C1 D2, and C1 D3 to the subject, is at a level that is safe for the subject to receive the target dose of cevostamab.

In another aspect, the disclosure features cevostamab for use in a method of reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), cevostamab is to be administered to the subject as (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3), wherein administration of cevostamab in the C1 to a first plurality of such human subjects results in a reduction in the number of CRS events experienced by each subject during the C1 , as compared to a second plurality of subjects being treated for R/R MM and administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose (DS-C1 D3) of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS- C1 D1 .

In yet another aspect, the disclosure provides cevostamab for use in a method of reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), cevostamab is to be administered to the subject as (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administration cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of subjects experiencing Grade >2 CRS events during the C1 , as compared to a second plurality of subjects being treated for R/R MM and administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

In another aspect, the disclosure provides cevostamab for use in a method of reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), cevostamab is to be administered to the subject as (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administration of cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of subjects experiencing at least two CRS events during the C1 , as compared to a second plurality of subjects being treated for R/R MM and administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

In another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for reducing the likelihood of CRS in a subject (e.g., a human subject) having MM (e.g., R/R MM), wherein the medicament is formulated for administration in a dosing regimen prior to a first administration of an effective amount of cevostamab to the subject, wherein the dosing regimen comprises at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg, and the C1 D3 is between about 3.6 mg to about 7.2 mg.

In another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for reducing the likelihood of CRS in a subject (e.g., a human subject) having MM (e.g., R/R MM) and being administered an effective amount of cevostamab, wherein the medicament is formulated for administration in a dosing regimen prior to a first administration of an effective amount of cevostamab to the subject, wherein the dosing regimen comprises at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; and the C1 D3 is about 3.6 mg.

In another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for reducing the likelihood of CRS in a subject (e.g., a human subject) having MM (e.g., R/R MM) and being administered an effective amount of cevostamab, wherein the medicament is formulated for administration in a dosing regimen prior to a first administration of an effective amount of cevostamab to the subject, wherein the dosing regimen comprises at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 3.3 mg; and the C1 D3 is about 7.2 mg.

In yet another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for achieving a median peak IL-6 level of less than about 30 pg/mL in a population of subjects having a MM (e.g., a R/R MM) and being administered an effective amount of cevostamab, wherein the medicament is formulated for administration to a subject in the population in a dosing regimen prior to the subject being administered the effective amount of cevostamab, wherein the dosing regimen comprises at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg, and the C1 D3 is between about 3.6 mg to about 7.2 mg.

In yet another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for achieving a peak IL-6 level of less than about 30 pg/mL in a subject (e.g., a human subject) having a MM (e.g., a R/R MM) and being administered an effective amount of cevostamab, wherein the medicament is formulated for administration to a subject in a dosing regimen prior to the subject being administered the effective amount of cevostamab, wherein the dosing regimen comprises at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3, the C1 D2 is between about 1 .2 mg to about 3.3 mg, and the C1 D3 is between about 3.6 mg to about 7.2 mg.

In yet another aspect, the disclosure provides a use of cevostamab in the manufacture of a medicament for treating a subject (e.g., a human subject) having MM (e.g., R/R MM), wherein the medicament is formulated for administration to the subject in an effective amount in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, wherein the C1 D1 is about 0.3 mg, the C1 D2 is about 1 .2 mg to about 3.3 mg (e.g., about 1 .2 mg or about 3.3 mg), the C1 D3 is about 3.6 mg to about 7.2 mg (e.g., about 3.6 mg or about 7.2 mg), and the C1 D4 is between about 20 mg to about 252 mg (e.g., about 160 mg).

In another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for treating a subject (e.g., a human subject) having MM (e.g., R/R MM), wherein the medicament is formulated for administration to the subject in an effective amount in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; the C1 D3 is about 3.6 mg; and the C1 D4 is about 160 mg.

In another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for treating a subject (e.g., a human subject) having MM (e.g., R/R MM), wherein the medicament is formulated for administration to the subject in an effective amount in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, the C1 D1 is about 0.3 mg; the C1 D2 is about 3.3 mg; the C1 D3 is about 7.2 mg; and the C1 D4 is about 160 mg.

In yet another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for treating a subject (e.g., a human subject) having an R/R MM, wherein the medicament is formulated for administration to the subject in an effective amount in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, wherein the C1 D1 is about 0.3 mg and is to be administered on Day 1 of C1 ; the C1 D2 is about 1 .2 mg and is to be administered on Day 2, Day 3, or Day 4 of C1 ; the C1 D3 is about 3.6 mg and is to be administered on Day 8 of C1 ; and the C1 D4 is the effective amount of cevostamab and is to be administered on Day 9, Day 10, or Day 11 of C1 . In another aspect, the disclosure provides use of cevostamab in a manufacture of a medicament for treating a subject (e.g., a human subject) having an R/R MM, wherein the medicament is formulated for administration to the subject in an effective amount in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, wherein the C1 D1 is about 0.3 mg and is to be administered on Day 1 ; the C1 D2 is about 3.3 mg and is to be administered on Day 2, Day 3, or Day 4; the C1 D3 is about 7.2 mg and is to be administered on Day 8; and the C1 D4 is the effective amount of cevostamab and is to be administered on Day 9, Day 10, or Day 11 .

In another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for reducing the likelihood of CRS in a subject having an R/R MM and being administered an effective amount of cevostamab, wherein the medicament is formulated for administration in a dosing regimen prior to a first administration to the subject of the effective amount of cevostamab, wherein the dosing regimen comprises at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is to be administered on Day 1 ; the C1 D2 is about

1 .2 mg and is to be administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 3.6 mg and is to be administered on Day 8.

3.3 mg and is to be administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 7.2 mg and is to be administered on Day 8.

In another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for achieving a median peak IL-6 level of less than about 30 pg/mL in a population of subjects having an R/R MM and being administered an effective amount of cevostamab, wherein the medicament is formulated for administration in a dosing regimen prior to administration of the effective amount of cevostamab to each subject in the population, wherein the dosing regimen comprises at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is to be administered on Day 1 ; the C1 D2 is about 1 .2 mg and is to be administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 3.6 mg and is to be administered on Day 8.

In another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for treating a subject having an R/R MM, wherein the medicament is formulated for administration in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is to be administered on Day 1 ; the C1 D2 is about 3.3 mg and is to be administered on Day 2, Day 3, or Day 4; the C1 D3 is about 7.2 mg and is to be administered on Day 8, and wherein an effective amount of tocilizumab is to be administered to the subject about 2 hours prior to administering the first dose of cevostamab.

In another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for treating a subject having an R/R MM, wherein the medicament is formulated for administration to the subject in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3), wherein the C1 D1 is about 0.3 mg and is to be administered on Day 1 ; the C1 D2 is about 1 .2 mg and is to be administered on Day 2, Day 3, or Day 4; the C1 D3 is about 3.6 mg and is to be administered on Day 8, and wherein an effective amount of tocilizumab is to be administered to the subject about 2 hours prior to administration of the first dose of cevostamab.

In another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for reducing the occurrence of CRS events in a subject being treated for an R/R MM with a target dose of cevostamab, wherein the medicament is formulated for administration in a dosing regimen prior to a first administration of the target dose to the subject, wherein the dosing regimen comprises a first dosing cycle (C1 ) comprising (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is to be administered on Day 1 ; the C1 D2 is about 1 .2 mg and is to be administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 3.6 mg and is to be administered on Day 8, wherein the length of the C1 is 21 days.

In another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for reducing the occurrence of CRS events in a subject being treated for a R/R MM with a target dose of cevostamab, wherein the medicament is formulated for administration in a dosing regimen prior to a first administration of the target dose to the subject, wherein the dosing regimen comprises a first dosing cycle (C1 ) comprising (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is to be administered on Day 1 ; the C1 D2 is about 3.3 mg and is to be administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 7.2 mg and is to be administered on Day 8, wherein the length of the C1 is 21 days.

In another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for reducing the occurrence of CRS events in a subject being treated for R/R MM with a target dose of cevostamab, wherein the medicament is formulated for administration to the subject prior to a first administration of the target dose in a first dosing cycle (C1 ) comprising (i) a first dose (TS-C1 D1 ), (ii) a second dose (TS-C1 D2), and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administration of such target dose to a first plurality of such subjects results in a reduction in the number of subjects experiencing a CRS event after first administration of the target dose, as compared to a second plurality of subjects (e.g., human subjects) being treated for R/R MM with a target dose of cevostamab and administered such target dose after administration of a first dose (DS-C1 D1 ) and a second dose (DS- C1 D2), with no third dose of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

In another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for reducing the occurrence of CRS events in a subject being treated for MM at a target dose of cevostamab, wherein the medicament is formulated for administration prior to a first administration of the target dose to the subject, and is formulated for administration to the subject in a first dosing cycle (C1 ) comprising (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein the administration of cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of CRS events experienced by each subject during the C1 , as compared to a second plurality of subjects administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose of cevostamab, and wherein the TS- D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

In another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for reducing the occurrence of CRS events in a subject being treated for MM at a target dose of cevostamab, wherein the medicament is formulated for administration in a first treatment cycle (C1 ) prior to first administration of the target dose to the subject, wherein C1 comprises (i) a first dose (TS- C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3), wherein administration of cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of subjects requiring tocilizumab treatment for CRS during the C1 , as compared to a second plurality of subjects administered a target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , and the TS- C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

In another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein the medicament is formulated for administration in a first treatment cycle (C1 ) prior to first administration of the target dose to the subject, wherein C1 comprises (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3), wherein administration of cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of subjects requiring tocilizumab treatment for CRS during the C1 , as compared to a plurality of subjects being treated for MM and administered a target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose of cevostamab, and wherein the TS-D1 D2 is greater than the TS- C1 D1 , and the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

In another aspect, the disclosure features a use of cevostamab in a manufacture of a medicament for pre-treating a subject for receiving a target dose of cevostamab, whreein the medicament is formulated for administration to the subject as (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D2 is greater than the C1 D1 , and the C1 D3 is greater than the C1 D2, wherein the risk of CRS events in the subject, after administration of the C1 D1 , C1 D2, and C1 D3 to the subject, is at a level that is safe for the subject to receive the target dose of cevostamab.

In another aspect, the disclosure features a use of cevostamab in the manufacture of a medicament for reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein, the medicament is formulated for administration to the subject prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), and wherein the medicament is formulated for administration to the subject as (i) a first dose (TS- C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3), wherein administration of cevostamab in the C1 to a first plurality of such human subjects results in a reduction in the number of CRS events experienced by each subject during the C1 , as compared to a second plurality of subjects being treated for R/R MM and administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose (DS-C1 D3) of cevostamab, and wherein the TS- D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

In another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein the medicament is formulated for administration prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), and wherein the medicament is formulated for administration to the subject as (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administration of cevostamab in the C1 to a first plurality of such subjects results in an increase in the number of subjects experiencing no CRS event during the C1 , as compared to a second plurality of subjects being treated for R/R MM and administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

In yet another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein the medicament is formulated for administration prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), and wherein the medicament is formulated for administration to the subject as (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administration cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of subjects experiencing Grade >2 CRS events during the C1 , as compared to a second plurality of subjects being treated for R/R MM and administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

In another aspect, the disclosure provides a use of cevostamab in a manufacture of a medicament for reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein the medicament is formulated for administration prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), and wherein the medicament is formulated for administration to the subject as (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administration of cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of subjects experiencing at least two CRS events during the C1 , as compared to a second plurality of subjects being treated for R/R MM and administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings are included to illustrate embodiments of the disclosure and further an understanding of its implementations.

FIG. 1 is a schematic diagram showing dose escalation schedules for triple step-up dose escalation Arm H1 and Arm H2 of Study GO39775, as described in Example 1 . C: cycle; D: day; Q21 : every 3 weeks (or 21 -days).

FIGS. 2A-2C are schematic diagrams showing the dose escalation schedules and suitable doses for the single step-up (FIG. 2A), double step-up (FIG. 2B), and triple step-up (FIG. 2C) dosing regimens described herein. Doses are depicted in milligrams.

FIG. 3 is a schematic diagram showing an exemplary triple step-up dose-escalation scenario for Arm H1 and Arm H2 across three different cohorts of Study GO39775, as described further in Example 1 . Doses are depicted in milligrams (mg). Asterisks (*) indicate hypothetical scenarios for dose exploration.

FIGS. 4A-4B are Sankey plots showing the proportion of patients that experienced no cytokine release syndrome (CRS), Grade 1 CRS, Grade 2 CRS, or Grade 3 CRS in Arms H1 and Arm 11 (FIG. 4A) or Arm H2 and Arm I2 (FIG. 4B) of the triple step-up regimen in Study GO39775, as described further in Example 1 . The CRS grade (e.g., Grade 1 , Grade 2, or no CRS), tocilizumab (toci) administration (e.g., yes or no), and no administered dose of cevostamab (“No Dose”) is also shown for each patient. ^T = five patients with Grade 1 CRS and treated with tocilizumab were not accounted for by the clinical cutoff date.

FIG. 5 is a table showing the number (n) and proportion of patients that experienced one or more CRS events and the grade of the highest CRS event in all cycles of the indicated dose-escalation regimen in Study GO39775, as described further in Example 1 . SS = single step-up dosing; DS = double step-up dosing; TS = triple step-up dosing; SU = step-up.

FIG. 6 is a table showing rates of CRS events in patients across all cycles of the indicated doseescalation regimen at the clinical cutoff date of October 9, 2023. CRS grade (Gr), number of CRS events, average number of events per patient, and proportion of CRS events with tocilizumab (TCZ) treatment is also shown. ^T = five patients with Grade 1 CRS and treated with tocilizumab were not accounted for by the clinical cutoff date. *** = one Grade 3 CRS, 1 Gr4 CRS.

FIG. 7 is a box-and-whiskers plot showing peak interleukin-6 (IL-6) levels following the 3.3 mg or 3.6 mg step-up dose across different dose-escalation treatment regimens in Study GO39775, as described further in Example 1 . Peak IL-6 levels are depicted as nanograms per liter (ng/L). Sample size (n), median peak IL-6 levels, and the range of peak IL-6 levels are depicted below the plot. SS = single step-up; DS = double step-up; TS = triple step-up.

FIG. 8 are tables presenting the efficacy of the indicated Arms in Study GO39775. sCR = stringent complete response; SD = stable disease; VGPR = very good partial response; MR = minimal response; SD = stable disease; PD = progressive disease; ORR = objective response rate. ORR is defined as the proportion of patients who achieved sCR, CR, VGPR, or PR as determined by investigator assessment according to the International Myeloma Working Group (IMWG) response criteria. Nonresponse includes MR, SD, and PD. * = Cohort B and G utilize same dose/schedule but enrollment occurred ~ 14 months apart. # = High proportion of PD as best overall response (BOR) noted for H1/I1 .

FIGS. 9A-9B is a set of exposure-response (E-R) plots showing the exposure-efficacy relationship of cevostamab for the probability of occurrence of partial response (PR) or better and the average concentrations at cycle 3 (Cavg, cycle 3; FIG. 9A) or the minimum concentrations at cycle 3 (Cmin, cycle 3; FIG. 9B) across the pooled single step-up, double step-up, and triple step-up dosing regimens. The E-R plot is divided into four intervals denoted by dashed vertical lines, which indicate the quartiles of the exposure metric. Filled circles shown at 0% and 100% probabilities represent the observed data across the cohorts using pooled data from the step-up dosing regimens. Black error bars represent the standard error for quartiles of exposure, plotted at the median value within each quartile. The shaded area of the curve represents the 90% confidence intervals (Cis), and the dashed lines bordering the shaded area median of fitted logistic regression model from 1 ,000 bootstrap samples. Horizontal bars in the graph below represent the population pharmacokinetic model-predicted exposures represented by geometric mean and 90% Cis at the planned dose cohorts of 500 simulations at each cohort. AIC = Akaike information criterion; EC50 = half-maximal effective concentration; EC90 = 90% maximal effective concentration

FIGS. 10A-10B is a set of E-R plots showing the exposure-efficacy relationship of cevostamab for the probability of very good partial response or better (>VGPR) rates and Cavg, cycle 3 (FIG. 10A) or Cmin, cycle 3 (FIG. 10B) the across the pooled single step-up, double step-up, and triple step-up dosing regimens.

FIGS. 11A-11B is a set of E-R plots showing the exposure-efficacy relationship of cevostamab for the probability of occurrence of PR or better (FIG. 11 A) or >VGPR rates (FIG. 11 B) and Cavg, cycle 3. Arrow 2 is pointing to a datapoint that represents the observed probability of the occurrence of PR or better or >VGPR rates plotted at the estimated geometric mean of Cavg, cycle 3 at 160 mg administered every three weeks in Study CO43476 (n=23); error bars represent the Wald’s 90% Cis for said observed probability. Arrow 1 is pointing to a datapoint that represents the observed probability of the occurrence of PR or better or >VGPR rates plotted at the estimated geometric mean of Cavg, cycle 3 at the 160 mg target dose administered every three weeks in Study GO39775 (N=152); error bars represent the Wald’s 90% Cis for said observed probability. The E-R plot is divided into five intervals denoted by dashed vertical lines, which indicate the quintiles of the exposure metric.

FIGS. 12A-12B is a set of E-R plots showing the exposure-safety relationship of cevostamab for the probability of occurrence of all-grade CRS events and the maximum concentration following the step- up dose administration on cycle 1 day 1 (Cmax at C1 D1 ; FIG. 12A) or the maximum concentration following the first target dose administration (Cmax, cycle 1 target dose; FIG. 12B) across the pooled single step-up, double step-up, and triple step-up dosing regimens, in which the target dose was administered on Day 8 for the single step-up regimen, Day 9-11 for the double step-up regimen, and Day 15 for the triple step-up regimen. Gr+1 = Grade 1 or higher event.

FIGS. 13A-13B is a set of E-R plots showing the exposure-safety relationship of cevostamab for the probability of occurrence of Grade >2 CRS events and Cmax at C1 D1 (FIG. 13A) or Cmax, cyle 1 target dose (FIG. 13B) across the pooled single step-up, double step-up, and triple step-up dosing regimens described in Study GO39775. Gr2+ = Grade 2 or higher event.

FIGS. 14A-14B is a set of E-R plots showing the exposure-safety relationship of cevostamab for the probability of occurrence of Grade >3 neutropenia and the maximum concentration following the step- up dose administration on C1 D1 (Cmax, step-up dose; FIG. 14A) or the maximum concentration following the target dose administration at cycle 3 (Cmax at C3; FIG. 14B) across the pooled single step-up, double step-up, and triple step-up dosing regimens described in Study GO39775. Gr3+ = Grade 3 or higher event.

FIGS. 15A-15B is a set of E-R plots showing the exposure-safety relationship of cevostamab for the probability of occurrence of Grade >3 anemia and Cmax, step-up dose (FIG. 15A) or Cmax at C3 (FIG. 15B) across the pooled single step-up, double step-up, and triple step-up dosing regimens described in Study GO39775.

FIGS. 16A-16B is a set of E-R plots showing the exposure-safety relationship of cevostamab for the probability of occurrence of Grade >3 thrombocytopenia (TCP) and Cmax, step-up dose (FIG. 16A) or Cmax at C3 (FIG. 16B) across the pooled single step-up, double step-up, and triple step-up dosing regimens described in Study GO39775.

FIGS. 17A-17B is a set of E-R plots showing the exposure-safety relationship of cevostamab for the probability of occurrence of Grade >3 lymphopenia and Cmax, step-up dose (FIG. 17A) or Cmax at C3 (FIG. 17B) across the pooled single step-up, double step-up, and triple step-up dosing regimens described in Study GO39775.

FIGS. 18A-18B is a set of E-R plots showing the exposure-safety relationship of cevostamab for the probability of occurrence of Grade >3 infections and Cmax, step-up dose (FIG. 18A) or Cmax at C3 (FIG. 18B) across the pooled single step-up, double step-up, and triple step-up dosing regimens described in Study GO39775.

FIGS. 19A-19B is a set of E-R plots showing the exposure-safety relationship of cevostamab for the probability of occurrence of a severe adverse event (SAE) and Cmax, step-up dose (FIG. 19A) or Cmax at C3 (FIG. 19B) across the pooled single step-up, double step-up, and triple step-up dosing regimens described in Study GO39775.

FIGS. 20A-20B is a set of E-R plots showing the exposure-safety relationship of cevostamab for the probability of occurrence of a Grade >3 adverse event (AE) and Cmax, step-up dose (FIG. 20A) or Cmax at C3 (FIG. 20B) across the pooled single step-up, double step-up, and triple step-up dosing regimens described in Study GO39775.

FIGS. 21A-21B is a set of E-R plots showing the exposure-safety relationship of cevostamab for the probability of occurrence of an AE that leads to a dose modification and Cmax, step-up dose (FIG. 21 A) or Cmax at C3 (FIG. 21 B) across the pooled single step-up, double step-up, and triple step-up dosing regimens described in Study GO39775. A dose modification included a dose interruption, reduction, or discontinuation.

FIG. 22 is an E-R plot showing the exposure-safety relationship of cevostamab for the probability of occurrence of Grade >3 infections and the average concentrations at cycle 3 (Cavg at C3). Arrow 2 is pointing to a datapoint that represents the observed probability of the occurrence of Grade >3 infections plotted at the estimated geometric mean of Cavg at C3 at 160 mg administered every three weeks in Study CO43476 (n=25); error bars represent the Wald’s 90% Cis for said observed probability. Arrow 1 is pointing to a datapoint that represents the observed probability of the occurrence of Grade >3 infections plotted at the estimated geometric mean of Cavg at C3 at the 160 mg target dose administered every three weeks in Study GO39775 (1X1=159); error bars represent the Wald’s 90% Cis for said observed probability.

FIG. 23 is an E-R plot showing the exposure-safety relationship of cevostamab for the probability of occurrence of an SAE at Cavg at C3. Arrow 2 is pointing to a datapoint that represents the observed probability of the occurrence of SAEs plotted at the estimated geometric mean of Cavg at C3 at 160 mg administered every three weeks in Study CO43476 (n=25); error bars represent the Wald’s 90% Cis for said observed probability. Arrow 1 is pointing to a datapoint that represents the observed probability of the occurrence of SAEs plotted at the estimated geometric mean of Cavg at C3 at the 160 mg target dose administered every three weeks in Study GO39775 (N=159); error bars represent the Wald’s 90% Cis for said observed probability.

FIG. 24 is a set of heatmaps that shows the maximum IL-6 peak ratio of the indicated triple step- up dosing regimen (e.g., 0.3 mg/1 .2 mg/3.6 mg followed by 160 mg of cevostamab) compared to a single step-up dosing regimen. A schematic diagram of the indicated doses and schedule is shown on the left of each heatmap. D1 = Day 1 ; D2 = Day 2; D3 = Day 3; D4 = Day 4; D8 = Day 8; D9 = Day 9; D10 = Day 10; D11 = Day 11.

FIG. 25 is a set of heatmaps that shows the maximum IL-6 peak ratio of the indicated double step-up dosing regimen (e.g., 0.3 mg/3.6 mg followed by 160 mg of cevostamab (left); or 0.3 mg/3.3 mg followed by 160 mg of cevostamab (right)) compared to a single step-up dosing regimen. A schematic diagram of the indicated doses and schedule are shown to the left of each heatmap. D1 = Day 1 ; D2 = Day 2; D3 = Day 3; D4 = Day 4; D8 = Day 8; D15 = Day 15.

FIG. 26 is a schematic diagram illustrating the overview of the QSP model calibration and validation workflow. Cyno = cynomolgus monkey; DScomp = compressed double step-up dosing regimen (e.g., Arm K); SS = single step-up; DS = double step-up; r/r = relaped or refractory; TDB = T-cell dependent bispecific antibody; Ph = Phase

FIG. 27 is a series of plots showing the model simulation results for IL-6 peak levels of digital twins and patients in each indicated dosing regimen cevostamab treatment cohort. Black line indicates median IL-6 peak concentrations, and the shaded region indicates the 5^,h-95^,h percentile of simulation of digital twins. LLOQ: lower-limit of quantification of observed IL-6 concentrations; NPTNM: number of patients in the cohort; Ndigitai twin : number of digital twins corresponding to the patients in the cohort, in which there were 100 digital twins per patient.

FIG. 28 is a graph showing the peak IL-6 levels following administration of cevostamab at the indicated C1 D1 step-up doses. The horizontal line indicates the median predicted IL-6 peak levels in the virtual population (8,400 digital twins) of the QSP model, and the shaded bar represents the 90% prediction interval. Filled circles represent observed data used for calibration of the model, and hollow circles represent observed data for validation of the QSP model. Filled diamonds represent the geometric mean of the observed data for the calibration data, and the hollow diamonds represent the geometric mean of the observed data for the validation data.

FIG. 29 is a graph showing peak IL-6 levels following administration of the 3.6 mg step-up dose of cevostamab in the single step-up dosing regimen.

FIG. 30 is a graph showing peak IL-6 levels following administration of the 3.3 mg or 3.6 mg dose of cevostamab in the indicated step-up dosing regimens.

FIG. 31 is a graph showing peak IL-6 levels following administration of the target dose of cevostamab in the indicated step-up dosing regimens

FIG. 32 is a series of graphs showing peak IL-6 levels at various days of the indicated dosing regimens. The solid lines indicate median IL-6 levels in the virtual population (8,400 digital twins) of the QSP model, and the shaded region in the graphs represents the 90% prediction interval.

FIGS. 33A-33C are a series of forest plots showing the predicted impact of baseline characteristics on steady-state cevostamab exposure based on a 160 mg target dose, in which FIG. 33A shows the steady-state area under the curve (AUC) of cevostamab, FIG. 33B shows the steady-state maximum serum concentrations (Cmax) of cevostamab, and FIG. 33C shows the steady-state minimum serum concentrations (Cmin) of cevostamab.

FIGS. 34A-34B are a set of box-and-whisker plots showing the relationship between anti-drug antibody (ADA) titer and dose-normalized Cmin of cevostamab (FIG. 34A) or dose-normalized Cmax of cevostamab (FIG. 34B) across the indicated doses in ADA-negative (ADA-) patients, patients with an ADA titer <4 (low titer), and patients with an ADA titer >4 (high titer).

FIGS. 35A-35B are a set of graphs showing the relationship between the observed M-protein blood levels (FIG. 35A) and the observed free-light chain blood levels (FIG. 35B) over time in response to the indicated target dose levels of cevostamab. Dashed lines indicate the median protein levels, and the shaded region represents the 90% Cis. Individual data points and corresponding dashed lines represent individual patient paraprotein dynamics.

FIGS. 36A-36B are a set of forest plots showing the predicted impact of baseline characteristics on the M-protein growth rate (FIG. 36A) or M-protein decay half-life as measured in days (FIG. 36B).

FIGS. 37A-37B are a set of forest plots showing the predicted impact of baseline characteristics on free-light chain growth rate (FIG. 37A) and free-light chain decay half-life as measured in days (FIG. 37B).

FIG. 38 is a graph showing the predicted paraprotein levels over time. FLC: free-light chain; MCPROT: M-protein.

FIGS. 39A-39B are a set of graphs showing the posterior predictive check (PPC) of the tumor growth inhibition model based on the overall response rate (FIG. 39A), in which there was at least a 50% decrease of paraprotein reduction at nadir, and VGPR response rate (FIG. 39B), in which VGPR is classified as at least a 90% decrease of paraprotein reduction at nadir, at the indicated target dose levels. Data points without numbers represent the median prediction, and error bars represent the 90% prediction interval. Data points with numbers (n, number of patients) represents observed patient responses in Study GO39775. FIGS. 40A-40B are a set of graphs showing the PPC of the tumor growth inhibition model based on the overall response rate (FIG. 40A) and VGPR response rate (FIG. 40B) at the indicated dose priming sequence of doses in Study GO39775. Data points without numbers represent the median prediction, and error bars represent the 90% prediction interval. Data points with numbers (n, number of patients) represents observed patient responses in Study GO39775.

FIGS. 41A-41B are a set of graphs showing the PPC of the tumor growth inhibition model based on the overall response rate (FIG. 41 A) and VGPR response rate (FIG. 41 B) at the indicated single step- up dose priming sequence of doses in Study GO39775.

FIGS. 42A-42B are a set of graphs showing the PPC of the tumor growth inhibition model based on the overall response rate (FIG. 42A) and VGPR response rate (FIG. 42B) at the indicated dose priming sequence of doses in Study GO39775.

FIGS. 43A-43C are schematic diagrams showing the possible single-step (SS), double-step (DS), and triple-step (TS) dosing regimens from the GO39775 Phase I dose-escalation study. Dose levels are in milligrams. A total of 324 patients were enrolled in the cevostamab monotherapy study (FIG. 43A), 167 patients were enrolled in the 160 mg target dose (TD) study (FIG. 43B), and 30 patients were enrolled in the cycle 1 (C1 ) 0.3mg/1 .2 mg/3.6 mg triple step-up plus 160mg TD study (FIG. 43C).

FIG. 44 is a table outlining the baseline characteristics of patients enrolled in the GO39775 Phase I dose-escalation study. Most patients enrolled had heavily pretreated and highly refractory disease, while more than 50% of patients had received a prior BCMA-targeted therapy. * = includes t(4;14), t(14;16) and del(17p); t = >1 IMiD, >1 PI and >1 anti-CD38 antibody; t = &2 IMiDs, >2 Pls and >1 anti-CD38 antibody; data cut-off: Aug 22, 2024; HR, high risk.

FIG. 45 is a flow chart outlining the treatment disposition of the 167 patients that were enrolled in the 160 mg target dose (TD) study.

FIG. 46 is a table (left) and graph (right) characterizing adverse effects that were observed in the GO39775 Phase I dose-escalation study. * = includes time after completion and/or discontinuation of treatment when AE reporting was limited to 90 days after the last dose of study drug or until initiation of another anti-cancer therapy, whichever occurred first, and to treatment-related SAEs thereafter; f = excludes 16 patients with Gr 5 AE of PD; $ = HLH (n=2) and pseudomonal sepsis in the context of DIC (n=1); §group term: neutropenia, neutrophil count decreased and febrile neutropenia; fl = group term: thrombocytopenia and platelet count decreased; data cut-off: Aug 22, 2024; ALT, alanine transaminase; DIC, disseminated intravascular coagulation; Gr, Grade; HLH, hemophagocytic lymphohistiocytosis; PT, Preferred Term; SAE, serious AE.

FIG. 47 is a set of tables summarizing adverse events (AE) of infection at the 160 mg target dose (TD) in the 167 patients that were enrolled in the 160 mg target dose (TD) study. * = System Organ Class level term; data cut-off: Aug 22, 2024; URI, upper respiratory tract infection; UTI, urinary tract infection.

FIG. 48 is a table (left) and bar graph (right) summarizing cytokine release syndrome (CRS) events that occurred in the 30 patients were enrolled in the cycle 1 (C1 ) 0.3mg/1 .2 mg/3.6 mg triple step- up plus 160mg TD study. Gr, Grade. * = Gr 2 CRS in 1 patient in C2 only; t = D3 or D4 depending on the emergence of CRS with the previous administration; $ = D10 or D11 ; data cut-off: Aug 22, 2024. FIG. 49 is a bar graph summarizing the overall response rate (ORR) of patients at the 160 mg target dose (TD) level. * = <10-5 level by NGS; f = all patients were in VGPR or better (VGPR+); $ = subgroups are not mutually exclusive; § = unvalidated analysis; data cut-off: Aug 22, 2024; CR, complete response; MRD, minimal residual disease; NGS, next generation sequencing; ORR, overall response rate; PR, partial response; sCR, stringent CR; VGPR, very good PR; BsAb, bispecific antibody.

FIG. 50 is a graph showing the durability of response of patients at the 160 mg target dose (TD) level. * = unvalidated analysis; data cut-off: Aug 22, 2024; DoR, duration of response; mDoR, median DoR.

FIG. 51 is a graph showing the durability of response after completion of cevostamab treatment in patients administered the 160mg target dose (TD) of cevostamab.

FIGS. 52A-52B are plots showing the best ORR in all patients and in those with or without prior BCMA-targeted therapies who received cevostamab at the 160 mg TD level (FIG. 52A) and duration of response among patients in PR, PR or better (PR+) or VGPR+ who received cevostamab at the 160 mg target-dose level (FIG. 52B).

FIG. 53 is a flow chart outlining the treatment disposition of the 324 patients that were enrolled in the 160 mg TD study described in Example 7.

FIG. 54 is a plot showing the PK profile of cevostamab within the indicated cohorts.

FIG. 55 shows a series of box and whisker plots demonstrating the relationship between patient response and FcRH5 expression levels on myeloma cells that were collected at baseline in patients who received cevostamab treatment at the 160 mg TD. Myeloma cells were collected by bone marrow aspiration. Bone marrow aspirates that were considered hemodiluted by the study pathologists were not included in the analysis. FcRH5 expression was assessed by flow cytometry (FC).

FIG. 56 is a line graph of progression-free survival (PFS) among patients who received cevostamab at the 160 mg TD, as described in Example 7.

FIGS. 57A-57D are Sankey plots showing the proportion of patients that experienced no CRS, Grade 1 CRS, Grade 2 CRS, or Grade 3 CRS in Arm A, Arm C, and Arm F of the single step-up regimen (FIG. 57A), in Arm B and Arm D of the double step-up regimen (FIG. 57B), in Arm B and Arm G of the double step-up regimen (FIG. 57C), and in Arm K of the double step-up regimen (FIG. 57D) in Study GO39775. The CRS grade (e.g., Grade 1 , Grade 2, or no CRS), tocilizumab (toci) administration (e.g., yes or no), and no administered dose of cevostamab (“No Dose”) is also shown for each patient.

DETAILED DESCRIPTION

I. DEFINITIONS

The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) aspects that are directed to that value or parameter per se.

It is understood that aspects of the disclosure described herein include “comprising,” “consisting,” and “consisting essentially of” aspects.

The term “FcRH5” or “fragment crystallizable receptor-like 5,” as used herein, refers to any native FcRH5 from any vertebrate source, including mammals such as primates (e.g. humans) and rodents (e.g., mice and rats), unless otherwise indicated, and encompasses “full-length,” unprocessed FcRH5, as well as any form of FcRH5 that results from processing in the cell. The term also encompasses naturally occurring variants of FcRH5, including, for example, splice variants or allelic variants. FcRH5 includes, for example, human FcRH5 protein (UniProtKB/Swiss-Prot ID: Q96RD9.3), which is 977 amino acids in length.

The terms “anti-FcRH5 antibody” and “an antibody that binds to FcRH5” refer to an antibody that is capable of binding FcRH5 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting FcRH5. In one embodiment, the extent of binding of an anti-FcRH5 antibody to an unrelated, non-FcRH5 protein is less than about 10% of the binding of the antibody to FcRH5 as measured, e.g., by a radioimmunoassay (RIA). In certain embodiments, an antibody that binds to FcRH5 has a dissociation constant (KD) of < 1 pM, < 250 nM, < 100 nM, < 15 nM, < 10 nM, < 6 nM, < 4 nM, < 2 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g. 10^-8 M or less, e.g. from 10^-8 M to 10^-13 M, e.g., from 10^-9 M to 10^-13 M). In certain embodiments, an anti-FcRH5 antibody binds to an epitope of FcRH5 that is conserved among FcRH5 from different species.

The term “cluster of differentiation 3” or “CD3,” as used herein, refers to any native CD3 from any vertebrate source, including mammals such as primates (e.g. humans) and rodents (e.g., mice and rats), unless otherwise indicated, including, for example, CD3e, CD3y, CD3a, and CD3p chains. The term encompasses “full-length,” unprocessed CD3 (e.g., unprocessed or unmodified CD3e or CD3y), as well as any form of CD3 that results from processing in the cell. The term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants. CD3 includes, for example, human CD3e protein (NCBI RefSeq No. NP_000724), which is 207 amino acids in length, and human CD3y protein (NCBI RefSeq No. NP_000064), which is 182 amino acids in length.

The terms “anti-CD3 antibody” and “an antibody that binds to CD3” refer to an antibody that is capable of binding CD3 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting CD3. In one embodiment, the extent of binding of an anti-CD3 antibody to an unrelated, non-CD3 protein is less than about 10% of the binding of the antibody to CD3 as measured, e.g., by a radioimmunoassay (RIA). In certain embodiments, an antibody that binds to CD3 has a dissociation constant (KD) of < 1 pM, < 250 nM, < 100 nM, < 15 nM, < 10 nM, < 5 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g. 10^-8 M or less, e.g. from 10^-8 M to 10^-13 M, e.g., from 10^-9 M to 10^-13 M). In certain embodiments, an anti-CD3 antibody binds to an epitope of CD3 that is conserved among CD3 from different species.

For the purposes herein, “cevostamab,” also referred to as BFCR4350A or RO7187797, is an Fc- engineered, humanized, full-length non-glycosylated lgG1 kappa T-cell-dependent bispecific antibody (TDB) that binds FcRH5 and CD3 and comprises an anti-FcRH5 arm comprising the heavy chain polypeptide sequence of SEQ ID NO: 35 and the light chain polypeptide sequence of SEQ ID NO: 36 and an anti-CD3 arm comprising the heavy chain polypeptide sequence of SEQ ID NO: 37 and the light chain polypeptide sequence of SEQ ID NO: 38. Cevostamab comprises a threonine to tryptophan amino acid substitution at position 366 on the heavy chain of the anti-FcRH5 arm (T366W) using EU numbering of Fc region amino acid residues and three amino acid substitutions (tyrosine to valine at position 407, threonine to serine at position 366, and leucine to alanine at position 368) on the heavy chain of the anti- CD3 arm (Y407V, T366S, and L368A) using EU numbering of Fc region amino acid residues to drive heterodimerization of the two arms (half-antibodies). Cevostamab also comprises an amino acid substitution (asparagine to glycine) at position 297 on each heavy chain (N297G) using EU numbering of Fc region amino acid residues, which results in a non-glycosylated antibody that has minimal binding to Fc (Fey) receptors and, consequently, prevents Fc-effector function. Cevostamab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Recommended INN: List 84, Vol. 34, No. 3, published 2020 (see page 701 ). Cevostamab is also listed as CAS Registry No.: 2249888-53-5.

The term “antibody” herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments (e.g., bis-Fabs) so long as they exhibit the desired antigen-binding activity.

“Affinity” refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1 :1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary aspects for measuring binding affinity are described in the following.

An “affinity matured” antibody refers to an antibody with one or more alterations in one or more hypervariable regions (HVRs), compared to a parent antibody which does not possess such alterations, such alterations resulting in an improvement in the affinity of the antibody for antigen.

The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein.

An “antibody fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to bis-Fabs; Fv; Fab; Fab, Fab’-SH; F(ab’)2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv, ScFab); and multispecific antibodies formed from antibody fragments.

A “single-domain antibody” refers to an antibody fragment comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain aspects, a single-domain antibody is a human single-domain antibody (see, e.g., U.S. Patent No. 6,248,516 B1 ). Examples of single-domain antibodies include but are not limited to a VHH.

A “Fab” fragment is an antigen-binding fragment generated by papain digestion of antibodies and consists of an entire L chain along with the variable region domain of the H chain (VH), and the first constant domain of one heavy chain (CH1 ). Papain digestion of antibodies produces two identical Fab fragments. Pepsin treatment of an antibody yields a single large F(ab’)2 fragment which roughly corresponds to two disulfide linked Fab fragments having divalent antigen-binding activity and is still capable of cross-linking antigen. Fab’ fragments differ from Fab fragments by having an additional few residues at the carboxy terminus of the CH1 domain including one or more cysteines from the antibody hinge region. Fab’-SH is the designation herein for Fab’ in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab’)2 antibody fragments originally were produced as pairs of Fab’ fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

“Fv” consists of a dimer of one heavy- and one light-chain variable region domain in tight, non- covalent association. From the folding of these two domains emanate six hypervariable loops (3 loops each from the H and L chain) that contribute the amino acid residues for antigen binding and confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although often at a lower affinity than the entire binding site.

The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain, including native sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxylterminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody. Accordingly, a composition of intact antibodies may comprise antibody populations with all Lys447 residues removed, antibody populations with no Lys447 residues removed, and antibody populations having a mixture of antibodies with and without the Lys447 residue.

A “functional Fc region” possesses an “effector function” of a native sequence Fc region. Exemplary “effector functions” include C1q binding; CDC; Fc receptor binding; ADCC; phagocytosis; down regulation of cell surface receptors {e.g., B cell receptor; BCR), etc. Such effector functions generally require the Fc region to be combined with a binding domain {e.g., an antibody variable domain) and can be assessed using various assays as disclosed, for example, in definitions herein.

A “native sequence Fc region” comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include a native sequence human IgG I Fc region (non-A and A allotypes); native sequence human lgG2 Fc region; native sequence human lgG3 Fc region; and native sequence human lgG4 Fc region as well as naturally occurring variants thereof.

A “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, preferably one or more amino acid substitution(s). Preferably, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, e.g., from about one to about ten amino acid substitutions, and preferably from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide. The variant Fc region herein will preferably possess at least about 80% homology with a native sequence Fc region and/or with an Fc region of a parent polypeptide, preferably at least about 90% homology therewith, or preferably at least about 95% homology therewith. “Fc complex” as used herein refers to CH3 domains of two Fc regions interacting together to form a dimer or, as in certain aspects, two Fc regions interact to form a dimer, wherein the cysteine residues in the hinge regions and/or the CH3 domains interact through bonds and/or forces (e.g., Van der Waals, hydrophobic forces, hydrogen bonds, electrostatic forces, or disulfide bonds).

“Fc component” as used herein refers to a hinge region, a CH2 domain or a CH3 domain of an Fc region.

“Hinge region” is generally defined as stretching from about residue 216 to 230 of an IgG (EU numbering), from about residue 226 to 243 of an IgG (Kabat numbering), or from about residue 1 to 15 of an IgG (IMGT unique numbering).

The “lower hinge region” of an Fc region is normally defined as the stretch of residues immediately C-terminal to the hinge region, i.e., residues 233 to 239 of the Fc region (EU numbering).

A “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, preferably one or more amino acid substitution(s). Preferably, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, e.g., from about one to about ten amino acid substitutions, and preferably from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide. The variant Fc region herein will preferably possess at least about 80% homology with a native sequence Fc region and/or with an Fc region of a parent polypeptide, and preferably at least about 90% homology therewith, more preferably at least about 95% homology therewith.

“Fc receptor” or “FcR” describes a receptor that binds to the Fc region of an antibody. A preferred FcR is a native sequence human FcR. Moreover, a preferred FcR is one that binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcyRII receptors include FcyRIIA (an “activating receptor”) and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Activating receptor FcyRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (see review M. in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991 ); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein. The term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)).

The term “knob-into-hole” or “KnH” technology as mentioned herein refers to the technology directing the pairing of two polypeptides together in vitro or in vivo by introducing a protuberance (knob) into one polypeptide and a cavity (hole) into the other polypeptide at an interface in which they interact. For example, KnHs have been introduced in the Fc:Fc interaction interfaces, CL:CH1 interfaces or VH/VL interfaces of antibodies (e.g., US2007/0178552, WO 96/027011 , WO 98/050431 and Zhu et al. (1997) Protein Science 6:781 -788). This is especially useful in driving the pairing of two different heavy chains together during the manufacture of multispecific antibodies. For example, multispecific antibodies having KnH in their Fc regions can further comprise single variable domains linked to each Fc region, or further comprise different heavy chain variable domains that pair with identical, similar, or different light chain variable domains. KnH technology can also be used to pair two different receptor extracellular domains together or any other polypeptide sequences that comprise different target recognition sequences.

“Framework” or “FR” refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1 , FR2, FR3, and FR4. Accordingly, the HVR and FR sequences generally appear in the following sequence in VH (or VL): FR1 - H1 (L1 )-FR2-H2(L2)-FR3-H3(L3)-FR4.

The “CH1 region” or “CH1 domain” comprises the stretch of residues from about residue 118 to residue 215 of an IgG (EU numbering), from about residue 114 to 223 of an IgG (Kabat numbering), or from about residue 1 .4 to residue 121 of an IgG (IMGT unique numbering) (Lefranc M-P, Giudicelli V, Duroux P, Jabado-Michaloud J, Folch G, Aouinti S, Carillon E, Duvergey H, Houles A, Paysan-Lafosse T, Hadi-Saljoqi S, Sasorith S, Lefranc G, Kossida S. IMGT®, the international ImMunoGeneTics information system® 25 years on. Nucleic Acids Res. 2015 Jan;43(Database issue):D413-22).

The “CH2 domain” of a human IgG Fc region usually extends from about residues 244 to about 360 of an IgG (Kabat numbering), from about residues 231 to about 340 of an IgG (EU numbering), or from about residues 1 .6 to about 125 of an IgG (IGMT unique numbering). The CH2 domain is unique in that it is not closely paired with another domain. Rather, two N-linked branched carbohydrate chains are interposed between the two CH2 domains of an intact native IgG molecule. It has been speculated that the carbohydrate may provide a substitute for the domain-domain pairing and help stabilize the CH2 domain. Burton, Molec. Immunol.22: 161 -206 (1985).

The “CH3 domain” comprises the stretch of residues C-terminal to a CH2 domain in an Fc region (i.e., from about amino acid residue 361 to about amino acid residue 478 of an IgG (Kabat numbering), from about amino acid residue 341 to about amino acid residue 447 of an IgG (EU numbering), or from about amino acid residue 1 .4 to about amino acid residue 130 of an IgG (IGMT unique numbering)).

The “CL domain” or “constant light domain” comprises the stretch of residues C-terminal to a light-chain variable domain (VL). The light chain of an antibody may be a kappa (K) (“CK”) or lambda (A) (“CA”) light chain region. The CK region generally extends from about residue 108 to residue 214 of an IgG (Kabat or EU numbering) or from about residue 1 .4 to residue 126 of an IgG (IMGT unique numbering). The CA residue generally extends from about residue 107a to residue 215 (Kabat numbering) or from about residue 1 .5 to residue 127 (IMGT unique numbering) (Lefranc M-P, Giudicelli V, Duroux P, Jabado-Michaloud J, Folch G, Aouinti S, Carillon E, Duvergey H, Houles A, Paysan-Lafosse T, Hadi-Saljoqi S, Sasorith S, Lefranc G, Kossida S. IMGT®, the international ImMunoGeneTics information system® 25 years on. Nucleic Acids Res. 2015 Jan;43(Database issue):D413-22).

The light chain (LC) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains. Depending on the amino acid sequence of the constant domain of their heavy chains (CH), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, having heavy chains designated a, 5, y, e, and p, respectively. The y and a classes are further divided into subclasses on the basis of relatively minor differences in CH sequence and function, e.g., humans express the following subclasses: IgG 1 , lgG2, lgG3, lgG4, lgA1 , and lgA2.

The term “chimeric” antibody refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.

The “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGi, lgG2, IgGs, lgG4, IgAi, and lgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 5, E, y, and p., respectively.

A “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage-display libraries. Hoogenboom and Winter. J. Mol. Biol. 227:381 ,1991 ; Marks et al. J. Mol. Biol. 222:581 , 1991 . Also available for the preparation of human monoclonal antibodies are methods described in Cole et al. Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al. J. Immunol., 147(1 ):86-95, 1991 . See also van Dijk and van de Winkel. Curr. Opin. Pharmacol. 5:368-74, 2001 . Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., immunized xenomice (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE™ technology). See also, for example, Li et al. Proc. Natl. Acad. Sci. USA. 103:3557-3562, 2006 regarding human antibodies generated via a human B-cell hybridoma technology.

A “human consensus framework” is a framework which represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al. Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91 -3242, Bethesda MD (1991 ), vols. 1 -3. In one aspect, for the VL, the subgroup is subgroup kappa I as in Kabat et al. supra. In one aspect, for the VH, the subgroup is subgroup III as in Kabat et al. supra.

A “humanized” antibody refers to a chimeric antibody comprising amino acid residues from non- human HVRs and amino acid residues from human FRs. In certain aspects, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody. In certain aspects in which all or substantially all of the FRs of a humanized antibody correspond to those of a human antibody, any of the FRs of the humanized antibody may contain one or more amino acid residues (e.g., one or more Vernier position residues of FRs) from non-human FR(s). A humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of an antibody, e.g., a nonhuman antibody, refers to an antibody that has undergone humanization.

The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindt et al. Kuby Immunology, 6^th ed. W.H. Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al. J. Immunol. 150:880-887, 1993; Clarkson et al. Nature 352:624-628, 1991.

The term “hypervariable region” or “HVR” as used herein refers to each of the regions of an antibody variable domain which are hypervariable in sequence (“complementarity determining regions” or “CDRs”). Generally, antibodies comprise six CDRs: three in the VH (CDR-H1 , CDR-H2, CDR-H3), and three in the VL (CDR-L1 , CDR-L2, CDR-L3). Exemplary CDRs herein include:

(a) CDRs occurring at amino acid residues 26-32 (L1 ), 50-52 (L2), 91 -96 (L3), 26-32 (H1 ), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901 -917, 1987);

(b) CDRs occurring at amino acid residues 24-34 (L1 ), 50-56 (L2), 89-97 (L3), 31 -35b (H1 ), SO- 65 (H2), and 95-102 (H3) (Kabat et al. Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991 )); and

(c) antigen contacts occurring at amino acid residues 27c-36 (L1 ), 46-55 (L2), 89-96 (L3), 30-35b (H1 ), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262: 732-745, 1996).

Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al. supra.

“Single-chain Fv” also abbreviated as “sFv” or “scFv” are antibody fragments that comprise the VH and VL antibody domains connected into a single polypeptide chain. Preferably, the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains, which enables the scFv to form the desired structure for antigen binding. For a review of scFv, see Pluckthun, The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer- Verlag, New York, pp. 269-315 (1994); Malmborg et al., J. Immunol. Methods 183:7-13, 1995.

By “targeting domain” is meant a part of a compound or a molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Targeting domains include but are not limited to antibodies (e.g., monoclonal, polyclonal, recombinant, humanized, and chimeric antibodies), antibody fragments or portions thereof (e.g., bis-Fab fragments, Fab fragments, F(ab’)2, scFab, scFv antibodies, SMIP, singledomain antibodies, diabodies, minibodies, scFv-Fc, affibodies, nanobodies, and VH and/or VL domains of antibodies), receptors, ligands, aptamers, peptide targeting domains (e.g., cysteine knot proteins (CKP)), and other molecules having an identified binding partner. A targeting domain may target, block, agonize, or antagonize the antigen to which it binds.

The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present disclosure may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.

The term “multispecific antibody” is used in the broadest sense and specifically covers an antibody that has polyepitopic specificity. In one aspect, the multispecific antibody binds to two different targets (e.g., bispecific antibody). Such multispecific antibodies include, but are not limited to, an antibody comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), where the VH/VL unit has polyepitopic specificity, antibodies having two or more VL and VH domains with each VH/VL unit binding to a different epitope, antibodies having two or more single variable domains with each single variable domain binding to a different epitope, full-length antibodies, antibody fragments such as Fab, Fv, dsFv, scFv, diabodies, bispecific diabodies and triabodies, antibody fragments that have been linked covalently or non-covalently. “Polyepitopic specificity” refers to the ability to specifically bind to two or more different epitopes on the same or different target(s). “Monospecific” refers to the ability to bind only one antigen. In one aspect, the monospecific biepitopic antibody binds two different epitopes on the same target/antigen. In one aspect, the monospecific polyepitopic antibody binds to multiple different epitopes of the same target/antigen. According to one aspect, the multispecific antibody is an IgG antibody that binds to each epitope with an affinity of 5 pM to 0.001 pM, 3 pM to 0.001 pM, 1 pM to 0.001 pM, 0.5 pM to 0.001 pM, or 0.1 pM to 0.001 pM.

A “naked antibody” refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical formulation.

“Native antibodies” refer to naturally occurring immunoglobulin molecules with varying structures. For example, native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From N- to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CH1 , CH2, and CH3). Similarly, from N- to C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody may be assigned to one of two types, called kappa (K) and lambda (A), based on the amino acid sequence of its constant domain.

As used herein, the term “immunoadhesin” designates molecules which combine the binding specificity of a heterologous protein (an “adhesin”) with the effector functions of immunoglobulin constant domains. Structurally, the immunoadhesins comprise a fusion of an amino acid sequence with a desired binding specificity, which amino acid sequence is other than the antigen recognition and binding site of an antibody {i.e., is “heterologous” compared to a constant region of an antibody), and an immunoglobulin constant domain sequence {e.g., CH2 and/or CH3 sequence of an IgG). The adhesin and immunoglobulin constant domains may optionally be separated by an amino acid spacer. Exemplary adhesin sequences include contiguous amino acid sequences that comprise a portion of a receptor or a ligand that binds to a protein of interest. Adhesin sequences can also be sequences that bind a protein of interest, but are not receptor or ligand sequences {e.g., adhesin sequences in peptibodies). Such polypeptide sequences can be selected or identified by various methods, include phage display techniques and high throughput sorting methods. The immunoglobulin constant domain sequence in the immunoadhesin can be obtained from any immunoglobulin, such as IgG 1 , lgG2, lgG3, or lgG4 subtypes, IgA (including lgA1 and lgA2), IgE, IgD, or IgM.

“Chemotherapeutic agent” includes chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate , salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CB1 -TM1 ); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin y11 and calicheamicin w11 (Angew Chem. Inti. Ed. Engl. 199433:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzi nostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5- fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2”-trichlorotriethylamine; trichothecenes (especially T- 2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, III.), and TAXOTERE® (docetaxel, doxetaxel; Sanofi-Aventis); chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine;

NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene , 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all transretionic acid, fenretinide, as well as troxacitabine (a 1 ,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN®, rlL-2; a topoisomerase 1 inhibitor such as LURTOTECAN®; ABARELIX® rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.

Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idee), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the disclosure include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, peefusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and the antiinterleukin-12 (ABT-874/J695, Wyeth Research and Abbott Laboratories) which is a recombinant exclusively human-sequence, full-length lgG1 A antibody genetically modified to recognize interleukin-12 p40 protein.

Chemotherapeutic agent also includes “EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an “EGFR antagonist.” Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, US Patent No. 4,943, 533, Mendelsohn et al.) and variants thereof, such as chimerized 225 (C225 or Cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see, WO 96/40210, Imclone Systems Inc.); IMC-11 F8, a fully human, EGFR-targeted antibody (Imclone); antibodies that bind type II mutant EGFR (US Patent No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in US Patent No. 5,891 ,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (see WO98/50433, Abgenix/Amgen); EMD 55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known as E1 .1 , E2.4, E2.5, E6.2, E6.4, E2.11 , E6. 3 and E7.6. 3 and described in US 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al., J. Biol. Chem. 279(29) :30375-30384 (2004)). The anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2, Merck Patent GmbH). EGFR antagonists include small molecules such as compounds described in US Patent Nos: 5,616,582, 5,457,105, 5,475,001 , 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521 ,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391 ,874, 6,344,455, 5,760,041 , 6,002,008, and 5,747,498, as well as the following PCT publications: WO98/14451 , W098/50038, W099/09016, and WO99/24037. Particular small molecule EGFR antagonists include OSI-774 (CP- 358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals); PD 183805 (Cl 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3’-Chloro-4’-fluoroanilino)-7-methoxy-6-(3- morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)- quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1 -methyl-piperidin-4-yl)- pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(1 -phenylethyl)amino]- 1 H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1 -phenylethyl)amino]-7H-pyrrolo[2,3- d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569 (N-[4- [(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271 ; Pfizer); dual EGFR/HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3 fluorophenyl)methoxy]phenyl]- 6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

Chemotherapeutic agents also include “tyrosine kinase inhibitors” including the EGFR-targeted drugs noted in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1 signaling; non-HER targeted TK inhibitors such as imatinib mesylate (GLEEVEC®, available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787/ZK222584, available from Novartis/Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines, such as PD 153035, 4-(3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; PD-0183805 (Warner-Lamber); antisense molecules (e.g. those that bind to HER-encoding nucleic acid); quinoxalines (US Patent No. 5,804,396); tryphostins (US Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI- 1033 (Pfizer); Affinitac (ISIS 3521 ; Isis/Lilly); imatinib mesylate (GLEEVEC®); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1 C1 1 (Imclone), rapamycin (sirolimus, RAPAMUNE®); or as described in any of the following patent publications: US Patent No. 5,804,396; WO 1999/09016 (American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).

Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa- 2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.

Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17- butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; immune selective antiinflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG) (IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such as azathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumor necrosis factor alpha (TNFa) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), interleukin 1 (IL-1 ) blockers such as anakinra (Kineret), T cell costimulation blockers such as abatacept (Orencia), interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMRA®); interleukin 13 (IL-13) blockers such as lebrikizumab; interferon alpha (IFN) blockers such as Rontalizumab; beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-M1 prime; Secreted homotrimeric LTa3 and membrane bound heterotrimer LTa1 /p2 blockers such as anti-lymphotoxin alpha (LTa); radioactive isotopes (e.g., At²¹¹ , I¹³¹ , I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹², and radioactive isotopes of Lu); miscellaneous investigational agents such as thioplatin, PS-341 , phenylbutyrate, ET-18- OCH3, or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta- lapachone; lapachol; colchicines; betulinic acid; acetylcamptothecin, scopolectin, and 9- aminocamptothecin); podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine; perifosine, COX-2 inhibitor (e.g. celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341 ); CCI-779; tipifarnib (R1 1577); orafenib, ABT510; Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®); pixantrone; farnesyltransferase inhibitors such as lonafarnib (SCH 6636, SARASARTM); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATIN™) combined with 5-FU and leucovorin.

Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects. NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, and valdecoxib. NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter’s syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.

The term “cytotoxic agent” as used herein refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At²¹¹ , I¹³¹ , 1¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹², and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; antibiotics; toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof; and the various antitumor or anticancer agents disclosed below.

A “disorder” is any condition that would benefit from treatment including, but not limited to, chronic and acute disorders or diseases including those pathological conditions which predispose a mammal to the disorder in question. In one aspect, the disorder is a cancer, e.g., a multiple myeloma (MM).

The terms “cell proliferative disorder” and “proliferative disorder” refer to disorders that are associated with some degree of abnormal cell proliferation. In one aspect, the cell proliferative disorder is cancer. In one aspect, the cell proliferative disorder is a tumor.

“Tumor,” as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” “cell proliferative disorder,” “proliferative disorder,” and “tumor” are not mutually exclusive as referred to herein.

The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth/proliferation. Aspects of cancer include solid tumor cancers and non-solid tumor cancers. Examples of cancer include, but are not limited to, B cell proliferative disorders, such as multiple myeloma (MM), which may be relapsed or refractory MM. The MM may be, e.g., typical MM (e.g., immunoglobulin G (IgG) MM, IgA MM, IgD MM, IgE MM, or IgM MM), light chain MM (LCMM) (e.g., lambda light chain MM or kappa light chain MM), or non-secretory MM. The MM may have one or more cytogenetic features (e.g., high-risk cytogenic features), e.g., t(4;14), t(11 ;14), t(14;16), and/or del ( 17p), as described in Table 1 and in the International Myeloma Working Group (IMWG) criteria provided in Sonneveld et al., Blood, 127(24): 2955-2962, 2016, and/or 1 q21 , as described in Chang et al., Bone Marrow Transplantation, 45: 117-121 , 2010. Cytogenic features may be detected, e.g., using fluorescent in situ hybridization (FISH).

Table 1. Cytogenic features of MM

The term “B cell proliferative disorder” or “B cell malignancy” refers to a disorder that is associated with some degree of abnormal B cell proliferation and includes, for example, lymphoma, leukemia, myeloma, and myelodysplastic syndrome. In one embodiment, the B cell proliferative disorder is a lymphoma, such as non-Hodgkin’s lymphoma (NHL), including, for example, diffuse large B cell lymphoma (DLBCL) (e.g., relapsed or refractory DLBCL). In another embodiment, the B cell proliferative disorder is a leukemia, such as chronic lymphocytic leukemia (CLL). Other specific examples of cancer also include germinal-center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL), activated B celllike (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenstrom macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt’s lymphoma (BL), B cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma/leukemia, unclassifiable, splenic diffuse red pulp small B cell lymphoma, hairy cell leukemia variant, heavy chain diseases, a heavy chain disease, y heavy chain disease, p heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma, pediatric nodal marginal zone lymphoma, pediatric follicular lymphoma, primary cutaneous follicle center lymphoma, T cell/histiocyte rich large B cell lymphoma, primary DLBCL of the CNS, primary cutaneous DLBCL, leg type, EBV-positive DLBCL of the elderly, DLBCL associated with chronic inflammation, lymphomatoid granulomatosis, primary mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, ALK-positive large B cell lymphoma, plasmablastic lymphoma, large B cell lymphoma arising in HHV8-associated multicentric Castleman disease, primary effusion lymphoma: B cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma, and B cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin’s lymphoma. Further examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies, including B cell lymphomas. More particular examples of such cancers include, but are not limited to, low grade/follicu lar NHL; small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; AIDS-related lymphoma; and acute lymphoblastic leukemia (ALL); chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD). Examples of solid tumors include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including smallcell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer and gastrointestinal stromal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer of the urinary tract, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, melanoma, superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanomas, nodular melanomas, as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), Meigs' syndrome, brain, as well as head and neck cancer, and associated metastases. In certain embodiments, cancers that are amenable to treatment by the antibodies of the disclosure include breast cancer, colorectal cancer, rectal cancer, non-small cell lung cancer, glioblastoma, non-Hodgkins lymphoma (NHL), renal cell cancer, prostate cancer, liver cancer, pancreatic cancer, soft-tissue sarcoma, Kaposi's sarcoma, carcinoid carcinoma, head and neck cancer, ovarian cancer, and mesothelioma.

“Effector functions” refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor); and B cell activation.

“Complement dependent cytotoxicity” or “CDC” refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to antibodies (of the appropriate subclass) that are bound to their cognate antigen. To assess complement activation, a CDC assay, e.g., as described in Gazzano- Santoro et al., J. Immunol. Methods 202:163 (1996), can be performed.

“Antibody-dependent cell-mediated cytotoxicity” or “ADCC” refers to a form of cytotoxicity in which secreted Ig bound onto Fc receptors (FcRs) present on certain cytotoxic cells {e.g., Natural Killer (NK) cells, neutrophils, and macrophages) enable these cytotoxic effector cells to bind specifically to an antigen-bearing target cell and subsequently kill the target cell with cytotoxic agents. The antibodies “arm” the cytotoxic cells and are absolutely required for such killing. The primary cells for mediating ADCC, NK cells, express FcyRIII only, whereas monocytes express FcyRI, FcyRII, and FcyRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet. Annu. Rev. Immunol. 9:457-92, 1991 . To assess ADCC activity of a molecule of interest, an in vitro ADCC assay, such as that described in U.S. Patent No. 5,500,362 or 5,821 ,337 can be performed. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest can be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Natl. Acad. Sci. USA. 95:652-656, 1998.

“Complex” or “complexed” as used herein refers to the association of two or more molecules that interact with each other through bonds and/or forces {e.g., Van der Waals, hydrophobic, hydrophilic forces) that are not peptide bonds. In one aspect, the complex is heteromultimeric. It should be understood that the term “protein complex” or “polypeptide complex” as used herein includes complexes that have a non-protein entity conjugated to a protein in the protein complex {e.g., including, but not limited to, chemical molecules such as a toxin or a detection agent).

As used herein, “delaying progression” of a disorder or disease means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease or disorder (e.g., a cell proliferative disorder, e.g., cancer). This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late-stage cancer, such as development of metastasis, may be delayed.

As used herein, an “effective amount” or “therapeutically effective amount” of a compound, for example, an anti-FcRH5/anti-CD3 T-cell-dependent bispecific antibody (TDB) of the disclosure (e.g., cevostamab) or a composition (e.g., pharmaceutical composition) thereof, is at least the minimum amount required to achieve the desired therapeutic or prophylactic result, such as a measurable improvement or prevention of a particular disorder (e.g., a cell proliferative disorder, e.g., cancer). An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival. In the case of cancer or tumor, an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting {i.e., slow to some extent or desirably stop) cancer cell infiltration into peripheral organs; inhibit {i.e., slow to some extent and desirably stop) tumor metastasis; inhibiting to some extent tumor growth; and/or relieving to some extent one or more of the symptoms associated with the disorder. An effective amount can be administered in one or more administrations. For purposes of this disclosure, an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.

As used herein, “overall survival” or “OS” refers to the percentage of individuals in a group who are likely to be alive after a particular duration of time.

As used herein, “objective response rate” (ORR) refers to the sum of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) rates as determined using the International Myeloma Working Group response criteria (Table 7).

The term “epitope” refers to the particular site on an antigen molecule to which an antibody binds. In some aspects, the particular site on an antigen molecule to which an antibody binds is determined by hydroxyl radical footprinting. In some aspects, the particular site on an antigen molecule to which an antibody binds is determined by crystallography.

A “growth inhibitory agent” when used herein refers to a compound or composition which inhibits growth of a cell either in vitro or in vivo. In one aspect, growth inhibitory agent is growth inhibitory antibody that prevents or reduces proliferation of a cell expressing an antigen to which the antibody binds. In another aspect, the growth inhibitory agent may be one which significantly reduces the percentage of cells in S phase. Aspects of growth inhibitory agents include agents that block cell cycle progression (at a place other than S phase), such as agents that induce G1 arrest and M-phase arrest. Classical M-phase blockers include the vincas (vincristine and vinblastine), taxanes, and topoisomerase II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Those agents that arrest G1 also spill over into S-phase arrest, for example, DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C. Further information can be found in Mendelsohn and Israel, eds., The Molecular Basis of Cancer, Chapter 1 , entitled “Cell cycle regulation, oncogenes, and antineoplastic drugs” by Murakami et al. (W.B. Saunders, Philadelphia, 1995), e.g., p. 13. The taxanes (paclitaxel and docetaxel) are anticancer drugs both derived from the yew tree. Docetaxel (TAXOTERE®, Rhone-Poulenc Rorer), derived from the European yew, is a semisynthetic analogue of paclitaxel (TAXOL®, Bristol-Myers Squibb). Paclitaxel and docetaxel promote the assembly of microtubules from tubulin dimers and stabilize microtubules by preventing depolymerization, which results in the inhibition of mitosis in cells.

An “immunoconjugate” is an antibody conjugated to one or more heterologous molecule(s), including but not limited to a cytotoxic agent.

The term “immunomodulatory agent” refers to a class of molecules that modifies the immune system response or the functioning of the immune system. Immunomodulatory agents include, but are not limited to, PD-L1 axis binding antagonists, thalidomide (a-N-phthalimido-glutarimide) and its analogues, OTEZLA® (apremilast), REVLIMID® (lenalidomide) and POMALYST® (pomalidomide), and pharmaceutically acceptable salts or acids thereof.

A “subject” or an “individual” is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain aspects, the subject or individual is a human.

An “isolated” protein or peptide is one which has been separated from a component of its natural environment. In some aspects, a protein or peptide is purified to greater than 95% or 99% purity as determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC).

An “isolated” nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

The term “PD-L1 axis binding antagonist” refers to a molecule that inhibits the interaction of a PD- L1 axis binding partner with either one or more of its binding partners, so as to remove T cell dysfunction resulting from signaling on the PD-L1 signaling axis - with a result being to restore or enhance T cell function (e.g., proliferation, cytokine production, target cell killing). As used herein, a PD-L1 axis binding antagonist includes a PD-1 binding antagonist, a PD-L1 binding antagonist and a PD-L2 binding antagonist. The term “PD-1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 , PD-L2. In some aspects, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In a specific aspect, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2. In one aspect, a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some aspects, the PD-1 binding antagonist is an anti-PD-1 antibody. In a specific aspect, a PD-1 binding antagonist is MDX- 1 106 (nivolumab). In another specific aspect, a PD-1 binding antagonist is MK-3475 (pembrolizumab). In another specific aspect, a PD-1 binding antagonist is AMP-224. In another specific aspect, a PD-1 binding antagonist is MED1 -0680. In another specific aspect, a PD-1 binding antagonist is PDR001 . In another specific aspect, a PD-1 binding antagonist is REGN2810. In another specific aspect, a PD-1 binding antagonist is BGB-108.

The term “PD-L1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1 , B7-1 . In some aspects, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1 and/or B7-1 . In some aspects, the PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD- 1 , B7-1 . In one aspect, a PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L1 so as to render a dysfunctional T cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some aspects, a PD-L1 binding antagonist is an anti-PD-L1 antibody. In still another specific aspect, an anti-PD-L1 antibody is MPDL3280A (atezolizumab, marketed as TECENTRIQ™ with a WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Recommended INN: List 74, Vol. 29, No. 3, 2015 (see page 387)). In a specific aspect, an anti-PD-L1 antibody is YW243.55.S70. In another specific aspect, an anti-PD-L1 antibody is MDX-1105. In another specific aspect, an anti PD-L1 antibody is MSB0015718C. In still another specific aspect, an anti-PD-L1 antibody is MEDI4736.

The term “PD-L2 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1 . In some aspects, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In a specific aspect, the PD-L2 binding antagonist inhibits binding of PD-L2 to PD-1 . In some aspects, the PD-L2 antagonists include anti-PD-L2 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1 . In one aspect, a PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L2 so as render a dysfunctional T cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some aspects, a PD-L2 binding antagonist is an immunoadhesin.

The term “protein,” as used herein, refers to any native protein from any vertebrate source, including mammals such as primates (e.g., human subjects) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses “full-length,” unprocessed protein as well as any form of the protein that results from processing in the cell. The term also encompasses naturally occurring variants of the protein, e.g., splice variants or allelic variants.

“Percent (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows:

100 times the fraction X/Y where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program’s alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

The term “pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.

A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

By “radiation therapy” is meant the use of directed gamma rays or beta rays to induce sufficient damage to a cell so as to limit its ability to function normally or to destroy the cell altogether. It will be appreciated that there will be many ways known in the art to determine the dosage and duration of treatment. Typical treatments are given as a one-time administration and typical dosages range from 10 to 200 units (Grays) per day.

As used herein, “treatment” (and grammatical variations thereof such as “treat” or “treating”) refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some aspects, antibodies of the disclosure (e.g., anti- FcRH5/anti-CD3 TDBs of the disclosure) are used to delay development of a disease or to slow the progression of a disease.

By “reduce” or “inhibit” is meant the ability to cause an overall decrease, for example, of 20% or greater, of 50% or greater, or of 75%, 85%, 90%, 95%, or greater. In certain aspects, reduce or inhibit can refer to the incidence or recurrence of cytokine release syndrome or events thereof. In certain aspects, reduce or inhibit can refer to the effector function of an antibody that is mediated by the antibody Fc region, such effector functions specifically including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP).

According to the disclosure, the term "vaccine" relates to a pharmaceutical preparation (pharmaceutical composition) or product that upon administration induces an immune response, in particular a cellular immune response, which recognizes and attacks a pathogen or a diseased cell such as a cancer cell. A vaccine may be used for the prevention or treatment of a disease. A vaccine may be a cancer vaccine. A “cancer vaccine” as used herein is a composition that stimulates an immune response in a subject against a cancer. Cancer vaccines typically consist of a source of cancer-associated material or cells (antigen) that may be autologous (from self) or allogenic (from others) to the subject, along with other components {e.g., adjuvants) to further stimulate and boost the immune response against the antigen. Cancer vaccines can result in stimulating the immune system of the subject to produce antibodies to one or several specific antigens, and/or to produce killer T cells to attack cancer cells that have those antigens.

As used herein, “administering” is meant a method of giving a dosage of a compound (e.g., an anti-FcRH5/anti-CD3 TDB) to a subject. In some aspects, the compositions utilized in the methods herein are administered intravenously. The compositions utilized in the methods described herein can be administered, for example, intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctivally, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, in cremes, or in lipid compositions. The method of administration can vary depending on various factors (e.g., the compound or composition being administered and the severity of the condition, disease, or disorder being treated).

“CD38” as used herein refers to a CD38 glycoprotein found on the surface of many immune cells, including CD4+, CD8+, B lymphocytes, and natural killer (NK) cells, and includes any native CD38 from any vertebrate source, including mammals such as primates (e.g., human subjects) and rodents (e.g., mice and rats), unless otherwise indicated. CD38 is expressed at a higher level and more uniformly on myeloma cells as compared to normal lymphoid and myeloid cells. The term encompasses “full-length,” unprocessed CD38, as well as any form of CD38 that results from processing in the cell. The term also encompasses naturally occurring variants of CD38, e.g., splice variants or allelic variants. CD38 is also referred to in the art as cluster of differentiation 38, ADP-ribosyl cyclase 1 , cADPr hydrolase 1 , and cyclic ADP-ribose hydrolase 1 . CD38 is encoded by the CD38 gene. The nucleic acid sequence of an exemplary human CD38 is shown under NCBI Reference Sequence: NM_001775.4 or in SEQ ID NO: 33. The amino acid sequence of an exemplary human CD38 protein encoded by CD38 is shown under UniProt Accession No. P28907 or in SEQ ID NO: 34.

The term “anti-CD38 antibody” encompasses all antibodies that bind CD38 with sufficient affinity such that the antibody is useful as a therapeutic agent in targeting a cell expressing the antigen, and does not significantly cross-react with other proteins such as a negative control protein in the assays described below. For example, an anti-CD38 antibody may bind to CD38 on the surface of a MM cell and mediate cell lysis through the activation of complement-dependent cytotoxicity, ADCC, antibody-dependent cellular phagocytosis (ADCP), and apoptosis mediated by Fc cross-linking, leading to the depletion of malignant cells and reduction of the overall cancer burden. An anti-CD38 antibody may also modulate CD38 enzyme activity through inhibition of ribosyl cyclase enzyme activity and stimulation of the cyclic adenosine diphosphate ribose (cADPR) hydrolase activity of CD38. In certain aspects, an anti-CD38 antibody that binds to CD38 has a dissociation constant (KD) of < 1 pM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10^-8 M or less, e.g., from 10^-8 M to 10^-13 M, e.g., from 10^-9 M to 10^-13 M). In certain aspects, the anti-CD38 antibody may bind to both human CD38 and chimpanzee CD38. Anti-CD38 antibodies also include anti-CD38 antagonist antibodies. Bispecific antibodies wherein one arm of the antibody binds CD38 are also contemplated. Also encompassed by this definition of anti-CD38 antibody are functional fragments of the preceding antibodies. Examples of antibodies which bind CD38 include: daratumumab (DARZALEX®) (U.S. Patent No: 7,829,673 and U.S. Pub. No: 20160067205 A1 ); “MOR202” (U.S. Patent No: 8,263,746); and isatuximab (SAR-650984).

As used herein, the term “target dose” refers to an effective amount of an anti-fragment crystallizable receptor-like 5 (FcRH5)/anti-cluster of differentiation 3 (CD3) bispecific antibody (e.g., cevostamab) that achieves a desired therapeutic effect, such as a desired clinical efficacy (e.g., an improved ORR, VGPR, CR, or PR rate) and, optionally, a desired safety profile (e.g., a reduced likelihood of an infection, serious adverse event (SAE), and/or adverse event (AE)). Target doses for a bispecific antibody that binds to FcRH5 and CD3 (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) may, for example, be about 20 mg to about 252 mg (e.g., about 160 mg). In some aspects, the dosage of a target dose may increase or decrease during a given dosing regimen, depending upon the frequency of its administration. As non-limiting examples, a target dose of about 20 mg to about 160 mg may be administered once every week (QW), a target dose of about 60 mg to about 180 mg (e.g., 90 mg) may be administered about once every two weeks (Q2W), a target dose of about 90 mg to about 240 mg (e.g., 160 mg) may be administered about once every three weeks (Q3W), and a target dose of about 60 mg to about 252 mg may be administered about once every four weeks (Q4W).

As used herein, the phrase “relapsed or refractory” or “R/R” refers to a status of a disease (e.g., a cancer, e.g., a MM) in patient in which the disease has either returned after a period of improvement (relapsed) or has failed to respond to treatment (refractory). Relapsed disease occurs when a patient initially achieves remission but later experiences disease progression, while refractory disease does not respond to therapy or it progresses shortly after treatment.

As used herein, the phrase “heavily pre-treated” refers to a cancer patient (e.g., subjects with an R/R MM) who has received at least three prior lines of treatment for their cancer (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 prior lines of treatment, or more, for their cancer (e.g., R/R MM)). Exemplary prior lines of treatment include proteasome inhibitors (e.g., bortezomib, carfilzomib, and ixazomib), immunomodulatory drugs (e.g., thalidomide, lenalidomide, and pomalidomide), and anti-CD38 antibodies (e.g., daratumumab, MOR202, and isatuximab).

As used herein, a level that is “safe” for the subject to receive a target dose of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) is a level at which the subject is unlikely to develop further CRS events or further signs or symptoms of CRS upon administration of a target dose (e.g., a C1 D4 or C2D1 dose) of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab), which can be determined, for example, by assessment of a biomarker (e.g., IL-6). In some instances, a peak IL-6 level of less than about 80 pg/mL (e.g., less than about 30 pg/mL) indicates that risk of CRS events in the subject is at a level that is safe for the subject to receive a target dose of the bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

11. THERAPEUTIC METHODS

The disclosure is based, in part, on methods of treating a subject having cancer (e.g., multiple myeloma (MM), e.g., relapsed or refractory (R/R) MM) using dose-escalation dosing regimens with antifragment crystallizable receptor-like 5 (FcRH5)/anti-cluster of differentiation 3 (CD3) bispecific antibodies (e.g., cevostamab). The methods are expected to reduce the likelihood of, minimize, or inhibit unwanted treatment effects, which include cytokine-driven toxicities (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRRs), macrophage activation syndrome (MAS), neurologic toxicities, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, and/or elevated liver enzymes. Therefore, the methods are useful for treating the subject while achieving a favorable benefit-risk profile.

A. Double Step-Up Dosing Regimens

The disclosure provides methods for treating a subject having a cancer (e.g., MM, e.g., R/R MM). The method includes a step of administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) in a double step-up dose-escalation dosing regimen described herein.

For example, the bispecific antibody may be administered to the subject in a double step-up dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose (C1 D1 ; cycle 1 , dose 1 ), a second dose (C1 D2; cycle 1 , dose 2), and a third dose (C1 D3; cycle 1 , dose 3) of the bispecific antibody. The first dosing cycle may be three weeks or 21 days long. In such instances, the C1 D1 of the bispecific antibody may be administered to the subject on Day 1 of the first dosing cycle; the C1 D2 of the bispecific antibody may be administered to the subject on Day 2, Day 3, or Day 4 (“D2-4”) of the first dosing cycle; and the C1 D3 of the bispecific antibody may be administered to the subject on Day 8 of the first dosing cycle.

In some embodiments, the method further includes the administration of one or more additional therapeutic agents described herein (e.g., tocilizumab). In such instances, the one or more additional therapeutic agents (e.g., tocilizumab) may be administered prior to (e.g., about 2 hours), subsequent to (e.g., about 2 hours), or concurrently with the administration of the bispecific antibody. In some embodiments, administration of the bispecific antibody that binds to FcRH5 and CD3 (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) occurs in a dosing regimen described herein for at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least one year. In some embodiments, administration of the bispecific antibody that binds to FcRH5 and CD3 (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) occurs in a dosing regimen described herein for about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about eleven months, or about twelve months (e.g., up to one year, e.g., up to 52 weeks).

The double step-up dosing regimens outlined above are described in further detail below, including exemplary dosages and days of administering the bispecific antibody.

Dosages

The C1 D1 of the bispecific antibody (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) may be administered to the subject at a dosage that is between about 0.01 milligram (mg) to about 0.9 mg. For example, the C1 D1 may be about 0.01 mg to about 0.1 mg, about 0.1 mg to about 0.5 mg, about 0.25 mg to about 0.75 mg, about 0.5 mg to about 0.9 mg, or about 0.2 mg to about 0.4 mg. In another example, the C1 D1 may be about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, or about 0.9 mg. In some aspects, the C1 D1 is about 0.3 mg.

The C1 D2 of the bispecific antibody (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) may be administered to the subject at a dosage that is greater than the C1 D1 (e.g., greater than 0.9 mg), preferably wherein the dosage is between about 1 mg to about 5.9 mg. For example, the C1 D2 may be about 1 mg to about 1 .5 mg, about 1 mg to about 2 mg, about 1 mg to about 2.9 mg, about 1 mg to about

3.4 mg, about 1 .1 mg to about 1 .3 mg, about 1 .2 mg to about 3.3 mg, about 1 .5 mg to about 4 mg, about 2 mg to about 3 mg, about 2 mg to about 4.5 mg, about 2.5 mg to about 5 mg, about 3 mg to about 4 mg, about 3 mg to about 5 mg, about 3.5 mg to about 5.9 mg, about 3.2 mg to about 3.4 mg, or about 3.5 mg to about 3.7 mg. In another example, the C1 D2 may be about 1 mg, about 1 .1 mg, about 1 .2 mg, about

1 .3 mg, about 1 .4 mg, about 1 .5 mg, about 1 .6 mg, about 1 .7 mg, about 1 .8 mg, about 1 .9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about

3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, or about 5.9 mg. In some aspects, the C1 D2 is about 3.3 mg.

The C1 D3 of the bispecific antibody (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) may be administered to the subject at a dosage that is greater than the C1 D2 (e.g., greater than 5.9 mg), preferably wherein the dosage is between about 20 mg to about 600 mg. For example, the C1 D3 may be about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 60 mg to about 350 mg, about 80 mg to about 300 mg, about 100 mg to about 200 mg, about 140 mg to about 180 mg, about 150 mg to about 170 mg, about 132 mg to about 160 mg, about 20 to about 252 mg, or about 100 mg to about 180 mg. In another example, the C1 D3 may be about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 252 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, about 505 mg, about 510 mg, about 515 mg, about 520 mg, about 525 mg, about 530 mg, about 535 mg, about 540 mg, about 545 mg, about 550 mg, about 555 mg, about 560 mg, about 565 mg, about 570 mg, about 575 mg, about 580 mg, about 585 mg, about 590 mg, about 595 mg, or about 600 mg. In some aspects, the C1 D3 is about 160 mg.

Exemplary combinations of double step-up dosages

While any combination of dosages (e.g., C1 D1 , C1 D2, and/or C1 D3, or later) described above can be used in a dosing regimen described herein, the following represent non-limiting examples of particular dosing combinations that can be used in a dosing regimen described herein.

As an example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., a MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 5.9 mg, e.g., about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 20 mg to about 252 mg, about 100 mg to about 180 mg, or about 132 mg to about 160 mg, e.g., about 160 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 , and the C1 D3 is greater than the C1 D2. In some aspects, the method further includes the administration of tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the first dose of the bispecific antibody. As another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., a MM, e.g., a R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg), and the C1 D3 is between about 20 mg to about 252 mg (e.g., between about 100 to about 180 mg or about 132 mg to about 160 mg, e.g., about 160 mg). In some aspects, the method further includes the administration of tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the first dose of the bispecific antibody.

Days of administration

The bispecific antibody (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) may be administered to the subject in a double step-up dosing regimen described herein (e.g., a dosing regimen comprising a C1 D1 , a C1 D2, and a C1 D3, as described above) comprising at least a first dosing cycle, wherein the first dosing cycle is three weeks or 21 days long.

In some aspects, the C1 D1 of the bispecific antibody is administered to the subject on Day 1 of the first dosing cycle; the C1 D2 of the bispecific antibody is administered to the subject on Day 2, Day 3, or Day 4 of the first dosing cycle; and the C1 D3 of the bispecific antibody is administered to the subject on Day 8 of the first dosing cycle.

In some aspects, the C1 D1 of the bispecific antibody is administered to the subject on Day 1 of the first dosing cycle; the C1 D2 of the bispecific antibody is administered to the subject on Day 2 of the first dosing cycle; and the C1 D3 of the bispecific antibody is administered to the subject on Day 8 of the first dosing cycle. In some aspects, the C1 D1 of the bispecific antibody is administered to the subject on Day 1 of the first dosing cycle; the C1 D2 of the bispecific antibody is administered to the subject on Day 3 of the first dosing cycle; and the C1 D3 of the bispecific antibody is administered to the subject on Day 8 of the first dosing cycle. In some aspects, the C1 D1 of the bispecific antibody is administered to the subject on Day 1 of the first dosing cycle; the C1 D2 of the bispecific antibody is administered to the subject on Day 4 of the first dosing cycle; and the C1 D3 of the bispecific antibody is administered to the subject on Day 8 of the first dosing cycle.

As an example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., a MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, and wherein the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 5.9 mg, e.g., about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 20 mg to about 252 mg, about 100 mg to about 180 mg, or about 132 mg to about 160 mg, e.g., about 160 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 , and the C1 D3 is greater than the C1 D2. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first dosing cycle. In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., a MM, e.g., a R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg), and the C1 D3 is between about 20 mg to about 252 mg (e.g., between about 100 mg to about 180 mg, e.g., between about 132 mg to about 160 mg, e.g., about 160 mg). In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first dosing cycle. In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of treating a subject having a MM, wherein the method comprises administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the bispecific antibody, and wherein: (a) the C1 D1 is about 0.3 mg and is administered to the subject on or about Day 1 of the first dosing cycle; (b) the C1 D2 is about 3.3 mg and is administered to the subject on or about Day 2, day 3, or Day 4 of the first dosing cycle; and (c) the C1 D3 is about 160 mg and is administered to the subject on or about Day 8 of the first dosing cycle. In some aspects, the method further comprises administering to the subject tocilizumab about 2 hours prior to administering the first dose (e.g., C1 D1 ) of the bispecific antibody.

Dosing cycles

The bispecific antibody (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) may be administered to the subject in a dosing regimen described above (e.g., a dosing regimen comprising a C1 D1 , a C1 D2, and a C1 D3) with only a single dosing cycle (e.g., one dosing cycle comprising a C1 D1 , a C1 D2, and a C1 D3). However, in some aspects, the dosing regimen further comprises a second dosing cycle, wherein the second dosing cycle includes at least a single dose (C2D1 ; cycle 2, dose 1 ) of the bispecific antibody. The second dosing cycle may be three weeks or 21 days long and may include administering to the subject the C2D1 on or about Day 1 of the second dosing cycle.

In some aspects, the C2D1 is equal to or greater than the C1 D3. For example, the C2D1 may be about 20 mg to about 600 mg, about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 60 mg to about 350 mg, about 80 mg to about 300 mg, about 100 mg to about 200 mg, about 140 mg to about 180 mg, about 150 mg to about 170 mg, about 132 mg to about 160 mg, about 20 mg to about 252 mg, or about 100 mg to about 180 mg. In another example, the C2D1 may be about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about

225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 252 mg, about

255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about

290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about

325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about

360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about

395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about

430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about

465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about

500 mg, about 505 mg, about 510 mg, about 515 mg, about 520 mg, about 525 mg, about 530 mg, about

535 mg, about 540 mg, about 545 mg, about 550 mg, about 555 mg, about 560 mg, about 565 mg, about

570 mg, about 575 mg, about 580 mg, about 585 mg, about 590 mg, about 595 mg, or about 600 mg. In some aspects, the C2D1 is about 160 mg.

While the bispecific antibody (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) may be administered to the subject with only a two dosing cycles (e.g., a first dosing cycle comprising a C1 D1 , a C1 D2, and a C1 D3, and a second dosing cycle comprising a C2D1 ), in some aspects, however, the dosing regimen may further include one or more additional dosing cycles. For example, the dosing regimen may include 1 to 15 additional dosing cycles (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 additional dosing cycles, e.g., 1 -3 additional dosing cycles, 1 -5 additional dosing cycles, 3-8 additional dosing cycles, 5-10 additional dosing cycles, 8-12 additional dosing cycles, 10-15 additional dosing cycles, or 12-15additional dosing cycles, i.e., the dosing regimen includes one or more of additional dosing cycle(s) C3, C4, C5, C6, C7, C8, C9, C10, C11 , C12, C13, C14, C15, C16, and C17. As another example, the dosing regimen may include 1 to 17 additional dosing cycles (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, or 17 additional dosing cycles, e.g., 1 -3 additional dosing cycles, 1 -5 additional dosing cycles, 3-8 additional dosing cycles, 5-10 additional dosing cycles, 8-12 additional dosing cycles, 10-15 additional dosing cycles, 12-17 additional dosing cycles, or 15-17 additional dosing cycles, i.e., the dosing regimen includes one or more of additional dosing cycle(s) C3, C4, C5, C6, C7, C8, C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, and C19. The length of each of the one or more additional dosing cycles may be 3 weeks or 21 days.

In some aspects, each of the one or more additional dosing cycles comprises a single dose of the bispecific antibody. In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is equal to the C2D1 (e.g., is about 20 mg to about 600 mg, about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 60 mg to about 350 mg, about 80 mg to about 300 mg, about 100 mg to about 200 mg, about 140 mg to about 180 mg, about 150 mg to about 170 mg, about 132 mg to about 160 mg, about 20 mg to about 252 mg, or about 100 mg to about 180 mg, e.g., is about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 1 10 mg, about 1 15 mg, about 120 mg, about 125 mg, about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 252 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, about 505 mg, about 510 mg, about 515 mg, about 520 mg, about 525 mg, about 530 mg, about 535 mg, about 540 mg, about 545 mg, about 550 mg, about 555 mg, about 560 mg, about 565 mg, about 570 mg, about 575 mg, about 580 mg, about 585 mg, about 590 mg, about 595 mg, or about 600 mg). In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is about 160 mg.

After the first dosing cycle, the bispecific antibody may be administered (e.g., as a monotherapy or combination therapy described herein) to the subject every three weeks or 21 days (Q3W) until progressive disease is observed, for up to 18 cycles, or until minimal residual disease (MRD) is observed.

B. Triple Step-Up Dosing Regimens

The disclosure provides (i) methods for treating a subject having a cancer (e.g., a MM, e.g., R/R MM), (ii) methods of reducing the likelihood of cytokine release syndrome (CRS) in a subject having a cancer (e.g., a MM, e.g., R/R MM), (iii) methods of achieving a median peak interleukin-6 (IL-6) level of less than about 80 pg/mL (e.g., less than 30 pg/mL) in a population of subjects having a cancer (e.g., a MM, e.g., R/R MM), (iv) methods of achieving a peak IL-6 level of less than about 80 pg/mL (e.g., less than 30 pg/mL, e.g., 18 pg/mL) in a subject having a cancer (e.g., a MM, e.g., R/R MM), and (v) methods of reducing the occurrence of CRS events in a subject being treated for a cancer (e.g., a MM, e.g., R/R MM) with a target dose (e.g., an effective amount) of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). Such methods include a step of administering a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) to the subject(s) using a triple step-up dosing regimen described herein. Such dosing regimens can be advantageous because they can achieve a favorable safety profile that facilitates dosing of anti-FcRH5/anti-CD3 bispecific antibodies (e.g., cevostamab) at their target dose while mitigating adverse effects, such as CRS, during the treatment of cancers (e.g., MM, e.g., R/R MM). For example, the priming sequence of doses (i.e., the C1 D1 , C1 D2, and C1 D3 of a triple step-up dosing regimen) of the anti-FcRH5/anti-CD3 bispecific antibody cevostamab described herein reduces the likelihood and/or severity of CRS in a subject upon receiving a target dose (e.g., upon receiving an effective amount of a target dose, such as the C1 D4 or later dose (e.g., C2D1 or later dose)) of cevostamab in a triple step-up dosing regimen described herein. Moreover, the target doses described herein (e.g., the C1 D4 or later dose (e.g., C2D1 or later dose) of the anti-FcRH5/anti-CD3 bispecific antibody, e.g., cevostamab, of a triple step-up dosing regimen) can provide improved efficacy and/or safety during treatment with an anti-FcRH5/anti-CD3 bispecific antibody (e.g., cevostamab). For example, the target doses described herein (e.g., the C1 D4 or later dose (e.g., C2D1 or later dose) of the anti- FcRH5/anti-CD3 bispecific antibody, e.g., cevostamab, of a triple step-up dosing regimen) can provide an improved objective response rate (ORR), very good partial response (VGPR) rate, complete response (CR) rate, or partial response (PR) rate in a subject or population of subjects having MM (e.g., R/R MM) while the occurrence of CRS events is reduced by administering the anti-FcRH5/anti-CD3 bispecific antibody, e.g., cevostamab, using a triple step-up dosing regimen described herein prior to the first administration of a target dose of the anti-FcRH5/anti-CD3 bispecific antibody, e.g., cevostamab. Additionally, the target doses described herein (e.g., the C1 D4 or later dose (e.g., C2D1 or later dose) of the anti-FcRH5/anti-CD3 bispecific antibody, e.g., cevostamab, of a triple step-up dosing regimen) can reduce the likelihood of an infection, a serious adverse event (SAE), and/or an adverse event (AE).

The bispecific antibody may be administered to the subject in a triple step-up dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose (C1 D1 ; cycle 1 , dose 1 ), a second dose (C1 D2; cycle 1 , dose 2), a third dose (C1 D3; cycle 1 , dose 3), and, optionally, a fourth dose (C1 D4; cycle 1 , dose 4) of the bispecific antibody. In some instances, the dosing regimen further comprises administering an additional dose of the bispecific antibody (e.g., cevostamab) after administration of the C1 D3 or, optionally, after the C1 D4. In some aspects, the additional dose of the bispecific antibody (e.g., cevostamab) is greater than the C1 D3. In some aspects, the additional dose of the bispecific antibody (e.g., cevostamab) is greater than or equal to the C1 D4.

The step-up doses (SUDs) (e.g., the C1 D1 , the C1 D2, and the C1 D3, also referred to herein as the SUD1 , the SUD2, and the SUD3, respectively) are referred to herein as the “priming sequence” or “priming sequence of doses,” while the target dose (e.g., the C1 D4 or later dose (e.g., C2D1 or later dose) of the bispecific antibody) is considered the dose that achieves a desired therapeutic effect, such as a desired clinical efficacy (e.g., an improved objective response rate (ORR), very good partial response (VGPR) rate, complete response (CR) rate, or partial response (PR) rate) and, optionally, a desired safety profile (e.g., a reduced likelihood of an infection, serious adverse event (SAE), and/or adverse event (AE)). The first dosing cycle may be three weeks or 21 days long. In such instances, the C1 D1 of the bispecific antibody may be administered to the subject on Day 1 of the first dosing cycle; the C1 D2 of the bispecific antibody may be administered to the subject on Day 2, Day 3, or Day 4 (“D2-4”) of the first dosing cycle; the C1 D3 of the bispecific antibody may be administered to the subject on Day 8 of the first dosing cycle; and, optionally, the C1 D4 of the bispecific antibody may be administered to the subject on Day 9, Day 10, or Day 11 (“D9-11 ”) of the first dosing cycle (e.g., about 1 day, 2 days, or three days after administration of the C1 D3).

In some aspects, the method further includes the administration of one or more additional therapeutic agents described herein (e.g., tocilizumab). In such instances, the one or more additional therapeutic agents (e.g., tocilizumab) may be administered prior to (e.g., about 2 hours before), subsequent to (e.g., about 2 hours after), or concurrently with the administration of the bispecific antibody. In some aspects, tocilizumab is administered about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to the administration of the bispecific antibody. Administering tocilizumab, for example, about 2 hours prior to the administration of the bispecific antibody (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) can further reduced the likelihood and/or severity of CRS in a subject upon receiving a target dose (e.g., the C1 D4 or later dose (e.g., C2D1 or later dose) of the bispecific antibody of a triple step-up dosing regimen).

In some aspects, administration of the bispecific antibody that binds to FcRH5 and CD3 (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) occurs in a dosing regimen described herein for at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least one year. In some aspects, administration of the bispecific antibody that binds to FcRH5 and CD3 (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) occurs in a dosing regimen described herein for about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about eleven months, or about twelve months (e.g., up to one year, e.g., up to 52 weeks).

The triple step-up dosing regimens outlined above are described in further detail below, including exemplary dosages and days of administering the bispecific antibody.

Dosages

The C1 D1 of the bispecific antibody (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) may be administered to the subject at a dosage that is between about 0.01 milligram (mg) to about 0.9 mg. For example, the C1 D1 may be about 0.01 mg to about 0.1 mg, about 0.1 mg to about 0.5 mg, about 0.25 mg to about 0.75 mg, about 0.5 mg to about 0.9 mg, or about 0.2 mg to about 0.4 mg. In another example, the C1 D1 may be about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, or about 0.9 mg. In some aspects, the C1 D1 is about 0.3 mg (e.g., 0.3 mg).

In some aspects, the C1 D2 of the bispecific antibody (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) may be administered to the subject at a dosage that is greater than the C1 D1 (e.g., greater than 0.9 mg), preferably wherein the dosage is between about 1 mg to about 3.4 mg. For example, the C1 D2 may be about 1 .1 mg to about 1 .3 mg, about 1 mg to about 2 mg, about 1 mg to about 2.5 mg, about 1 mg to about 2.9 mg, about 1 .2 mg to about 3.3 mg, about 1 .5 mg to about 3 mg, about 2 mg to about 3.4 mg, or about 3.2 mg to about 3.4 mg. In another example, the C1 D2 may be about 1 .1 mg, about 1 .2 mg, about 1 .3 mg, about 1 .4 mg, about 1 .5 mg, about 1 .6 mg, about 1 .7 mg, about 1 .8 mg, about 1 .9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about

2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, or about 3.4 mg. In some aspects, the C1 D2 is about 1 .2 mg. In some aspects, the C1 D2 is about 3.3 mg (e.g., 3.3 mg).

In other aspects, the C1 D2 of the bispecific antibody (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) may be administered to the subject at a dosage that is greater than the C1 D1 (e.g., greater than 0.9 mg), preferably wherein the dosage is between about 1 mg to about 2.9 mg. For example, the C1 D2 may be about 1 mg to about 1 .5 mg, about 1 mg to about 2 mg, about 1 .1 mg to about 1 .3 mg, about 1 .2 mg to about 1 .7 mg, about 1 .5 mg to about 2 mg, about 1 .5 mg to about 2.5 mg, about 2 mg to about 2.5 mg, or about 2 mg to about 2.9 mg. In another example, the C1 D2 may be about 1 mg, about 1 .1 mg, about 1 .2 mg, about 1 .3 mg, about 1 .4 mg, about 1 .5 mg, about 1 .6 mg, about 1 .7 mg, about 1 .8 mg, about 1 .9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, or about 2.9 mg. In some aspects, the C1 D2 is about 1 .2 mg (e.g., 1 .2 mg).

In yet other aspects, the C1 D2 of the bispecific antibody (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) may be administered to the subject at a dosage that is greater than the C1 D1 (e.g., greater than 0.9 mg), preferably wherein the dosage is between about 1 mg to about 5.9 mg. For example, the C1 D2 may be about 1 mg to about 1 .5 mg, about 1 mg to about 2 mg, about 1 mg to about 2.9 mg, about 1 mg to about 3.4 mg, about 1 .1 mg to about 1 .3 mg, about 1 .2 mg to about 3.3 mg, about

1 .5 mg to about 4 mg, about 2 mg to about 3 mg, about 2 mg to about 4.5 mg, about 2.5 mg to about 5 mg, about 3 mg to about 4 mg, about 3 mg to about 5 mg, about 3.5 mg to about 5.9 mg, about 3.2 mg to about 3.4 mg, or about 3.5 mg to about 3.7 mg. In another example, the C1 D2 may be about 1 mg, about

1 .1 mg, about 1 .2 mg, about 1 .3 mg, about 1 .4 mg, about 1 .5 mg, about 1 .6 mg, about 1 .7 mg, about 1 .8 mg, about 1 .9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about

5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, or about 5.9 mg. In some aspects, the C1 D2 is about

1 .2 mg (e.g., 1 .2 mg). In some aspects, the C1 D2 is about 3.3 mg (e.g., 3.3 mg).

In some aspects, the C1 D3 of the bispecific antibody (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) may be administered to the subject at a dosage that is greater than the C1 D2 (e.g., greater than 3.4 mg), preferably wherein the dosage is between about 3.5 mg to about 19.9 mg. For example, the C1 D3 may be about 3.5 mg to about 3.7 mg, about 3.5 mg to about 7 mg, about 3.6 mg to about 7.2 mg, about 5 mg to about 7 mg, about 5 mg to about 10 mg, about 5 mg to about 15 mg, about 6 mg to about 19.9 mg, about 6.5 mg to about 10 mg, about 7 mg to about 15 mg, about 7.1 mg to about

7.3 mg, about 10 mg to about 15 mg, about 12 mg to about 17 mg, or about 15 mg to about 19.9 mg. In another example, the C1 D3 is about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, about 10 mg, about 10.1 mg, about 10.2 mg, about 10.3 mg, about 10.4 mg, about 10.5 mg, about 10.6 mg, about 10.7 mg, about 10.8 mg, about 10.9 mg, about 11 mg, about 11.1 mg, about 11 .2 mg, about 11 .3 mg, about 11 .4 mg, about 11 .5 mg, about 11 .6 mg, about 11 .7 mg, about

11 .8 mg, about 11 .9 mg, about 12 mg, about 12.1 mg, about 12.2 mg, about 12.3 mg, about 12.4 mg, about 12.5 mg, about 12.6 mg, about 12.7 mg, about 12.8 mg, about 12.9 mg, about 13 mg, about 13.1 mg, about 13.2 mg, about 13.3 mg, about 13.4 mg, about 13.5 mg, about 13.6 mg, about 13.7 mg, about

13.8 mg, about 13.9 mg, about 14 mg, about 14.1 mg, about 14.2 mg, about 14.3 mg, about 14.4 mg, about 14.5 mg, about 14.6 mg, about 14.7 mg, about 14.8 mg, about 14.9 mg, about 15 mg, about 15.1 mg, about 15.2 mg, about 15.3 mg, about 15.4 mg, about 15.5 mg, about 15.6 mg, about 15.7 mg, about

15.8 mg, about 15.9 mg, about 16 mg, about 16.1 mg, about 16.2 mg, about 16.3 mg, about 16.4 mg, about 16.5 mg, about 16.6 mg, about 16.7 mg, about 16.8 mg, about 16.9 mg, about 17 mg, about 17.1 mg, about 17.2 mg, about 17.3 mg, about 17.4 mg, about 17.5 mg, about 17.6 mg, about 17.7 mg, about

17.8 mg, about 17.9 mg, about 18 mg, about 18.1 mg, about 18.2 mg, about 18.3 mg, about 18.4 mg, about 18.5 mg, about 18.6 mg, about 18.7 mg, about 18.8 mg, about 18.9 mg, about 19 mg, about 19.1 mg, about 19.2 mg, about 19.3 mg, about 19.4 mg, about 19.5 mg, about 19.6 mg, about 19.7 mg, about

19.8 mg, or about 19.9 mg. In some aspects, the C1 D3 is about 3.6 mg (e.g., 3.6 mg). In some aspects, the C1 D3 is about 7.2 mg (e.g., 7.2 mg).

In other aspects, the C1 D3 of the bispecific antibody (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) may be administered to the subject at a dosage that is greater than the C1 D2 (e.g., greater than 2.9 mg), preferably wherein the dosage is between about 3 mg to about 19.9 mg. For example, the C1 D3 may be about 3 mg to about 10 mg, about 3 mg to about 7.5 mg, about 3 mg to about 5 mg, about 3 mg to about 5.9 mg, about 3 mg to about 4 mg, about 3.5 mg to about 3.7 mg, about 3.5 mg to about 7 mg, about 3.6 mg to about 7.2 mg, about 5 mg to about 7 mg, about 5 mg to about 10 mg, about 5 mg to about 15 mg, about 6 mg to about 19.9 mg, about 6.5 mg to about 10 mg, about 7 mg to about 15 mg, about 7.1 mg to about 7.3 mg, about 10 mg to about 15 mg, about 12 mg to about 17 mg, or about 15 mg to about 19.9 mg. In another example, the C1 D3 is about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about

9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, about 10 mg, about 10.1 mg, about 10.2 mg, about

10.3 mg, about 10.4 mg, about 10.5 mg, about 10.6 mg, about 10.7 mg, about 10.8 mg, about 10.9 mg, about 1 1 mg, about 1 1 .1 mg, about 1 1 .2 mg, about 1 1 .3 mg, about 1 1 .4 mg, about 1 1 .5 mg, about 1 1 .6 mg, about 1 1 .7 mg, about 1 1 .8 mg, about 1 1 .9 mg, about 12 mg, about 12.1 mg, about 12.2 mg, about

12.3 mg, about 12.4 mg, about 12.5 mg, about 12.6 mg, about 12.7 mg, about 12.8 mg, about 12.9 mg, about 13 mg, about 13.1 mg, about 13.2 mg, about 13.3 mg, about 13.4 mg, about 13.5 mg, about 13.6 mg, about 13.7 mg, about 13.8 mg, about 13.9 mg, about 14 mg, about 14.1 mg, about 14.2 mg, about

14.3 mg, about 14.4 mg, about 14.5 mg, about 14.6 mg, about 14.7 mg, about 14.8 mg, about 14.9 mg, about 15 mg, about 15.1 mg, about 15.2 mg, about 15.3 mg, about 15.4 mg, about 15.5 mg, about 15.6 mg, about 15.7 mg, about 15.8 mg, about 15.9 mg, about 16 mg, about 16.1 mg, about 16.2 mg, about

16.3 mg, about 16.4 mg, about 16.5 mg, about 16.6 mg, about 16.7 mg, about 16.8 mg, about 16.9 mg, about 17 mg, about 17.1 mg, about 17.2 mg, about 17.3 mg, about 17.4 mg, about 17.5 mg, about 17.6 mg, about 17.7 mg, about 17.8 mg, about 17.9 mg, about 18 mg, about 18.1 mg, about 18.2 mg, about

18.3 mg, about 18.4 mg, about 18.5 mg, about 18.6 mg, about 18.7 mg, about 18.8 mg, about 18.9 mg, about 19 mg, about 19.1 mg, about 19.2 mg, about 19.3 mg, about 19.4 mg, about 19.5 mg, about 19.6 mg, about 19.7 mg, about 19.8 mg, or about 19.9 mg. In some aspects, the C1 D3 is about 3.6 mg (e.g.,

3.6 mg). In some aspects, the C1 D3 is about 7.2 mg (e.g., 7.2 mg).

In yet other aspects, the C1 D3 of the bispecific antibody (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) may be administered to the subject at a dosage that is greater than the C1 D2 (e.g., greater than 5.9 mg), preferably wherein the dosage is between about 6 mg to about 19.9 mg. For example, the C1 D3 may be about 6 mg to about 15 mg, about 6.5 mg to about 10 mg, about 6 mg to about 9 mg, about 6 mg to about 8 mg, about 6 mg to about 7 mg, about 7 mg to about 7.5 mg, about 7.1 mg to about 7.3 mg, about 7 mg to about 8 mg, about 7 mg to about 10 mg, about 8 mg to about 15 mg, about 10 mg to about 15 mg, about 12 mg to about 17 mg, or about 15 mg to about 19.9 mg. In another example, the C1 D3 may be about 6 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about

6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about

8.7 mg, about 8.8 mg, about 8.9 mg, about 9 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, about 10 mg, about 10.1 mg, about 10.2 mg, about 10.3 mg, about 10.4 mg, about 10.5 mg, about 10.6 mg, about 10.7 mg, about 10.8 mg, about 10.9 mg, about 1 1 mg, about 1 1 .1 mg, about 1 1 .2 mg, about 1 1 .3 mg, about 1 1 .4 mg, about

1 1 .5 mg, about 1 1 .6 mg, about 1 1 .7 mg, about 1 1 .8 mg, about 1 1 .9 mg, about 12 mg, about 12.1 mg, about 12.2 mg, about 12.3 mg, about 12.4 mg, about 12.5 mg, about 12.6 mg, about 12.7 mg, about 12.8 mg, about 12.9 mg, about 13 mg, about 13.1 mg, about 13.2 mg, about 13.3 mg, about 13.4 mg, about

19.5 mg, about 19.6 mg, about 19.7 mg, about 19.8 mg, or about 19.9 mg. In some aspects, the C1 D3 is about 7.2 mg (e.g., 7.2 mg).

The C1 D4 of the bispecific antibody (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) may be administered to the subject at a dosage that is greater than the C1 D3 (e.g., greater than 19.9 mg), preferably wherein the dosage is between about 20 mg to about 600 mg. For example, the C1 D4 may be about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 60 mg to about 350 mg, about 80 mg to about 300 mg, about 100 mg to about 200 mg, about 140 mg to about 180 mg, about 150 mg to about 170 mg, about 132 mg to about 160 mg, about 20 mg to about 252 mg, or about 100 mg to about 180 mg. In another example, the C1 D4 may be about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about

195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about

230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 252 mg, about 255 mg, about

260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about

295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about

330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about

365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about

400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about

435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about

470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, about

505 mg, about 510 mg, about 515 mg, about 520 mg, about 525 mg, about 530 mg, about 535 mg, about

540 mg, about 545 mg, about 550 mg, about 555 mg, about 560 mg, about 565 mg, about 570 mg, about

575 mg, about 580 mg, about 585 mg, about 590 mg, about 595 mg, or about 600 mg. In some aspects, the C1 D4 is about 160 mg.

Exemplary combinations of dosages

While any combination of dosages (e.g., C1 D1 , C1 D2, C1 D3, and/or C1 D4, or later) described above can be used in a dosing regimen described herein, the following represent non-limiting examples of particular dosing combinations that can be used. As an example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, a C1 D3, and a C1 D4 of the bispecific antibody, and wherein the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about

3.4 mg, e.g., about 1 .2 mg or about 3.3 mg), the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about

3.5 mg to about 19.9 mg, e.g., about 3.6 mg or about 7.2 mg), and the C1 D4 is greater than the C1 D3 (e.g., the C1 D4 is about 20 mg to about 252 mg, about 100 mg to about 180 mg, or about 132 mg to about 160 mg, e.g., about 160 mg). The C1 D1 , C1 D2, C1 D3, and C1 D4 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 , the C1 D3 is greater than the C1 D2, and the C1 D4 is greater than the C1 D3. In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, a C1 D3, and a C1 D4 of the bispecific antibody, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 3.4 mg (e.g., between about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), the C1 D3 is between about 3.5 mg to about 19.9 mg (e.g., between about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg), and the C1 D4 is between about 20 mg to about 252 mg, (e.g., between about 100 mg to about 180 mg, e.g., between about 132 mg to about 160 mg, e.g., about 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, a C1 D3, and a C1 D4 of the bispecific antibody, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., 1 .2 mg), the C1 D3 is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.6 mg), and the C1 D4 is between about 20 mg to about 252 mg (e.g., between about 100 mg to about 180 mg, e.g., between about 132 mg to about 160 mg, e.g., about 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody. As yet another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, a C1 D3, and a C1 D4 of the bispecific antibody, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg), the C1 D3 is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg), and the C1 D4 is between about 20 mg to about 252 mg (e.g., between about 100 mg to about 180 mg, e.g., between about 132 mg to about 160 mg, e.g., about 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg, e.g., about 3.6 mg or about 7.2 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 and the C1 D3 is greater than the C1 D2. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg or about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 3.4 mg (e.g., between about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is between about 3.5 mg to about 19.9 mg (e.g., between about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg). In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg, e.g., between about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., 1 .2 mg), and the C1 D3 is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.6 mg). In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg or about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg), and the C1 D3 is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg). In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg or about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ) (e.g., a first 21 -day dosing cycle), wherein the C1 comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg or about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg or about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 and the C1 D3 is greater than the C1 D2. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is an effective amount that is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg or about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of reducing the likelihood and/or severity of CRS a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg, e.g., about 3.6 mg or about 7.2 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 and the C1 D3 is greater than the C1 D2. This priming sequence of dosages may reduce the likelihood and/or severity of CRS in a subject after each doseescalation, including after administration of any target dose described herein (e.g., a C1 D4 or later dose (e.g., a C2D1 or later dose)). In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of reducing the likelihood and/or severity of CRS a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 3.4 mg (e.g., between about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is between about 3.5 mg to about 19.9 mg (e.g., between about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg). This priming sequence of dosages may reduce the likelihood and/or severity of CRS in a subject after each doseescalation, including after administration of any target dose described herein (e.g., a C1 D4 or later dose (e.g., a C2D1 or later dose)). In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of reducing the likelihood and/or severity of CRS a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., 1 .2 mg), and the C1 D3 is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.6 mg). This priming sequence of dosages may reduce the likelihood and/or severity of CRS in a subject after each dose-escalation, including after administration of any target dose described herein (e.g., a C1 D4 or later dose (e.g., a C2D1 or later dose)). In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252, mg or between about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of reducing the likelihood and/or severity of CRS a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg), and the C1 D3 is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg). This priming sequence of dosages may reduce the likelihood and/or severity of CRS in a subject after each dose-escalation, including after administration of any target dose described herein (e.g., a C1 D4 or later dose (e.g., a C2D1 or later dose)). In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg, e.g., between about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of reducing the likelihood and/or severity of CRS a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ) (e.g., a first 21 -day dosing cycle), wherein the C1 comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg or about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg or about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 and the C1 D3 is greater than the C1 D2. This priming sequence of dosages may reduce the likelihood and/or severity of CRS in a subject after each dose-escalation, including after administration of any target dose described herein (e.g., a C1 D4 or later dose (e.g., a C2D1 or later dose)). In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is an effective dose and is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another aspect, the disclosure provides a method of reducing the likelihood of CRS in a subject (e.g., a human subject) being treated for a cancer (e.g., MM, e.g., R/R MM) with a target dose (e.g., an effective dose) of cevostamab (e.g., a target dose of between about 20 mg to about 252 mg) in at least a first dosing cycle (C1 ) of 21 days, wherein prior to administration of the target dose of cevostamab, the C1 further comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab. In some aspects, the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg (e.g., 1 .2 mg or 3.3 mg), and the C1 D3 is between about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 and the C1 D3 is greater than the C1 D2.

In another aspect, the disclosure provides a method of reducing the likelihood of CRS in a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM) and being treated with an effective amount of cevostamab, the method comprising at least a first dosing cycle (C1 ) of 21 days, wherein prior to administration to the subject of the therapeutically effective amount of cevostamab in C1 , the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; and the C1 D3 is about 3.6 mg.

In another aspect, the disclosure provides a method of reducing the likelihood of CRS in a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM) and being treated with an effective amount of cevostamab, the method comprising at least a first dosing cycle (C1 ) of 21 days, wherein prior to administration to the subject of the therapeutically effective amount of cevostamab in C1 , the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 3.3 mg; and the C1 D3 is about 7.2 mg.

As yet another example, the disclosure provides a method of achieving a median peak IL-6 level of less than about 80 pg/mL (e.g., less than about 30 pg/mL, e.g., less than about 18 pg/mL, e.g., about 18 pg/mL) in a population of subjects (e.g., human subjects) having a cancer (e.g., MM, e.g., R/R MM) following administration of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab), the method comprising administering to a subject in the population the bispecific antibody (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg, e.g., about 3.6 mg or about 7.2 mg). In some aspects, the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg (e.g., 1 .2 mg or 3.3 mg), and the C1 D3 is between about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 and the C1 D3 is greater than the C1 D2. In some aspects, the median peak IL-6 level is measured in blood (e.g., peripheral blood) samples obtained from the population of subjects. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg, e.g., between about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of achieving a median peak IL-6 level of less than about 80 pg/mL (e.g., less than about 30 pg/mL, e.g., less than about 18 pg/mL, e.g., about 18 pg/mL) in a population of subjects (e.g., human subjects) having a cancer (e.g., MM, e.g., R/R MM) following administration of a bispecific antibody that binds to FcRH5 and CD3, the method comprising administering to a subject in the population the bispecific antibody (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 3.4 mg (e.g., between about 1 mg to about 2.9 mg or about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is between about 3.5 mg to about 19.9 mg (e.g., between about 3 mg to about 5.9 mg or about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg). In some aspects, the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg (e.g., 1 .2 mg or 3.3 mg), and the C1 D3 is between about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg). In some aspects, the median peak IL-6 level is measured in blood (e.g., peripheral blood) samples obtained from the population of subjects. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg, e.g., between about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of achieving a median peak IL-6 level of less than about 80 pg/mL (e.g., less than about 30 pg/mL, e.g., less than about 18 pg/mL, e.g., about 18 pg/mL) in a population of subjects (e.g., human subjects) having a cancer (e.g., MM, e.g., R/R MM) following administration of a bispecific antibody that binds to FcRH5 and CD3, the method comprising administering to a subject in the population the bispecific antibody (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., 1 .2 mg), and the C1 D3 is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5.9 mg or about 3 mg to about 5 mg, e.g., 3.6 mg). In some aspects, the median peak IL-6 level is measured in blood (e.g., peripheral blood) samples obtained from the population of subjects. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg, e.g., between about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of achieving a median peak IL-6 level of less than about 80 pg/mL (e.g., less than about 30 pg/mL, e.g., less than about 18 pg/mL, e.g., about 18 pg/mL) in a population of subjects (e.g., human subjects) having a cancer (e.g., MM, e.g., R/R MM) following administration of a bispecific antibody that binds to FcRH5 and CD3, the method comprising administering to a subject in the population the bispecific antibody (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg), and the C1 D3 is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg). In some aspects, the median peak IL-6 level is measured in blood (e.g., peripheral blood) samples obtained from the population of subjects. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg, e.g., between about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of achieving a peak IL-6 level of than about 30 pg/mL (e.g., less than about 18 pg/mL, e.g., about 18 pg/mL) in a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM) following administration of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab), the method comprising administering to the subject the bispecific antibody (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1) (e.g., a first 21 -day dosing cycle), wherein the C1 comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., 1 .2 mg), and the C1 D3 is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5.9 mg, e.g., 3.6 mg). In some aspects, the peak IL-6 level is measured in a blood (e.g., peripheral blood) sample obtained from the subject. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg, e.g., between about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of achieving a peak IL-6 level of than about 30 pg/mL (e.g., less than about 18 pg/mL, e.g., about 18 pg/mL) in a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM) following administration of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab), the method comprising administering to a subject in the population the bispecific antibody (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a C1 D1 , a C1 D2, and a C1 D2, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg), and the C1 D3 is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg). In some aspects, the peak IL-6 level is measured in a blood (e.g., peripheral blood) sample obtained from the subject. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg, e.g., between about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of achieving a median peak IL-6 level of less than about 80 pg/mL (e.g., less than about 30 pg/mL, e.g., less than about 18 pg/mL, e.g., about 18 pg/mL) in a population of subjects (e.g., human subjects) having a cancer (e.g., MM, e.g., R/R MM) following administration of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ) (e.g., a first 21 -day dosing cycle), wherein the C1 comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg or about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg or about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg). In some aspects, the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg (e.g., 1 .2 mg or 3.3 mg), and the C1 D3 is between about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 and the C1 D3 is greater than the C1 D2. In some aspects, the median peak IL-6 level is measured in blood (e.g., peripheral blood) samples obtained from the population of subjects. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is an effective amount that that is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg, e.g., between about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

In yet another aspect, the disclosure provides a method of achieving a median peak IL-6 level of less than about 80 pg/mL (e.g., less that about 30 pg/mL) in a population of human subjects having MM (e.g., R/R MM) and being administered a therapeutically effective amount of cevostamab, the method comprising administering to each subject (e.g., a human subject) in the population, prior to being administered the therapeutically effective amount of cevostamab, a first dosing regimen (C1 ) comprising a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg or about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg) and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg or about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg). In some aspects, the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg (e.g., 1 .2 mg or 3.3 mg), and the C1 D3 is between about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 and the C1 D3 is greater than the C1 D2. In some aspects, the median peak IL-6 level is measured in blood (e.g., peripheral blood) samples obtained from the population of subjects. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is an effective amount and is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg, e.g., between about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody. As yet another example, the disclosure provides a method of reducing the occurrence of CRS events in a subject (e.g., a human subject) being treated for a cancer (e.g., MM, e.g., R/R MM) with a target dose of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab), the method comprising administering to the subject, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ) (e.g., a first 21 -day dosing cycle), (i) a first dose (C1 D1 ) of between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), (ii) a second dose (C1 D2) of between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., about 1 .2 mg), and (iii) a third dose (C1 D3) of between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5.9 mg, e.g., about 3.6 mg) of the bispecific antibody (e.g., cevostamab). In some aspects, the target dose of the bispecific antibody (e.g., cevostamab) is greater than the C1 D3 (e.g., the target dose is between about 20 mg to about 252 mg).

As yet another example, the disclosure provides a method of reducing the occurrence of CRS events in a subject (e.g., a human subject) being treated for a cancer (e.g., MM, e.g., R/R MM) with a target dose of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab), the method comprising administering to the subject, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ) (e.g., a first 21 -day dosing cycle), (i) a first dose (C1 D1 ) of between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), (ii) a second dose (C1 D2) of between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., about 3.3 mg), and (iii) a third dose (C1 D3) of between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., about 7.2 mg) of the bispecific antibody (e.g., cevostamab). In some aspects, the target dose of the bispecific antibody (e.g., cevostamab) is greater than the C1 D3 (e.g., the target dose is between about 20 mg to about 252 mg).

As yet another example, the disclosure provides a method of reducing the occurrence of CRS events in a subject being treated for R/R MM with a target dose (e.g., a dose of about 20 mg to 252 mg) of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method includes administering to the subject (i) a first step-up dose (SUD), (ii) a second SUD, and (iii) a third SUD of cevostamab, wherein administering such target dose to a first plurality of such subjects results in at least a 10% reduction (e.g., at least a 10% reduction, at least an 11 % reduction, at least a 12% reduction, at least a 13% reduction, at least a 14% reduction, or at least a 15% reduction) in the number of subjects experiencing a CRS event after first administration of the target dose, as compared to a second plurality of such subjects administered such target dose after administration of a first SUD and a second SUD, with no third SUD, and wherein the second SUD is greater than the first SUD, and the third SUD is greater than the second SUD. In some aspects, the first SUD is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the second SUD is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., about 1 .2 mg), and the third SUD is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5.9 mg, e.g., about 3.6 mg). In some aspects the first SUD is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the second SUD is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg), and the third SUD is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg). In some aspects, a target dose of cevostamab is administered to the subject (e.g., a target dose of between about 20 mg to about 252 mg).

As yet another example, the disclosure provides a method of reducing the occurrence of CRS events in a subject being treated for R/R MM with a target dose (e.g., a dose of about 20 mg to 252 mg) of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first step-up dose (SUD), (ii) a second SUD, and (iii) a third SUD of cevostamab, wherein administering such target dose to a first plurality of such subjects results in at least a 10% reduction (e.g., at least a 10% reduction, at least an 11 % reduction, at least a 12% reduction, at least a 13% reduction, at least a 14% reduction, or at least a 15% reduction) in the number of subjects experiencing a CRS event during the C1 , as compared to a second plurality of such subjects administered such target dose after administration of a first SUD and a second SUD, with no third SUD, and wherein the second SUD is greater than the first SUD, and the third SUD is greater than the second SUD. In some aspects, the first SUD is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the second SUD is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., about 1 .2 mg), and the third SUD is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5.9 mg, e.g., about 3.6 mg). In some aspects the first SUD is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the second SUD is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg), and the third SUD is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg). In some aspects, a target dose of cevostamab is administered to the subject (e.g., a target dose of between about 20 mg to about 252 mg).

As yet another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is about 0.3 mg (e.g., 0.3 mg), the C1 D2 is about 1 .2 mg (e.g., 1 .2 mg), and the C1 D3 is about 3.6 mg (e.g., 3.6 mg). In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody (e.g., a target dose), wherein the additional dose (e.g., target dose) of the bispecific antibody is between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg).

As yet another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is about 0.3 mg (e.g., 0.3 mg), the C1 D2 is about 3.3 mg (e.g., 3.3 mg), and the C1 D3 is about 7.2 mg (e.g., 7.2 mg). In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody (e.g., a target dose), wherein the additional dose (e.g., target dose) of the bispecific antibody is between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). As yet another example, the disclosure provides a method of reducing the likelihood and/or severity of CRS a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is about 0.3 mg (e.g., 0.3 mg), the C1 D2 is about 1 .2 mg (e.g., 1 .2 mg), and the C1 D3 is about 3.6 mg (e.g., 3.6 mg). In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody (e.g., a target dose), wherein the additional dose (e.g., target dose) of the bispecific antibody is between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg).

As yet another example, the disclosure provides a method of reducing the likelihood and/or severity of CRS a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is about 0.3 mg (e.g., 0.3 mg), the C1 D2 is about 3.3 mg (e.g., 3.3 mg), and the C1 D3 is about 7.2 mg (e.g., 7.2 mg). In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody (e.g., a target dose), wherein the additional dose (e.g., target dose) of the bispecific antibody is between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg).

As yet another example, the disclosure provides a method of achieving a median peak IL-6 level of less than about 80 pg/mL (e.g., less than about 30 pg/mL, e.g., less than about 18 pg/mL, e.g., about 18 pg/mL) in a population of subjects (e.g., human subjects) having a cancer (e.g., MM, e.g., R/R MM) following administration of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab), the method comprising administering to a subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is about 0.3 mg (e.g., 0.3 mg), the C1 D2 is about 1 .2 mg (e.g., 1 .2 mg), and the C1 D3 is about 3.6 mg (e.g., 3.6 mg). In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody (e.g., a target dose), wherein the additional dose (e.g., target dose) of the bispecific antibody is between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg).

As yet another example, the disclosure provides a method of achieving a median peak IL-6 level of less than about 80 pg/mL (e.g., less than about 30 pg/mL, e.g., less than about 18 pg/mL, e.g., about 18 pg/mL) in a population of subjects (e.g., human subjects) having a cancer (e.g., MM, e.g., R/R MM) following administration of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab), the method comprising administering to a subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is about 0.3 mg (e.g., 0.3 mg), the C1 D2 is about 3.3 mg (e.g., 3.3 mg), and the C1 D3 is about 7.2 mg (e.g., 7.2 mg). In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody (e.g., a target dose), wherein the additional dose (e.g., target dose) of the bispecific antibody is between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg).

As yet another example, the disclosure provides a method of achieving a peak IL-6 level of less than about 30 pg/mL (e.g., less than about 18 pg/mL, e.g., about 18 pg/mL) in a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM) following administration of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ) (e.g., a first 21 -day dosing cycle), wherein the C1 comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is about 0.3 mg (e.g., 0.3 mg), the C1 D2 is about 1 .2 mg (e.g., 1 .2 mg), and the C1 D3 is about 3.6 mg (e.g., 3.6 mg). In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody (e.g., a target dose), wherein the additional dose (e.g., target dose) of the bispecific antibody is between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg).

As yet another example, the disclosure provides a method of achieving a peak IL-6 level of less than about 80 pg/mL (e.g., less than about 30 pg/mL, e.g., less than about 18 pg/mL, e.g., about 18 pg/mL) in a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM) following administration of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ) (e.g., a first 21 -day dosing cycle), wherein the C1 comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D1 is about 0.3 mg (e.g., 0.3 mg), the C1 D2 is about 3.3 mg (e.g., 3.3 mg), and the C1 D3 is about

7.2 mg (e.g., 7.2 mg). In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody (e.g., a target dose), wherein the additional dose (e.g., target dose) of the bispecific antibody is between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg).

As yet another example, the disclosure provides a method of reducing the occurrence of CRS events in a subject (e.g., a human subject) being treated for a cancer (e.g., MM, e.g., R/R MM) with a target dose (e.g., a dose that is between about 20 mg to about 252 mg) of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). The method includes administering to the subject, prior to a first administration of the target dose (e.g., a dose that is between about 20 mg to about 252 mg), the bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a triple step-up dosing regimen described herein. For example, the bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) may be administered to the subject in a dosing regimen comprising a first dose (C1 D1 ) of about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), a second dose (C1 D2) of about 1 mg to about 3.4 mg (e.g., about 1 .2 mg or about 3.3 mg), and a third dose (C1 D3) of about 3.5 mg to about 19.9 mg (e.g., about 3.6 mg or about 7.2 mg). In some aspects, the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about

3.3 mg (e.g., 1 .2 mg or 3.3 mg), and the C1 D3 is between about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 and the C1 D3 is greater than the C1 D2. In some aspects, the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., 1 .2 mg), and the C1 D3 is between about 3.5 mg to about 19.9 mg (e.g., between about 3.5 mg to about 5 mg, e.g., 3.6 mg). In some aspects, the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg (e.g., 1 .2 mg or 3.3 mg), and the C1 D3 is between about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg). In some aspects, the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is between about 3 mg to about 3.4 mg (e.g., about 3.3 mg), and the C1 D3 is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg).

Days of administration

The bispecific antibody (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) may be administered to the subject in a triple step-up dosing regimen described herein (e.g., a dosing regimen comprising a C1 D1 , a C1 D2, a C1 D3, and, optionally, a C1 D4, as described above) comprising at least a first dosing cycle, wherein the first dosing cycle is three weeks or 21 days long.

In some aspects, the C1 D1 of the bispecific antibody is administered to the subject on Day 1 of the first dosing cycle; the C1 D2 of the bispecific antibody is administered to the subject on Day 2, Day 3, or Day 4 of the first dosing cycle; the C1 D3 of the bispecific antibody is administered to the subject on Day 8 of the first dosing cycle; and, optionally, the C1 D4 of the bispecific antibody is administered to the subject on Day 9, Day 10, or Day 1 1 of the first dosing cycle. In aspects comprising an administration of a C1 D4 of the bispecific antibody, the C1 D4 may be administered about 1 day after administration of the C1 D3, about 2 days after administration of the C1 D3, or about 3 days after administration of the C1 D3.

In some aspects, the C1 D1 of the bispecific antibody is administered to the subject on Day 1 of the first dosing cycle; the C1 D2 of the bispecific antibody is administered to the subject on Day 2 of the first dosing cycle; the C1 D3 of the bispecific antibody is administered to the subject on Day 8 of the first dosing cycle; and, optionally, the C1 D4 of the bispecific antibody is administered to the subject on Day 9 of the first dosing cycle. In some aspects, the C1 D1 of the bispecific antibody is administered to the subject on Day 1 of the first dosing cycle; the C1 D2 of the bispecific antibody is administered to the subject on Day 2 of the first dosing cycle; the C1 D3 of the bispecific antibody is administered to the subject on Day 8 of the first dosing cycle; and, optionally, the C1 D4 of the bispecific antibody is administered to the subject on Day 10 of the first dosing cycle. In some aspects, the C1 D1 of the bispecific antibody is administered to the subject on Day 1 of the first dosing cycle; the C1 D2 of the bispecific antibody is administered to the subject on Day 2 of the first dosing cycle; the C1 D3 of the bispecific antibody is administered to the subject on Day 8 of the first dosing cycle; and, optionally, the

C1 D4 of the bispecific antibody is administered to the subject on Day 1 1 of the first dosing cycle.

In some aspects, the C1 D1 of the bispecific antibody is administered to the subject on Day 1 of the first dosing cycle; the C1 D2 of the bispecific antibody is administered to the subject on Day 3 of the first dosing cycle; the C1 D3 of the bispecific antibody is administered to the subject on Day 8 of the first dosing cycle; and, optionally, the C1 D4 of the bispecific antibody is administered to the subject on Day 9 of the first dosing cycle. In some aspects, the C1 D1 of the bispecific antibody is administered to the subject on Day 1 of the first dosing cycle; the C1 D2 of the bispecific antibody is administered to the subject on Day 3 of the first dosing cycle; the C1 D3 of the bispecific antibody is administered to the subject on Day 8 of the first dosing cycle; and, optionally, the C1 D4 of the bispecific antibody is administered to the subject on Day 10 of the first dosing cycle. In some aspects, the C1 D1 of the bispecific antibody is administered to the subject on Day 1 of the first dosing cycle; the C1 D2 of the bispecific antibody is administered to the subject on Day 3 of the first dosing cycle; the C1 D3 of the bispecific antibody is administered to the subject on Day 8 of the first dosing cycle; and, optionally, the

C1 D4 of the bispecific antibody is administered to the subject on Day 11 of the first dosing cycle.

In some aspects, the C1 D1 of the bispecific antibody is administered to the subject on Day 1 of the first dosing cycle; the C1 D2 of the bispecific antibody is administered to the subject on Day 4 of the first dosing cycle; the C1 D3 of the bispecific antibody is administered to the subject on Day 8 of the first dosing cycle; and, optionally, the C1 D4 of the bispecific antibody is administered to the subject on Day 9 of the first dosing cycle. In some aspects, the C1 D1 of the bispecific antibody is administered to the subject on Day 1 of the first dosing cycle; the C1 D2 of the bispecific antibody is administered to the subject on Day 4 of the first dosing cycle; the C1 D3 of the bispecific antibody is administered to the subject on Day 8 of the first dosing cycle; and, optionally, the C1 D4 of the bispecific antibody is administered to the subject on Day 10 of the first dosing cycle. In some aspects, the C1 D1 of the bispecific antibody is administered to the subject on Day 1 of the first dosing cycle; the C1 D2 of the bispecific antibody is administered to the subject on Day 4 of the first dosing cycle; the C1 D3 of the bispecific antibody is administered to the subject on Day 8 of the first dosing cycle; and, optionally, the

Exemplary timing of administration

While any combination of days of administration described above can be used in a dosing regimen described herein, the following represent non-limiting examples of a particular timing of administration that can be used in a dosing regimen described herein.

As an example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a C1 D1 , a C1 D2, a C1 D3, and a C1 D4 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), Day 8, and Day 9-11 (i.e., Day 9, Day 10, or Day 11 ), respectively, and wherein the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg, e.g., about 1 .2 mg or about 3.3 mg), the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg, e.g., about 3.6 mg or about 7.2 mg), and the C1 D4 is greater than the C1 D3 (e.g., the C1 D4 is about 20 mg to about 252 mg, about 100 mg to about 180 mg, or about 132 mg to about 160 mg, e.g., about 160 mg). In some aspects, the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg (e.g., 1 .2 mg or 3.3 mg), and the C1 D3 is between about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg). The C1 D1 , C1 D2, C1 D3, and C1 D4 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 , the C1 D3 is greater than the C1 D2, and the C1 D4 is greater than the C1 D3. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle and the C1 D4 is administered on Day 9, Day 10, or Day 1 1 of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 -day dosing cycle and the C1 D4 is administered on Day 9, Day 10, or Day 1 1 of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 -day dosing cycle and the C1 D4 is administered on Day 9, Day 10, or Day 1 1 of the first 21 -day dosing cycle. In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a C1 D1 , a C1 D2, a C1 D3, and a C1 D4 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), Day 8, and Day 9-1 1 (i.e., Day 9, Day 10, or Day 1 1 ), respectively, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 3.4 mg (e.g., between about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), the C1 D3 is between about 3.5 mg to about 19.9 mg (e.g., between about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg), and the C1 D4 is between about 20 mg to about 252 mg (e.g., between about 100 mg to about 180 mg, e.g., between about 132 mg to about 160 mg, e.g., about 160 mg). In some aspects, the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg (e.g., 1 .2 mg or 3.3 mg), and the C1 D3 is between about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg). In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle and the C1 D4 is administered on Day 9, Day 10, or Day 1 1 of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 -day dosing cycle and the C1 D4 is administered on Day 9, Day 10, or Day 1 1 of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 -day dosing cycle and the C1 D4 is administered on Day 9, Day 10, or Day 1 1 of the first 21 - day dosing cycle. In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a C1 D1 , a C1 D2, a C1 D3, and a C1 D4 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), Day 8, and Day 9-1 1 (i.e., Day 9, Day 10, or Day 1 1 ), respectively, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., 1 .2 mg), the C1 D3 is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.6 mg), and the C1 D4 is between about 20 mg to about 252 mg (e.g., between about 100 mg to about 180 mg, e.g., between 132 mg to about 160 mg, e.g., about 160 mg). In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle and the C1 D4 is administered on Day 9, Day 10, or Day 11 of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 -day dosing cycle and the C1 D4 is administered on Day 9, Day 10, or Day 11 of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 -day dosing cycle and the C1 D4 is administered on Day 9, Day 10, or Day 11 of the first 21 -day dosing cycle. In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a C1 D1 , a C1 D2, a C1 D3, and a C1 D4 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), Day 8, and Day 9-11 (i.e., Day 9, Day 10, or Day 11 ), respectively, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg), the C1 D3 is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg), and the C1 D4 is between about 20 mg to about 252 mg (e.g., between about 100 mg to about 180 mg, e.g., about 132 mg to about 160 mg, e.g., about 160 mg). In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle and the C1 D4 is administered on Day 9, Day 10, or Day 11 of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 -day dosing cycle and the C1 D4 is administered on Day 9, Day 10, or Day 11 of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 -day dosing cycle and the C1 D4 is administered on Day 9, Day 10, or Day 11 of the first 21 -day dosing cycle. In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, and wherein the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg, e.g., about 3.6 mg or about 7.2 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 and the C1 D3 is greater than the C1 D2. In some aspects, the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 mg to about 2.9 mg (e.g., about 1 .2 mg), and the C1 D3 is between about 3 mg to about 5.9 mg (e.g., about 3.6 mg). In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 3.4 mg (e.g., between about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is between about 3.5 mg to about 19.9 mg (e.g., between about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg). In some aspects, the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg (e.g., 1 .2 mg or 3.3 mg), and the C1 D3 is between about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg). In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., 1 .2 mg), and the C1 D3 is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.6 mg). In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg), and the C1 D3 is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg). In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 - day dosing cycle. In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ) (e.g., a first 21 -day dosing cycle), wherein the C1 comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg or about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg or about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 and the C1 D3 is greater than the C1 D2. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is an effective dose that is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg or about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody. As yet another example, the disclosure provides a method of reducing the likelihood and/or severity of CRS a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, and wherein the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg, e.g., about 3.6 mg or about 7.2 mg). In some aspects, the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg (e.g., 1 .2 mg or 3.3 mg), and the C1 D3 is between about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 and the C1 D3 is greater than the C1 D2. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 -day dosing cycle. This priming sequence of dosages may reduce the likelihood and/or severity of CRS in a subject after each dose-escalation, including after administration of any target dose described herein (e.g., a C1 D4 or later dose (e.g., a C2D1 or later dose)). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of reducing the likelihood and/or severity of CRS a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 3.4 mg (e.g., between about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is between about 3.5 mg to about 19.9 mg (e.g., between about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg). In some aspects, the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg (e.g., 1 .2 mg or 3.3 mg), and the C1 D3 is between about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg). In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 -day dosing cycle. This priming sequence of dosages may reduce the likelihood and/or severity of CRS in a subject after each doseescalation, including after administration of any target dose described herein (e.g., a C1 D4 or later dose (e.g., a C2D1 or later dose)). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of reducing the likelihood and/or severity of CRS a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., 1 .2 mg), and the C1 D3 is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.6 mg). In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 - day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 -day dosing cycle. This priming sequence of dosages may reduce the likelihood and/or severity of CRS in a subject after each dose-escalation, including after administration of any target dose described herein (e.g., a C1 D4 or later dose (e.g., a C2D1 or later dose)). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of reducing the likelihood and/or severity of CRS a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg), and the C1 D3 is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg). In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 - day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 -day dosing cycle. This priming sequence of dosages may reduce the likelihood and/or severity of CRS in a subject after each dose-escalation, including after administration of any target dose described herein (e.g., a C1 D4 or later dose (e.g., a C2D1 or later dose)). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

In another aspect, the disclosure provides a method of reducing the likelihood and/or severity of CRS in a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., a R/R MM) and being treated with an effective amount of cevostamab, the method comprising at least a first dosing cycle (C1 ) of 21 days, wherein prior to administration to the subject of the effective amount of cevostamab, the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 1 .2 mg and is administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 3.6 mg and is administered on Day 8 of C1 .

In another aspect, the disclosure provides a method of reducing the likelihood and/or severity of CRS in a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., a R/R MM) and being treated with a therapeutically effective amount of cevostamab, the method comprising at least a first dosing cycle (C1 ) of 21 days, wherein prior to administration to the subject of the effective amount of cevostamab, the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 3.3 mg and is administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 7.2 mg and is administered on Day 8 of C1.

As yet another example, the disclosure provides a method of reducing the likelihood and/or severity of CRS a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ) (e.g., a first 21 -day dosing cycle), wherein the C1 comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, and wherein the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg or about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg or about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg). In some aspects, the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg (e.g., 1 .2 mg or 3.3 mg), and the C1 D3 is between about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 and the C1 D3 is greater than the C1 D2. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 -day dosing cycle. This priming sequence of dosages may reduce the likelihood and/or severity of CRS in a subject after each dose-escalation, including after administration of any target dose described herein (e.g., a C1 D4 or later dose (e.g., a C2D1 or later dose)). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of achieving a median peak IL-6 level of less than about 80 pg/mL (e.g., less than about 30 pg/mL, e.g., less than about 18 pg/mL, e.g., about 18 pg/mL) in a population of subjects (e.g., human subjects) having a cancer (e.g., MM, e.g., R/R MM) following administration of a bispecific antibody that binds to FcRH5 and CD3, the method comprising administering to a subject in the population the bispecific antibody (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, and wherein the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg, e.g., about 3.6 mg or about 7.2 mg). In some aspects, the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg (e.g., 1 .2 mg or 3.3 mg), and the C1 D3 is between about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 and the C1 D3 is greater than the C1 D2. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 - day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the median peak IL-6 level is measured in blood (e.g., peripheral blood) samples obtained from the population of subjects. In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of achieving a median peak IL-6 level of less than about 80 pg/mL (e.g., less than about 30 pg/mL, e.g., less than about 18 pg/mL, e.g., about 18 pg/mL) in a population of subjects (e.g., human subjects) having a cancer (e.g., MM, e.g., R/R MM) following administration of a bispecific antibody that binds to FcRH5 and CD3, the method comprising administering to a subject in the population the bispecific antibody (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 3.4 mg (e.g., between about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is between about 3.5 mg to about 19.9 mg (e.g., between about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg). In some aspects, the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg (e.g., 1 .2 mg or 3.3 mg), and the C1 D3 is between about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg). In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the median peak IL-6 level is measured in blood (e.g., peripheral blood) samples obtained from the population of subjects. In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of achieving a median peak IL-6 level of less than about 80 pg/mL (e.g., less than about 30 pg/mL, e.g., less than about 18 pg/mL, e.g., about 18 pg/mL) in a population of subjects (e.g., human subjects) having a cancer (e.g., MM, e.g., R/R MM) following administration of a bispecific antibody that binds to FcRH5 and CD3, the method comprising administering to a subject in the population the bispecific antibody (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., 1 .2 mg), and the C1 D3 is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5.9 mg, e.g., 3.6 mg). In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 - day dosing cycle. In some aspects, the median peak IL-6 level is measured in blood (e.g., peripheral blood) samples obtained from the population of subjects. In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of achieving a median peak IL-6 level of less than about 80 pg/mL (e.g., less than about 30 pg/mL, e.g., less than about 18 pg/mL, e.g., about 18 pg/mL) in a population of subjects (e.g., human subjects) having a cancer (e.g., MM, e.g., R/R MM) following administration of a bispecific antibody that binds to FcRH5 and CD3, the method comprising administering to a subject in the population the bispecific antibody (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle, wherein the length of the first dosing cycle is 21 days, wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg), and the C1 D3 is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg). In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 - day dosing cycle. In some aspects, the median peak IL-6 level is measured in blood (e.g., peripheral blood) samples obtained from the population of subjects. In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of achieving a peak IL-6 level of than about 30 pg/mL (e.g., less than about 18 pg/mL, e.g., about 18 pg/mL) in a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM) following administration of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab), the method comprising administering to a subject in the population the bispecific antibody (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., 1 .2 mg), and the C1 D3 is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5.9 mg, e.g., 3.6 mg). In some aspects, the peak IL-6 level is measured in a blood (e.g., peripheral blood) sample obtained from the subject. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg, e.g., between about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of achieving a peak IL-6 level of than about 30 pg/mL (e.g., less than about 18 pg/mL, e.g., about 18 pg/mL) in a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM) following administration of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab), the method comprising administering to a subject in the population the bispecific antibody (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, and wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg), and the C1 D3 is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg). In some aspects, the peak IL-6 level is measured in a blood (e.g., peripheral blood) sample obtained from the subject. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg, e.g., between about 100 mg to about 180 mg, e.g., 160 mg). The additional dose of the bispecific antibody may be administered during any cycle; for example, the additional dose may be administered during the first dosing cycle as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of achieving a median peak IL-6 level of less than about 80 pg/mL (e.g., less than about 30 pg/mL, e.g., less than about 18 pg/mL, e.g., about 18 pg/mL) in a population of subjects (e.g., human subjects) having a cancer (e.g., MM, e.g., R/R MM) following administration of a bispecific antibody that binds to FcRH5 and CD3, the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (C1 ) (e.g., a first 21 -day dosing cycle), wherein the C1 comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e. , Day 2, Day 3, or Day 4), and Day 8, respectively, and wherein the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg or about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg or about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 and the C1 D3 is greater than the C1 D2. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is an effective dose and is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg or about 100 mg to about 180 mg, e.g., 160 mg). In some aspects, the median peak IL-6 level is measured in blood (e.g., peripheral blood) samples obtained from the population of subjects. In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

In yet another aspect, the disclosure provides a method of limiting median peak IL-6 levels to less than about 80 pg/mL (e.g., less that about 30 pg/mL) in a population of human subjects having MM (e.g., a R/R MM) and being administered a therapeutically effective amount of cevostamab (e.g., a target dose), the method comprising administering to each subject (e.g., a human subject) in the population, prior to being administered the therapeutically effective amount of cevostamab, a first dosing regimen (C1 ) comprising a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, and wherein the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg or about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg or about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 and the C1 D3 is greater than the C1 D2. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 -day dosing cycle. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody, wherein the additional dose of the bispecific antibody is an effective dose and is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg or about 100 mg to about 180 mg, e.g., 160 mg). In some aspects, the median peak IL-6 level is measured in blood (e.g., peripheral blood) samples obtained from the population of subjects. In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

As yet another example, the disclosure provides a method of reducing the occurrence of CRS events in a subject (e.g., a human subject) being treated for a cancer (e.g., MM, e.g., R/R MM) with a target dose of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab), the method comprising administering to the subject, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ) (e.g., a first 21 -day dosing cycle), (i) a first dose (C1 D1 ) of between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), (ii) a second dose (C1 D2) of between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., about 1 .2 mg), and (iii) a third dose (C1 D3) of between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5.9 mg, e.g., about 3.6 mg) of the bispecific antibody (e.g., cevostamab), wherein the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, of the C1 .

As yet another example, the disclosure provides a method of reducing the occurrence of CRS events in a subject (e.g., a human subject) being treated for a cancer (e.g., MM, e.g., R/R MM) with a target dose of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab), the method comprising administering to the subject, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ) (e.g., a first 21 -day dosing cycle), (i) a first dose (C1 D1 ) of between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), (ii) a second dose (C1 D2) of between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., about 3.3 mg), and (iii) a third dose (C1 D3) of between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., about 7.2 mg) of the bispecific antibody (e.g., cevostamab), wherein the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2-4 (i.e., Day 2, Day 3, or Day 4), and Day 8, respectively, of the C1 .

As yet another example, the disclosure provides a method of reducing the occurrence of CRS events in a subject being treated for R/R MM with a target dose (e.g., a dose of about 20 mg to 252 mg) of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method includes administering to the subject (i) a first step-up dose (SUD), (ii) a second SUD, and (iii) a third SUD of cevostamab, wherein administering such target dose to a first plurality of such subjects results in at least a 10% reduction (e.g., at least a 10% reduction, at least an 11 % reduction, at least a 12% reduction, at least a 13% reduction, at least a 14% reduction, or at least a 15% reduction) in the number of subjects experiencing a CRS event after first administration of the target dose, as compared to a second plurality of such subjects administered such target dose after administration of a first SUD and a second SUD, with no third SUD, and wherein the second SUD is greater than the first SUD, and the third SUD is greater than the second SUD. In some aspects, the C1 is 21 days. In some aspects, the first SUD is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg) and is administered on Day 1 of the C1 , the second SUD is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., about 1 .2 mg) and is administered on Day 2, Day 3, or Day 4 of the C1 , and the third SUD is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5.9 mg, e.g., about 3.6 mg) and is administered on Day 8 of the C1 . In some aspects the first SUD is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg) and is administered on Day 1 of the C1 , the second SUD is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg) and is administered on Day 2, Day 3, or Day 4 of the C1 , and the third SUD is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg) and is administered on Day 8 of the C1 . In some aspects, a target dose of cevostamab is administered to the subject (e.g., a target dose of between about 20 mg to about 252 mg).

As yet another example, the disclosure provides a method of reducing the occurrence of CRS events in a subject being treated for R/R MM with a target dose (e.g., a dose of about 20 mg to 252 mg) of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first step-up dose (SUD), (ii) a second SUD, and (iii) a third SUD of cevostamab, wherein administering such target dose to a first plurality of such subjects results in at least a 10% reduction (e.g., at least a 10% reduction, at least an 11 % reduction, at least a 12% reduction, at least a 13% reduction, at least a 14% reduction, or at least a 15% reduction) in the number of subjects experiencing a CRS event during the C1 , as compared to a second plurality of such subjects administered such target dose after administration of a first SUD and a second SUD, with no third SUD, and wherein the second SUD is greater than the first SUD, and the third SUD is greater than the second SUD. In some aspects, the C1 is 21 days. In some aspects, the first SUD is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg) and is administered on Day 1 of the C1 , the second SUD is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., about 1 .2 mg) and is administered on Day 2, Day 3, or Day 4 of the C1 , and the third SUD is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5.9 mg, e.g., about 3.6 mg) and is administered on Day 8 of the C1 . In some aspects the first SUD is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg) and is administered on Day 1 of the C1 , the second SUD is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg) and is administered on Day 2, Day 3, or Day 4 of the C1 , and the third SUD is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg) and is administered on Day 8 of the C1 . In some aspects, a target dose of cevostamab is administered to the subject (e.g., a target dose of between about 20 mg to about 252 mg). As yet another example, the disclosure provides a method of treating a subject having MM comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of the bispecific antibody, wherein the C1 D1 is about 0.3 mg (e.g., 0.3 mg); the C1 D2 is about 1 .2 mg (e.g., 1 .2 mg); the C1 D3 is about 3.6 mg (e.g., 3.6 mg); and the C1 D4 is about 160 mg (e.g., 160 mg), wherein the length of the first dosing cycle is 21 days, and wherein the method comprises administering to the subject: (a) the C1 D1 on or about Day 1 of the first dosing cycle; (b) the C1 D2 on or about Day 2, Day 3, or Day 4 of the first dosing cycle; (c) the C1 D3 on or about Day 8 of the first dosing cycle; and (d) the C1 D4 on or about Day 9, Day 10, or Day 11 of the first dosing cycle.

As yet another example, the disclosure provides a method of treating a subject having MM comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of the bispecific antibody, wherein the C1 D1 is about 0.3 mg (e.g., 0.3 mg); the C1 D2 is about 3.3 mg (e.g., 3.3 mg); the C1 D3 is about 7.2 mg (e.g., 7.2 mg); and the C1 D4 is about 160 mg (e.g., 160 mg), wherein the length of the first dosing cycle is 21 days, and wherein the method comprises administering to the subject: (a) the C1 D1 on or about Day 1 of the first dosing cycle; (b) the C1 D2 on or about Day 2, Day 3, or Day 4 of the first dosing cycle; (c) the C1 D3 on or about Day 8 of the first dosing cycle; and (d) the C1 D4 on or about Day 9, Day 10, or Day 11 of the first dosing cycle.

As yet another example, the disclosure provides a method of reducing the likelihood of CRS in a subject having MM, wherein the method comprises administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the bispecific antibody, wherein the C1 D1 is about 0.3 mg (e.g., 0.3 mg); the C1 D2 is about 1 .2 mg (e.g., 1 .2 mg); and the C1 D3 is about 3.6 mg (e.g., 3.6 mg), wherein the length of the first dosing cycle is 21 days, and wherein the method comprises administering to the subject: (a) the C1 D1 on or about Day 1 of the first dosing cycle; (b) the C1 D2 on or about Day 2, Day 3, or Day 4 of the first dosing cycle; and (c) the C1 D3 on or about Day 8 of the first dosing cycle. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody (e.g., a target dose) on Day 9, Day 10, or Day 11 of the first dosing cycle, wherein the additional dose (e.g., target dose) of the bispecific antibody is between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg).

As yet another example, the disclosure provides a method of reducing the likelihood of CRS in a subject having MM, wherein the method comprises administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the bispecific antibody, wherein the C1 D1 is about 0.3 mg (e.g., 0.3 mg); the C1 D2 is about 3.3 mg (e.g., 3.3 mg); and the C1 D3 is about 7.2 mg (e.g., 7.2 mg), wherein the length of the first dosing cycle is 21 days, and wherein the method comprises administering to the subject: (a) the C1 D1 on or about Day 1 of the first dosing cycle; (b) the C1 D2 on or about Day 2, Day 3, or Day 4 of the first dosing cycle; and (c) the C1 D3 on or about Day 8 of the first dosing cycle. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody (e.g., a target dose) on Day 9, Day 10, or Day 1 1 of the first dosing cycle, wherein the additional dose (e.g., target dose) of the bispecific antibody is between about 20 mg to about 252 mg, or between about 100 mg to about 180 mg (e.g., 160 mg).

As yet another example, the disclosure provides a method of reducing the occurrence of CRS events in a subject being treated for R/R MM with a target dose of cevostamab, the method comprising administering to the subject, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg (e.g. 0.3 mg) and is administered on Day 1 ; the C1 D2 is about 1 .2 mg (e.g., 1 .2 mg) and is administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 3.6 mg (e.g., 3.6 mg) and is administered on Day 8, wherein the length of the C1 is 21 days. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody (e.g., a target dose), wherein the additional dose (e.g., target dose) of the bispecific antibody is between about 20 mg to about 252 mg.

As yet another example, the disclosure provides a method of reducing the occurrence of CRS events in a subject being treated for R/R MM with a target dose of cevostamab, the method comprising administering to the subject, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg (e.g., 0.3 mg) and is administered on Day 1 ; the C1 D2 is about 3.3 mg (e.g., 3.3 mg) and is administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 7.2 mg (e.g., 7.2 mg) and is administered on Day 8, wherein the length of the C1 is 21 days. In some aspects, the method further includes administering to the subject an additional dose of the bispecific antibody (e.g., a target dose), wherein the additional dose (e.g., target dose) of the bispecific antibody is between about 20 mg to about 252 mg.

As yet another example, the disclosure provides a method of reducing the occurrence of CRS events in a subject (e.g., a human subject) being treated for a cancer (e.g., MM, e.g., R/R MM) with a target dose (e.g., a dose that is between about 20 mg to about 252 mg) of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). The method includes administering to the subject, prior to a first administration of the target dose (e.g., a target dose that is between about 20 mg to about 252 mg), the bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a triple step-up dosing regimen described herein. For example, the bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) may be administered to the subject in a dosing regimen comprising a first dose (C1 D1 ) of about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), a second dose (C1 D2) of about 1 mg to about 3.4 mg (e.g., about 1 .2 mg or about 3.3 mg), and a third dose (C1 D3) of about 3.5 mg to about 19.9 mg (e.g., about 3.6 mg or about 7.2 mg). In some aspects, the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg (e.g., 1 .2 mg or 3.3 mg), and the C1 D3 is between about 3.6 mg to about 7.2 mg (e.g., 3.6 mg or 7.2 mg). The C1 D1 , C1 D2, and C1 D3 may be administered at any dosage described above so long as the C1 D2 is greater than the C1 D1 and the C1 D3 is greater than the C1 D2. In some aspects, the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., 1 .2 mg), and the C1 D3 is between about 3.5 mg to about 19.9 mg (e.g., between about 3.5 mg to about 5 mg, e.g., 3.6 mg). In some aspects, the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is between about 3 mg to about

3.4 mg (e.g., about 3.3 mg), and the C1 D3 is between about 6 mg to about 19.9 mg (e.g., between about

6.5 mg to about 10 mg, e.g., 7.2 mg). In some aspects, the C1 D1 , C1 D2, and C1 D3 may be administered in a dosing regimen including at least a first dosing cycle (C1 ) (e.g., a 21 -day dosing cycle). In some aspects, the C1 D1 is administered on Day 1 of the C1 ; the C1 D2 is administered on Day 2, Day 3, or Day 4 of the C1 ; and the C1 D3 is administered on Day 8 of the C1 . In some aspects, the method further includes administering to the subject an additional dose (e.g., a target dose) of the bispecific antibody, wherein the additional dose (e.g., target dose) of the bispecific antibody is greater than the C1 D3 (e.g., an effective amount between about 20 mg to about 252 mg); for example, the additional dose (e.g., target dose) may be administered during the C1 as a fourth dose (C1 D4) of the bispecific antibody and may be between about 20 mg to about 252 mg (e.g., the C1 D4 is a target dose between about 20 mg and about 252 mg). In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody.

Notably, the aforementioned priming sequence of doses (i.e. , the C1 D1 , C1 D2, and C1 D3) can minimize a CRS response (e.g., reduce CRS severity) in a subject after each dose-escalation, particularly after administration of a target dose described herein (e.g., a C1 D4 or later dose (e.g., a C2D1 or later dose)). Thus, due to the administration of the triple step-up priming sequence of doses (i.e., the C1 D1 , C1 D2, and C1 D3) described above, a subject can experience a reduced likelihood of CRs and/or a minimized CRS response (as compared to, for example, a double step-up (e.g., C1 D1 and C1 D2) priming sequence of doses) upon administration of the additional dose (e.g., target dose), thereby providing a favorable safety profile for an immunotherapy using a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). Methods of assessing the presence of a reduced/minimized CRS response in a subject are readily apparent to a clinician (e.g., an oncologist); for example, it may be assessed clinically (e.g., for signs and symptoms of CRS) and/or molecularly (e.g., using inflammatory biomarkers, such as IL-6). CRS severity may be graded according to the Modified Cytokine Release Syndrome Grading System established by Lee et al., Blood, 124: 188-195, 2014 or Lee et al., Biol Blood Marrow Transplant, 25(4): 625-638, 2019, as described in Table 3. The absence of a CRS response altogether upon administration of a target dose is still considered a reduced or minimized CRS response.

Dosing cycles

The bispecific antibody (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) may be administered to the subject in a dosing regimen described above (e.g., a dosing regimen comprising a C1 D1 , a C1 D2, a C1 D3, and, optionally, a C1 D4) with only a single dosing cycle (e.g., one dosing cycle comprising a C1 D1 , a C1 D2, a C1 D3, and, optionally, a C1 D4). However, in some aspects, the dosing regimen further comprises a second dosing cycle, wherein the second dosing cycle includes at least a single dose (C2D1 ; cycle 2, dose 1 ) of the bispecific antibody. The second dosing cycle may be three weeks or 21 days long and may include administering to the subject the C2D1 on or about Day 1 of the second dosing cycle.

In some aspects, the C2D1 is equal to or greater than the C1 D4. For example, the C2D1 may be about 20 mg to about 600 mg, about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 60 mg to about 350 mg, about 80 mg to about 300 mg, about 100 mg to about 200 mg, about 140 mg to about 180 mg, about 150 mg to about 170 mg, about 132 mg to about 160 mg, about 20 mg to about 252 mg, or about 100 mg to about 180 mg. In another example, the C2D1 may be about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 1 10 mg, about 1 15 mg, about 120 mg, about 125 mg, about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about

While the bispecific antibody (e.g., an anti-FcRH5/anti-CD3 antibody, e.g., cevostamab) may be administered to the subject with only a two dosing cycles (e.g., a first dosing cycle comprising a C1 D1 , a C1 D2, a C1 D3, and, optionally, a C1 D4, and a second dosing cycle comprising a C2D1 ), in some aspects, however, the dosing regimen may further include one or more additional dosing cycles. For example, the dosing regimen my include 1 to 17 additional dosing cycles (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, or 17 additional dosing cycles, e.g., 1 -3 additional dosing cycles, 1 -5 additional dosing cycles, 3-8 additional dosing cycles, 5-10 additional dosing cycles, 8-12 additional dosing cycles, 10-15 additional dosing cycles, 12-17 additional dosing cycles, or 15-17 additional dosing cycles, i.e., the dosing regimen includes one or more of additional dosing cycle(s) C3, C4, C5, C6, C7, C8, C9, C10, C1 1 , C12, C13, C14, C15, C16, C17, C18, and C19. The length of each of the one or more additional dosing cycles may be 3 weeks or 21 days.

In some aspects, each of the one or more additional dosing cycles comprises a single dose of the bispecific antibody. In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is equal to the C2D1 (e.g., is about 20 mg to about 600 mg, about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 60 mg to about 350 mg, about 80 mg to about 300 mg, about 100 mg to about 200 mg, about 140 mg to about 180 mg, about 150 mg to about 170 mg, about 132 mg to about 160 mg, about 20 mg to about 252 mg, or about 100 mg to about 180 mg, e.g., is about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 252 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, about 505 mg, about 510 mg, about 515 mg, about 520 mg, about 525 mg, about 530 mg, about 535 mg, about 540 mg, about 545 mg, about 550 mg, about 555 mg, about 560 mg, about 565 mg, about 570 mg, about 575 mg, about 580 mg, about 585 mg, about 590 mg, about 595 mg, or about 600 mg). In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is about 160 mg.

C. IL-6 and CD8+ T cell activation thresholds

When compared to other dosing regimens, the dosing regimens described herein may alter peak interleukin 6 (IL-6) levels and/or cluster of differentiation 8 (CD8)-positive (CD8+) T cell activation such that unwanted effects (e.g., cytokine-driven toxicities, e.g., CRS) of antibody administration are reduced during treatment.

Peak IL-6 levels

In some aspects of the dosing regimens (e.g., triple step-up dosing regimens) described herein, the peak IL-6 level in a sample from a patient or population of patients does not exceed a threshold for clinical significance, e.g., a threshold associated with increased risk of CRS. Peak IL-6 is the highest measured or reported IL-6 value taken during the time period following a dose of the bispecific antibody that binds to FcRH5 and CD3 (e.g., a time period between end of infusion (EOI) of the dose and the administration of the next dose). IL-6 level may be measured in any appropriate sample. In some aspects, the IL-6 level is measured in a blood (e.g., peripheral blood) sample. In some aspects, the peak IL-6 level in a subject or the median peak IL-6 level in a population of subjects treated according to a method provided herein (e.g., a triple step-up dosing regimen) does not exceed 80 pg/mL (e.g., does not exceed 80 pg/mL, 79 pg/mL, 78 pg/mL, 77 pg/mL, 76 pg/mL, 75 pg/mL, 74 pg/mL, 73 pg/mL, 72 pg/mL, 71 pg/mL, 70 pg/mL, 69 pg/mL, 68 pg/mL, 67 pg/mL, 66 pg/mL, 65 pg/mL, 64 pg/mL, 63 pg/mL, 62 pg/mL, 61 pg/mL, 60 pg/mL, 59 pg/mL, 58 pg/mL, 57 pg/mL, 56 pg/mL, 55 pg/mL, 54 pg/mL, 53 pg/mL, 52 pg/mL, 51 pg/mL, or 50 pg/mL) between the C1 D1 and the C1 D2. For example, in some aspects, in which the C1 D1 is administered on Day 1 and the C1 D2 is administered on Day 2 of a dosing cycle, the peak IL-6 level in the subject or the median peak IL-6 level in the population of subjects does not exceed 80 pg/mL on Day 1 following administration of the C1 D1 or on Day 2 before the administration of the C1 D2. As another example, in some aspects, in which the C1 D1 is administered on Day 1 and the C1 D2 is administered on Day 3 of a dosing cycle, the peak IL-6 level in the subject or the median peak IL-6 level in the population of subjects does not exceed 80 pg/mL on Day 1 following administration of the C1 D1 , on Day 2, or on Day 3 before the administration of the C1 D2. As yet another example, in some aspects, in which the C1 D1 is administered on Day 1 and the C1 D2 is administered on Day 4 of a dosing cycle, the peak IL-6 level in the subject or the median peak IL-6 level in the population of subjects does not exceed 80 pg/mL on Day 1 following administration of the C1 D1 , on Day 2, on Day 3, or on Day 4 before the administration of the C1 D2.

In some aspects, the peak IL-6 level in a subject or the median peak IL-6 level in a population of subjects treated according to a method provided herein (e.g., a triple step-up dosing regimen) does not exceed 80 pg/mL (e.g., does not exceed 80 pg/mL, 79 pg/mL, 78 pg/mL, 77 pg/mL, 76 pg/mL, 75 pg/mL, 74 pg/mL, 73 pg/mL, 72 pg/mL, 71 pg/mL, 70 pg/mL, 69 pg/mL, 68 pg/mL, 67 pg/mL, 66 pg/mL, 65 pg/mL, 64 pg/mL, 63 pg/mL, 62 pg/mL, 61 pg/mL, 60 pg/mL, 59 pg/mL, 58 pg/mL, 57 pg/mL, 56 pg/mL, 55 pg/mL, 54 pg/mL, 53 pg/mL, 52 pg/mL, 51 pg/mL, or 50 pg/mL) between the C1 D2 and the C1 D3. For example, in some aspects, in which the C1 D2 is administered on Day 2 and the C1 D3 is administered on Day 8 of a dosing cycle, the peak IL-6 level in the subject or the median peak IL-6 level in the population of subjects does not exceed 80 pg/mL on Day 2 following administration of the C1 D1 , on any of Days 3-7, or on Day 8 before the administration of the C1 D3. As another example, in some aspects, in which the C1 D2 is administered on Day 3 and the C1 D3 is administered on Day 8 of a dosing cycle, the peak IL-6 level in the subject or the median peak IL-6 level in the population of subjects does not exceed 80 pg/mL on Day 3 following administration of the C1 D2, on any of Days 4-7, or on Day 8 before the administration of the C1 D3. As yet another example, in some aspects, in which the C1 D2 is administered on Day 4 and the C1 D3 is administered on Day 8 of a dosing cycle, the peak IL-6 level in the subject or the median peak IL-6 level in the population of subjects does not exceed 80 pg/mL on Day 4 following administration of the C1 D2, on any of Days 5-7, or on Day 8 before the administration of the C1 D3.

In some aspects, the peak IL-6 level in a subject or the median peak IL-6 level in a population of subjects treated according to a method provided herein (e.g., a triple step-up dosing regimen) does not exceed 80 pg/mL (e.g., does not exceed 80 pg/mL, 79 pg/mL, 78 pg/mL, 77 pg/mL, 76 pg/mL, 75 pg/mL, 74 pg/mL, 73 pg/mL, 72 pg/mL, 71 pg/mL, 70 pg/mL, 69 pg/mL, 68 pg/mL, 67 pg/mL, 66 pg/mL, 65 pg/mL, 64 pg/mL, 63 pg/mL, 62 pg/mL, 61 pg/mL, 60 pg/mL, 59 pg/mL, 58 pg/mL, 57 pg/mL, 56 pg/mL, 55 pg/mL, 54 pg/mL, 53 pg/mL, 52 pg/mL, 51 pg/mL, or 50 pg/mL) between the C1 D1 and the C1 D3. For example, in some aspects, in which the C1 D1 is administered on Day 1 and the C1 D3 is administered on Day 8 of a dosing cycle, the peak IL-6 level in the subject or the median peak IL-6 level in the population of subjects does not exceed 80 pg/mL on Day 1 following administration of the C1 D1 , on any of Days 2-7, or on Day 8 before the administration of the C1 D3.

In some aspects, the peak IL-6 level in a subject or the median peak IL-6 level in a population of subjects treated according to a method provided herein (e.g., a triple step-up dosing regimen) does not exceed 30 pg/mL (e.g., does not exceed 30 pg/mL, 29 pg/mL, 28 pg/mL, 27 pg/mL, 26 pg/mL, 25 pg/mL, 24 pg/mL, 23 pg/mL, 22 pg/mL, 21 pg/mL, 20 pg/mL, 19 pg/mL, 18 pg/mL, 17 pg/mL, 16 pg/mL, 15 pg/mL, 14 pg/mL, 13 pg/mL, 12 pg/mL, 1 1 pg/mL, 10 pg/mL, 9 pg/mL, 8 pg/mL, 7 pg/mL, 6 pg/mL, 5 pg/mL, 4 pg/mL, 3 pg/mL, 2 pg/mL, or 1 pg/mL) between the C1 D1 and the C1 D2. For example, in some aspects, in which the C1 D1 is administered on Day 1 and the C1 D2 is administered on Day 2 of a dosing cycle, the peak IL-6 level in the subject or the median peak IL-6 level in the population of subjects does not exceed 30 pg/mL on Day 1 following administration of the C1 D1 or on Day 2 before the administration of the C1 D2. As another example, in some aspects, in which the C1 D1 is administered on Day 1 and the C1 D2 is administered on Day 3 of a dosing cycle, the peak IL-6 level in the subject or the median peak IL- 6 level in the population of subjects does not exceed 30 pg/mL on Day 1 following administration of the C1 D1 , on Day 2, or on Day 3 before the administration of the C1 D2. As yet another example, in some aspects, in which the C1 D1 is administered on Day 1 and the C1 D2 is administered on Day 4 of a dosing cycle, the peak IL-6 level in the subject or the median peak IL-6 level in the population of subjects does not exceed 30 pg/mL on Day 1 following administration of the C1 D1 , on Day 2, on Day 3, or on Day 4 before the administration of the C1 D2.

In some aspects, the peak IL-6 level in a subject or the median peak IL-6 level in a population of subjects treated according to a method provided herein (e.g., a triple step-up dosing regimen) does not exceed 30 pg/mL (e.g., does not exceed 30 pg/mL, 29 pg/mL, 28 pg/mL, 27 pg/mL, 26 pg/mL, 25 pg/mL, 24 pg/mL, 23 pg/mL, 22 pg/mL, 21 pg/mL, 20 pg/mL, 19 pg/mL, 18 pg/mL, 17 pg/mL, 16 pg/mL, 15 pg/mL, 14 pg/mL, 13 pg/mL, 12 pg/mL, 1 1 pg/mL, 10 pg/mL, 9 pg/mL, 8 pg/mL, 7 pg/mL, 6 pg/mL, 5 pg/mL, 4 pg/mL, 3 pg/mL, 2 pg/mL, or 1 pg/mL) between the C1 D2 and the C1 D3. For example, in some aspects, in which the C1 D2 is administered on Day 2 and the C1 D3 is administered on Day 8 of a dosing cycle, the peak IL-6 level in the subject or the median peak IL-6 level in the population of subjects does not exceed 30 pg/mL on Day 2 following administration of the C1 D1 , on any of Days 3-7, or on Day 8 before the administration of the C1 D3. As another example, in some aspects, in which the C1 D2 is administered on Day 3 and the C1 D3 is administered on Day 8 of a dosing cycle, the peak IL-6 level in the subject or the median peak IL-6 level in the population of subjects does not exceed 30 pg/mL on Day 3 following administration of the C1 D2, on any of Days 4-7, or on Day 8 before the administration of the C1 D3. As yet another example, in some aspects, in which the C1 D2 is administered on Day 4 and the C1 D3 is administered on Day 8 of a dosing cycle, the peak IL-6 level in the subject or the median peak IL- 6 level in the population of subjects does not exceed 30 pg/mL on Day 4 following administration of the C1 D2, on any of Days 5-7, or on Day 8 before the administration of the C1 D3.

In some aspects, the peak IL-6 level in a subject or the median peak IL-6 level in a population of subjects treated according to a method provided herein (e.g., a triple step-up dosing regimen) does not exceed 30 pg/mL (e.g., does not exceed 30 pg/mL, 29 pg/mL, 28 pg/mL, 27 pg/mL, 26 pg/mL, 25 pg/mL, 24 pg/mL, 23 pg/mL, 22 pg/mL, 21 pg/mL, 20 pg/mL, 19 pg/mL, 18 pg/mL, 17 pg/mL, 16 pg/mL, 15 pg/mL, 14 pg/mL, 13 pg/mL, 12 pg/mL, 1 1 pg/mL, 10 pg/mL, 9 pg/mL, 8 pg/mL, 7 pg/mL, 6 pg/mL, 5 pg/mL, 4 pg/mL, 3 pg/mL, 2 pg/mL, or 1 pg/mL) between the C1 D1 and the C1 D3. For example, in some aspects, in which the C1 D1 is administered on Day 1 and the C1 D3 is administered on Day 8 of a dosing cycle, the peak IL-6 level in the subject or the median peak IL-6 level in the population of subjects does not exceed 30 pg/mL on Day 1 following administration of the C1 D1 , on any of Days 2-7, or on Day 8 before the administration of the C1 D3.

In some aspects, the peak IL-6 level in a subject or the median peak IL-6 level in a population of subjects treated according to a method provided herein (e.g., a triple step-up dosing regimen) does not exceed 80 pg/mL (e.g., does not exceed 80 pg/mL, 79 pg/mL, 78 pg/mL, 77 pg/mL, 76 pg/mL, 75 pg/mL, 74 pg/mL, 73 pg/mL, 72 pg/mL, 71 pg/mL, 70 pg/mL, 69 pg/mL, 68 pg/mL, 67 pg/mL, 66 pg/mL, 65 pg/mL, 64 pg/mL, 63 pg/mL, 62 pg/mL, 61 pg/mL, 60 pg/mL, 59 pg/mL, 58 pg/mL, 57 pg/mL, 56 pg/mL, 55 pg/mL, 54 pg/mL, 53 pg/mL, 52 pg/mL, 51 pg/mL, 50 pg/mL49 pg/mL, 48 pg/mL, 47 pg/mL, 46 pg/mL, 45 pg/mL, 44 pg/mL, 43 pg/mL, 42 pg/mL, 41 pg/mL, 40 pg/mL, 39 pg/mL, 38 pg/mL, 37 pg/mL, 36 pg/mL, 35 pg/mL, 34 pg/mL, 33 pg/mL, 32 pg/mL, 31 pg/mL, 30 pg/mL, 29 pg/mL, 28 pg/mL, 27 pg/mL, 26 pg/mL, 25 pg/mL, 24 pg/mL, 23 pg/mL, 22 pg/mL, 21 pg/mL, 20 pg/mL, 19 pg/mL, 18 pg/mL, 17 pg/mL, 16 pg/mL, 15 pg/mL, 14 pg/mL, 13 pg/mL, 12 pg/mL, 1 1 pg/mL, 10 pg/mL, 9 pg/mL, 8 pg/mL, 7 pg/mL, 6 pg/mL, 5 pg/mL, 4 pg/mL, 3 pg/mL, 2 pg/mL, or 1 pg/mL) at any point during the dosing cycle (e.g., any point after the C1 D1 , after C1 D2, after the C1 D3, and after the C1 D4).

In some aspects, the disclosure features a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen (e.g., a triple step-up dosing regimen) comprising at least a first dosing cycle (e.g., a 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, a C1 D3, and a C1 D4 of the bispecific antibody, wherein the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg, e.g., about 1 .2 mg or about 3.3 mg), the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg, e.g., about 3.6 mg or about 7.2 mg), and the C1 D4 is greater than the C1 D3 (e.g., the C1 D4 is about 20 mg to about 600 mg, e.g., between about 20 mg to about 252 mg, about 100 mg to about 180 mg, or about 132 mg to about 160 mg, e.g., about 160 mg), and wherein a peak IL-6 level in the subject or a median peak IL-6 level in a population of subjects treated according to the method does not exceed 80 pg/mL (e.g., does not exceed 30 pg/mL) between the C1 D1 and the C1 D2; between the C1 D2 and the C1 D3; between the C1 D3 and the C1 D4; and/or following the C1 D4.

In some aspects, the disclosure features a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen (e.g., a triple step-up dosing regimen) comprising at least a first dosing cycle (e.g., a 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, a C1 D3, and a C1 D4 of the bispecific antibody, wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 3.4 mg (e.g., between about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), the C1 D3 is between about 3.5 mg to about 19.9 mg (e.g., between about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg), and the C1 D4 is between about 20 mg to about 600 mg (e.g., between about 80 mg to about 300 mg, about 20 mg to about 252 mg, about 100 mg to about 180 mg, or about 132 mg to about 160 mg, e.g., about 160 mg), and wherein a peak IL-6 level in the subject or a median peak IL-6 level in a population of subjects treated according to the method does not exceed 80 pg/mL (e.g., does not exceed 30 pg/mL) between the C1 D1 and the C1 D2; between the C1 D2 and the C1 D3; between the C1 D3 and the C1 D4; and/or following the C1 D4.

In some aspects, the disclosure features a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen (e.g., a triple step-up dosing regimen) comprising at least a first dosing cycle (e.g., a 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, a C1 D3, and a C1 D4 of the bispecific antibody, wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g.,

1 .2 mg), the C1 D3 is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.6 mg), and the C1 D4 is between about 20 mg to about 600 mg (e.g., between about 80 mg to about 300 mg, about 20 mg to about 252 mg, about 100 mg to about 180 mg, or about 132 mg to about 160 mg, e.g., about 160 mg), and wherein a peak IL-6 level in the subject or a median peak IL-6 level in a population of subjects treated according to the method does not exceed 80 pg/mL (e.g., does not exceed 30 pg/mL) between the C1 D1 and the C1 D2; between the C1 D2 and the C1 D3; between the C1 D3 and the C1 D4; and/or following the C1 D4.

In some aspects, the disclosure features a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen (e.g., a triple step-up dosing regimen) comprising at least a first dosing cycle (e.g., a 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, a C1 D3, and a C1 D4 of the bispecific antibody, wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g.,

3.3 mg), the C1 D3 is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg), and the C1 D4 is between about 20 mg to about 600 mg (e.g., between about 80 mg to about 300 mg, about 20 mg to about 252 mg, about 100 mg to about 180 mg, or about 132 mg to about 160 mg, e.g., about 160 mg), and wherein a peak IL-6 level in the subject or a median peak IL-6 level in a population of subjects treated according to the method does not exceed 80 pg/mL (e.g., does not exceed 30 pg/mL) between the C1 D1 and the C1 D2; between the C1 D2 and the C1 D3; between the C1 D3 and the C1 D4; and/or following the C1 D4.

In some aspects, the disclosure features a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen (e.g., a triple step-up dosing regimen) comprising at least a first dosing cycle (e.g., a 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3, of the bispecific antibody, wherein the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg, e.g., about 3.6 mg or about 7.2 mg), and wherein a peak IL-6 level in the subject or a median peak IL-6 level in a population of subjects treated according to the method does not exceed 80 pg/mL (e.g., does not exceed 30 pg/mL) between the C1 D1 and the C1 D2; between the C1 D2 and the C1 D3; and/or following the C1 D3.

In some aspects, the disclosure features a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, wherein the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg or about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg or about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg), and wherein a peak IL-6 level in the subject or a median peak IL-6 level in a population of subjects treated according to the method does not exceed 80 pg/mL (e.g., does not exceed 30 pg/mL) between the C1 D1 and the C1 D2; between the C1 D2 and the C1 D3; and/or following the C1 D3.

In some aspects, the disclosure features a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen (e.g., a triple step-up dosing regimen) comprising at least a first dosing cycle (e.g., a 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 3.4 mg (e.g., between about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is between about 3.5 mg to about 19.9 mg (e.g., between about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg), and wherein a peak IL-6 level in the subject or a median peak IL-6 level in a population of subjects treated according to the method does not exceed 80 pg/mL (e.g., does not exceed 30 pg/mL) between the C1 D1 and the C1 D2; between the C1 D2 and the C1 D3; and/or following the C1 D3.

In some aspects, the disclosure features a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen (e.g., a triple step-up dosing regimen) comprising at least a first dosing cycle (e.g., a 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., 1 .2 mg), and the C1 D3 is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.6 mg), and wherein a peak IL-6 level in the subject or a median peak IL-6 level in a population of subjects treated according to the method does not exceed 80 pg/mL (e.g., does not exceed 30 pg/mL) between the C1 D1 and the C1 D2; between the C1 D2 and the C1 D3; and/or following the C1 D3.

In some aspects, the disclosure features a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen (e.g., a triple step-up dosing regimen) comprising at least a first dosing cycle (e.g., a 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg), and the C1 D3 is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg), and wherein a peak IL-6 level in the subject or a median peak IL-6 level in a population of subjects treated according to the method does not exceed 80 pg/mL (e.g., does not exceed 30 pg/mL) between the C1 D1 and the C1 D2; between the C1 D2 and the C1 D3; and/or following the C1 D3.

T cell activation

In some aspects of the dosing regimens described herein, the peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs between the C1 D1 and the C1 D2. For example, in some aspects, in which the C1 D1 is administered on Day 1 and the C1 D2 is administered on Day 2 of a dosing cycle, the peak level of CD8+ T cell activation in the subject occurs on Day 1 following administration of the C1 D1 or on Day 2 before the administration of the C1 D2. As another example, in some aspects, in which the C1 D1 is administered on Day 1 and the C1 D2 is administered on Day 3 of a dosing cycle, the peak level of CD8+ T cell activation in the subject occurs on Day 1 following administration of the C1 D1 or on Day 3 before the administration of the C1 D2. As yet another example, in some aspects, in which the C1 D1 is administered on Day 1 and the C1 D2 is administered on Day 4 of a dosing cycle, the peak level of CD8+ T cell activation in the subject occurs on Day 1 following administration of the C1 D1 or on Day 4 before the administration of the C1 D2.

In some aspects of the dosing regimens described herein, the peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs between the C1 D2 and the C1 D3. For example, in some aspects, in which the C1 D2 is administered on Day 2 and the C1 D3 is administered on Day 8 of a dosing cycle, the peak level of CD8+ T cell activation in the subject occurs on Day 2 following administration of the C1 D2, on any of Days 3-7, or on Day 8 before the administration of the C1 D3. As another example, in some aspects, in which the C1 D2 is administered on Day 3 and the C1 D3 is administered on Day 8 of a dosing cycle, the peak level of CD8+ T cell activation in the subject occurs on Day 3 following administration of the C1 D2, on any of Days 4-7, or on Day 8 before the administration of the C1 D3. As yet another example, in some aspects, in which the C1 D2 is administered on Day 4 and the C1 D3 is administered on Day 8 of a dosing cycle, the peak level of CD8+ T cell activation in the subject occurs on Day 4 following administration of the C1 D2, on any of Days 5-7, or on Day 8 before the administration of the C1 D3.

In some aspects of the dosing regimens described herein, the peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs between the C1 D1 and the C1 D3. For example, in some aspects, in which the C1 D1 is administered on Day 1 and the C1 D3 is administered on Day 8 of a dosing cycle, the peak level of CD8+ T cell activation in the subject occurs on Day 1 following administration of the C1 D1 , on any of Days 2-7, or on Day 8 before the administration of the C1 D3.

In some aspects of the triple step-up dosing regimens described herein, the peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs between the C1 D1 and the C1 D4. For example, in some aspects, in which the C1 D1 is administered on Day 1 and the C1 D4 is administered on Day 9 of a dosing cycle, the peak level of CD8+ T cell activation in the subject occurs on Day 1 following administration of the C1 D1 , on any of Days 2-8, or on Day 9 before the administration of the C1 D4. As another example, in some aspects, in which the C1 D1 is administered on Day 1 and the C1 D4 is administered on Day 10 of a dosing cycle, the peak level of CD8+ T cell activation in the subject occurs on Day 1 following administration of the C1 D1 , on any of Days 2-9, or on Day 10 before the administration of the C1 D4. As yet another example, in some aspects, in which the C1 D1 is administered on Day 1 and the C1 D4 is administered on Day 1 1 of a dosing cycle, the peak level of CD8+ T cell activation in the subject occurs on Day 1 following administration of the C1 D1 , on any of Days 2-10, or on Day 1 1 before the administration of the C1 D4.

In some aspects of the double step-up dosing regimens described herein, the peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs at any point during the dosing cycle prior to a first administration of a target dose (e.g., prior to a C1 D3 of a double step-up dosing regimen described herein). In some aspects, the peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs within 24 hours of the C1 D1 , e.g., occurs within 20 hours, 18 hours, 16 hours, 14 hours, or 12 hours of the C1 D1 . In some aspects, the peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs within 24 hours of the C1 D2, e.g., occurs within 20 hours, 18 hours, 16 hours, 14 hours, or 12 hours of the C1 D2.

In some aspects of the triple step-up dosing regimens described herein, the peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs at any point during the dosing cycle prior to a first administration of a target dose (e.g., prior to a C1 D4 of a triple step-up dosing regimen described herein). In some aspects, the peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs within 24 hours of the C1 D1 , e.g., occurs within 20 hours, 18 hours, 16 hours, 14 hours, or 12 hours of the C1 D1 . In some aspects, the peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs within 24 hours of the C1 D2, e.g., occurs within 20 hours, 18 hours, 16 hours, 14 hours, or 12 hours of the C1 D2. In some aspects, the peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs within 24 hours of the C1 D3, e.g., occurs within 20 hours, 18 hours, 16 hours, 14 hours, or 12 hours of the C1 D3.

In some aspects, the disclosure features a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, a C1 D3, and a C1 D4 of the bispecific antibody, wherein the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg, e.g., about 1 .2 mg or about 3.3 mg), the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg, e.g., about 3.6 mg or about 7.2 mg), and the C1 D4 is greater than the C1 D3 (e.g., the C1 D4 is about 20 mg to about 600 mg, 20 mg to about 252 mg, about 100 mg to about 180 mg, or about 132 mg to about 160 mg, e.g., about 160 mg), and wherein a peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs between the C1 D1 and the C1 D2; between the C1 D2 and the C1 D3; and/or between the C1 D3 and the C1 D4.

In some aspects, the disclosure features a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, a C1 D3, and a C1 D4 of the bispecific antibody, wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 3.4 mg (e.g., between about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), the C1 D3 is between about 3.5 mg to about 19.9 mg (e.g., between about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg), and the C1 D4 is between about 20 mg to about 600 mg (e.g., between about 80 mg to about 300 mg, about 20 mg to about 252 mg, about 100 mg to about 180 mg, or about 132 mg to about 160 mg, e.g., about 160 mg), and wherein a peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs between the C1 D1 and the C1 D2; between the C1 D2 and the C1 D3; and/or between the C1 D3 and the C1 D4.

In some aspects, the disclosure features a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, a C1 D3, and a C1 D4 of the bispecific antibody, wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., 1 .2 mg), the C1 D3 is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.6 mg), and the C1 D4 is between about 20 mg to about 600 mg (e.g., between about 80 mg to about 300 mg, about 20 mg to about 252 mg, about 100 mg to about 180 mg, or about 132 mg to about 160 mg, e.g., about 160 mg), and wherein a peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs between the C1 D1 and the C1 D2; between the C1 D2 and the C1 D3; and/or between the C1 D3 and the C1 D4.

In some aspects, the disclosure features a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, a C1 D3, and a C1 D4 of the bispecific antibody, wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg), the C1 D3 is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg), and the C1 D4 is between about 20 mg to about 600 mg (e.g., between about 80 mg to about 300 mg, about 20 mg to about 252 mg, about 100 mg to about 180 mg, or about 132 mg to about 160 mg, e.g., about 160 mg), and wherein a peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs between the C1 D1 and the C1 D2; between the C1 D2 and the C1 D3; and/or between the C1 D3 and the C1 D4.

In some aspects, the disclosure features a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, wherein the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg, e.g., about 3.6 mg or about 7.2 mg), and wherein a peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs between the C1 D1 and the C1 D2; between the C1 D2 and the C1 D3; and/or following the C1 D3 (yet prior to any optionally administered target dose).

In some aspects, the disclosure features a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a first 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, wherein the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg or about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg or about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg), and wherein a peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs between the C1 D1 and the C1 D2; between the C1 D2 and the C1 D3; and/or following the C1 D3 (yet prior to any optionally administered target dose).

In some aspects, the disclosure features a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 3.4 mg (e.g., between about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), and the C1 D3 is between about 3.5 mg to about 19.9 mg (e.g., between about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg), and wherein a peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs between the C1 D1 and the C1 D2; between the C1 D2 and the C1 D3; and/or following the C1 D3 (yet prior to any optionally administered target dose).

In some aspects, the disclosure features a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 2.9 mg (e.g., between about 1 mg to about 2 mg, e.g., 1 .2 mg), and the C1 D3 is between about 3 mg to about 19.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.6 mg), and wherein a peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs between the C1 D1 and the C1 D2; between the C1 D2 and the C1 D3; and/or following the C1 D3 (yet prior to any optionally administered target dose).

In some aspects, the disclosure features a method of treating a subject (e.g., a human subject) having a cancer (e.g., MM, e.g., R/R MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) in a dosing regimen comprising at least a first dosing cycle (e.g., a 21 -day dosing cycle), wherein the first dosing cycle comprises a C1 D1 , a C1 D2, and a C1 D3 of the bispecific antibody, wherein the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 5.9 mg (e.g., between about 3 mg to about 5 mg, e.g., 3.3 mg), and the C1 D3 is between about 6 mg to about 19.9 mg (e.g., between about 6.5 mg to about 10 mg, e.g., 7.2 mg), and wherein a peak level of CD8+ T cell activation in the subject in the first dosing cycle occurs between the C1 D1 and the C1 D2; between the C1 D2 and the C1 D3; and/or following the C1 D3 (yet prior to any optionally administered target dose).

D. Combination therapies

In any of the double step-up or triple step-up dosing regimens described herein, the bispecific anti-FcRH5/anti-CD3 antibody (e.g., cevostamab) may be administered to the subject in a combination therapy. For example, the bispecific anti-FcRH5/anti-CD3 antibody may be co-administered with one or more additional therapeutic agents described herein.

/'. Tocilizumab and treatment of CRS

In one instance, the additional therapeutic agent is an effective amount of tocilizumab (ACTEMRA®). In some instances, the subject has a cytokine release syndrome (CRS) event (e.g., has a CRS event following treatment with the bispecific antibody, e.g., has a CRS event following a C1 D1 , a C1 D2, a C1 D3, a C1 D4, a C2D1 , or an additional dose of the bispecific antibody), and the method further comprises treating the symptoms of the CRS event (e.g., treating the CRS event by administering to the subject an effective amount of tocilizumab) while suspending treatment with the bispecific antibody. In some aspects, tocilizumab is administered intravenously to the subject as a single dose of about 8 mg/kg. In some aspects, the CRS event does not resolve or worsens within 24 hours of treating the symptoms of the CRS event, and the method further comprising administering to the subject one or more additional doses of tocilizumab to manage the CRS event, e.g., administering one or more additional doses of tocilizumab intravenously to the subject at a dose of about 8 mg/kg.

In some aspects, treating the symptoms of the CRS event further comprises treatment with a high-dose vasopressor (e.g., norepinephrine, dopamine, phenylephrine, epinephrine, or vasopressin and norepinephrine), e.g., as described in Table 2. In some aspects, the tocilizumab is administered intravenously to the subject as a single dose of about 8 mg/kg. Table 2. High-dose vasopressors min = minute; VASST = Vasopressin and Septic Shock Trial. a VASST vasopressor equivalent equation: norepinephrine equivalent dose = [norepinephrine (pg /min)] + [dopamine (pg Zkg/min) - 2] + [epinephrine (pg /min)] + [phenylephrine (pg /min) - 10].

CRS symptoms and grading

CRS may be graded according to the Modified Cytokine Release Syndrome Grading System established by Lee et al., Blood, 124: 188-195, 2014 or Lee et al., Biol Blood Marrow Transplant, 25(4): 625-638, 2019, and as described in Table 3. In addition to diagnostic criteria, recommendations on management of CRS based on its severity, including early intervention with corticosteroids and/or anticytokine therapies described herein.

Table 3. Cytokine release syndrome grading systems

ASTCT consensus grading: Lee et al., Biol Blood Marrow Transplant, 25(4): 625-638, 2019. a Low-dose vasopressor: single vasopressor at doses below that shown in Table 2. b High-dose vasopressor: as defined in Table 2.

*Fever is defined as temperature >38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. tCRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS.

^Low-flow nasal cannula is defined as oxygen delivered at <6L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6L/minute.

Mild to moderate presentations of CRS and/or infusion-related reaction (IRR) may include symptoms such as fever, headache, and myalgia, and may be treated symptomatically with analgesics, anti-pyretics, and antihistamines as indicated. Severe or life-threatening presentations of CRS and/or IRR, such as hypotension, tachycardia, dyspnea, or chest discomfort should be treated aggressively with supportive and resuscitative measures as indicated, including the use of high-dose corticosteroids, IV fluids, admission to intensive care unit, and other supportive measures. Severe CRS may be associated with other clinical sequelae such as disseminated intravascular coagulation, capillary leak syndrome, or macrophage activation syndrome (MAS). Standard of care for severe or life threatening CRS resulting from immune-based therapy has not been established; case reports and recommendations using anticytokine therapy such as tocilizumab have been published (Teachey et al., Blood, 121 : 5154-5157, 2013; Lee et al., Blood, 124: 188-195, 2014; Maude et al., New Engl J Med, 371 : 1507-1517, 2014).

As noted in Table 3, even moderate presentations of CRS in subjects with extensive comorbidities should be monitored closely, with consideration given to intensive care unit admission and tocilizumab administration.

Administration of tocilizumab as a premedication

In any of the double step-up or triple step-up dosing regimens described herein, an effective amount of tocilizumab may be administered as a premedication (prophylaxis), e.g., is administered to the subject prior to the administration of the bispecific antibody (e.g., administered about 2 hours prior to the administration of the bispecific antibody). Administration of tocilizumab as a premedication may reduce the frequency or severity of CRS.

In a double step-up dosing regimen described herein, tocilizumab may be administered as a premedication in Cycle 1 , e.g., is administered prior to a first dose (C1 D1 ; cycle 1 , dose 1 ), a second dose (C1 D2; cycle 1 , dose, 2), and/or a third dose (C1 D3; cycle 1 , dose 3) of the bispecific anti- FcRH5/anti-CD3 antibody. For example, tocilizumab may be administered (e.g., as a premedication) to the subject on Day 1 , prior to the administration of the C1 D1 ; on Day 2, prior to the administration of the C1 D2; and/or on Day 8, prior to the administration of the C1 D3. As another example, tocilizumab may be administered (e.g., as a premedication) to the subject on Day 1 , prior to the administration of the C1 D1 ; on Day 3, prior to the administration of the C1 D2; and/or on Day 8, prior to the administration of the C1 D3. As yet another example, tocilizumab may be administered (e.g., as a premedication) to the subject on Day 1 , prior to the administration of the C1 D1 ; on Day 4, prior to the administration of the C1 D2; and/or on Day 8, prior to the administration of the C1 D3.

In a triple step-up dosing regimen described herein, tocilizumab may be administered as a premedication in Cycle 1 , e.g., is administered prior to a first dose (C1 D1 ; cycle 1 , dose 1 ), a second dose (C1 D2; cycle 1 , dose, 2), a third dose (C1 D3; cycle 1 , dose 3) and/or a fourth dose (C1 D4; cycle 1 , dose 4) of the bispecific anti-FcRH5/anti-CD3 antibody. For example, tocilizumab may be administered (e.g., as a premedication) to the subject on Day 1 , prior to the administration of the C1 D1 ; on Day 2, prior to the administration of the C1 D2; and/or on Day 8, prior to the administration of the C1 D3. Additionally, tocilizumab may be administered (e.g., as a premedication) to the subject on any one of Days 9-11 (e.g., on Day 9, on Day 10, or on Day 11 ), prior to the administration of the C1 D4. As another example, tocilizumab may be administered (e.g., as a premedication) to the subject on Day 1 , prior to the administration of the C1 D1 ; on Day 3, prior to the administration of the C1 D2; and/or on Day 8, prior to the administration of the C1 D3. Additionally, tocilizumab may be administered (e.g., as a premedication) to the subject on any one of Days 9-11 (e.g., on Day 9, on Day 10, or on Day 11 ), prior to the administration of the C1 D4. As yet another example, tocilizumab may be administered (e.g., as a premedication) to the subject on Day 1 , prior to the administration of the C1 D1 ; on Day 4, prior to the administration of the C1 D2; and/or on Day 8, prior to the administration of the C1 D3. Additionally, tocilizumab may be administered (e.g., as a premedication) to the subject on any one of Days 9-11 (e.g., on Day 9, on Day 10, or on Day 11 ), prior to the administration of the C1 D4.

In a triple step-up dosing regimen described herein, tocilizumab may be administered as a premedication in Cycle 1 , e.g., is administered prior to a first dose (C1 D1 ; cycle 1 , dose 1 ), a second dose (C1 D2; cycle 1 , dose, 2), and/or a third dose (C1 D3; cycle 1 , dose 3) of the bispecific anti- FcRH5/anti-CD3 antibody. For example, tocilizumab may be administered (e.g., as a premedication) to the subject on Day 1 , prior to the administration of the C1 D1 ; on Day 2, prior to the administration of the C1 D2; and/or on Day 8, prior to the administration of the C1 D3. As another example, tocilizumab may be administered (e.g., as a premedication) to the subject on Day 1 , prior to the administration of the C1 D1 ; on Day 3, prior to the administration of the C1 D2; and/or on Day 8, prior to the administration of the C1 D3. As yet another example, tocilizumab may be administered (e.g., as a premedication) to the subject on Day 1 , prior to the administration of the C1 D1 ; on Day 4, prior to the administration of the C1 D2; and/or on Day 8, prior to the administration of the C1 D3.

In any dosing regimen described herein, tocilizumab may be administered intravenously to the subject as a single dose of about 1 mg/kg to about 15 mg/kg, e.g., about 4 mg/kg to about 10 mg/kg, e.g., about 6 mg/kg to about 10 mg/kg, e.g., about 8 mg/kg. In some aspects, the tocilizumab is administered intravenously to the subject as a single dose of about 8 mg/kg. In some aspects, the tocilizumab is administered intravenously to the subject as a single dose of about 8 mg/kg for patients weighing 30 kg or more (maximum 800 mg) and at a dose of about 12 mg/kg for patients weighing less than 30 kg. Other anti-l L-6R antibodies that could be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061 ), SA-237, and variants thereof.

For example, in one aspect, the bispecific antibody is co-administered with tocilizumab (ACTEMRA® / ROACTEMRA®), wherein the subject is first administered with tocilizumab (ACTEMRA® / ROACTEMRA®) and then separately administered with the bispecific antibody (e.g., the subject is pretreated with tocilizumab (ACTEMRA® / ROACTEMRA®)).

In some aspects, the incidence of CRS (e.g., Grade 1 CRS, Grade 2 CRS, and/or Grade 3+ CRS) is reduced in patients who are treated with tocilizumab as a premedication relative to patients who are not treated with tocilizumab as a premedication. In some aspects, less intervention to treat CRS (e.g., less need for additional tocilizumab, IV fluids, steroids, or O2) is required in patients who are treated with tocilizumab as a premedication relative to patients who are not treated with tocilizumab as a premedication. In some aspects, CRS symptoms have decreased severity (e.g., are limited to fevers and rigors) in patients who are treated with tocilizumab as a premedication relative to patients who are not treated with tocilizumab as a premedication.

Tocilizumab administered to treat CRS

In some aspects, the subject experiences a CRS event during treatment with the therapeutic bispecific antibody and an effective amount of tocilizumab is administered to manage the CRS event.

In some aspects, the subject has a CRS event (e.g., has a CRS event following treatment with the bispecific antibody, e.g., has a CRS event following a first dose or a subsequent dose of the bispecific antibody), and the method further includes treating the symptoms of the CRS event while suspending treatment with the bispecific antibody.

In some aspects, the subject experiences a CRS event, and the method further includes administering to the subject an effective amount of an interleukin-6 receptor (IL-6R) antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to manage the CRS event while suspending treatment with the bispecific antibody. In some aspects, the IL-6R antagonist (e.g., tocilizumab) is administered intravenously to the subject as a single dose of about 1 mg/kg to about 15 mg/kg, e.g., about 4 mg/kg to about 10 mg/kg, e.g., about 6 mg/kg to about 10 mg/kg, e.g., about 8 mg/kg. In some aspects, the tocilizumab is administered intravenously to the subject as a single dose of about 8 mg/kg. Other anti-IL-6R antibodies that could be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061 ), SA-237, and variants thereof.

In some aspects, the CRS event does not resolve or worsens within 24 hours of treating the symptoms of the CRS event, and the method further includes administering to the subject one or more additional doses of the IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab) to manage the CRS event, e.g., administering one or more additional doses of tocilizumab intravenously to the subject at a dose of about 1 mg/kg to about 15 mg/kg, e.g., about 4 mg/kg to about 10 mg/kg, e.g., about 6 mg/kg to about 10 mg/kg, e.g., about 8 mg/kg. In some aspects, the one or more additional doses of tocilizumab are administered intravenously to the subject as a single dose of about 8 mg/kg.

In some aspects, the method further includes administering to the subject an effective amount of a corticosteroid. The corticosteroid may be administered intravenously to the subject. In some aspects, the corticosteroid is methylprednisone (methylprednisolone). In some instances, the methylprednisone is administered at a dose of about 1 mg/kg per day to about 5 mg/kg per day, e.g., about 2 mg/kg per day. In some instances, the corticosteroid is dexamethasone. In some instances, the dexamethasone is administered at a dose of about 10 mg (e.g., a single dose of about 10 mg intravenously) or at a dose of about 0.5 mg/kg/day.

The subject may be administered a corticosteroid, such as methylprednisolone or dexamethasone, if the CRS event is not managed with administration of the IL-6R antagonist (e.g., tocilizumab) alone. In some aspects, treating the symptoms of the CRS event further includes treatment with a high-dose vasopressor (e.g., norepinephrine, dopamine, phenylephrine, epinephrine, or vasopressin and norepinephrine), e.g., as described in Table 5A, Table 5B, and Table 6. Table 2 and Table 5A provide details about tocilizumab treatment of severe or life-threatening CRS.

Management of CRS events by grade

Management of the CRS events may be tailored based on the grade of the CRS (Table 3 and Table 9) and the presence of comorbidities. Table 9 provides recommendations for the management of CRS syndromes by grade.

Management of Grade 2 CRS events

If the subject has a grade 2 CRS event (e.g., a grade 2 CRS event in the absence of comorbidities or in the presence of minimal comorbidities) following administration of the therapeutic bispecific antibody, the method may further include treating the symptoms of the grade 2 CRS event while suspending treatment with the bispecific antibody. If the grade 2 CRS event then resolves to a grade < 1 CRS event for at least three consecutive days, the method may further include resuming treatment with the bispecific antibody without altering the dose. On the other hand, if the grade 2 CRS event does not resolve or worsens to a grade > 3 CRS event within 24 hours of treating the symptoms of the grade 2 CRS event, the method may further involve administering to the subject an effective amount of an interleukin-6 receptor (IL-6R) antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to manage the grade 2 or grade > 3 CRS event. In some instances, tocilizumab is administered intravenously to the subject as a single dose of about 8 mg/kg. Other anti-IL-6R antibodies that could be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061 ), SA-237, and variants thereof.

If the subject has a grade 2 CRS event in the presence of extensive comorbidities following administration of the therapeutic bispecific antibody, the method may further include administering to the subject a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® I ROACTEMRA®)) to manage the grade 2 CRS event while suspending treatment with the bispecific antibody. In some instances, the first dose of tocilizumab is administered intravenously to the subject at a dose of about 8 mg/kg. Other anti-IL-6R antibodies that could be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061 ), SA-237, and variants thereof. In some instances, if the grade 2 CRS event resolves to a grade < 1 CRS event within two weeks, the method further includes resuming treatment with the bispecific antibody at a reduced dose. In some instances, the reduced dose is 50% of the initial infusion rate of the previous cycle if the event occurred during or within 24 hours of the infusion. If, on the other hand, the grade 2 CRS event does not resolve or worsens to a grade > 3 CRS event within 24 hours of treating the symptoms of the grade 2 CRS event, the method may further include administering to the subject one or more (e.g., one, two, three, four, or five or more) additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab) to manage the grade 2 or grade > 3 CRS event. In some particular instances, the grade 2 CRS event does not resolve or worsens to a grade > 3 CRS event within 24 hours of treating the symptoms of the grade 2 CRS event, and the method may further include administering to the subject one or more additional doses of tocilizumab to manage the grade 2 or grade > 3 CRS event. In some instances, the one or more additional doses of tocilizumab is administered intravenously to the subject at a dose of about 1 mg/kg to about 15 mg/kg, e.g., about 4 mg/kg to about 10 mg/kg, e.g., about 6 mg/kg to about 10 mg/kg, e.g., about 8 mg/kg. In some instances, the method further includes administering to the subject an effective amount of a corticosteroid. The corticosteroid may be administered before, after, or concurrently with the one or more additional doses of tocilizumab or other anti-IL-6 R antibody. In some instances, the corticosteroid is administered intravenously to the subject. In some instances, the corticosteroid is methylprednisolone. In some instances, the methylprednisolone is administered at a dose of about 1 mg/kg per day to about 5 mg/kg per day, e.g., about 2 mg/kg per day. In some instances, the corticosteroid is dexamethasone. In some instances, the dexamethasone is administered at a dose of about 10 mg (e.g., a single dose of about 10 mg intravenously) or at a dose of about 0.5 mg/kg/day.

Management of Grade 3 CRS events

If the subject has a grade 3 CRS event following administration of the therapeutic bispecific antibody, the method may further include administering to the subject a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to manage the grade 3 CRS event while suspending treatment with the bispecific antibody. In some instances, the first dose of tocilizumab is administered intravenously to the subject at a dose of about 8 mg/kg. Other anti-IL-6R antibodies that could be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX- 0061 ), SA-237, and variants thereof. In some instances, the subject recovers (e.g., is afebrile and off vasopressors) within 8 hours following treatment with the bispecific antibody, and the method further includes resuming treatment with the bispecific antibody at a reduced dose. In some instances, the reduced dose is 50% of the initial infusion rate of the previous cycle if the event occurred during or within 24 hours of the infusion. In other instances, if the grade 3 CRS event does not resolve or worsens to a grade 4 CRS event within 24 hours of treating the symptoms of the grade 3 CRS event, the method may further include administering to the subject one or more (e.g., one, two, three, four, or five or more) additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab) to manage the grade 3 or grade 4 CRS event. In some particular instances, the grade 3 CRS event does not resolve or worsens to a grade 4 CRS event within 24 hours of treating the symptoms of the grade 3 CRS event, and the method further includes administering to the subject one or more additional doses of tocilizumab to manage the grade 3 or grade 4 CRS event. In some instances, the one or more additional doses of tocilizumab is administered intravenously to the subject at a dose of about 1 mg/kg to about 15 mg/kg, e.g., about 4 mg/kg to about 10 mg/kg, e.g., about 6 mg/kg to about 10 mg/kg, e.g., about 8 mg/kg. In some instances, the method further includes administering to the subject an effective amount of a corticosteroid. The corticosteroid may be administered before, after, or concurrently with the one or more additional doses of tocilizumab or other anti-IL-6 R antibody. In some instances, the corticosteroid is administered intravenously to the subject. In some instances, the corticosteroid is methylprednisolone. In some instances, the methylprednisolone is administered at a dose of about 1 mg/kg per day to about 5 mg/kg per day, e.g., about 2 mg/kg per day. In some instances, the corticosteroid is dexamethasone. In some instances, the dexamethasone is administered at a dose of about 10 mg (e.g., a single dose of about 10 mg intravenously) or at a dose of about 0.5 mg/kg/day. Management of Grade 4 CRS events

If the subject has a grade 4 CRS event following administration of the therapeutic bispecific antibody, the method may further include administering to the subject a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to manage the grade 4 CRS event and permanently discontinuing treatment with the bispecific antibody. In some instances, the first dose of tocilizumab is administered intravenously to the subject at a dose of about 8 mg/kg. Other anti-l L-6R antibodies that could be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061 ), SA-237, and variants thereof. The grade 4 CRS event may, in some instances, resolve within 24 of treating the symptoms of the grade 4 CRS event. If the grade 4 CRS event does not resolve within 24 hours of treating the symptoms of the grade 4 CRS event, the method may further include administering to the subject one or more additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to manage the grade 4 CRS event. In some particular instances, the grade 4 CRS event does not resolve within 24 hours of treating the symptoms of the grade 4 CRS event, and the method further includes administering to the subject one or more (e.g., one, two, three, four, or five or more) additional doses of tocilizumab to manage the grade 4 CRS event. In some instances, the one or more additional doses of tocilizumab is administered intravenously to the subject at a dose of about 1 mg/kg to about 15 mg/kg, e.g., about 4 mg/kg to about 10 mg/kg, e.g., about 6 mg/kg to about 10 mg/kg, e.g., about 8 mg/kg. In some instances, the method further includes administering to the subject an effective amount of a corticosteroid. The corticosteroid may be administered before, after, or concurrently with the one or more additional doses of tocilizumab or other anti-l L-6R antibody. In some instances, the corticosteroid is administered intravenously to the subject. In some instances, the corticosteroid is methylprednisolone. In some instances, the methylprednisolone is administered at a dose of about 1 mg/kg per day to about 5 mg/kg per day, e.g., about 2 mg/kg per day. In some instances, the corticosteroid is dexamethasone. In some instances, the dexamethasone is administered at a dose of about 10 mg (e.g., a single dose of about 10 mg intravenously) or at a dose of about 0.5 mg/kg/day.

/'/. Anti-myeloma agents

In another instance, the additional therapeutic agent is an effective amount of an anti-myeloma agent, e.g., an anti-myeloma agent that augments and/or complements T-cell-mediated killing of myeloma cells. The anti-myeloma agent may be, e.g., pomalidomide, daratumumab, and/or a B-cell maturation antigen (BCMA)-directed therapy (e.g., an antibody-drug conjugate targeting BCMA (BCMA- ADC)). In some aspects, the anti-myeloma agent is administered to the subject as a premedication, e.g., is administered prior to the administration of the bispecific anti-FcRH5/anti-CD3 antibody.

Hi. Corticosteroids

In another instance, the additional therapeutic agent is an effective amount of a corticosteroid. The corticosteroid may be administered intravenously to the subject. In some aspects, the corticosteroid is methylprednisone. The methylprednisone may be administered to the subject at a dose of about 80 mg. In other aspects, the corticosteroid is dexamethasone. The dexamethasone may be administered to the subject at a dose of about 20 mg. In some aspects, the corticosteroid (e.g., methylprednisone or dexamethasone) is administered to the subject prior to the administration of the bispecific anti- FcRH5/anti-CD3 antibody, e.g., administered one hour prior to the administration of the bispecific anti- FcRH5/anti-CD3 antibody. iv. Anti-myeloma agents in combination with corticosteroids

In another instance, a bispecific antibody that binds to FcRH5 and CD3 (e.g., an anti-FcRH5/anti- CD3 antibody, e.g., cevostamab) is administered according to a double step-up or triple step-up dosing regimen described herein in combination with a corticosteroid and an anti-myeloma agent described herein.

As an example, any of the methods provided herein may comprise administering to a subject (i) a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab), (ii) a corticosteroid (e.g., dexamethasone or methylprednisolone), and (iii) an anti-myeloma agent (e.g., pomalidomide), in a dosing regimen comprising a first dosing cycle and at least a second dosing cycle, wherein the length of the first dosing cycle is 21 days and the length of the second dosing cycle is 28 days.

The first dosing cycle (C1 ) comprises (i) a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and, optionally, a fourth dose (C1 D4) of the bispecific antibody being administered on Day 1 , Day 2-4 (i.e. , Day 2, Day 3, or Day 4), Day 8, and Day 9-11 (i.e., Day 9, Day 10, or Day 11 ), respectively, and (ii) the corticosteroid (e.g., dexamethasone or methylprednisolone) being administered about 1 ±0.25 hours prior to any administration of the bispecific antibody (e.g., about 1 ±0.25 hours prior to the C1 D1 , C1 D2, C1 D3, and/or C1 D4). In aspects comprising the administration of a C1 D4 of the bispecific antibody, the C1 D4 may be administered about 1 day after administration of the C1 D3, about 2 days after administration of the C1 D3, or about 3 days after administration of the C1 D3.

The second dosing cycle (C2) comprises (i) a first dose (C2D1 ) and a second dose (C2D2) of the bispecific antibody being administered on Day 1 and Day 15, respectively, (ii) the corticosteroid (e.g., dexamethasone or methylprednisolone) being administered about 1 ±0.25 hours prior to the C2D1 and/or C2D2, and optionally, on Days 8 and 22, and (iii) the anti-myeloma agent (e.g., pomalidomide) being administered on each of Days 1 to 21 .

In some aspects, the C1 D1 is between about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), the C1 D2 is greater than the C1 D1 (e.g., the C1 D2 is about 1 mg to about 3.4 mg, e.g., about 1 .2 mg or about 3.3 mg), the C1 D3 is greater than the C1 D2 (e.g., the C1 D3 is about 3.5 mg to about 19.9 mg, e.g., about 3.6 mg or about 7.2 mg), and the C1 D4, C2D1 , and C2D2 are greater than the C1 D3 (e.g., the C1 D4, C2D1 , and C2D2 are about 20 mg to 600 mg, about 20 mg to about 252 mg, about 100 mg to about 180 mg, or about 132 mg to about 160 mg, e.g., about 160 mg). In some aspects, the C1 D1 is between about 0.01 mg to about 0.9 mg (e.g., between about 0.1 mg to about 0.6 mg, e.g., about 0.3 mg), the C1 D2 is between about 1 mg to about 3.4 mg (e.g., between about 1 .2 mg to about 3.3 mg, e.g., about 1 .2 mg or about 3.3 mg), the C1 D3 is between about 3.5 mg to about 19.9 mg (e.g., between about 3.6 mg to about 7.2 mg, e.g., about 3.6 mg or about 7.2 mg), and the C1 D4 is between about 20 mg to about 600 mg (e.g., an effective amount between about 20 mg to about 252 mg, about 100 mg to about 180 mg, or between about 132 mg to about 160 mg, e.g., about 160 mg). Any dosage described above may be used so long as the C1 D2 is greater than the C1 D1 , the C1 D3 is greater than the C1 D2, the C1 D4 is greater than the C1 D3 and the C2D1 and C2D2 are greater than or equal to the C1 D4.

In some aspects, the corticosteroid is dexamethasone and is between about 10 mg to about 30 mg (e.g., 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg). In some aspects, the corticosteroid is methylprednisolone and is between about 70 mg to about 90 mg (e.g., 70 mg, 75 mg, 80 mg, 85 mg, or 90 mg). In some aspects, the corticosteroid (e.g., dexamethasone or methylprednisolone) is administered orally. In some aspects, the corticosteroid (e.g., dexamethasone or methylprednisolone) is administered intravenously.

In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 2, and Day 8, respectively, of the first 21 -day dosing cycle and, optionally, the C1 D4 is administered on Day 9, Day 10, or Day 1 1 of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 3, and Day 8, respectively, of the first 21 -day dosing cycle and, optionally, the C1 D4 is administered on Day 9, Day 10, or Day 1 1 of the first 21 -day dosing cycle. In some aspects, the C1 D1 , C1 D2, and C1 D3 are administered on Day 1 , Day 4, and Day 8, respectively, of the first 21 -day dosing cycle and, optionally, the C1 D4 is administered on Day 9, Day 10, or Day 1 1 of the first 21 -day dosing cycle.

In some aspects, the dosing regimen further comprises a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), a seventh dosing cycle (C7), an eighth dosing cycle (C8), a ninth dosing cycle (C9), a tenth dosing cycle (C10), an eleventh dosing cycle (C1 1 ), a twelfth dosing cycle (C12), a thirteenth dosing cycle (C13), a fourteenth dosing cycle (C14), a fifteenth dosing cycle (C15), a sixteenth dosing cycle (C16), a seventeenth dosing cycle (C17), or an eighteenth dosing cycle (C18). In some aspects, the length of the C3, C4, C5, C6, C7, C8, C9, C10, C1 1 , C12, C13, C14, C15, C16, C17, or C18 is 28 days. In some aspects, the dosing regimen further comprises a C3, a C4, a C5, a C6, and a C7, wherein the length of each cycle is 28 day, and wherein (i) the bispecific antibody is administered on Day 1 and Day 15 of each cycle, (ii) the corticosteroid (e.g., dexamethasone or methylprednisolone) is administered about 1 ±0.25 hours prior to administration of the bispecific antibody, and optionally, on Days 8 and 22 of each cycle, and (iii) the anti-myeloma agent (e.g., pomalidomide) is administered on each of Days 1 to 21 of each cycle. In a further aspect, the dosing regimen comprises a C8 or beyond (e.g., a C8 to a C18), wherein the length of each cycle is 28 days, and wherein (i) the bispecific antibody is administered on Day 1 of each cycle, (ii) the corticosteroid (e.g., dexamethasone or methylprednisolone) is optionally administered about 1 ±0.25 hours prior to administration of the bispecific antibody, and, further optionally, on Days 8, 15, and 22 of each cycle, and (iii) the anti-myeloma agent (e.g., pomalidomide) is administered on each of Days 1 to 21 of each cycle.

In some aspects, the method further includes administering tocilizumab about one to three hours (e.g., about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, or about 3 hours) prior to administering the bispecific antibody. v. Acetaminophen or paracetamol

In another instance, the additional therapeutic agent is acetaminophen or paracetamol. The acetaminophen or paracetamol may be administered orally to the subject, e.g., administered orally at a dose of between about 500 mg to about 1000 mg. In some aspects, the acetaminophen or paracetamol is administered to the subject as a premedication, e.g., is administered prior to the administration of the bispecific anti-FcRH5/anti-CD3 antibody. vi. Diphenhydramine

In another instance, the additional therapeutic agent is diphenhydramine. The diphenhydramine may be administered orally to the subject, e.g., administered orally at a dose of between about 25 mg to about 50 mg. In some aspects, the diphenhydramine is administered to the subject as a premedication, e.g., is administered prior to the administration of the bispecific anti-FcRH5/anti-CD3 antibody. vii. Other combination therapies

In some aspects, the one or more additional therapeutic agents comprise a PD-L1 axis binding antagonist, an immunomodulatory agent, an anti-neoplastic agent, a chemotherapeutic agent, a growth inhibitory agent, an anti-angiogenic agent, a radiation therapy, a cytotoxic agent, a cell-based therapy, or a combination thereof.

PD-L 1 axis binding antagonists

In some aspects, the additional therapeutic agent is a PD-L1 axis binding antagonist. Exemplary PD-L1 axis binding antagonists include agents that inhibit the interaction of a PD-L1 axis binding partner with one or more of its binding partners, so as to remove T cell dysfunction resulting from signaling on the PD-1 signaling axis, with a result being to restore or enhance T cell function (e.g., proliferation, cytokine production, target cell killing). As used herein, a PD-L1 axis binding antagonist includes a PD-1 binding antagonist, a PD-L1 binding antagonist, and a PD-L2 binding antagonist.

Growth inhibitory agents

In some aspects, the additional therapeutic agent is a growth inhibitory agent. Exemplary growth inhibitory agents include agents that block cell cycle progression at a place other than S phase, e.g., agents that induce G1 arrest (e.g., DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, or ara-C) or M-phase arrest (e.g., vincristine, vinblastine, taxanes (e.g., paclitaxel and docetaxel), doxorubicin, epirubicin, daunorubicin, etoposide, or bleomycin).

Radiation therapies

In some aspects, the additional therapeutic agent is a radiation therapy. Radiation therapies include the use of directed gamma rays or beta rays to induce sufficient damage to a cell so as to limit its ability to function normally or to destroy the cell altogether. Typical treatments are Treatments may be given as a one-time administration (e.g., 8 Gray) or as multiple administrations (e.g., over multiple days or weeks, such as about 1 .5 to 3 Gray (150 to 300 rad) per day.

Cytotoxic agents

In some aspects, the additional therapeutic agent is a cytotoxic agent, e.g., a substance that inhibits or prevents a cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At²¹¹ , I¹³¹ , 1¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹², and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; antibiotics; toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof; and antitumor or anticancer agents.

Anti-cancer therapies

In some instances, the methods include administering to the individual an anti-cancer therapy other than, or in addition to, a bispecific anti-FcRH5/anti-CD3 antibody (e.g., an anti-neoplastic agent, a chemotherapeutic agent, a growth inhibitory agent, an anti-angiogenic agent, a radiation therapy, or a cytotoxic agent).

In some instances, the methods further involve administering to the patient an additional therapeutic agent. In some instances, the additional therapeutic agent is selected from the group consisting of an anti-neoplastic agent, a chemotherapeutic agent, a growth inhibitory agent, an anti- angiogenic agent, a radiation therapy, a cytotoxic agent, and combinations thereof. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a chemotherapy or chemotherapeutic agent. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a radiation therapy agent. In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with a targeted therapy or targeted therapeutic agent. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an immunotherapy or immunotherapeutic agent, for example a monoclonal antibody. In some instances, the additional therapeutic agent is an agonist directed against a co-stimulatory molecule. In some instances, the additional therapeutic agent is an antagonist directed against a co-inhibitory molecule.

Without wishing to be bound to theory, it is thought that enhancing T-cell stimulation, by promoting a co-stimulatory molecule or by inhibiting a co-inhibitory molecule, may promote tumor cell death thereby treating or delaying progression of cancer. In some instances, a bispecific anti-FcRH5/anti- CD3 antibody may be administered in conjunction with an agonist directed against a co-stimulatory molecule. In some instances, a co-stimulatory molecule may include CD40, CD226, CD28, 0X40, GITR, CD137, CD27, HVEM, or CD127. In some instances, the agonist directed against a co-stimulatory molecule is an agonist antibody that binds to CD40, CD226, CD28, 0X40, GITR, CD137, CD27, HVEM, or CD127. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antagonist directed against a co-inhibitory molecule. In some instances, a co- inhibitory molecule may include CTLA-4 (also known as CD152), TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO, TIGIT, MICA/B, or arginase. In some instances, the antagonist directed against a co- inhibitory molecule is an antagonist antibody that binds to CTLA-4, TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO, TIGIT, MICA/B, or arginase.

In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antagonist directed against CTLA-4 (also known as CD152), e.g., a blocking antibody. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with ipilimumab (also known as MDX-010, MDX-101 , or YERVOY®). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with tremelimumab (also known as ticilimumab or CP- 675,206). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antagonist directed against B7-H3 (also known as CD276), e.g., a blocking antibody. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with MGA271 . In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antagonist directed against a TGF-beta, e.g., metelimumab (also known as CAT-192), fresolimumab (also known as GC1008), or LY2157299.

In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a treatment comprising adoptive transfer of a T-cell (e.g., a cytotoxic T-cell or CTL) expressing a chimeric antigen receptor (CAR). In some instances, bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a treatment comprising adoptive transfer of a T-cell comprising a dominant-negative TGF beta receptor, e.g., a dominant-negative TGF beta type II receptor. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a treatment comprising a HERCREEM protocol (see, e.g., ClinicalTrials.gov Identifier NCT00889954).

In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an agonist directed against CD137 (also known as TNFRSF9, 4-1 BB, or ILA), e.g., an activating antibody. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with urelumab (also known as BMS-663513). In some instances, a bispecific anti-FcRH5/anti- CD3 antibody may be administered in conjunction with an agonist directed against CD40, e.g., an activating antibody. In some instances, bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with CP-870893. In some instances, bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an agonist directed against 0X40 (also known as CD134), e.g., an activating antibody. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an anti-OX40 antibody (e.g., AgonOX). In some instances, a bispecific anti-FcRH5/anti- CD3 antibody may be administered in conjunction with an agonist directed against CD27, e.g., an activating antibody. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with CDX-1127. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antagonist directed against indoleamine-2,3-dioxygenase (IDO). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with the IDO antagonist 1 -methyl-D-tryptophan (also known as 1 -D-MT). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antibody-drug conjugate. In some instances, the antibody-drug conjugate comprises mertansine or monomethyl auristatin E (MMAE). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an anti-NaPi2b antibody-MMAE conjugate (also known as DNIB0600A or RG7599). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with trastuzumab emtansine (also known as T-DM1 , ado-trastuzumab emtansine, or KADCYLA®, Genentech). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with DMUC5754A. In some instances, a bispecific anti-FcRH5/anti- CD3 antibody may be administered in conjunction with an antibody-drug conjugate targeting the endothelin B receptor (EDNBR), e.g., an antibody directed against EDNBR conjugated with MMAE.

In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an anti-angiogenesis agent. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antibody directed against a VEGF, e.g., VEGF-A. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with bevacizumab (also known as AVASTIN®, Genentech). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antibody directed against angiopoietin 2 (also known as Ang2). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with MEDI3617.

In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antineoplastic agent. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an agent targeting CSF-1 R (also known as M-CSFR or CD115). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with anti-CSF- 1 R (also known as IMC-CS4). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an interferon, for example interferon alpha or interferon gamma. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with Roferon-A (also known as recombinant Interferon alpha-2a). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with GM-CSF (also known as recombinant human granulocyte macrophage colony stimulating factor, rhu GM-CSF, sargramostim, or LEUKINE®). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with IL-2 (also known as aldesleukin or PROLEUKIN®). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with IL-12. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antibody targeting CD20. In some instances, the antibody targeting CD20 is obinutuzumab (also known as GA101 or GAZYVA®) or rituximab. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an antibody targeting GITR. In some instances, the antibody targeting GITR is TRX518.

In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a cancer vaccine. In some instances, the cancer vaccine is a peptide cancer vaccine, which in some instances is a personalized peptide vaccine. In some instances, the peptide cancer vaccine is a multivalent long peptide, a multi-peptide, a peptide cocktail, a hybrid peptide, or a peptide-pulsed dendritic cell vaccine (see, e.g., Yamada et al., Cancer Sci. 104:14-21 , 2013). In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with an adjuvant. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a treatment comprising a TLR agonist, e.g., Poly-ICLC (also known as HILTONOL®), LPS, MPL, or CpG ODN. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with tumor necrosis factor (TNF) alpha. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with IL-1 . In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with HMGB1 . In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an IL-10 antagonist. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an IL-4 antagonist. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an IL-13 antagonist. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an HVEM antagonist. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an ICOS agonist, e.g., by administration of ICOS-L, or an agonistic antibody directed against ICOS. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a treatment targeting CX3CL1 . In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with a treatment targeting CXCL9. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a treatment targeting CXCL10. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a treatment targeting CCL5. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an LFA-1 or ICAM1 agonist. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a Selectin agonist.

In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a targeted therapy. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an inhibitor of B-Raf. In some instances, a bispecific anti-FcRH5/anti- CD3 antibody may be administered in conjunction with vemurafenib (also known as ZELBORAF®). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with dabrafenib (also known as TAFINLAR®). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with erlotinib (also known as TARCEVA®). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an inhibitor of a MEK, such as MEK1 (also known as MAP2K1 ) or MEK2 (also known as MAP2K2). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with cobimetinib (also known as GDC-0973 or XL-518). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with trametinib (also known as MEKINIST®). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an inhibitor of K-Ras. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an inhibitor of c-Met. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with onartuzumab (also known as MetMAb). In some instances, a bispecific anti-FcRH5/anti- CD3 antibody may be administered in conjunction with an inhibitor of Aik. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with AF802 (also known as CH5424802 or alectinib). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an inhibitor of a phosphatidylinositol 3-kinase (PI3K). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with BKM120. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with idelalisib (also known as GS-1101 or CAL-101 ). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with perifosine (also known as KRX-0401 ). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an inhibitor of an Akt. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with MK2206. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with GSK690693. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with GDC-0941 . In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with an inhibitor of mTOR. In some instances, a bispecific anti-FcRH5/anti- CD3 antibody may be administered in conjunction with sirolimus (also known as rapamycin). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with temsirolimus (also known as CCI-779 or TORISEL®). In some instances, a bispecific anti-FcRH5/anti- CD3 antibody may be administered in conjunction with everolimus (also known as RAD001 ). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with ridaforolimus (also known as AP-23573, MK-8669, or deforolimus). In some instances, a bispecific anti- FcRH5/anti-CD3 antibody may be administered in conjunction with OSI-027. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with AZD8055. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with INK128. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a dual PI3K/mTOR inhibitor. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with XL765. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with GDC-0980. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with BEZ235 (also known as NVP-BEZ235). In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with BGT226. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with GSK2126458. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with PF-04691502. In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with PF-05212384 (also known as PKI-587).

In some instances, a bispecific anti-FcRH5/anti-CD3 antibody may be administered in conjunction with a chemotherapeutic agent. A chemotherapeutic agent is a chemical compound useful in the treatment of cancer. Exemplary chemotherapeutic agents include, but are not limited to erlotinib (TARCEVA®, Genentech/OSI Pharm.), anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idee), pertuzumab (OMNITARG®, 2C4, Genentech), or trastuzumab (HERCEPTIN®, Genentech), EGFR inhibitors (EGFR antagonists), tyrosine kinase inhibitors, and chemotherapeutic agents also include nonsteroidal anti-inflammatory drugs (NSAIDs) with analgesic, antipyretic and anti-inflammatory effects. In instances for which the methods described herein involve a combination therapy, such as a particular combination therapy noted above, the combination therapy encompasses the co-administration of the bispecific anti-FcRH5/anti-CD3 antibody with one or more additional therapeutic agents, and such co-administration may be combined administration (where two or more therapeutic agents are included in the same or separate formulations) or separate administration, in which case, administration of the bispecific anti-FcRH5/anti-CD3 antibody can occur prior to, simultaneously, and/or following, administration of the additional therapeutic agent or agents. In one embodiment, administration of the bispecific anti-FcRH5/anti-CD3 antibody and administration of an additional therapeutic agent or exposure to radiotherapy can occur within about one month, or within about one, two or three weeks, or within about one, two, three, four, five, or six days, of each other.

In some aspects, the subject does not have an increased risk of CRS (e.g., has not experienced Grade 3+ CRS during treatment with a bispecific antibody or CAR-T therapy; does not have detectable circulating plasma cells; and/or does not have extensive extramedullary disease).

E. Cancers

Any of the methods of the disclosure described herein may be useful for treating cancer, such as a B cell proliferative disorder, including multiple myeloma (MM), which may be relapsed or refractory (R/R) MM. In some aspects, the patient has received at least three prior lines of treatment for the B cell proliferative disorder (e.g., MM), e.g., is 4L+, e.g., has received three, four, five, six, or more than six prior lines of treatment. For example, the patient may have been exposed to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), an autologous stem cell transplant (ASCT), an anti-CD38 therapy (e.g., anti-CD38 antibody therapy, e.g., daratumumab therapy), a CAR-T therapy, or a therapy comprising a bispecific antibody. In some instances, the patient has been exposed to all three of PI, IMiD, and anti- CD38 therapies. Other examples of B cell proliferative disorders/malignancies amenable to treatment with a bispecific anti-FcRH5/anti-CD3 antibody in accordance with the methods described herein include, without limitation, non-Hodgkin’s lymphoma (NHL), including diffuse large B cell lymphoma (DLBCL), which may be relapsed or refractory DLBCL, as well as other cancers including germinal-center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL), activated B cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenstrom macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt’s lymphoma (BL), B cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma/leukemia, unclassifiable, splenic diffuse red pulp small B cell lymphoma, hairy cell leukemia variant, Waldenstrom macroglobulinemia, heavy chain diseases, a heavy chain disease, y heavy chain disease, p heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma, pediatric nodal marginal zone lymphoma, pediatric follicular lymphoma, primary cutaneous follicle centre lymphoma, T cell/histiocyte rich large B cell lymphoma, primary DLBCL of the CNS, primary cutaneous DLBCL, leg type, EBV-positive DLBCL of the elderly, DLBCL associated with chronic inflammation, lymphomatoid granulomatosis, primary mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, ALK-positive large B cell lymphoma, plasmablastic lymphoma, large B cell lymphoma arising in HHV8-associated multicentric Castleman disease, primary effusion lymphoma: B cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma, and B cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin’s lymphoma. Further examples of B cell proliferative disorders include, but are not limited to, multiple myeloma (MM); low grade/follicular NHL; small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; AIDS-related lymphoma; and acute lymphoblastic leukemia (ALL); chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD). Further examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies, including B cell lymphomas. More particular examples of such cancers include, but are not limited to, low grade/follicular NHL; small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; AIDS-related lymphoma; and acute lymphoblastic leukemia (ALL); chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD). Solid tumors that may by amenable to treatment with a bispecific anti-FcRH5/anti-CD3 antibody in accordance with the methods described herein include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer and gastrointestinal stromal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer of the urinary tract, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, melanoma, superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanomas, nodular melanomas, as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), Meigs' syndrome, brain, as well as head and neck cancer, and associated metastases. In certain embodiments, cancers that are amenable to treatment by the antibodies of the disclosure include breast cancer, colorectal cancer, rectal cancer, non-small cell lung cancer, glioblastoma, non-Hodgkins lymphoma (NHL), renal cell cancer, prostate cancer, liver cancer, pancreatic cancer, soft-tissue sarcoma, Kaposi's sarcoma, carcinoid carcinoma, head and neck cancer, ovarian cancer, and mesothelioma.

In some aspects, the subject has previously received a standard of care treatment for MM prior to being administered the C1 D1 . The standard of care treatment received may include a PI, an I Mi D, and/or an anti-CD38 monoclonal antibody (mAb). In some aspects, the subject has received a BCMA-targeted therapy prior to administering the C1 D1 . In some aspects, the subject may become refractory to the standard of care treatment for MM. F. Prior anti-cancer therapy

In some aspects, the subject has previously been treated for the B cell proliferative disorder (e.g., MM). In some aspects, the subject has received at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more than fifteen lines of treatment for the B cell proliferative disorder, e.g., is 2L+, 3L+, 4L+, 5L+, 6L+, 7L+, 8L+, 9L+, 10L+, 11 L+, 12L+, 13L+, 14L+, or 15L+. In some aspects, the subject has received at least three prior lines of treatment for the B cell proliferative disorder (e.g., MM), e.g., is 4L+, e.g., has received three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more than fifteen lines of treatment. In some aspects, the subject has relapsed or refractory (R/R) multiple myeloma (MM), e.g., has 4L+ R/R MM.

In some aspects, the prior lines of treatment include one or more of a proteasome inhibitor (PI), e.g., bortezomib, carfilzomib, or ixazomib; an immunomodulatory drug (IMiD), e.g., thalidomide, lenalidomide, or pomalidomide; an autologous stem cell transplant (ASCT); an anti-CD38 agent, e.g., daratumumab (DARZALEX®) (U.S. Patent No: 7,829,673 and U.S. Pub. No: 20160067205 A1 ), “MOR202” (U.S. Patent No: 8,263,746), isatuximab (SAR-650984); a CAR-T therapy; a therapy comprising a bispecific antibody; an anti-SLAMF7 therapeutic agent (e.g., an anti-SLAMF7 antibody, e.g., elotuzumab); a nuclear export inhibitor (e.g., selinexor); and a histone deacetylase (HDAC) inhibitor (e.g., panobi nostat). In some aspects, the prior lines of treatment include an antibody-drug conjugate (ADC). In some aspects, the prior lines of treatment include a B-cell maturation antigen (BCMA)-directed therapy, e.g., an antibody-drug conjugate targeting BCMA (BCMA-ADC).

In some aspects, the prior lines of treatment include all three of a proteasome inhibitor (PI), an IMiD, and an anti-CD38 agent (e.g., daratumumab).

In some aspects, the B cell proliferative disorder (e.g., MM) is refractory to the lines of treatment, e.g., is refractory to one or more of daratumumab, a PI, an IMiD, an ASCT, an anti-CD38 agent, a CAR-T therapy, a therapy comprising a bispecific antibody, an anti-SLAMF7 therapeutic agent, a nuclear export inhibitor, a HDAC inhibitor, an ADC, or a BCMA-directed therapy. In some aspects, the B cell proliferative disorder (e.g., MM) is refractory to daratumumab.

G. Risk-benefit profile

The methods described herein may result in an improved benefit-risk profile for patients having cancer (e.g., MM, e.g., R/R MM), e.g., a 2L+ R/R MM, being treated with a bispecific anti-FcRH5/anti-CD3 antibody. In some instances, treatment using the methods described herein that result in administering the bispecific anti-FcRH5/anti-CD3 antibody in the context of adose-escalation dosing regimen may result in a reduction (e.g., by 20% or greater, 25% or greater, 30% or greater, 35% or greater, 40% or greater, 45% or greater, 50% or greater, 55% or greater, 60% or greater, 65% or greater, 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater) or complete inhibition (100% reduction) of undesirable events, such as cytokine-driven toxicities (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRRs), macrophage activation syndrome (MAS), neurologic toxicities, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes, and/or central nervous system (CNS) toxicities, following treatment with a bispecific anti-FcRH5/anti-CD3 antibody using the dose-escalation dosing regimen of the disclosure relative to treatment with a bispecific anti-FcRH5/anti-CD3 antibody using a non-dose-escalation dosing regimen.

H. Safety and efficacy /'. Safety

Described above are: (i) methods for treating a subject having a cancer (e.g., MM, e.g., R/R MM), (ii) methods of reducing the likelihood of cytokine release syndrome (CRS) in a subject having a cancer (e.g., MM, e.g., R/R MM), (iii) methods of achieving a median peak IL-6 level of less than about 80 pg/mL (e.g., less than 30 pg/mL) in a population of subjects having a cancer (e.g., MM, e.g., R/R MM), (iv) methods of achieving a peak IL-6 level of less than about 80 pg/mL (e.g., less than 30 pg/mL, e.g., 18 pg/mL) in a subject having a cancer (e.g., MM, e.g., R/R MM), and (v) methods of reducing the occurrence of CRS events in a subject being treated for a cancer (e.g., MM, e.g., R/R MM) with a target dose of a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). The dosing regimens associated with these described methods are advantageous in that they may achieve favorable safety profiles relative to prior methods of dosing therapeutic bispecific antibodies (e.g., anti-FcRH5/anti-CD3 bispecific antibodies) for the treatment of cancers (e.g., MM, e.g., R/R MM).

Any of these methods may further include a step of measuring CRS in a subject to determine the safety of the administered bispecific antibody (e.g., cevostamab). Thus, in some aspects, the methods described herein further include measuring CRS after the administration of any dose of the bispecific antibody that binds FcRH5 and CD3 (e.g., cevostamab), e.g., after administration of the C1 D1 , the C1 D2, the C1 D3, and/or a target dose (e.g., a C1 D4 or C2D1 ). In some aspects, CRS is measured after the C1 D1 . In some aspects, CRS is measured after the C1 D2. In some aspects, CRS is measured after the C1 D3. In some aspects, CRS is measured after the C1 D1 and the C1 D2. In some aspects, CRS is measured after the C1 D2 and the C1 D3. In some aspects CRS is measured after the C1 D1 and the C1 D3. In some aspects CRS is measured after the C1 D1 , the C1 D2, and C1 D3. In some aspects, CRS is measured after the C1 D1 , the C1 D2, and the C1 D3. In some aspects the CRS is measured after a target dose (e.g., after administration of a dose that is between 20 mg and about 252 mg, such as a C1 D4 or C2D1 described herein). In some aspects, CRS is measured after the C1 D4. In some aspects, CRS is measured after the C2D1 . In some aspects, CRS is measured after the C1 D4 and the C2D1 .

If CRS (e.g., a sign or symptom of CRS) is present, then administration of the next dose may be delayed until the CRS has resolved. For example, if CRS is observed after administration of a C1 D1 , then administration of the C1 D2 may not proceed until the CRS has resolved. Typically, CRS resolves within 1 -3 days (e.g., see Example 1 ); thus, if CRS is observed after the C1 D1 , which is administered on Day 1 of a 21 -day dosing cycle, then the C1 D2 may be administered on Day 2, Day 3, or Day 4 (“Days 2-4”), upon expected CRS resolution. Similarly, if CRS is observed after administration of a C1 D3, which is administered on Day 8 of a 21 -day dosing cycle, then the target dose may be administered on Day 9, Day 10, or Day 11 (“Days 9-11 ”), upon expected CRS resolution.

In some aspects, the methods described herein reduce the likelihood of the subject experiencing Grade >1 CRS. In some aspects, the methods described herein reduce the likelihood of the subject experiencing Grade >2 CRS. In some aspects, the methods described herein reduce the likelihood of the subject experiencing Grade >3 CRS. In some aspects, the likelihood of the subject experiencing Grade 1 CRS after the C1 D1 is less than 10%. In some aspects, the likelihood of the subject experiencing Grade 1

CRS after the C1 D2 is less than 25%. In some aspects, the likelihood of the subject experiencing Grade 1

CRS after the C1 D3 is less than 15%. In some aspects, the likelihood of the subject experiencing Grade 2

CRS after the C1 D1 is less than 10%. In some aspects, the likelihood of the subject experiencing Grade 2

CRS after the C1 D2 is less than 25%. In some aspects, the likelihood of the subject experiencing Grade 2

CRS after the C1 D3 is less than 15%. In some aspects, the likelihood of the subject experiencing at least one Grade 1 or Grade 2 CRS event after the first administration of the C1 D4 is less than 65%.

In some aspects, less than 10% (e.g., less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%, e.g. 0%) of patients (e.g., a population of subjects having MM) treated using the methods described herein experience a Grade 3 or Grade 4 CRS event. In some aspects, about 0% to about 5% (e.g., about 0%, about 1%, about 2%, about 3%, about 4%, or about 5%) of patients (e.g., a population of subjects having MM) treated using the methods described herein experience a Grade 3 or Grade 4 CRS event. In some aspects, 0% of patients (e.g., a population of subjects having MM) treated using the methods described herein experience a Grade 3 or Grade 4 CRS even (e.g., the dosing regimen does not result in any grade >3 CRS event in the population of subjects having MM).

In some aspects, less than 19% (e.g., less than 19%, less than 18%, less than 17%, less than 16%, less than 15%, less than 14%, less than 13%, less than 12%, less than 11 %, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%, e.g. 0%) of patients (e.g., a population of subjects having MM) treated using the methods described herein experience a Grade 2 CRS event. In some aspects, about 15% to about 19% (e.g., about 17%) of patients (e.g., a population of subjects having MM) treated using the methods described herein experience a Grade 2 CRS event.

In some aspects, less than 68% (e.g., less than 68%, less than 67%, less than 66%, less than 65%, less than 64%, less than 63%, less than 62%, less than 61%, less than 60%, less than 59%, or less than 58%) of patients (e.g., a population of subjects having MM) treated using the methods described herein experience a CRS event. In some aspects, about 58% to about 68% (e.g., about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, or about 68%) of patients (e.g., a population of subjects having MM) treated using the methods described herein experience a CRS event. In some aspects, about 63% of patients (e.g., a population of subjects having MM) treated using the methods described herein experience a CRS event.

In some aspects, symptoms of immune effector cell-associated neurotoxicity syndrome (ICANS) are limited to confusion, disorientation, and expressive aphasia and resolve with steroids.

In some aspects, less than 10% (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) of patients treated using the methods described herein experience seizures or other Grade 3+ neurologic adverse events. In some aspects, less than 5% of patients experience seizures or other Grade 3+ neurologic adverse events. In some aspects, no patients experience seizures or other Grade 3+ neurologic adverse events.

In some aspects, all neurological symptoms are either self-limited or resolved with steroids and/or tocilizumab therapy.

/'/. Efficacy

In embodiments that require a target dose, the dosing regimens described herein are advantageous in that they may achieve favorable efficacy profiles relative to prior methods of dosing therapeutic bispecific antibodies (e.g., anti-FcRH5/anti-CD3 bispecific antibodies) for the treatment of cancers (e.g., MM, e.g., R/R MM).

In some aspects, the objective response rate (ORR) for patients treated using the methods described herein is at least 20%, e.g., is at least 20%, at least 21 %, at least 22%, at least 23%, at least 23.3%, at least 24%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100%. In some aspects, the ORR is about 23.3%. In some aspects, the ORR is at least 40% (e.g., at least 41 %, at least 41 .5%, at least 42%, at least 42.5%, at least 43%, at least 43.3%, at least 43.5%, at least 44%, at least 44.5%, at least 45%, at least 45.5%, at least 46%, at least 46.5% at least 47%, at least 47.5%, at least 48%, at least 48.5%, at least 49%, at least 49.5%, or at least 50%) at least 55%, or at least 65%. In some aspects, the ORR is about 43.1 %. In some aspects, the ORR is about 43.3%. In some aspects, the ORR is 75% or greater. In some aspects, at least 1 % of patients (e.g., at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1 1 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21 %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31 %, 32%, 33%, 34%, 35%,

36%, 37%, 38%, 39%, 40%, 41 %, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51 %, 52%, 53%,

54%, 55%, 56%, 57%, 58%, 59%, 60%, 61 %, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71 %,

72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,

90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of patients) have a complete response (CR) or a very good partial response (VGPR). In some aspects, the ORR is 20% to 45%, and 5% to 25% of patients have a CR or a VGPR. In some aspects, the ORR is at least 20%, and at least 6% of patients have a CR or a VGPR. In some aspects, the ORR is at least 40%, and at least 20% of patients have a CR or a VGPR.

In some aspects, the average duration of response (DoR) for patients treated using the methods described herein is at least two months, e.g., at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least one year, or more than one year. In some aspects, the average DoR is at least four months. In some aspects, the average DoR is at least ten months. In some aspects, the average DoR is at least eleven months. In some aspects, the average DoR is at least 12 months.

In some aspects, the six-month progression-free survival (PFS) rate for patients treated using the methods described herein is at least 10%, e.g., is at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In some aspects, the six month PFS rate is at least 25%. In some aspects, the six month PFS rate is at least 40%. In some aspects, the six month PFS rate is at least 55%.

I. Methods of administration

The methods may involve administering the bispecific anti-FcRH5/anti-CD3 antibody (and/or any additional therapeutic agent) by any suitable means, including parenteral, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intravenous, subcutaneous, intramuscular, intraarterial, and intraperitoneal administration routes. In some embodiments, the bispecific anti-FcRH5/anti-CD3 antibody is administered by intravenous infusion. In other instances, the bispecific anti-FcRH5/anti-CD3 antibody is administered subcutaneously.

In some aspects, the bispecific anti-FcRH5/anti-CD3 antibody is administered intravenously over 4 hours (± 15 minutes), e.g., the first dose of the antibody is administered over 4 hours ± 15 minutes.

In some aspects, the first dose second dose, and third dose of the antibody are administered intravenously with a median infusion time of less than four hours (e.g., less than three hours, less than two hours, or less than one hour) and further doses of the antibody are administered intravenously with a median infusion time of less than 120 minutes (e.g., less than 90 minutes, less than 60 minutes, or less than 30 minutes).

In some aspects, the first dose, the second dose, and the third dose of the antibody are administered intravenously with a median infusion time of less than three hours and further doses of the antibody are administered intravenously with a median infusion time of less than 90 minutes.

In some aspects, the first dose, the second dose, and the third dose of the antibody are administered intravenously with a median infusion time of less than three hours and further doses of the antibody are administered intravenously with a median infusion time of less than 60 minutes. In some aspects, the patient is hospitalized (e.g., hospitalized for 72 hours, 48 hours, 24 hours, or less than 24 hours) during one or more administrations of the anti-FcRH5/anti-CD3 antibody, e.g., hospitalized for the C1 D1 (cycle 1 , dose 1 ), the C1 D1 and the C1 D2 (cycle 1 , dose 2), the C1 D1 , the C1 D2, and the C1 D3 (cycle 1 , dose 3), or the C1 D1 , the C1 D2, the C1 D3, and the C1 D4 (cycle 1 , dose 4). In some aspects, the patient is hospitalized for 72 hours following administration of the C1 D1 . In some aspects, the patient is hospitalized for 72 hours following administration of the C1 D1 and the C1 D2. In some aspects, the patient is hospitalized for 72 hours following administration of the C1 D1 , the C1 D2, and the C1 D3. In some aspects, the patient is hospitalized for 24 hours following administration of the C1 D1 . In some aspects, the patient is hospitalized for 24 hours following administration of the C1 D1 and the C1 D2. In some aspects, the patient is hospitalized for 24 hours following administration of the C1 D1 , the C1 D2, and/or the C1 D3. In some aspects, the patient is not hospitalized following the administration of any dose of the anti-FcRH5/anti-CD3 antibody.

For all the methods described herein, the bispecific anti-FcRH5/anti-CD3 antibody would be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The bispecific anti-FcRH5/anti-CD3 antibody need not be, but is optionally formulated with, one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of the bispecific anti-FcRH5/anti-CD3 antibody present in the formulation, the type of disorder or treatment, and other factors discussed above. The bispecific anti- FcRH5/anti-CD3 antibody may be suitably administered to the patient over a series of treatments.

J. Anti-FcRH5/Anti-CD3 bispecific antibodies

The methods described herein include administering to a subject having a cancer (e.g., multiple myeloma, e.g., an R/R multiple myeloma) a bispecific antibody that binds to FcRH5 and CD3 (i.e., a bispecific anti-FcRH5/anti-CD3 antibody).

In some instances, any of the methods described herein may include administering a bispecific antibody that includes an anti-FcRH5 arm having a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) an HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO:3); (d) an HVR-L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody comprises at least one (e.g., 1 , 2, 3, or 4) of the heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 17-20, respectively, and/or at least one (e.g., 1 , 2, 3, or 4) of the light chain framework regions FR-L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 21 -24, respectively.

In some instances, any of the methods described herein may include administering a bispecific antibody that includes an anti-FcRH5 arm having a first binding domain comprising the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO:3); (d) an HVR-L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6). In some instances, the bispecific anti-FcRH5/anti-CD3 antibody comprises at least one (e.g., 1 , 2, 3, or 4) of the heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 17-20, respectively, and/or at least one (e.g., 1 , 2, 3, or 4) of the light chain framework regions FR-L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 21 -24, respectively.

In some instances, the bispecific antibody comprises an anti-FcRH5 arm comprising a first binding domain comprising (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 8; or (c) a VH domain as in (a) and a VL domain as in (b). Accordingly, in some instances, the first binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO: 7 and a VL domain comprising an amino acid sequence of SEQ ID NO: 8.

In some instances, any of the methods described herein may include administering a bispecific anti-FcRH5/anti-CD3 antibody that includes an anti-CD3 arm having a second binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) an HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) an HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11 ); (d) an HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) an HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) an HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14). In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises at least one (e.g., 1 , 2, 3, or 4) of heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 25-28, respectively, and/or at least one (e.g., 1 , 2, 3, or 4) of the light chain framework regions FR-L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 29-32, respectively.

In some instances, any of the methods described herein may include administering a bispecific anti-FcRH5/anti-CD3 antibody that includes an anti-CD3 arm having a second binding domain comprising the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) an HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) an HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11 ); (d) an HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) an HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) an HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14). In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises at least one (e.g., 1 , 2, 3, or 4) of heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 25-28, respectively, and/or at least one (e.g., 1 , 2, 3, or 4) of the light chain framework regions FR-L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 29-32, respectively.

In some instances, the bispecific antibody comprises an anti-CD3 arm comprising a second binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b). Accordingly, in some instances, the second binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and a VL domain comprising an amino acid sequence of SEQ ID NO: 16.

In some instances, any of the methods described herein may include administering a bispecific antibody that includes (1 ) an anti-FcRH5 arm having a first binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO:3); (d) an HVR-L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6) and (2) an anti-CD3 arm having a second binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) an HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) an HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11 ); (d) an HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) an HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) an HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

In some instances, any of the methods described herein may include administering a bispecific antibody that includes (1 ) an anti-FcRH5 arm having a first binding domain comprising the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO:3); (d) an HVR-L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6) and (2) an anti-CD3 arm having a second binding domain comprising the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) an HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) an HVR- H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11 ); (d) an HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) an HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) an HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises (1 ) at least one (e.g., 1 , 2, 3, or 4) of heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 17-20, respectively, and/or at least one (e.g., 1 , 2, 3, or 4) of the light chain framework regions FR-L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 21 -24, respectively, and (2) at least one (e.g., 1 , 2, 3, or 4) of heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 25-28, respectively, and/or at least one (e.g., 1 , 2, 3, or 4) of the light chain framework regions FR-L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 29-32, respectively. In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises (1 ) all four of heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 17-20, respectively, and/or all four of the light chain framework regions FR-L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 21 -24, respectively, and (2) all four of heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 25-28, respectively, and/or all four (e.g., 1 , 2, 3, or 4) of the light chain framework regions FR-L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 29-32, respectively.

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises (1 ) an anti-FcRH5 arm comprising a first binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 7; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 8; or (c) a VH domain as in (a) and a VL domain as in (b), and (2) an anti-CD3 arm comprising a second binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b). In some instances, the anti- FcRH5/anti-CD3 bispecific antibody comprises (1 ) a first binding domain comprising a VH domain comprising an amino acid sequence of SEQ ID NO: 7 and a VL domain comprising an amino acid sequence of SEQ ID NO: 8 and (2) a second binding domain comprising a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and a VL domain comprising an amino acid sequence of SEQ ID NO: 16.

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1 ) and a light chain polypeptide (L1 ), wherein (a) H1 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 35 and/or (b) L1 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 36.

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1 ) and a light chain polypeptide (L1 ), wherein (a) H1 comprises the amino acid sequence of SEQ ID NO: 35 and/or (b) L1 comprises the amino acid sequence of SEQ ID NO: 36.

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), wherein (a) H2 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 37 and/or (b) L2 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 38.

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), wherein (a) H2 comprises the amino acid sequence of SEQ ID NO: 37; and (b) L2 comprises the amino acid sequence of SEQ ID NO: 38. In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1 ) and a light chain polypeptide (L1 ) and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), and wherein (a) H1 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 35; (b) L1 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 36; (c) H2 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 37; and (d) L2 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 38.

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1 ) and a light chain polypeptide (L1 ) and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), and wherein (a) H1 comprises the amino acid sequence of SEQ ID NO: 35; (b) L1 comprises the amino acid sequence of SEQ ID NO: 36; (c) H2 comprises the amino acid sequence of SEQ ID NO: 37; and (d) L2 comprises the amino acid sequence of SEQ ID NO: 38.

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody is cevostamab.

In some instances, the anti-FcRH5/anti-CD3 bispecific antibody according to any of the above embodiments described above may incorporate any of the features, singly or in combination, as described in Sections 1 -7 below.

1. Antibody affinity

In certain embodiments, an antibody provided herein has a dissociation constant (KD) of < 1 pM, < 250 nM, < 100 nM, < 15 nM, < 10 nM, < 6 nM, < 4 nM, < 2 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g. 10^-8 M or less, e.g. from 10^-8 M to 10^-13 M, e.g., from 10^-9 M to 10^-13 M).

In one embodiment, KD is measured by a radiolabeled antigen binding assay (RIA). In one embodiment, an RIA is performed with the Fab version of an antibody of interest and its antigen. For example, solution binding affinity of Fabs for antigen is measured by equilibrating Fab with a minimal concentration of (¹²⁵l)-labeled antigen in the presence of a titration series of unlabeled antigen, then capturing bound antigen with an anti-Fab antibody-coated plate (see, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999)). To establish conditions for the assay, MICROTITER® multi-well plates (Thermo Scientific) are coated overnight with 5 pg/ml of a capturing anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and subsequently blocked with 2% (w/v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23°C). In a non-adsorbent plate (Nunc #269620), 100 pM or 26 pM [¹²⁵l]-antigen are mixed with serial dilutions of a Fab of interest (e.g., consistent with assessment of the anti-VEGF antibody, Fab-12, in Presta et al., Cancer Res. 57:4593-4599 (1997)). The Fab of interest is then incubated overnight; however, the incubation may continue for a longer period (e.g., about 65 hours) to ensure that equilibrium is reached. Thereafter, the mixtures are transferred to the capture plate for incubation at room temperature (e.g., for one hour). The solution is then removed and the plate washed eight times with 0.1% polysorbate 20 (TWEEN-20®) in PBS. When the plates have dried, 150 pl/well of scintillant (MICROSCINT-20 ™; Packard) is added, and the plates are counted on a TOPCOUNT™ gamma counter (Packard) for ten minutes. Concentrations of each Fab that give less than or equal to 20% of maximal binding are chosen for use in competitive binding assays.

According to another embodiment, KD is measured using a BIACORE® surface plasmon resonance assay. For example, an assay using a BIACORE®-2000 or a BIACORE®-3000 (BIAcore, Inc., Piscataway, NJ) is performed at 37°C with immobilized antigen CM5 chips at -10 response units (RU). In one embodiment, carboxymethylated dextran biosensor chips (CM5, BIACORE, Inc.) are activated with A/-ethyl- N (3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and A/-hydroxysuccinimide (NHS) according to the supplier’s instructions. Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 pg/ml (~0.2 pM) before injection at a flow rate of 5 pl/minute to achieve approximately 10 response units (RU) of coupled protein. Following the injection of antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetics measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with 0.05% polysorbate 20 (TWEEN-20™) surfactant (PBST) at 37°C at a flow rate of approximately 25 pl/min. Association rates (k_On, or k_a) and dissociation rates (k_otf, or kd) are calculated using a simple one-to-one Langmuir binding model (BIACORE® Evaluation Software version 3.2) by simultaneously fitting the association and dissociation sensorgrams. The equilibrium dissociation constant (KD) is calculated as the ratio k₀tf/k₀n. See, for example, Chen et al., J. Mol. Biol. 293:865-881 (1999). If the on- rate exceeds 10⁶M‘¹s"¹ by the surface plasmon resonance assay above, then the on-rate can be determined by using a fluorescent quenching technique that measures the increase or decrease in fluorescence emission intensity (excitation = 295 nm; emission = 340 nm, 16 nm band-pass) at 37°C of a 20 nM anti-antigen antibody (Fab form) in PBS, pH 7.2, in the presence of increasing concentrations of antigen as measured in a spectrometer, such as a stop-flow equipped spectrophotometer (Aviv Instruments) or a 8000-series SLM-AMINCO™ spectrophotometer (ThermoSpectronic) with a stirred cuvette.

2. Antibody fragments

In certain embodiments, an antibody provided herein (e.g., an anti-FcRH5/anti-CD3 TDB) is an antibody fragment that binds FcRH5 and CD3. Antibody fragments include, but are not limited to, Fab, Fab’, Fab’-SH, F(ab’)2, Fv, and scFv fragments, and other fragments described below. For a review of certain antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, e.g., Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); see also WO 93/16185; and U.S. Patent Nos. 5,571 ,894 and 5,587,458. For discussion of Fab and F(ab’)2 fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see U.S. Patent No. 5,869,046.

Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993/01161 ; Hudson et al. Nat. Med. 9:129-134 (2003); and Hollinger et al. Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al. Nat. Med. 9:129-134 (2003). Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see, e.g., U.S. Patent No. 6,248,516 B1 ).

Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g. E. coli or phage), as described herein.

3. Chimeric and humanized antibodies

In certain embodiments, an antibody provided herein (e.g., an anti-FcRH5/anti-CD3 TDB) is a chimeric antibody. Certain chimeric antibodies are described, e.g., in U.S. Patent No. 4,816,567; and Morrison et al. Proc. Natl. Acad. Sci. USA, 81 :6851 -6855 (1984)). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region. In a further example, a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

In certain embodiments, a chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which HVRs (or portions thereof), for example, are derived from a non-human antibody, and FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody optionally will also comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.

Humanized antibodies and methods of making them are reviewed, e.g., in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and are further described, e.g., in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat’l Acad. Sci. USA 86:10029-10033 (1989); US Patent Nos. 5, 821 ,337, 7,527,791 , 6,982,321 , and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity determining region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991 ) (describing “resurfacing”); Dall’Acqua et al., Methods 36:43-60 (2005) (describing “FR shuffling”); and Osbourn et al., Methods 36:61 -68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing the “guided selection” approach to FR shuffling).

Human framework regions that may be used for humanization include but are not limited to: framework regions selected using the “best-fit” method (see, e.g., Sims et al. J. Immunol. 151 :2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151 :2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271 :22611 -22618 (1996)).

4. Human antibodies

In certain embodiments, an antibody provided herein (e.g., an anti-FcRH5/anti-CD3 TDB) is a human antibody. Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001 ) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal’s chromosomes. In such transgenic mice, the endogenous immunoglobulin loci have generally been inactivated. For review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584 describing XENOMOUSE™ technology; U.S. Patent No. 5,770,429 describing HUMAB® technology; U.S. Patent No. 7,041 ,870 describing K-M MOUSE® technology, and U.S. Patent Application Publication No. US 2007/0061900, describing VELOCIMOUSE® technology). Human variable regions from intact antibodies generated by such animals may be further modified, e.g., by combining with a different human constant region.

Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described. (See, e.g., Kozbor J. Immunol., 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51 -63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147: 86 (1991 ).) Human antibodies generated via human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Additional methods include those described, for example, in U.S. Patent No. 7,189,826 (describing production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (Trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).

Human antibodies may also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences may then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.

5. Bispecific antibodies

In any one of the above aspects, any anti-FcRH5/anti-CD3 bispecific antibody known in the art (e.g., cevostamab) may be administered to a subject or population of subjects having cancer (e.g., MM, e.g., R/R MM). Anti-FcRH5/anti-CD3 bispecific antibodies (e.g., cevostamab) have a binding specificity for two cell surface antigens (e.g., FcRH5 and CD3).

In some aspects, the cell surface antigen (e.g., FcRH5 and/or CD3) may be expressed in low copy number on the target cell. For example, in some aspects, the cell surface antigen (e.g., FcRH5 and/or CD3) is expressed or present at less than 35,000 copies per target cell. In some embodiments, the low copy number cell surface antigen (e.g., FcRH5 and/or CD3) is present between 100 and 35,000 copies per target cell; between 100 and 30,000 copies per target cell; between 100 and 25,000 copies per target cell; between 100 and 20,000 copies per target cell; between 100 and 15,000 copies per target cell; between 100 and 10,000 copies per target cell; between 100 and 5,000 copies per target cell; between 100 and 2,000 copies per target cell; between 100 and 1 ,000 copies per target cell; or between 100 and 500 copies per target cell. Copy number of the cell surface antigen (e.g., FcRH5 and/or CD3) can be determined, for example, using a standard Scatchard plot.

In some embodiments, anti-FcRH5/anti-CD3 bispecific antibodies (e.g., cevostamab) may be used to localize a cytotoxic agent to a cell that expresses FcRH5. Anti-FcRH5/anti-CD3 bispecific antibodies (e.g., cevostamab) may be prepared as full-length antibodies or antibody fragments.

Techniques for making anti-FcRH5/anti-CD3 bispecific antibodies (e.g., cevostamab) include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs having different specificities (see Milstein and Cuello, Nature 305: 537 (1983)), WO 93/08829, and Traunecker et al., EMBO J. 10: 3655 (1991 )), and “knob-in-hole” engineering (see, e.g., U.S. Patent No. 5,731 ,168). “Knob-in-hole” engineering of multispecific antibodies may be utilized to generate a first arm containing a knob and a second arm containing the hole into which the knob of the first arm may bind. The knob of the bispecific antibodies of the disclosure may be an anti-CD3 arm. Alternatively, the knob of the bispecific antibodies of the disclosure may be an anti-FcRH5 arm.

Anti-FcRH5/anti-CD3 bispecific antibodies (e.g., cevostamab) may also be engineered using immunoglobulin crossover (also known as Fab domain exchange or CrossMab format) technology (see, e.g., W02009/080253; Schaefer et al., Proc. Natl. Acad. Sci. USA, 108:11187-11192 (2011 )). Anti- FcRH5/anti-CD3 bispecific antibodies (e.g., cevostamab) may also be made by engineering electrostatic steering effects for making antibody Fc-heterodimeric molecules (WO 2009/089004A1 ); cross-linking two or more antibodies or fragments (see, e.g., US Patent No. 4,676,980, and Brennan et al., Science, 229: 81 (1985)); using leucine zippers to produce bi-specific antibodies (see, e.g., Kostelny et al., J. Immunol., 148(5):1547-1553 (1992)); using “diabody” technology for making bispecific antibody fragments (see, e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)); and using single-chain Fv (sFv) dimers (see, e.g. Gruber et al., J. Immunol., 152:5368 (1994)); and preparing trispecific antibodies as described, e.g., in Tutt et al. J. Immunol. 147: 60 (1991 ).

Engineered antibodies with three or more functional antigen binding sites, including “Octopus antibodies,” are also included herein (see, e.g. US 2006/0025576A1 ).

The bispecific antibodies, or antibody fragments thereof, may also include a “Dual Acting FAb” or “DAF” comprising an antigen binding site that binds to CD3 as well as another, different antigen (e.g., a second biological molecule) (see, e.g., US 2008/0069820). 6. Antibody variants

In some aspects, amino acid sequence variants of the bispecific anti-FcRH5/anti-CD3 antibodies of the disclosure arecontemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody. Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, for example, antigen-binding. a. Substitution, insertion, and deletion variants

In certain embodiments, antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include the CDRs and FRs. Conservative substitutions are shown in Table 5 under the heading of “preferred substitutions.” More substantial changes are provided in Table 5 under the heading of “exemplary substitutions,” and as further described below in reference to amino acid side chain classes. Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, for example, retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.

Table 5. Exemplary and Preferred Amino Acid Substitutions

Amino acids may be grouped according to common side-chain properties:

(1 ) hydrophobic: Norleucine, Met, Ala, Vai, Leu, lie;

(2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin;

(3) acidic: Asp, Glu;

(4) basic: His, Lys, Arg;

(5) residues that influence chain orientation: Gly, Pro;

(6) aromatic: Trp, Tyr, Phe.

Non-conservative substitutions will entail exchanging a member of one of these classes for another class.

One type of substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variant(s) selected for further study will have modifications (e.g., improvements) in certain biological properties (e.g., increased affinity, reduced immunogenicity) relative to the parent antibody and/or will have substantially retained certain biological properties of the parent antibody. An exemplary substitutional variant is an affinity matured antibody, which may be conveniently generated, e.g., using phage display-based affinity maturation techniques such as those described herein. Briefly, one or more CDR residues are mutated and the variant antibodies displayed on phage and screened for a particular biological activity (e.g. binding affinity).

Alterations (e.g., substitutions) may be made in CDRs, e.g., to improve antibody affinity. Such alterations may be made in CDR “hotspots,” i.e., residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/or residues that contact an antigen, with the resulting variant VH or VL being tested for binding affinity. Affinity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178:1 -37 (O’Brien et al., ed., Human Press, Totowa, NJ, (2001 )). In some embodiments of affinity maturation, diversity is introduced into the variable genes chosen for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity. Another method to introduce diversity involves CDR-directed approaches, in which several CDR residues (e.g., 4-6 residues at a time) are randomized. CDR residues involved in antigen binding may be specifically identified, e.g., using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted. In certain embodiments, substitutions, insertions, or deletions may occur within one or more CDRs so long as such alterations do not substantially reduce the ability of the antibody to bind antigen. For example, conservative alterations (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in CDRs. Such alterations may, for example, be outside of antigen contacting residues in the CDRs. In certain embodiments of the variant VH and VL sequences provided above, each CDR either is unaltered, or contains no more than one, two or three amino acid substitutions.

A useful method for identification of residues or regions of an antibody that may be targeted for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells (1989) Science, 244:1081 -1085. In this method, a residue or group of target residues (e.g., charged residues such as arg, asp, his, lys, and glu) are identified and replaced by a neutral or negatively charged amino acid (e.g., alanine or polyalanine) to determine whether the interaction of the antibody with antigen is affected. Further substitutions may be introduced at the amino acid locations demonstrating functional sensitivity to the initial substitutions. Alternatively, or additionally, a crystal structure of an antigenantibody complex to identify contact points between the antibody and antigen. Such contact residues and neighboring residues may be targeted or eliminated as candidates for substitution. Variants may be screened to determine whether they contain the desired properties.

Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody with an N-terminal methionyl residue. Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g. for ADEPT) or a polypeptide which increases the serum half-life of the antibody. b. Glycosylation variants

In certain embodiments, bispecific anti-FcRH5/anti-CD3 antibodies of the disclosure canbe altered to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to anti-FcRH5 antibody of the disclosure maybe conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.

Where the antibody comprises an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GIcNAc), galactose, and sialic acid, as well as a fucose attached to a GIcNAc in the “stem” of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharide in an antibody of the disclosure may be made in order to create antibody variants with certain improved properties.

In one embodiment, bispecific anti-FcRH5/anti-CD3 antibody variants are provided having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region. For example, the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e. g. complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546, for example. Asn297 refers to the asparagine residue located at about position 297 in the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located about ± 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to “defucosylated” or “fucose-deficient” antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621 ; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; W02005/053742;

W02002/031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Led 3 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Pat Appl No US 2003/0157108 A1 , Presta, L; and WO 2004/056312 A1 , Adams et al., especially at Example 11 ), and knockout cell lines, such as alpha-1 ,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and W02003/085107).

Bispecific anti-FcRH5/anti-CD3 antibody variants are further provided with bisected oligosaccharides, for example, in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GIcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, e.g., in WO 2003/011878 (Jean- Mairet et al.); US Patent No. 6,602,684 (Umana et al.); and US 2005/0123546 (Umana et al.). Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, e.g., in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.). c. Fc region variants

In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of a bispecific anti-FcRH5/anti-CD3 antibody, thereby generating an Fc region variant (see e.g., US 2012/0251531 ). The Fc region variant may comprise a human Fc region sequence {e.g., a human IgG 1 , lgG2, lgG3 or lgG4 Fc region) comprising an amino acid modification {e.g., a substitution) at one or more amino acid positions.

In certain embodiments, the disclosure contemplates a bispecific anti-FcRH5/anti-CD3 antibody variant that possesses some but not all effector functions, which make it a desirable candidate for applications in which the half-life of the antibody in vivo is important, yet certain effector functions (such as complement and ADCC) are unnecessary or deleterious. In vitro and/or in vivo cytotoxicity assays can be conducted to confirm the reduction/depletion of CDC and/or ADCC activities. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks FcyR binding (hence likely lacking ADCC activity), but retains FcRn binding ability. The primary cells for mediating ADCC, NK cells, express Fc(RII I only, whereas monocytes express Fc(RI, Fc(RI I and Fc(RI II . FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991 ). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in U.S. Patent No. 5,500,362 (see, e.g. Hellstrom, I. et al. Proc. Nat’l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc. Nat’l Acad. Sci. USA 82:1499-1502 (1985); 5,821 ,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351 -1361 (1987)). Alternatively, non-radioactive assays methods may be employed (see, for example, ACTI™ non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA; and CytoTox 96® non-radioactive cytotoxicity assay (Promega, Madison, Wl). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Nat’l Acad. Sci. USA 95:652-656 (1998). C1q binding assays may also be carried out to confirm that the antibody is unable to bind C1q and hence lacks CDC activity. See, e.g., C1 q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402. To assess complement activation, a CDC assay may be performed (see, for example, Gazzano-Santoro et al. J. Immunol. Methods 202:163 (1996); Cragg, M.S. et al. Blood. 101 :1045-1052 (2003); and Cragg, M.S. and M.J. Glennie Blood. 103:2738-2743 (2004)). FcRn binding and in v/'vo clearance/half life determinations can also be performed using methods known in the art (see, e.g., Petkova, S.B. et al. Int’l. Immunol. 18(12):1759-1769 (2006)).

Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Patent Nos. 6,737,056 and 8,219,149). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called “DANA” Fc mutant with substitution of residues 265 and 297 to alanine (US Patent No. 7,332,581 and 8,219,149).

In certain embodiments, the proline at position 329 of a wild-type human Fc region in the antibody is substituted with glycine or arginine or an amino acid residue large enough to destroy the proline sandwich within the Fc/Fc.gamma. receptor interface that is formed between the proline 329 of the Fc and tryptophan residues Trp 87 and Trp 110 of FcgRIII (Sondermann et al. Nature. 406, 267-273, 2000). In certain embodiments, the antibody comprises at least one further amino acid substitution. In one embodiment, the further amino acid substitution is S228P, E233P, L234A, L235A, L235E, N297A, N297D, or P331 S, and still in another embodiment the at least one further amino acid substitution is L234A and L235A of the human IgG 1 Fc region or S228P and L235E of the human lgG4 Fc region (see e.g., US 2012/0251531 ), and still in another embodiment the at least one further amino acid substitution is L234A and L235A and P329G of the human IgG 1 Fc region.

Certain antibody variants with improved or diminished binding to FcRs are described. (See, e.g., U.S. Patent No. 6,737,056; WO 2004/056312, and Shields et al., J. Biol. Chem. 9(2): 6591 -6604 (2001 ).) In certain embodiments, an antibody variant comprises an Fc region with one or more amino acid substitutions which improve ADCC, e.g., substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues). In some embodiments, alterations are made in the Fc region that result in altered (/'.e., either improved or diminished) C1 q binding and/or Complement Dependent Cytotoxicity (CDC), e.g., as described in US Patent No. 6,194,551 , WO 99/51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000).

Antibodies with increased half lives and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 1 17:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)), are described in US2005/0014934A1 (Hinton et al.). Those antibodies comprise an Fc region with one or more substitutions therein which improve binding of the Fc region to FcRn. Such Fc variants include those with substitutions at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 31 1 , 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, e.g., substitution of Fc region residue 434 (US Patent No. 7,371 ,826).

See also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821 ; and WO 94/29351 concerning other examples of Fc region variants.

In some aspects, the anti-FcRH5 and/or anti-CD3 antibody (e.g., bispecific anti-FcRH5 antibody) comprises an Fc region comprising an N297G mutation (EU numbering). In some aspects, the anti- FcRH5 arm of the bispecific anti-FcRH5 antibody comprises a N297G mutation and/or the anti-CD3 arm of the bispecific anti-FcRH5 antibody comprises an Fc region comprising an N297G mutation.

In some embodiments, the anti-FcRH5 antibody comprising the N297G mutation comprises an anti-FcRH5 arm comprising a first binding domain comprising the following six HVRs (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1 ; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6; and an anti-CD3 arm comprising an N297G mutation. In some embodiments, the anti-CD3 arm comprising the N297G mutation comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 9; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 10; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 1 1 ; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 13; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14.

In some embodiments, the anti-FcRH5 antibody comprising the N297G mutation comprises an anti-FcRH5 arm comprising a first binding domain comprising (a) a VH domain comprising an amino acid sequence of SEQ ID NO: 7 and (b) a VL domain comprising an amino acid sequence of SEQ ID NO: 8, and an anti-CD3 arm comprising an N297G mutation. In some embodiments, the anti-CD3 arm comprising the N297G mutation comprises comprising (a) a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and (b) a VL domain comprising an amino acid sequence of SEQ ID NO: 16.

In some embodiments, the anti-FcRH5 antibody comprising the N297G mutation comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH1 1) domain, a first CH2 (CH2j) domain, a first CH3 (CH3y) domain, a second CH1 (CH1₂) domain, second CH2 (CH2₂) domain, and a second CH3 (CH3₂) domain. In some aspects, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some aspects, the CH3y and CH32 domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH3y domain is positionable in the cavity or protuberance, respectively, in the CH32 domain. In some aspects, the CH3y and CH32 domains meet at an interface between said protuberance and cavity. In some aspects, the CH2j and CH2₂ domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2j domain is positionable in the cavity or protuberance, respectively, in the CH2₂ domain. In other instances, the CH2j and CH2₂ domains meet at an interface between said protuberance and cavity. In some aspects, the anti-FcRH5 antibody is an IgGi antibody.

In some embodiments, the anti-FcRH5 antibody comprising the N297G mutation comprises an anti-FcRH5 arm comprising a first binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 7 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 8, and an anti-CD3 arm, wherein (a) the anti-FcRH5 arm comprises T366S, L368A, Y407V, and N297G amino acid substitution mutations (EU numbering) and (b) the anti-CD3 arm comprises T366W and N297G substitution mutations (EU numbering). In some embodiments, the anti-CD3 arm comprising the T366W and N297G mutations comprises comprising (a) a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and (b) a VL domain comprising an amino acid sequence of SEQ ID NO: 16.

In other embodiments, the anti-FcRH5 antibody comprising the N297G mutation comprises an anti-FcRH5 arm comprising a first binding domain comprising (a) a VH domain comprising an amino acid sequence of SEQ ID NO: 7 and (b) a VL domain comprising an amino acid sequence of SEQ ID NO: 8, and an anti-CD3 arm, wherein (a) the anti-FcRH5 arm comprises T366W and N297G substitution mutations (EU numbering) and (b) the anti-CD3 arm comprises T366S, L368A, Y407V, and N297G mutations (EU numbering). In some embodiments, the anti-CD3 arm comprising the N297G mutation comprises comprising (a) a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and (b) a VL domain comprising an amino acid sequence of SEQ ID NO: 16. d. Cysteine engineered antibody variants

In certain embodiments, it may be desirable to create cysteine engineered antibodies, e.g., “thioMAbs,” in which one or more residues of an antibody are substituted with cysteine residues. In particular embodiments, the substituted residues occur at accessible sites of the antibody. By substituting those residues with cysteine, reactive thiol groups are thereby positioned at accessible sites of the antibody and may be used to conjugate the antibody to other moieties, such as drug moieties or linkerdrug moieties, to create an immunoconjugate, as described further herein. In certain embodiments, any one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) of the light chain; A1 18 (EU numbering) of the heavy chain; and S400 (EU numbering) of the heavy chain Fc region. Cysteine engineered antibodies may be generated as described, for example, in U.S. Patent No. 7,521 ,541 . e. Antibody derivatives

In certain embodiments, a bispecific anti-FcRH5/anti-CD3 antibody provided herein may be further modified to contain additional nonproteinaceous moieties that are known in the art and readily available. The moieties suitable for derivatization of the antibody include but are not limited to water soluble polymers. Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1 , 3-dioxolane, poly-1 ,3, 6-trioxane, ethylene/maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidone)polyethylene glycol, propropylene glycol homopolymers, prolypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may be of any molecular weight, and may be branched or unbranched. The number of polymers attached to the antibody may vary, and if more than one polymer are attached, they can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in a therapy under defined conditions, etc.

In another embodiment, conjugates of an antibody and nonproteinaceous moiety that may be selectively heated by exposure to radiation are provided. In one embodiment, the nonproteinaceous moiety is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102: 1 1600-1 1605 (2005)). The radiation may be of any wavelength, and includes, but is not limited to, wavelengths that do not harm ordinary cells, but which heat the nonproteinaceous moiety to a temperature at which cells proximal to the antibody-nonproteinaceous moiety are killed.

7. Charged regions

In some aspects, the binding domain that binds FcRH5 or CD3 comprises a VH1 comprising a charged region (CRy) and a VL1 comprising a charged region (CR2), wherein the CRy in the VH1 forms a charge pair with the CR2 in the VL1 . In some aspects, the CRy comprises a basic amino acid residue and the CR2 comprises an acidic amino acid residue. In some aspects, the CRy comprises a Q39K substitution mutation (Kabat numbering). In some aspects, the CRy consists of the Q39K substitution mutation. In some aspects, the CR2 comprises a Q38E substitution mutation (Kabat numbering). In some aspects, the CR2 consists of the Q38E substitution mutation. In some aspects, the second binding domain that binds CD3 comprises a VH2 comprising a charged region (CR3) and a VL2 comprising a charged region (CR4), wherein the CR4 in the VL2 forms a charge pair with the CR3 in the VH2. In some aspects, the CR^comprises a basic amino acid residue and the CRscomprises an acidic amino acid residue. In some aspects, the CR4 comprises a Q38K substitution mutation (Kabat numbering). In some aspects, the CR4 consists of the Q38K substitution mutation. In some aspects, the CR3 comprises a Q39E substitution mutation (Kabat numbering). In some aspects, the CR3 consists of the Q39E substitution mutation. In some aspects, the VL1 domain is linked to a light chain constant domain (CL1 ) domain and the VH1 is linked to a first heavy chain constant domain (CH1 ), wherein the CL1 comprises a charged region (CR5) and the CH1 comprises a charged region (CRe), and wherein the CR5 in the CL1 forms a charge pair with the CRgin the CH1 y. In some aspects, the CR5 comprises a basic amino acid residue and the CRe comprises an acidic residue. In some aspects, the CR5 comprises a V133K substitution mutation (EU numbering). In some aspects, the CRs consists of the V133K substitution mutation. In some aspects, the CRe comprises a S183E substitution mutation (EU numbering). In some aspects, the CRs consists of the S183E substitution mutation.

In other aspects, the VL2 domain is linked to a CL domain (CL2) and the VH2 is linked to a CH1 domain (CH1₂), wherein the CL2 comprises a charged region (CR/) and the CH1₂ comprises a charged region (CRs), and wherein the CRs in the CH1₂ forms a charge pair with the CR/ in the CL2. In some aspects, the CRs comprises a basic amino acid residue and the CR/comprises an acidic amino acid residue. In some aspects, the CRs comprises a S183K substitution mutation (EU numbering). In some aspects, the CRs consists of the S183K substitution mutation. In some aspects, the CR/ comprises a V133E substitution mutation (EU numbering). In some aspects, the CR/ consists of the V133E substitution mutation.

In other aspects, the VL2 domain is linked to a CL domain (CL2) and the VH2 is linked to a CH1 domain (CH1₂), wherein (a) the CL2 comprises one or more mutations at amino acid residues F1 16, L135, S174, S176, and/or T178 (EU numbering) and (b) the CH1₂ comprises one or more mutations at amino acid residues A141 , F170, S181 , S183, and/or V185 (EU numbering). In some aspects, the CL2 comprises one or more of the following substitution mutations: F1 16A, L135V, S174A, S176F, and/or T178V. In some aspects, the CL2 comprises the following substitution mutations: F1 16A, L135V, S174A, S176F, and T178V. In some aspects, the CH1₂ comprises one or more of the following substitution mutations: A141 1, F170S, S181 M, S183A, and/or V185A. In some aspects, the CH1₂ comprises the following substitution mutations: A141 I, F170S, S181 M, S183A, and V185A.

In other aspects, the binding domain that binds FcRH5 or CD3 comprises a VH domain (VH1 ) comprising a charged region (CRy) and a VL domain (VL1 ) comprising a charged region (CR2), wherein the CR₂ in the VLy forms a charge pair with the CRy in the VH1 . In some aspects, the CR2 comprises a basic amino acid residue and the CRy comprises an acidic amino acid residue. In some aspects, the CR₂ comprises a Q38K substitution mutation (Kabat numbering). In some aspects, the CR₂ consists of the Q38K substitution mutation. In some aspects, the CRy comprises a Q39E substitution mutation (Kabat numbering). In some aspects, the CRy consists of the Q39E substitution mutation. In some aspects, the second binding domain that binds CD3 comprises a VH domain (VH2) comprising a charged region (CR3) and a VL domain (VL2) comprising a charged region (CR4), wherein the CR3 in the VH2 forms a charge pair with the CR4 in the VL2. In some aspects, the CRscomprises a basic amino acid residue and the CR4 comprises an acidic amino acid residue. In some aspects, the CR3 comprises a Q39K substitution mutation (Kabat numbering). In some aspects, the CR3 consists of the Q39K substitution mutation. In some aspects, the CR4 comprises a Q38E substitution mutation (Kabat numbering). In some aspects, the CR4 consists of the Q38E substitution mutation. In some aspects, the VL1 domain is linked to a light chain constant domain (CL1 ) and the VH1 is linked to a first heavy chain constant domain (CH1 y), wherein the CL1 comprises a charged region (CRs) and the CH1 y comprises a charged region (CRs), and wherein the CRs in the CH1 y forms a charge pair with the CRs in the CL1 . In some aspects, the CRs comprises a basic amino acid residue and the CRs comprises an acidic amino acid residue. In some aspects, the CRs comprises a S183K substitution mutation (EU numbering). In some aspects, the CRs consists of the S183K substitution mutation. In some aspects, the CRs comprises a V133E substitution mutation (EU numbering). In some aspects, the CRs consists of the V133E substitution mutation.

In other aspects, the VL2 domain is linked to a CL domain (CL2) and the VH2 is linked to a CH1 domain (CH1₂), wherein the CL2 comprises a charged region (CR/) and the CH1₂ comprises a charged region (CRs), and wherein the CR/ in the CL2 forms a charged pair with the CRs in the CH1₂. In some aspects, the CR/ comprises a basic amino acid residue and the CRs comprises an acidic residue. In some aspects, the CR/ comprises a V133K substitution mutation (EU numbering). In some aspects, the CR/ consists of the V133K substitution mutation. In some aspects, the CRs comprises a S183E substitution mutation (EU numbering). In some aspects, the CRs consists of the S183E substitution mutation.

In other aspects, the VL2 domain is linked to a CL domain (CL2) and the VH2 is linked to a CH1 domain (CH1₂), wherein (a) the CL2 comprises one or more mutations at amino acid residues F1 16, L135, S174, S176, and/or T178 (EU numbering) and (b) the CH1₂ comprises one or more mutations at amino acid residues A141 , F170, S181 , S183, and/or V185 (EU numbering). In some aspects, the CL2 comprises one or more of the following substitution mutations: F1 16A, L135V, S174A, S176F, and/or T178V. In some aspects, the CL2 comprises the following substitution mutations: F1 16A, L135V, S174A, S176F, and T178V. In some aspects, the CH1₂ comprises one or more of the following substitution mutations: A141 1, F170S, S181 M, S183A, and/or V185A. In some aspects, the CH1₂ comprises the following substitution mutations: A141 I, F170S, S181 M, S183A, and V185A. In some aspects, the anti- FcRH5 antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH2 domain (CH2y), a first CH3 domain (CH3y), a second CH2 domain (CH2₂), and a second CH3 domain (CH3₂). In some aspects, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some aspects, the CH3y and the CH3₂ each comprise a protuberance (Py) or a cavity (Cy), and wherein the Py or the Cy in the CH3y is positionable in the Cy or the Py, respectively, in the CH3₂. In some aspects, the CH3y and the CH3₂ meet at an interface between the Py and the Cy. In some aspects, the CH2y and the CH2₂ each comprise (P₂) or a cavity (C₂), and wherein the P₂ or the C₂ in the CH2y is positionable in the C₂ or the P₂, respectively, in the CH2₂. In some aspects, the CH2y and the CH2₂ meet at an interface between the P₂ and the C₂.

/<. Recombinant methods and compositions

Bispecific anti-FcRH5/anti-CD3 antibodies of the disclosure may be produced using recombinant methods and compositions, for example, as described in U.S. Patent No. 4,816,567. In one embodiment, an isolated nucleic acid encoding an anti-FcRH5 antibody described herein is provided. Such nucleic acid may encode an amino acid sequence comprising the VL and/or an amino acid sequence comprising the VH of the antibody (e.g., the light and/or heavy chains of the antibody). In another embodiment, an isolated nucleic acid encoding an anti-CD3 antibody described herein is provided. Such a nucleic acid may encode an amino acid sequence comprising the VL and/or an amino acid sequence comprising the VH of the antibody (e.g., the light and/or heavy chains of the antibody). In a further embodiment, one or more vectors (e.g., expression vectors) comprising such a nucleic acid are provided. In a further embodiment, a host cell comprising such a nucleic acid is provided. In one such embodiment, a host cell comprises (e.g., has been transformed with): (1 ) a vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody, or (2) a first vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid that encodes an amino acid sequence comprising the VH of the antibody. In one embodiment, the host cell is eukaryotic, e.g. a Chinese Hamster Ovary (CHO) cell or lymphoid cell (e.g., YO, NSO, Sp20 cell). In one embodiment, a method of making a bispecific anti-FcRH5/anti-CD3 antibody is provided, wherein the method comprises culturing a host cell comprising a nucleic acid encoding the antibody, as provided above, under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).

For recombinant production of a bispecific anti-FcRH5/anti-CD3 antibody, a nucleic acid encoding an antibody, e.g., as described above, is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell. Such nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody).

1. Two-cell methods for manufacturing bispecific antibodies

In some aspects, an antibody of the disclosure (e.g., a bispecific anti-FcRH5/anti-CD3 antibody) is manufactured using a method comprising two host cell lines. In some aspects, a first arm of the antibody (e.g., a first arm comprising a hole region) is produced in a first host cell line, and a second arm of the antibody (e.g., a second arm comprising a knob region) is produced in a second host cell line. The arms of the antibody are purified from the host cell lines and assembled in vitro.

2. One-cell methods for manufacturing bispecific antibodies

In some aspects, an antibody of the disclosure (e.g., a bispecific anti-FcRH5/anti-CD3 antibody) is manufactured using a method comprising a single host cell line. In some aspects, a first arm of the antibody (e.g., a first arm comprising a hole region) and a second arm of the antibody (e.g., a second arm comprising a knob region) are produced in and purified from a single host cell line. Preferably, the first arm and the second arm are expressed at comparable levels in the host cell, e.g., are both expressed at a high level in the host cell. Similar levels of expression increase the likelihood of efficient TDB production and decrease the likelihood of light chain (LC) mispairing of TDB components. The first arm and second arm of the antibody may each further comprise amino acid substitution mutations introducing charge pairs, as described in Section I IB (7) herein. The charge pairs promote the pairing of heavy and light chain cognate pairs of each arm of the bispecific antibody, thereby minimizing mispairing.

3. Host cells

Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein. For example, antibodies may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed. For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, describing expression of antibody fragments in E. coli.) After expression, the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified.

In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody-encoding vectors, including fungi and yeast strains whose glycosylation pathways have been “humanized,” resulting in the production of an antibody with a partially or fully human glycosylation pattern. See Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li et al., Nat. Biotech. 24:210-215 (2006).

Suitable host cells for the expression of glycosylated antibody are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.

Plant cell cultures can also be utilized as hosts. See, e.g., US Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIES™ technology for producing antibodies in transgenic plants).

Vertebrate cells may also be used as hosts. For example, mammalian cell lines that are adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells as described, e.g., in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1 ); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Annals N.Y. Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR- CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines such as Y0, NS0 and Sp2/0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).

L. Immunoconjugates

The disclosure also provides immunoconjugates comprising a bispecific anti-FcRH5/anti-CD3 antibody herein conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes.

In one embodiment, an immunoconjugate is an antibody-drug conjugate (ADC) in which an antibody is conjugated to one or more drugs, including but not limited to a maytansinoid (see U.S. Patent Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 B1 ); an auristatin such as monomethylauristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Patent Nos. 5,635,483 and 5,780,588, and 7,498,298); a dolastatin; a calicheamicin or derivative thereof (see U.S. Patent Nos. 5,712,374, 5,714,586, 5,739,1 16, 5,767,285, 5,770,701 , 5,770,710, 5,773,001 , and 5,877,296; Hinman et al., Cancer Res. 53:3336-3342 (1993); and Lode et al., Cancer Res. 58:2925-2928 (1998)); an anthracycline such as daunomycin or doxorubicin (see Kratz et al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem. Letters 12:1529-1532 (2002); King et al., J. Med. Chem. 45:4336-4343 (2002); and U.S. Patent No. 6,630,579); methotrexate; vindesine; a taxane such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel; a trichothecene; and CC1065.

In another embodiment, an immunoconjugate comprises a bispecific anti-FcRH5/anti-CD3 antibody as described herein conjugated to an enzymatically active toxin or fragment thereof, including but not limited to diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.

In another embodiment, an immunoconjugate comprises a bispecific anti-FcRH5/anti-CD3 antibody described herein conjugated to a radioactive atom to form a radioconjugate. A variety of radioactive isotopes are available for the production of radioconjugates. Examples include At²¹¹ , I¹³¹ , I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactive isotopes of Lu. When the radioconjugate is used for detection, it may comprise a radioactive atom for scintigraphic studies, for example tc99m or 1123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, mri), such as iodine-123 again, iodine-131 , indium-11 1 , fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.

Conjugates of an antibody and cytotoxic agent may be made using a variety of bifunctional protein coupling agents such as N-succinimidyl-3-(2-pyridyldith io) propionate (SPDP), succinimidyl-4-(N- maleimidomethyl) cyclohexane-1 -carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCI), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1 ,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14-labeled 1 -isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX- DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO94/1 1026. The linker may be a “cleavable linker” facilitating release of a cytotoxic drug in the cell. For example, an acid-labile linker, peptidase-sensitive linker, photolabile linker, dimethyl linker or disulfide- containing linker (Chari et al., Cancer Res. 52:127-131 (1992); U.S. Patent No. 5,208,020) may be used.

The immunoconjugates or ADCs herein expressly contemplate, but are not limited to such conjugates prepared with cross-linker reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo- KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4- vinylsulfone)benzoate) which are commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, IL., U.S.A).

M. Pharmaceutical compositions and formulations

Pharmaceutical compositions and formulations of the anti-FcRH5/anti-CD3 bispecific antibodies can be prepared by mixing such antibodies having the desired degree of purity with one or more optional pharmaceutically acceptable carriers {Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as L-Histidine/glacial acetic acid (e.g., at pH 5.8), phosphate, citrate, and other organic acids; tonicity agents, such as sucrose; stabilizers, such as L-methionine; antioxidants including N-acetyl-DL-tryptophan, ascorbic acid, and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as polysorbate 20 or polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include insterstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in US Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.

Exemplary lyophilized antibody formulations are described in US Patent No. 6,267,958. Aqueous antibody formulations include those described in US Patent No. 6,171 ,586 and W02006/044908, the latter formulations including a histidine-acetate buffer.

The formulation herein may also contain more than one active ingredients as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to further provide an additional therapeutic agent (e.g., a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, and/or an anti-hormonal agent, such as those recited herein above). Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended.

Active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Flemington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, for example, films, or microcapsules.

The formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.

III. ARTICLES OF MANUFACTURE

In another aspect of the disclosure, an article of manufacture containing materials useful for the treatment, prevention, and/or diagnosis of the disorders described above is provided. The article of manufacture comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is by itself or combined with another composition effective for treating, preventing and/or diagnosing the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is an anti-FcRH5/anti-CD3 bispecific antibody described herein. In some aspects, the article of manufacture comprises at least four containers (e.g., vials), a first container holding an amount of the composition suitable for a C1 D1 (cycle 1 , dose 1 ), a second container holding an amount of the composition suitable for a C1 D2 (cycle 1 , dose 2), and a third container holding an amount of the composition suitable for a C1 D3 (cycle 1 , dose 3). In other aspects, the article of manufacture comprises at least four containers (e.g., vials), a first container holding an amount of the composition suitable for a C1 D1 (cycle 1 , dose 1 ), a second container holding an amount of the composition suitable for a C1 D2 (cycle 1 , dose 2), a third container holding an amount of the composition suitable for a C1 D3 (cycle 1 , dose 3), and a fourth container holding an amount of the composition suitable for a C1 D4 (cycle 1 , dose 4). In some aspects, the containers (e.g., vials) may be different sizes, e.g., may have sizes proportional to the amount of the composition they contain. Articles of manufacture comprising containers (e.g., vials) proportional to the intended doses may, e.g., increase convenience, minimize waste, and/or increase cost-effectiveness. The label or package insert indicates that the composition is used for treating the condition of choice (e.g., a multiple myeloma (MM), e.g., relapsed or refractory MM, e.g., 4L+ R/R MM) and further includes information related to at least one of the dosing regimens described herein. Moreover, the article of manufacture may comprise (a) a first container with a composition contained therein, wherein the composition comprises an anti-FcRH5/anti-CD3 bispecific antibody described herein; and (b) a second container with a composition contained therein, wherein the composition comprises a further cytotoxic or otherwise therapeutic agent. Alternatively, or additionally, the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer’s solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes. IV. EXAMPLES

The following are examples of the methods of the disclosure. It is understood that various other embodiments may be practiced, given the general description provided above, and the examples are not intended to limit the scope of the claims.

Example 1. Phase I trial evaluating the safety and efficacy of escalating doses of cevostamab in patients with R/R MM

Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed exclusively in the B-cell lineage, and at a higher level on multiple myeloma (MM) cells than on normal B cells. Cevostamab is a bispecific antibody that targets FcRH5 and CD3 and facilitates T cell-mediated killing of MM cells. This example describes Study GO39775, a Phase I, multicenter, open-label, dose-escalation study of cevostamab administered as a single agent by IV infusion to patients with R/R MM for whom no established therapy for MM is appropriate and available or who are intolerant to those established therapies (e.g., see clinical trial identifier: NCT03275103). This example also includes data from Study CO43476, a multicenter, multi-cohort, non-randomized, open-label, Phase l/ll trial investigating the efficacy, safety, pharmacokinetics, pharmacodynamics, and immunogenicity of cevostamab in patients with triple class refractory multiple myeloma (MM) and prior exposure to a B cell maturation factor (BCMA)-targeted agent (see clinical trial identifier NCT05535244; and International Patent Application Publication No. WO 2024/015897, each of which is incorporated herein by reference in their entirety). The dosing regimens of the specific arms investigated in Study GO39775 and Study CO43476 are provided in Table 6A. Specific objectives and corresponding endpoints for Study GO39775 are outlined in Table 6B. Additional details on the single step-up and double step-up dosing regimens discussed herein may be found in International Patent Application Publication No. WO/2022/076462, which is herein incorporated by reference in its entirety.

Table 6A. Dosing Regimens of Study GO39776

CRS = cytokine release syndrome; IV = intravenous; Q3W = every 3 weeks; SUD = step-up dose; TD = target dose; n/a = not applicable

Notes: Clinical cutoff dates are 9 October 2023 for Studies GO39775. In Study GO39775, intrapatient dose escalation of the target dose was allowed in the dose-escalation arms. Initial dose exploration in 31 patients with varied priming sequence of doses in Study GO39775 are not included in this table or other tables presenting the priming sequence data.

In Study CO43476, the second SUD is scheduled on Day 2 if there was no CRS event occurring after the first SUD on Day 1 . A minimum of 20 hours from the end of infusion of the first SUD to initiation of the second SUD is respected for doses that are administered 1 day apart. In the event that the patient experienced CRS following the first SUD on Day 1 , the second SUD is given on Day 2, 3, or 4 upon full resolution of CRS.

For the triple-step regimens in Study GO39775, the second SUD is scheduled on Day 2, 3 or 4 based on investigator’s discretion. If the second SUD is scheduled one day apart from the first SUD, there may be no clinical signs and symptoms of CRS and, optionally, a minimum of 20 hours from the end of infusion of the first SUD to initiation of the second SUD. For example, in the event that the patient experienced CRS following the first SUD on Day 1 , the second SUD is given on Day 2, 3, or 4 upon resolution of CRS signs and symptoms.

For the triple-step regimens in Study GO39775, the first target dose is scheduled on Day 9, 10, or 1 1 based on investigator’s discretion. If the first TD is scheduled one day apart from the third SUD, there may be no clinical signs and symptoms of CRS and, optionally, a minimum of 20 hours from the end of infusion of the third SUD to initiation of the first TD. For example, in the event that the patient experienced CRS following the third SUD on Day 8, the first TD is given on Day 9, 10, or 1 1 upon resolution of CRS signs and symptoms.

Table 6B: Objectives and Corresponding Endpoints

ADA = anti-drug antibody; ASTCT = American Society of Transplantation and Cellular Therapy;

CRS = cytokine-release syndrome; DLT = dose-limiting toxicity; IMWG = International Myeloma Working Group; MM = multiple myeloma; MTD = maximum tolerated dose; NCI CTCAE v4.0 = National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0; PD = pharmacodynamic; PK = pharmacokinetic.

As shown in Table 6A and described further herein, patients were enrolled in double step-up dosing regimens (e.g., Arm J or K (dose-expansion)) and a triple step-up dosing regimens (e.g., Arms H1/H2 (dose-escalation) and Arms 11/12 (dose-expansion)). Other dosing regimens shown in Table 6A (e.g., Arms A, C, E, and F (single step-up dosing regimens) and Arms B, D, and G (double step-up dosing regimens)) are described in International Patent Application Publication No. WO/2022/076462, which is herein incorporated by reference in its entirety.

Cevostamab was administered in 21 -day cycles. Patients with acceptable toxicity and evidence of clinical benefit continued to receive cevostamab up to a maximum of 17 cycles until disease progression according to International Myeloma Working Group (IMWG) (e.g., see criteria in Table 7) or unacceptable toxicity, whichever occurred first. An exception was made for patients who underwent intrapatient dose escalation; these patients continued to receive cevostamab up to a maximum of 17 cycles at the new, increased dose until disease progression or unacceptable toxicity, whichever occurred first. Patients who completed 17 cycles of treatment were eligible for cevostamab re-treatment. Table 6C below provides key demographics and baseline characteristics of all safety-evaluable patients across priming regimens in Study GO39775 and Study CO43476. Most patients were exposed to prior therapies, including IMiD, PI, and anti-CD38 classes of therapy.

Table 6C: Demographics and Baseline Characteristics of Patients Across Priming Regimens in Safety-Evaluable Population In Studies GO39775 and CO43476

BCMA=B-cell maturation antigen; CAR=chimeric antigen receptor; CD38=cluster of differentiation 38; ECOG=Eastern Cooperative Oncology Group; IMiD=immunomodulatory drug; LDH=lactate dehydrogenase; mAb=monoclonal antibody; MM=multiple myeloma; NC=not collected; Pl=proteasome inhibitor; sBCMA=soluble B-cell maturation antigen in blood; SUD=step-up dose; TD=target dose. a One patient in Study CO43476 had an ECOG score of 2 at study entry, which was a protocol deviation. b Defined as translocation t(4;14) or translocation t(14;16), or deletion 17p. Percentage is based on the number of patients with available cytogenetics data. c All patients enrolled in Study CO43476 had received at least one prior anti-BCMA therapy. One patient was noted to not have received prior anti-BCMA therapy due to a data entry error. The exposure of all safety-evaluable patients across priming regimens in Study GO39775 and Study CO43476 is presented in Table 6D. All patients received at least one dose of cevostamab. All safety-evaluable patients who received cevostamab monotherapy in Study GO39775 had a median of 4 cycles of treatment (range: 1 -34 cycles), with a median time on treatment of 64 days (range: 1 -703 days) and a median of follow-up of 301 days (range: 6-1905 days).

Patients receiving the 0.3/1 .2/3.6/160 mg triple-step regimen in Study GO39775 had a median number of treatment cycles of 2 (range: 1 -17 cycles) and a median of time on treatment of 26.5 days (range: 9-339 days). A total of 4 of 30 patients (13.3%) who received the regimen remained on treatment, while 26 patients (86.7%) had discontinued from treatment at the time of clinical cutoff date. Overall, the main reason for treatment discontinuation was progressive disease (21 patients (70.0%)). Two patients (6.7%) each had discontinued from treatment due to AEs (e.g., Grade 2 acute kidney injury and Grade 3 acute febrile neutrophilic dermatosis) or death (e.g., fatal event of COVID-19 and death due to progressive disease within the AE reporting period). One patient (3.3%) had discontinued due to withdrawal by subject.

Table 6D: Exposure Across Priming Regimens in Safety-Evaluable Population in Study GO39775 and Study CO43476

SUD=step-up dose; TD = target dose. Notes: Exposure during initial treatment (excluding re-treatment) is shown. Exposure during intrapatient dose escalation is included. a Dose intensity is calculated as the total actual dose divided by the protocol-defined planned dose within each dosing cycle or throughout the study. c One patient received the correct SUD of 7.2 mg on Cycle 1 Day 8 but was noted to receive 160 mg SUD due to a data entry error. d One patient did not have a study discontinuation date reported.

Table 7: International Myeloma Working Group Uniform Response Criteria (2016)

Note: Patients should be categorized as having stable disease until they meet criteria for any response category or have progressive disease. Patients will continue in the last confirmed response category until there is confirmation of progression or improvement to a higher response status; patients cannot move to a lower response category. a Special attention should be given to the emergence of a different M-protein following treatment, especially in the setting of patients having achieved a conventional CR, often related to oligoclonal reconstitution of the immune system. These bands typically disappear over time, and in some studies, have been associated with a better outcome. Also, appearance of IgGk in patients receiving monoclonal antibodies should be differentiated from the therapeutic antibody. b In some cases it is possible that the original M-protein light-chain isotype is still detected on immunofixation, but the accompanying heavy-chain component has disappeared; this would not be considered a CR even though the heavy-chain component is not detectable, since it is possible that the clone evolved to one that secreted only light chains. Thus, if a patient has IgA lambda myeloma, then to qualify as a CR there should be no IgA detectable on serum or urine immunofixation; if free lambda is detected without IgA, then it must be accompanied by a different heavy-chain isotype (IgG, IgM, etc.). Modified from Durie et al. 2006. Requires two consecutive assessments to be carried out at any time before the institution of any new therapy (Durie et al. 2015). c For patients achieving very good partial response by other criteria, a soft tissue plasmacytoma must decrease by more than 90% in the sum of the maximal perpendicular diameter (SPD) compared with baseline. d Plasmacytoma measurements should be taken from the computed tomography (CT) portion of the positron emission tomography/computed tomography (PET/CT), or magnetic resonance imaging (MRI) scans, or dedicated CT scans where applicable. For patients with only skin involvement, the skin lesions should be measured with a ruler. Measurement of tumor size will be determined by the SPD. Any soft tissue plasmacytoma documented at baseline must undergo serial monitoring; otherwise, the patient is classified as not evaluable. e Positive immunofixation alone in a patient previously classified as achieving a CR will not be considered progression. Criteria for relapse from a CR should be used only when calculating disease-free survival. f In the case where a value is felt to be a spurious result per investigator discretion (e.g., a possible laboratory error), that value will not be considered when determining the lowest value.

⁹ CRAB features = calcium elevation, renal failure, anemia, lytic bone lesions.

Patients who completed 17 cycles of study treatment (with the exception of re-treatment), continued to have tumor and additional assessments for up to 12 months or until disease progression, start of new anti-cancer therapy, or withdrawal from study participation, whichever occurred first. All patients were closely monitored for adverse events throughout the study and for at least 90 days after the last dose of study treatment. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0), with the exception of CRS, which were graded according to American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine Release Syndrome (shown below in Table 8). Initially, all enrolled patients were required to be hospitalized after the completion of each cevostamab infusion during Cycle 1 .

Table 8: ASTCT Cytokine Release Syndrome (CRS) Consensus Grading

Note: Organ toxicities associated with CRS may be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0) but they do not influence CRS grading.

Fever is defined as temperature >38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anti-cytokine therapy such as tocilizumab or corticosteroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. b CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as Grade 3 CRS. c Low-flow nasal cannula is defined as oxygen delivered at < 6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at > 6 L/minute.

Source: Lee et al., Biol Blood Marrow Transplant, 25(4): 625-638, 2019

The end of this study was defined as the date when the last patient, last visit occurred or the date at which the last data point required for statistical analysis or protocol-defined safety monitoring was received from the last patient, whichever occurred later. Efficacy of the single step-up, double step-up, and triple step-up dosing regimens described herein is shown in FIG. 8.

A. Dose-Escalation Stage

Triple step-up dose-escalation Arms H1 and H2 assessed the safety, tolerability, and pharmacokinetics of cevostamab administered by IV infusion on Day 1 , Days 2-4 (i.e., Day 2, Day 3, or Day 4), Day 8, and Day 9-1 1 (i.e., Day 9, Day 10, or Day 1 1 ) of the first 21 -day cycle, followed thereafter by IV infusion on Day 1 of each 21 -day cycle. For both arms, the target dose (TD) refers to the highest dose administered in Cycle 1 ; the target dose" was administered on Day 1 of subsequent cycles.

Arms H1 and H2 were conducted using a standard 3 + 3 design based on the criteria provided in the dose-escalation rules. Dose-escalation cohorts consisted of at least 3 patients, unless dose-limiting toxicities (DLTs) were observed in the first 2 patients prior to enrollment of a third patient, according to a standard 3 + 3 design. In Cycle 1 , patients in Arms H1 and H2 received 3 step-up doses and a target dose; these four doses were administered on Days 1 , 2-4, 8, and 9-1 1 ; flexibility of timing was implemented for the second step-up dose and target dose to allow for patients to meet the criteria for subsequent dosing. Dosing days for the dose-escalation arms H1 and H2 are illustrated in FIG. 1. Arms H1 and H2 assessed different ratios between the step-up doses. The doses were as follows:

• Arm H1 , Cohort 1 : 0.3 / 1 .2 / 3.6 / 160 mg

• Arm H2, Cohort 1 : 0.3 / 3.3 / 7.2 / 160 mg

The DLT assessment windows was utilized as follows:

• DLT Window 1 will be from Cycle 1 Day 1 to Cycle 1 Day 7 and included the first two stepdoses.

• DLT Window 2 was from Cycle 1 Day 8 to the end of Cycle 1 and included the third stepdose and the first target dose.

The first step-up dose (0.3 mg) for both Arms H1 and H2 was fixed. Escalation of other doses must follow the dose-escalation rules.

For each dose-escalation cohort, treatment with the first dose of cevostamab was staggered such that the second patient enrolled in the cohort received cevostamab at least 72 hours after the first patient received cevostamab to allow assessment of any severe and unexpected acute or subacute drug or infusion-related toxicities; dosing in subsequent patients in each cohort was staggered by at least 24 hours. Exemplary single step-up, double step-up, and triple step-up dosing procedures are illustrated in FIG. 2.

Patients who discontinued from the study prior to completing the dose-limiting toxicity (DLT) assessment windows for reasons other than a DLT were considered non-evaluable for dose-escalation decisions and maximum tolerated dose (MTD) assessments and were replaced by an additional patient at that same dose level. Patients who missed any dose during the DLT assessment windows for reasons other than a DLT were also replaced. Patients who received supportive care (including radiotherapy) during the DLT assessment windows that confounded the evaluation of DLTs (not including supportive care described below as part of the DLT definition) were replaced at the discretion of the investigator. DLTs were treated according to clinical practice and were monitored through their resolution. All adverse events were considered related to cevostamab unless such events were clearly attributed to another clearly identifiable cause (e.g., disease progression, concomitant medication, or preexisting medical condition).

Decreases in B cells, lymphopenia, and/or leukopenia due to decreases in B cells or T cells were not considered DLTs as they were expected pharmacodynamic (PD) outcomes of cevostamab treatment based on nonclinical testing of this molecule.

A DLT was defined as any of the following adverse events occurring during the DLT assessment windows:

• Any Grade 4 or 5 adverse event not considered to be attributable to another clearly identifiable cause, with the following exceptions:

Grade 4 lymphopenia, which is an expected outcome of therapy

Grade 4 neutropenia that was not accompanied by temperature elevation (oral or tympanic temperature of >100.4°F [38°C]) and improved to Grade < 2 (or to

>80% of the baseline ANC, whichever was lower) within 1 week with or without G-CSF

- Grade 4 thrombocytopenia that improved to Grade < 2 (or to >80% of the baseline platelet count, whichever was lower) within 1 week, did not require platelet transfusion, or was not associated with bleeding

• Any Grade 3 hematologic adverse event not considered to be attributable to another clearly identifiable cause, with the following exceptions:

Grade 3 lymphopenia, which was an expected outcome of therapy

Grade 3 neutropenia that was not accompanied by temperature elevation (oral or tympanic temperature of >100.4°F [38°C]) and improved to Grade < 2 (or to

>80% of the baseline ANC, whichever was lower) within 1 week with or without G-CSF Grade 3 thrombocytopenia that improves to Grade < 2 (or to >80% of the baseline platelet count, whichever was lower) within 1 week without platelet transfusion and was not associated with bleeding that was considered clinically significant by the investigator

• Any Grade 3 non-hematologic adverse event not considered to be attributable to another clearly identifiable cause, with the following exceptions:

Grade 3 nausea or vomiting in the absence of premedication or that was managed with resulting resolution to Grade < 2 with oral or IV anti-emetics within 24 hours

Grade 3 nausea or vomiting that requires total parenteral nutrition or hospitalization were not excluded and were considered a DLT.

Grade 3 fatigue that lasted < 3 days

Grade 3 laboratory abnormalities that were asymptomatic and resolved to Grade < 1 or baseline within 7 days

• Any hepatic function abnormality as defined by the following:

- AST or ALT > 3 x the upper limit of normal (ULN) and total bilirubin > 2 x ULN, with the following exception: Any AST or ALT > 3 x the ULN and total bilirubin > 2 x ULN where no individual laboratory value exceeds Grade 3 that occurred in the context of Grade < 2 CRS (as defined by the criteria established by Lee et al. [2019]; see ASTCT Cytokine Release Syndrome Consensus Grading); and resolved to Grade < 1 within < 3 days were not considered a DLT.

- Any Grade 3 AST or ALT elevation with the following exception:

Any Grade 3 AST or ALT elevation that occurred in the context of Grade < 2 CRS (as defined by the criteria established by Lee et al. [2019]; see ASTCT Cytokine Release Syndrome Consensus Grading) and resolved to Grade < 1 within < 3 days were not considered a DLT.

• Any Grade 2 neurologic toxicity mapping to a MedDRA High-Level Group Term listed below that was not considered to be attributable to another clearly identifiable cause and that did not resolve to baseline within 72 hours was considered a DLT:

Cranial nerve disorders (excluding neoplasms)

Demyelinating disorders

Encephalopathies

Mental impairment disorders

Movement disorders (including parkinsonism)

Neurological disorders not elsewhere classified

Seizures (including subtypes)

Cognitive and attention disorders and disturbances

Communication disorders and disturbances

Delirium (including confusion)

• Dementia and amnestic conditions Grade 1 depressed level of consciousness or Grade 1 dysarthria that was not considered to be attributable to another clearly identifiable cause and that did not resolve to baseline within 72 hours was considered a DLT.

• Any grade seizure that was not considered to be attributable to another clearly identifiable cause was considered a DLT.

For the initial assessment of cevostamab in patients, the interval between repeat dosing was 21 days. As outlined herein, the DLT observation period for dose escalation was the 21 -day period following the first dose of cevostamab. In the nonclinical toxicity studies in cynomolgus monkeys, this observation period allowed for adequate recovery from observed toxicities related to cevostamab.

B. Dose-Escalation Rules

Cevostamab was administered using a step-dose approach in Cycle 1 . For Arms H1 and H2, 3 step-up doses were given on Days 1 , 2-4 (i.e. , Day 2, Day 3, or Day 4), and 8 followed by administration of the target dose on Day 9-1 1 (i.e., Day 9, Day 10, or Day 1 1 ). The target dose was administered about 1 -3 days after the last step-up dose. Prior to each dose, patients must have met all requirements outlined in the dose and schedule modifications section. If the patient experienced CRS with the previous dose, clinical symptoms of CRS (e.g., fever, hypotension, etc.) were resolved prior to administration of the subsequent dose. Patients were hospitalized during Cycle 1 according to the cevostamab infusion and hospitalization rules outlined herein.

For both arms, the Cycle 2, Day 1 dose was given no earlier than 21 (+ 2) days after the Cycle 1 Day 1 dose is given, with a minimum of 7 days between the target dose and Cycle 2 Day 1 . Thereafter, cevostamab was administered on Day 1 of a 21 -day cycle as described but could have been administered up to ± 2 days from the scheduled date (e.g., with a minimum of 19 days between doses) for logistic/scheduling reasons. The Cycle 2 Day 1 dose and all subsequent doses were equal to the Cycle 1 target dose unless a dose modification was required or intrapatient dose escalation occurs.

The step-up and target doses was increased up to a maximum of 3-fold of the preceding dose levels for each successive cohort until a safety threshold (defined as the observation of a Grade >2 adverse event not considered to be attributable to another clearly identifiable cause in >34% of patients is observed) was reached. Once this safety threshold was met during a DLT window of a given cohort, the corresponding dose was increased by up to a maximum of 2-fold of the preceding dose for subsequent cohorts.

Following the observation of a DLT in < 17% of >6 patients during a DLT window of a given cohort, the corresponding dose were increased no more than 50% of the preceding dose for subsequent cohorts.

An example of a possible triple step-up dose-escalation scenario is illustrated in FIG. 3.

Dose escalation occurred in accordance with the rules listed below.

DLT criteria was the same for all DLT assessment windows. The totality of safety data from both arms of the study was considered when making dose escalation decisions. However, for dose escalation decisions, DLTs was counted independently for each study arm.

Rules for dose escalation of the step-up dose(s) were as follows:

• If none of the first 3 DLT-evaluable patients in a given cohort experienced a DLT during the step-up dose DLT window, the step-up dose was escalated in the next cohort according to the rules described above.

• If 1 of the first 3 DLT-evaluable patients experienced a DLT during the step-up dose DLT window, the cohort was expanded to 6 patients. If there were no further DLTs in the 6 DLT- evaluable patients during the step-up dose DLT window, the step-up dose was escalated by no more than 50% of the preceding step-up dose in subsequent cohorts.

• If 2 or more of the first 3 DLT-evaluable patients in a given cohort experienced a DLT during the step-up dose DLT window, the corresponding step-up dose MTD was exceeded and escalation at that step-up dose was stopped. An additional 3 patients were evaluated for DLTs using a dosing scheme consisting of the preceding step-up dose level and the highest cleared target dose level, unless 6 patients had already been evaluated at that level.

- If the step-up dose level at which the dose MTD is exceeded is >25% higher than the preceding tested step-up dose, additional dose cohorts of at least 6 patients were evaluated at intermediate step-up dose(s) for evaluation as the MTD.

Rules for dose escalation of the target dose were as follows:

• If none of the first 3 DLT-evaluable patients in a given cohort experienced a DLT during the target dose DLT window, enrollment of the next cohort at the next highest dose level for the target dose DLT window proceeded according to the dose-escalation rules outlined above.

• If 1 of the first 3 DLT-evaluable patients experienced a DLT during the target dose DLT window, the cohort was expanded to 6 patients at the same dose level. If the step-up dose at a given level had been shown to exceed the step-up dose MTD, the additional patients enrolled in the cohort were enrolled at a lower, previously cleared step-up dose. If there were no further DLTs in 6 DLT-evaluable patients during the target dose DLT window, enrollment of the next cohort proceeded with the target dose being escalated by no more than 50% of the preceding target dose.

• If 2 or more DLT-evaluable patients in a cohort experienced a DLT during the target dose DLT window, the target dose MTD had been exceeded and escalation of the target dose was stopped, with the following exception:

- If all DLTs experienced at a given target dose were reported as CRS or its symptoms, an additional 3 patients were evaluated for DLTs by dose escalating the step-up dose(s) (if allowed per criteria above) and using a lower, previously cleared target dose. If all 3 patients did not experience CRS or its symptoms in the new regimen, then the previously tested target dose was retested using a higher step-up regimen and was further escalated after review and approval by the ISC.

• If the target dose MTD was exceeded and no escalation of the step-up dose was planned, the following rules applied:

- An additional 3 patients were evaluated for DLTs using a dosing scheme consisting of the highest cleared step-up dose level and the highest cleared target dose level, unless 6 patients had already been evaluated at that level.

- If the target dose MTD was exceeded at any dose level, the highest target dose at which fewer than 2 of 6 DLT-evaluable patients (i.e., < 17%) experienced a DLT was declared the target dose MTD.

- If the target dose level at which the target dose MTD was exceeded is >25% higher than the preceding tested target dose, additional dose cohorts of at least 6 patients were evaluated at intermediate target dose(s) for evaluation as the MTD.

• Additional dose cohorts that assessed intermediate dose levels between two dose levels that had been demonstrated to not exceed the MTD were evaluated to further characterize dosedependent toxicities.

- Enrollment of cohorts to evaluate intermediate dose levels occurred concurrently with enrollment of dose-escalation cohorts to identify the MTD.

For triple step-up dose-escalation, the first step-up dose in Arms H1 and H2 (0.3 mg) was fixed, and only one dose (step-up or target) was escalated in each cohort. If there were multiple doses within a DLT window, dose-escalation limitations and MTD considerations applied to the most recent dose received in relation to the DLT within the window.

For each dose-escalation arm, if the target dose MTD was not exceeded at any dose level, the highest doses administered in this study for step-up and target dose in a single cohort was declared the maximum achieved doses. On the basis of a real-time review of safety data and available preliminary PK data, dose escalation was halted or modified as deemed appropriate. Relevant demographic, adverse event, laboratory, dose administration, and available PK and PD data was reviewed prior to each doseescalation decision.

To acquire additional safety and PD data to better fully inform the recommended Phase II dose, additional patients were enrolled at dose levels that had been shown to not exceed the MTD based on the dose-escalation criteria described above, and at which there was evidence of anti-tumor activity and/or PD biomarker modulation. Up to approximately 12 additional patients per dose level were enrolled. For the purposes of dose-escalation decisions, these patients were not included as part of the DLT-evaluable population.

The dose-escalation rules outlined herein were designed to ensure patient safety while minimizing the number of patients exposed to sub-therapeutic doses of study treatment. For this reason, single-patient dose-escalation cohorts were initially used with dose-escalation intervals not exceeding 200% of the preceding dose level, with conversion to a standard 3 + 3 dose-escalation design and lower dose-escalation intervals based on rules outlined herein.

/'. Intrapatient Dose Escalation

To maximize the collection of information at relevant doses and minimize the exposure of patients to suboptimal doses of cevostamab, intrapatient dose escalation was permitted. The dose of cevostamab for an individual patient was increased to the highest cleared dose level that was tolerated by completed cohorts through at least one cycle of cevostamab administration. Patients were able to undergo intrapatient dose escalation after completing at least two cycles at their originally assigned dose level. Subsequent intrapatient dose escalations occurred after at least one cycle of any subsequently higher cleared dose level without any adverse event that met the definition of a DLT or necessitated postadministration hospitalization. Once the MTD was declared and the recommended Phase II dose was determined, intrapatient dose escalation directly to the recommended Phase II dose was permitted for patients who remained on study and continued to tolerate cevostamab.

Because the starting dose for cevostamab is based on a minimum anticipated biological effect level and to minimize the number of patients exposed to sub-therapeutic doses of study treatment, the option for intrapatient dose escalation was allowed per the criteria detailed herein. To obtain adequate safety data at each dose level, patients were required to receive at least two cycles of cevostamab at their originally assigned dose level before undergoing intrapatient dose escalation. Subsequent intrapatient dose escalations were to the highest dose level that has cleared the DLT observation period. Because intrapatient dose escalation was conducted in this manner, additional information regarding step dosing as a mitigation strategy against treatment-emergent toxicity was acquired.

/'/. Rules for Continued Dosing Beyond Cycle 1

Patients who did not experience a DLT during the DLT observation period were eligible to receive additional infusions of cevostamab as follows:

• Clinical benefit: Patients had no clinical signs or symptoms of progressive disease (patients will be clinically assessed for disease progression on Day 1 of each cycle). Patients were also assessed at the beginning of each cycle for progression based on the IMWG criteria provided herein. Patients with solely biochemical disease progression (defined as an increase of monoclonal paraprotein in absence of organ dysfunction and clinical symptoms) and who qualified for intrapatient dose escalation received additional infusions. For determining disease progression according to IMWG criteria after a patient has undergone intrapatient dose escalation, baseline will be reestablished at each new dose level assessed for a patient.

• Acceptable toxicity: Patients who experienced Grade 4 non-hematologic adverse events except Grade 4 tumor lysis syndrome (TLS) discontinued study treatment and were not re-treated.

Patients who experienced Grade 4 TLS were considered for continued study treatment provided they met the dose and schedule modification criteria. All other study treatment-related adverse events from prior study treatment infusions must have been decreased to Grade < 1 or baseline grade by the next infusion. Exceptions on the basis of ongoing overall clinical benefit were allowed after a careful assessment of benefit-risk. Any treatment delay for adverse events not attributed to study treatment may not have required study treatment discontinuation. Dose reductions of cevostamab were allowed if it was determined that clinical benefit could have been maintained according to the rules outlined herein.

C. Dose-Expansion Stage

The dose-expansion stage of this study is designed to obtain additional safety, tolerability, PK, and preliminary clinical activity data with cevostamab treatment. At no time will a cevostamab dose level studied in the expansion stage exceed the highest dose level tested and cleared in the dose-escalation stage. Additionally, for the expansion cohort, interim analyses will be conducted to guide potential early stopping of enrollment in the event of unacceptable toxicity/tolerability or lower than expected response rate.

The expansion stage consisted of single step-up dose-expansion arms (Arms C, E, and F); double step-up dose-expansion arms (Arms D, G, J, and K); and triple step-up dose-expansion arms (Arm 11 and Arm I2). Not all expansion arms were opened at the same time. Arms 11 and I2 are doseexpansion arms to obtain safety, tolerability, pharmacokinetic, and preliminary clinical activity data with triple step-up cevostamab treatment at different doses, based on emergent clinical data from Arms H1 and H2.

D. Cevostamab Re-T eatment

Patients who initially responded to cevostamab, but subsequently developed recurrent or progressive disease either after the completion of therapy or after a dose delay of more than 28 days, may have benefitted from additional cycles of cevostamab treatment. Patients were eligible for cevostamab re-treatment as described below. The cevostamab dose and schedule for these patients was the dose and schedule that was found to be safe at the time of re-treatment, provided the following criteria was met:

• Pertinent eligibility criteria (e.g. inclusion and exclusion criteria detailed herein) was met at the time that cevostamab treatment is re-initiated, with the following exceptions:

Prior therapy with cevostamab was allowed.

Serology tests to demonstrate HIV, hepatitis C virus (HCV), and hepatitis B virus (HBV) status did not need to be repeated unless clinically indicated. Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpes virus 6 (HHV-6) polymerase chain reaction (PCR) should have been repeated.

Manageable and reversible immune-related adverse events with initial cevostamab treatment were allowed and did not constitute an exclusionary history of autoimmune disease.

Radiotherapy was allowed within 4 weeks of cevostamab re-treatment.

• Patients had documented objective response (complete response (CR), very good partial response (VGPR), or partial response (PR)) per IMWG criteria at the end of initial cevostamab treatment and for at least one post-treatment tumor assessment after the end of treatment.

• Patients without biochemical disease progression (defined as an increase of monoclonal paraprotein in absence of organ dysfunction and clinical symptoms) but who have clear indication of recurrent disease (e.g., development of new bone lesions or soft tissue plasmacytomas or an increase in size of existing bone lesions or soft tissue plasmacytomas) were allowed.

• Patients did not experience Grade 4 non-hematologic adverse events related to study treatment during initial cevostamab treatment.

• Patients who experienced Grade 2 or Grade 3 adverse events during initial treatment resolved these toxicities to < Grade 1 .

• Patients required hospitalization following the first re-treatment infusion of cevostamab.

• No intervening systemic anti-cancer therapy was administered between the completion of initial cevostamab treatment and re-initiation of cevostamab treatment.

• Patients can receive re-treatment within 12 months of their last treatment.

• Written informed consent was provided to acknowledge deferring any standard treatment options that may have existed in favor of re-initiating cevostamab and undergoing a biopsy of recurrent or progressing tumor if clinically feasible.

Patients who received fewer than 17 cycles of treatment but met all re-treatment criteria were qualified for re-treatment.

A repeat bone marrow biopsy and aspirate to assess FcRH5 expression status and the tumor microenvironment was obtained prior to cevostamab re-treatment. The dose and schedule of cevostamab administered to patients receiving re-treatment were on a previously tested dose and schedule that cleared the DLT observation period. After a recommended phase 2 dose (RP2D) has been determined, all patients will be treated at the RP2D unless contraindicated and/or after consultation with a clinician. Patients were eligible for additional rounds of cevostamab study re-treatment provided the aforementioned criteria continued to be met. The schedule of activities for patients who received cevostamab re-treatment followed the schedule of activities implemented in dose escalation or expansion. Patients who completed 17 cycles of re-treatment (or discontinue re-treatment due to AE) are followed for safety outcomes for 90 days following the patient’s last dose of cevostamab or until the patient receives another anti-cancer therapy, whichever occurred first.

The above rules for re-treatment applied both to dose-escalation and dose-expansion cohorts.

E. Rationale for Study Design

This study enrolled patients with a history of R/R MM that were expected to express the FcRH5 antigen and who met the inclusion and exclusion criteria as described herein. Bone marrow samples obtained from all patients were retrospectively analyzed for FcRH5 expression with validation of assays (e.g., quantitative reverse transcription-PCR, immunohistochemistry, and quantitative flow cytometry).

/'. Rationale for Triple Step-up Doses and Dosing Schedule

Two triple step-up dose-escalation arms (Arms H1 and H2) were added to assess the safety, tolerability, and pharmacokinetics of a triple step-up dosing regimen in Cycle 1 . Triple step-up dosing assessed whether an additional step-up dose further improved the CRS profile for the priming sequences of cevostamab. To minimize the time to administration of target doses, in each of the initial two hospitalizations, two cevostamab doses were administered. Patients were hospitalized and monitored for a minimum of 48 hours during Cycle 1 after the Day 2-4 doses and Day 9-11 doses.

Quantitative Systems Pharmacology (QSP) modelling was performed to guide dosage exploration strategies aimed at identifying alternative priming sequences and dosing schedules (e.g., range of dosages, number of doses, and timing of doses) having potential to mitigate peak IL-6 expression (a biomarker of CRS) in patients. The QSP model utilizes an established model previously developed for mosunetuzumab (e.g., see Hosseini et al., NPJ. Syst. Biol. Appl., 6(1 ):28, 2020; and Susilo et al., Clin. Transl. Sci., 16(7):1134-1148, 2023, each of which is incorporated herein in its entirety) but was adapted for the present study by incorporating cevostamab’s mechanism of action and various aspects of MM biology. For example, the model includes mechanisms involving the activation of CD8+ T cells, subsequent target cell killing, and IL-6 release, as well as MM tumor dynamics (e.g., using paraproteins measurements produced by malignant plasma cells) and aspects of the bone marrow environment (e.g., baseline levels of T cells, FcRH5-expressing plasma cells, and B cells) in an MM patient. These variables and their incorporation into the QSP model are discussed further in Example 3. QSP modelling and analysis identified starting doses for the first cohort of Arm H1 as 0.3 / 1 .2 / 3.6 / 160 mg (also referred herein as “low”), and identified starting doses for the first cohort of Arm H2 as 0.313.3 I 7.2 / 160 mg (also referred herein as “high”). The doses were given on Day 1 , Day 2-4, Day 8, and Day 9- 11 of Cycle 1 , respectively. The final Cycle 1 dose (target dose) was also administered on Day 1 of each subsequent cycle.

Arm H1 assessed whether the addition of an intermediate step-up dose between the two step-up doses tested in double step-up Arms B and D (e.g., 0.3 / 3.6 / 160 mg) reduced the incidence of CRS at both the 3.6 mg and 160 mg doses. QSP modeling predicted that the addition of a 1 .2 mg step-up dose prior to the 3.6 mg step-up dose in Arm H1 would lead to a reduction in peak IL-6 levels and associated CRS risk at the 3.6-mg dose compared with the 3.6-mg dose in the 0.3 / 3.6 / 160-mg double step-up regimen. Indeed, this prediction is corroborated by clinical data from Study GO39775. For example, subjects administered step-up doses of 0.3 / 1 .2 / 3.6 mg (e.g., Arm H1 ) showed lower median peak IL-6 levels compared to subjects administered 0.313.6 mg step-up doses (Arms B and D; see FIG. 7).

Arm H2 assessed the addition of a step-up dose after the priming sequences from Arms B and D prior to reaching the target dose. Because the initial two step-up doses were given in close proximity, the dose for the second step-up dose was lowered (from 3.6 mg in double step-up Arm B and D) to 3.3 mg such that the total overall exposure from the two initial step-up doses was <3.6 mg. The QSP model predicted that the addition of a 7.2 mg step-up dose prior to the 160 mg target dose in Arm H2 would lead to a reduction in peak IL-6 levels and associated CRS risk at the 160 mg dose compared with the 160 mg target dose in the 0.3 / 3.6 / 160 mg double step-up regimen. In addition, the model predicted that the administration of a 7.2 mg step-up dose in Arm H2 would lead to similar peak IL-6 levels and CRS risk as that of the 3.6 mg step-up dose in Arm H1 .

Taken together, the pharmacological insights from the QSP model supported the testing of the proposed starting doses for the triple step-up dose-escalation arms.

/'/. Rationale for Fixed Doses

On the basis of this simulations-based evaluation, fixed doses were proposed for this study, in which the dose was not adjusted for weight. Fixed dosing has been utilized and approved for multiple monoclonal antibodies (e.g., obinutuzumab; GAZYVA® USPI).

Hi. Rationale for Continued Dosing Beyond the Dose-Limiting Toxicity Observation Period and Cevostamab Re-Treatment

Dosing beyond Cycle 1 for patients with R/R MM was allowed in the absence of unacceptable toxicity or objective evidence of disease progression and following a careful assessment and discussion of the potential risks and benefits with the patient.

Patients were treated with cevostamab for up to a maximum of 17 cycles. Patients who underwent intrapatient dose-escalation received up to 17 cycles at the intended target dose, providing maximal anti-myeloma effect.

The rationale for limiting the duration of cevostamab treatment to 17 cycles was 3-fold. First, chronic, and/or cumulative toxicity potentially associated with prolonged treatment duration was minimized. Second, a limited duration of treatment provided an opportunity to assess the duration of response once cevostamab treatment was discontinued. Finally, limiting cevostamab treatment to 17 cycles provided an opportunity to explore the possibility of cevostamab re-treatment in patients who achieved an objective response (PR or CR) or SD with initial cevostamab treatment provided that the retreatment criteria outlined herein were met. Because patients eligible for re-treatment must have had a documented objective response at the time of discontinuing cevostamab therapy following 17 cycles, retreatment was considered if the patient was likely to achieve another response and derive clinical benefit. iv. Rationale for Pharmacokinetic, Pharmacodynamic, and Anti-Drug Antibody Sampling Schedule The PK sampling schedule that followed the cevostamab administration was designed to capture cevostamab exposure data at a sufficient number of timepoints to provide a detailed profile of the concentration-time curve. Additionally, the PD sampling schedule was designed to provide a detailed profile of the magnitude and kinetics of T-cell activation, possible peripheral blood B-cell depletion, and cytokine release following cevostamab treatment. These data inform the relationship of dose to exposure and to support PK- and/or PD-based dose selection and schedules of cevostamab administration as a single agent and in combination with other agents used to treat MM.

F. Materials and Methods

Enrolled patients with R/R MM in this study were as follows:

• ~15 patients in each of the dose-escalation Arms H1 and H2

• ~15 patients in each of the expansion Arms 11 and I2

/'. Inclusion Criteria

Patients must have met the following criteria for study entry:

• Signed Informed Consent Form(s)

• Age >18 years at time of signing Informed Consent Form

• Ability to comply with the study protocol, in the investigator's judgment

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

• Patients must have R/R MM for which no established therapy for MM is appropriate and available or be intolerant to those established therapies

• Agreement to provide bone marrow biopsy and aspirate samples

• Adverse events from prior anti-cancer therapy resolved to Grade < 1 , with the following exceptions:

Any grade alopecia

Peripheral sensory or motor neuropathy must have resolved to Grade < 2

• Measurable disease defined as at least one of the following:

Serum monoclonal protein (M-protein) >0.5 g/dL (>5 g/L)

Urine M-protein >200 mg/24 hr

Serum free light chain (SFLC) assay: Involved SFLCs >10 mg/dL (>100 mg/L) and an abnormal SFLC ratio (< 0.26 or > 1 .65)

• Laboratory values as follows:

Hepatic function

AST and ALT < 2.5 x ULN

Total bilirubin < 1 .5 x ULN; patients with a documented history of Gilbert syndrome and in whom total bilirubin elevations are accompanied by elevated indirect bilirubin are eligible.

Hematologic function (requirement prior to first dose of cevostamab) Platelet count >50,000/mm³ without transfusion within 7 days prior to first dose

ANC >1000/mm³

Total hemoglobin >8 g/dL

Note: Patients may have received supportive care to meet hematologic function eligibility criteria (e.g., transfusions, G-CSF, etc.).

Creatinine < 2.0 mL/dL and creatinine clearance (CrCI) >30 mL/min (either calculated or per 24-hr urine collection)

Serum calcium (corrected for albumin) level at or below Grade 1 hypercalcemia (patient may have received treatment for hypercalcemia to meet eligibility criteria)

/'/. Exclusion Criteria

Patients who met any of the following criteria were excluded from study entry:

• Inability to comply with protocol-mandated hospitalization and activities restrictions

• Prior use of any monoclonal antibody, radioimmunoconjugate, or antibody-drug conjugate as anti-cancer therapy within 4 weeks before first cevostamab infusion

• Prior treatment with systemic immunotherapeutic agents, including, but not limited to, cytokine therapy and anti-CTLA4, anti-PD-1 , and anti-PD-L1 therapeutic antibodies, within 12 weeks or 5 half-lives of the drug, whichever is shorter, before first cevostamab infusion

• Prior treatment with chimeric antigen receptor (CAR) T-cell therapy within 12 weeks before first cevostamab infusion

• Known treatment-related, immune-mediated adverse events associated with prior immunotherapeutic agents as follows:

- Prior PD-L1/PD-1 or CTLA-4 inhibitor: Grade >3 adverse events with the exception of Grade 3 endocrinopathy managed with replacement therapy

Grade 1 -2 adverse events that did not resolve to baseline after treatment discontinuation

• Treatment with radiotherapy, any chemotherapeutic agent, or treatment with any other anticancer agent (investigational or otherwise) within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to first cevostamab infusion

• Autologous stem cell transplantation (SCT) within 100 days prior to first cevostamab infusion

• Prior allogeneic SCT

• Absolute plasma cell count exceeding 500/pL or 5% of the peripheral blood white cells

• Prior solid organ transplantation

• History of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis

Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study. Patients with history of confirmed progressive multifocal leukoencephalopathy

Known history of hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS)

History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (or recombinant antibody-related fusion proteins)

Patients with known history of amyloidosis (e.g., positive Congo Red stain or equivalent in tissue biopsy)

Patients with lesions in proximity of vital organs that may develop sudden decompensation/deterioration in the setting of a tumor flare

History of other malignancy that could have affected compliance with the protocol or interpretation of results

Patients with a history of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix were allowed.

Patients with a malignancy that had been treated with curative intent were also allowed if the malignancy had been in remission without treatment for >2 years prior to first cevostamab infusion.

Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, neurodegenerative disease, or CNS involvement by MM

- Patients with a history of stroke who had not experienced a stroke or transient ischemic attack in the past 2 years and had no residual neurologic deficits as judged by the investigator were allowed.

Patients with a history of epilepsy who had no seizures in the past 2 years while not receiving any anti-epileptic medications were allowed.

Significant cardiovascular disease (such as, but not limited to, New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last

6 months, uncontrolled arrhythmias, or unstable angina) that may limit a patient's ability to adequately respond to a CRS event

Symptomatic active pulmonary disease or requiring supplemental oxygen

Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics within 14 days prior to first cevostamab infusion Positive and quantifiable EBV PCR or CMV PCR prior to first study treatment Known or suspected chronic active EBV infection

Guidelines for diagnosing chronic active EBV infection are provided by Okano et al. (2005).

Recent major surgery within 4 weeks prior to first cevostamab infusion

Protocol-mandated procedures (e.g., bone marrow biopsies) were permitted.

Positive serologic or PCR test results for acute or chronic HBV infection

Patients whose HBV infection status could not be determined by serologic test results must have been negative for HBV by PCR for eligibility for study participation. Acute or chronic HCV infection

- Patients who were positive for HCV antibody must have been negative for HCV by PCR for eligibility for study participation.

• Known history of HIV seropositivity

• Any episode of active, symptomatic COVID-19 infection, or requiring treatment with IV antivirals for COVID-19 (not including COVID-19 primary prophylaxis) within 14 days, prior to first study treatment

Patients with symptomatic COVID-19 infection must have had two negative antigen tests at least 1 day apart prior to first study treatment.

• Administration of a live, attenuated vaccine within 4 weeks before first cevostamab infusion or anticipation that such a live attenuated vaccine was required during the study

Influenza vaccination should have been given during influenza season (approximately October to May in the Northern Hemisphere; approximately May to October in the Southern Hemisphere). Patients must not have received live, attenuated influenza vaccine (e.g., FLUMIST®) at any time during the study treatment period.

SARS-CoV-2 vaccines may have been given in accordance with the approved/authorized vaccine label and official/local immunization guidance. SARS-CoV-2 vaccines must not have been administered within 1 week before first study treatment or during Cycle 1 . Investigators reviewed the vaccination status of potential study patients that were considered for this study and followed the U.S. Centers for Disease Control and Prevention guidelines for adult vaccination with any other non-live vaccines intended to prevent infectious diseases prior to study.

• Received systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents), with the exception of corticosteroid treatment < 10 mg/day prednisone or equivalent within 2 weeks prior to first dose of cevostamab and, if applicable, tocilizumab premedication prior to first dose of cevostamab

Patients who received acute, low-dose, systemic immunosuppressant medications (e.g., single dose of dexamethasone for nausea) could enrolled in the study after discussion with and approval of the Medical Monitor.

The use of inhaled corticosteroids was permitted.

The use of mineralocorticoids for management of orthostatic hypotension was permitted. The use of physiologic doses of corticosteroids for management of adrenal insufficiency was permitted.

Hi. Cevostamab Administration

Flat dosing independent of body weight was used for cevostamab. The dose of cevostamab for each patient depended on their dose level assignment as described herein. Cevostamab was administered to patients by IV infusion using standard medical syringes and syringe pumps or IV bags where applicable. Compatibility testing has shown that cevostamab is stable in extension sets and polypropylene syringes. The final cevostamab volume was determined by the dose. Hospitalization requirements for patients receiving cevostamab are described herein.

Cevostamab was administered in a setting with immediate access to trained critical care personnel and facilities equipped to respond to and manage medical emergencies.

Cevostamab dosing only occurred if a patient's clinical assessment and laboratory test values are acceptable. All cevostamab doses were administered to well-hydrated patients. Corticosteroid premedication consisting of dexamethasone 20 mg IV or methylprednisolone 80 mg IV must have been administered 1 hour (± 15 minutes) prior to the administration of each cevostamab dose in Cycle 1 and Cycle 2, or in the subsequent cycle if the patient experienced CRS with the prior dose. From Cycle 3 onward, corticosteroid premedication was discontinued in patients who did not have CRS with the prior dose. In addition, premedication with oral or intravenous (IV) acetaminophen or paracetamol (e.g., 500- 1000 mg) and 25-50 mg diphenhydramine must have been administered prior to administration of cevostamab, unless contraindicated. For sites that did not have access to diphenhydramine, an equivalent medication was substituted per local practice.

Initially, cevostamab was administered over 4 hours (± 15 minutes). The infusion was slowed or interrupted for patients that experienced infusion-related reactions. At the end of the cevostamab infusions during Cycle 1 , patients were hospitalized. Patients were observed every 60 (± 10) minutes until 6 hours after the end of infusion for fever, chills, rigors, hypotension, nausea, or other signs and symptoms of IRRs and CRS following each subsequent cevostamab infusion in Cycle 1 . Also, in the absence of IRRs and CRS after receiving the first target dose, the infusion time of cevostamab in subsequent cycles was reduced to 2 hours. If repeat step-up dosing was required due to a dose delay, the next two doses (step and target dose) were administered over 4 hours.

Patients who received less than 80% of the initial step-dose repeated the step-dose (if the patient met all the dosing requirements) prior to receiving the higher target dose.

In Cycle 1 , a repeat step-up dose was allowed if a patient experiences an adverse event during a step-up dose that was determined to be clinically significant and warranted a repeat step-up dose at the next dosing. The step-up dose was repeated for any patient that experienced a Grade 3 CRS following the Cycle 1 Day 1 dose (or intermediate dose).

Patients who underwent intrapatient dose escalation received the first higher infusion of cevostamab over a minimum of 4 hours.

For Arms H1 , H2, 11 , I2, and J, for doses that are scheduled 1 day apart, there must have been a minimum of 20 hours from the end of infusion of the previous cevostamab dose to the initiation of the next dose.

Management of infusion-related reactions (IRRs) and guidelines for dosage and schedule modification and treatment interruption or discontinuation are provided herein. G. Safety Plan

Measures were taken to ensure the safety of patients participating in this trial, including the use of stringent inclusion and exclusion criteria described herein and close monitoring, as described below. Enrollment of the first 2 patients in each dose-escalation cohort was staggered such that the respective C1 D1 treatments were administered >72 hours apart. Subsequent patients in each cohort were staggered such that their C1 D1 treatments are administered >24 hours apart.

All patients were monitored closely for toxicity. Patients were assessed clinically for toxicity prior to each dose using the NCI CTCAE v4.0 grading scale, except for CRS in which the ASTCT grading scale was used. All adverse events and serious adverse events were recorded during the trial and for up to 90 days after the last dose of study treatment or until the initiation of another systemic anti-cancer therapy, whichever occurred first. To mitigate potential unknown risks, dosing beyond Cycle 1 was limited to patients who did not demonstrate unacceptable toxicity or compelling evidence of disease progression. Specific anticipated or potential toxicities associated with administration of cevostamab, as well as the measures taken to avoid or minimize such toxicities in this trial, are described in the following sections.

/'. Cevostamab Infusion and Hospitalization

Administration of cevostamab occurred in an outpatient or inpatient setting, so long as the administration was performed in a clinical setting with immediate access to a critical care unit and staff who were trained to monitor for and respond to medical emergencies. Neurology consultation services were readily available to address any neurologic adverse events that may have arisen as a result of cevostamab treatment.

All patients enrolled in dose-escalation cohorts and dose-expansion arms were observed in a hospital inpatient unit immediately following completion of the cevostamab infusion through at least 48 hours after the completion of infusion during Cycle 1 doses. Before a patient could be discharged, physical examination and relevant laboratory results, obtained 48 hours after infusion, must have indicated no evidence of ongoing CRS/IRR, MAS, or neurological toxicity.

During Cycle 1 , hospitalization following cevostamab administration was not required if that dose had been shown to be tolerated in a previous cohort on the same day during Cycle 1 , unless hospitalization was determined to be clinically indicated. Examples where such hospitalization was warranted included, but were not limited to, prior Grade >2 adverse events potentially attributable to cevostamab at the same or similar dose, and TLS monitoring and prophylaxis.

Patients who experienced Grade 2 or lower IRR/CRS with the Cycle 1 target dose may not have required hospitalization for the next dose on C2D1 after consultation with the Medical Monitor.

Patients who did not experience IRR or CRS with the Cycle 1 target dose did not require hospitalization for the next dose on C2D1 and subsequent doses.

In subsequent doses, patients were monitored for at least 90 minutes post-dose and must have indicated no evidence of ongoing CRS/IRR, MAS, or neurological toxicity prior to discharge. A patient who developed Grade 2 or higher CRS at any subsequent dose was then hospitalized for the next dose to monitor for recurrent CRS as outlined in Table 9 below. If no IRR/CRS occurred with the subsequent dose, subsequent dosing was administered as outpatient. Patients that underwent repeat step-up (or intermediate) dosing were hospitalized and monitored for treatment-emergent toxicities for at least 48 hours following the repeat step-up dose (or respectively intermediate dose).

Patients that underwent intrapatient dose escalation were also hospitalized and monitored for treatment-emergent toxicities for at least 24 hours following their first dose- escalated infusion.

Table 9: Recommendations for Management of Cytokine Release Syndrome

CRS = cytokine release syndrome; HLH = hemophagocytic lymphohistiocytosis; ICU = intensive care unit; IV = intravenous.

Note: CRS is characterized by a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells. Symptoms can be progressive, must include fever at the onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction. a Guidance for CRS management based on Lee et al., Biol Blood Marrow Transplant, 25(4): 625-638, 2019; Riegler et al., Then Clin. Manag., 15:323-335, 2019; and Rodriguez-Otero eta!., Lancet. Concol., (5):e205-e216, 2024. b Fever may not be prominent in patients who have received antipyretics, corticosteroids, or anticytokine therapy. In this case, management is driven by hypotension and/or hypoxia. Patients should be treated with acetaminophen/paracetamol and an antihistamine (e.g., diphenhydramine) if they have not been administered in the previous

4 hours. For bronchospasm, urticaria, or dyspnea, treat as clinically indicated. Perform an infection workup, including assessment for bacterial, fungal, and viral infections, and cultures. Treat fever and neutropenia as required; administer broad-spectrum antibiotics and/or granulocyte colony-stimulating factor if indicated. d Tocilizumab should be administered at a dose of 8 mg/kg IV (8 mg/kg for patients >30 kg weight only; 12 mg/kg for patients < 30 kg weight; doses exceeding 800 mg per infusion are not recommended); tocilizumab can be repeated generally for a maximum of three doses in 24 hours. If CRS persists or recurs after 1 -3 doses of tocilizumab, second-line therapy can be started, such as corticosteroids (e.g., dexamethasone 10 mg IV every 6 hours until resolution) and alternative cytokine therapy (e.g., see Rodriguez-Otero et a!., Lancet. Concol., (5):e205-e216, 2024). e If the patient does not experience CRS during the next dose at the up to 50% reduced rate, the infusion rate can be increased to the initial rate for subsequent doses. However, if this patient experiences another CRS event, the infusion rate should be reduced by 25%-50% depending on the severity of the event.

/'/. Dose and Schedule Modifications

Cevostamab dosing occurred only if a patient's clinical assessment and laboratory test values were acceptable. If scheduled dosing coincides with a holiday that precludes dosing, dosing commenced on the nearest following date, with subsequent dosing continuing on a 21 -day schedule as applicable.

Management guidelines, including study treatment dose and schedule modifications for specific adverse events, are described herein.

After Cycle 1 Day 1 , the following hematologic laboratory thresholds were met prior to dosing with cevostamab:

• Platelet count >20,000/mm³

• ANC >500/mm³

• Hemoglobin >7 g/dL

• Corrected serum calcium must have been at or below Grade 1 hypercalcemia Supportive care may have been provided per institutional standard practice.

If the patient experienced CRS with the previous dose, clinical symptoms of CRS (e.g., fever, hypotension, etc.) must have been resolved prior to administration of the subsequent dose. Additional dose delay may have been necessary depending on the clinical presentation of the CRS event.

For Arms H1 , H2, 11 , and I2, and for which doses that were scheduled 1 day apart, there was no clinical symptoms of CRS and a minimum of 20 hours from the end of infusion of the previous cevostamab dose to initiation of the next dose.

The following guidelines regarding dose and schedule modifications were followed:

• In general, patients receiving cevostamab who experience a Grade 4 adverse event that was not considered to be attributable to another clearly identifiable cause permanently discontinued all study treatment. However, for patients with Grade 4 adverse events of asymptomatic laboratory changes, study treatment resumed upon resolution to Grade < 1 with approval.

• For patients who experienced IRRs with the first dose of cevostamab or were at increased risk of recurrent IRRs with subsequent doses, the infusion rate was slowed by 50% (see, e.g., Table 10). If the patient did not experience IRR with the subsequent dose, the infusion rate was brought back to the initial rate during the infusion based on the investigator’s discretion.

• In general, patients who experienced either an adverse event that met the definition of a DLT or other Grade 3 adverse event that was not considered to be attributable to another clearly identifiable cause (e.g., disease progression, concomitant medication, or preexisting medical condition) were allowed to delay dosing for up to 2 weeks (or longer if approved by the Medical Monitor) in order to recover from the toxicity. Patients continued to receive additional infusions of cevostamab, provided that the toxicity has resolved to Grade < 1 (or for laboratory abnormalities, return to >80% of the baseline value), within 2 weeks.

- A reduced dose for subsequent infusions of cevostamab were considered and discussed with the Medical Monitor. If the intended reduced dose (e.g., to the next highest cleared dose level assessed during dose escalation) was to a dose level where there was no evidence of cevostamab PD activity (e.g., no evidence of changes in serum cytokine levels), the patient was discontinued from study treatment. Decisions on continued treatment following a DLT or other study treatment-related Grade 3 toxicity were made following a careful assessment and discussion of risk versus benefit with the patient, including in the following scenarios:

If an elevation of AST or ALT > 3x ULN and/or total bilirubin > 2x ULN, with no individual laboratory value exceeding Grade 3, occurred in the context of Grade < 2 CRS that lasts < 3 days, cevostamab dosing continued without dose reduction.

Patients with Grade 3 events of anemia if manageable by red blood cell transfusions as per institutional practice continued without dose reduction.

Patients with Grade 3 or 4 events of thrombocytopenia or neutropenia if manageable by transfusions (platelets) or granulocyte colony-stimulating factor (GCSF) as per institutional practice continued without dose reduction.

Patients with a Grade 3 or 4 event of neutropenia or thrombocytopenia that was considered due to disease and did not require transfusions or GCSF continued dosing without dose reduction.

- Any patient in whom similar toxicity recurred at a reduced dose were discontinued from further cevostamab treatment.

• Patients who did not fulfill the criteria for dosing after the additional 2 weeks elapsed were discontinued from study treatment (unless a longer dose delay was approved) and were followed for safety outcomes. Exceptions to this on the basis of ongoing clinical benefit were allowed following assessment of risk versus benefit. In addition, delay of therapy because of toxicities not attributed to study drug did not require discontinuation.

• Depending on the length of treatment delay, the patient may have been required to repeat step- up dosing. If a patient’s dose was delayed more than 2 to 4 weeks beyond their normally scheduled dose, repeat step-up dosing was considered. If a patient’s dose was delayed by more than 4 weeks beyond their normally scheduled dose, repeat step-up dosing was mandatory. Patients required hospitalization following the repeat step-up infusion of cevostamab. Table 10: Recommendations for Management of Infusion-Related Reactions

NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.

Refer to NCI CTCAE v4.0 for the grading of symptoms. b Supportive treatment: Patients should be treated with acetaminophen/paracetamol and an antihistamine such as diphenhydramine if they have not been administered in the last 4 hours. Intravenous fluids (e.g., normal saline) may be administered as clinically indicated. For bronchospasm, urticaria, or dyspnea, antihistamines, oxygen, corticosteroids (e.g., 100 mg IV prednisolone or equivalent), and/or bronchodilators may be administered per institutional practice. Provide vasopressor support for hypotension if required. c Subsequent infusions of cevostamab may be started at the original rate.

H. Risks Associated with Cevostamab

/'. Infusion-Related Reactions and Cytokine Release Syndrome

The mechanism of action of cevostamab is immune cell-activation against FcRF5-expressing cells; therefore, a spectrum of events involving IRRs, target-mediated cytokine release, and/or hypersensitivity with or without emergent ADAs, may occur. Other bispecific antibody therapeutics involving T-cell activation have been associated with IRR, CRS, and/or hypersensitivity reactions.

Based on nonclinical data, cevostamab has the potential to cause rapid increases in plasma cytokine levels. Thus, IRR may be clinically indistinguishable from manifestations of CRS, defined as a disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath (NCI CTCAE v.4.0), given the expected human pharmacology of cevostamab, where T-cell engagement with plasma cells and B cells results in T-cell activation and cytokine release. The selection of minimum anticipated biological effect level as the initial dose of cevostamab and the design of the dose-escalation scheme were specifically intended to minimize risk of exaggerated cytokine release.

To minimize the risk and sequelae of IRR and CRS, cevostamab was administered over a minimum of 4 hours in Cycle 1 in a clinical setting. Corticosteroid premedication must have been administered as described herein.

Mild to moderate presentations of IRR and/or CRS may include symptoms such as fever, headache, and myalgia, and were treated symptomatically with analgesics, anti-pyretics, and antihistamines as indicated. Severe or life-threatening presentations of IRR and/or CRS, such as hypotension, tachycardia, dyspnea, or chest discomfort were treated aggressively with supportive and resuscitative measures as indicated, including the use of high-dose corticosteroids, IV fluids, admission to intensive care unit, and other supportive measures per institutional practice. Severe CRS may be associated with other clinical sequelae such as disseminated intravascular coagulation, capillary leak syndrome, or MAS. Standard of care for severe or life-threatening CRS resulting from immune-based therapy has not been established; case reports and recommendations using anti-cytokine therapy such as tocilizumab have been published (see, e.g., Teachey et al., Blood, 121 (26) :5154-7, 2013; Lee et al., Blood, 124: 188-195, 2014; and Maude et al., New Engl J Med, 371 : 1507-1517, 2014).

Management guidelines for IRR and CRS are summarized Table 9 and Table 10, respectively, with the grading of CRS following the ASTCT grading scale described in Table 8.

Table 11 A shows an overview of CRS events across the single step-up, double step-up, and triple step-up dosing regimens. Grade 1 -4 CRS events were reported. No Grade 5 CRS events were reported. Most CRS events occurred in Cycle 1 . Table 11B shows a more detailed distribution of these CRS events across each step-up dose (SUD) and target dose (TD). Table 11C shows an overview of CRS events in given intervals (days) following a given step-up dose and target dose.

In the triple step-up dosing regimen (e.g., Arm H1 ), CRS was observed in 63.3% of patients, with all events of Grade 1 (46.7%) or Grade 2 (16.7%) maximum severity. No Grade >3 CRS was reported. The median time to onset of CRS events from the end of infusion in this regimen is 1 1 .4 hours (range: 0- 57.1 hours), with the majority of events (64.7%) occurring within 24 hours from the end of infusion. The time to resolution of CRS events is 1 day (range: 0-5 days), which is comparable across different regimens. All CRS events in this regimen resolved.

Table 11 A: Overview of Cytokine Release Syndrome Across Step-Up Dosing Regimens in Safety- Evaluable Population in Studies GO39775 and CO43476

CRS=cytokine release syndrome; SAE=serious adverse event; SUD=step-up dose; TD=target dose.

Note: CRS was graded according to American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading scale (e.g., see Lee et al., Biol Blood Marrow Transplant, 25(4): 625-638, 2019). Multiple occurrences of events in one individual within a given cycle were counted once at the highest grade. ^a This Grade 4 CRS event, reported in a 69-year-old female patient, is confounded by prior onset of pneumonia. She was intubated with a diagnosis of acute hypoxic respiratory failure, and multiple antimicrobials were started. She had persistent fevers and was treated with pressors for hypotension, a single dose of tocilizumab, and was started on dexamethasone. The investigator assessed this as a Grade 4 delayed CRS event because the fever and hypotension resolved after treatment with tocilizumab and dexamethasone. Approximately one week later, the patient was diagnosed with an event of Grade 2 confusional state, which was treated with dexamethasone and anakinra. Subsequently, the patient was diagnosed with pseudomonal sepsis (Grade 4 to Grade 5) and developed septic shock, which was treated with antibiotics, multiple pressors, continuous renal replacement therapy, and intubation. The patient died due to pseudomonal sepsis. ^b Time to resolution is calculated as the end date of CRS in day minus the start date of CRS in day. ^c One Grade 1 CRS event with Grade 1 confusion occurring after the administration of a step-up dose of 3.6 mg in a patient enrolled in the 3.6/90 mg cohort in Study GO39775 was not resolved. This patient did not continue to receive target dose due to disease progression and soon after died. Because the confusion event had not resolved at the time of progression, the site did not report the resolution of the CRS event.

Table 11B. Distribution of CRS at Step-up Doses (Including First Target Dose) and Subsequent

Target Doses Across Dosing Regimens in Safety-Evaluable Population in Study GO39775

ASTCT = American Society for Transplantation and Cellular Therapy (e.g., see Lee eta!., Biol Blood Marrow Transplant, 25(4): 625-638, 2019); CRS = cytokine release syndrome; SUD = step-up dose; TD = target dose; n/a = not applicable

Notes: TD was given Q3W starting from Cycle 2 and up to Cycle 17 in Study GO39775 and until disease progression, unacceptable toxicity, withdrawal of consent, or death. CRS was graded according to ASTCT 2019 grading scale. Percentages are based on patients who received the specified dose (n is specified on each dose row). Multiple occurrences of events in one individual within a given cycle were counted once at the highest grade. a This patient in Study GO39775 reported a CRS event that could not be graded according to the ASTCT 2019 grading criteria due to the lack of reported fever; therefore, no ASTCT grade was derived. b This Grade 4 CRS event, reported in a 69-year-old female patient, is confounded by prior onset of pneumonia. She was intubated with a diagnosis of acute hypoxic respiratory failure, and multiple antimicrobials were started. She had persistent fevers and was treated with pressors for hypotension, a single dose of tocilizumab, and was started on dexamethasone. The investigator assessed this as a Grade 4 delayed CRS event because the fever and hypotension resolved after treatment with tocilizumab and dexamethasone. Approximately one week later, the patient was diagnosed with an event of Grade 2 confusional state, which was treated with dexamethasone and anakinra. Subsequently, the patient was diagnosed with pseudomonal sepsis (Grade 4 to Grade 5) and developed septic shock, which was treated with antibiotics, multiple pressors, continuous renal replacement therapy, and intubation. The patient died due to pseudomonal sepsis.

All CRS events after the second SUD occurred in patients who received the dose 1 day or 2 days after the first SUD (Table 11C). No CRS events were reported in patients who received the second SUD 3 days and 6 days from the first SUD. The third SUD of 3.6 mg is administered on Day 8 (e.g., 4, 5, or 6 days after the second SUD of 1 .2 mg):

• The median time from the second SUD to the third SUD was 6 days (range: 4-28 days). In patients who developed CRS after receiving the second SUD, the median time to the third SUD was 6 days (range: 5-6 days). • CRS after the third SUD was reported only in patients who received the dose 5 days and 6 days after the second SUD (Table 11C). Patients who received the third SUD 4 days or > 7 days (e.g., 7, 8, 13, or 28 days) after the second SUD did not experience CRS. All CRS events reported following these first, second, and third SUDs were Grade 1 .

The first target dose of 160 mg was administered on Day 10 or 11 (i.e., 2 or 3 days after the third SUD of 3.6 mg if there were no CRS events or if CRS signs and symptoms from the previous dose had resolved). The data below reflect those collected from Study GO39775, which allows the administration of the first target dose of 160 mg on Day 9, 10, or 11 (e.g., 1 , 2, or 3 days after the third SUD of 3.6 mg).

• The median time from the third SUD to the first target dose was 1 day (range: 1 -3 days). The three patients who developed CRS after receiving the third SUD were able to receive the first target dose within the expected days of interval (e.g., 2 or 3 days after the third SUD).

• At the first target dose, the highest proportion of CRS was observed in patients who received the dose 1 day after the third SUD, with Grade 1 events in 33.3% (7 of 21 patients receiving the dose) and Grade 2 events in 19.0% (4 of 21 patients receiving the dose) (Table 11C). Patients who received the target dose 2 or 3 days after the third SUD also developed CRS, although all of these events were Grade 1 .

These data indicate acceptable CRS risk at the second SUD and third SUD when given within the expected days of interval from the last dose. The data support the administration of the second SUD of 1 .2 mg on Day 2, 3, or 4 (e.g., 1 , 2, or 3 days after the first SUD of 0.3 mg) and the third SUD of 3.6 mg on Day 8 (e.g., 4, 5, or 6 days after the second SUD). Grade 2 CRS events were reported when the first target dose of 160 mg was administered only 1 day after the third SUD of 3.6 mg.

Table 11 C: CRS at Step-Up Doses and Target Doses by Interval from the Last Dose in the Safety- Evaluable Population of Triple-Step Priming Regimen of 0.3/1.2/3.6/160 mg in Study GO39775

CRS=cytokine release syndrome; SUD = step-up dose; TD = target dose.

Note: Per the protocol of Study GO39775, the expected days of administration for this priming regimen is Day 1 for first SUD, Day 2, 3, or 4 for second SUD, Day 8 for third SUD, and Day 9, 10, or 11 for first TD. The table shows the actual days of interval from the previous dose. The expected days of interval from the last dose are shown as boxes with black thick border. a Percentage is based on the number of patients receiving the specified dose in the middle column.

All CRS events across all regimens resolved without intervention or with standard supportive care, tocilizumab, and/or steroids. Generally, CRS was manageable across dosing regimens with very few patients requiring vasopressor, high flow oxygen, or intensive care unit care, and only a single patient discontinued treatment due to CRS (e.g., see Table 11 D).

Table 11D: Management of CRS Events in All Treatment Cycles Across Priming Regimens in Safety-Evaluable Populations in Study GO39775 and Study CO43476

CRS=cytokine release syndrome; SUD=step-up dose; TD=target dose. a Percentages are based on the number of patients with CRS.

Associated signs and symptoms of CRS were collected with each event. The most frequent signs and symptoms associated with CRS in >10% of patients are presented in Table 11E. The most frequent

CRS sign and symptom was pyrexia. In all priming regimen cohorts, including the selected

0.3/1 .2/3.6/160 mg triple-step regimen cohort, signs and symptoms observed with the CRS events were monitorable, manageable, and reversible with the use of supportive therapy to treat CRS according to the guidelines described herein.

Table 11E: CRS Signs and Symptoms (>10%) Across Priming Regimens in Safety-Evaluable Populations in Study GO39775 and Study CO43476

CRS=cytokine release syndrome; SUD=step-up dose; TD=target dose. All signs and symptoms with incidence of >10% at any priming regimen are included in the table. a Per American Society for Transplantation and Cellular Therapy 2019 grading scale, Grade 2 and above CRS is driven by the presence of hypotension and/or hypoxia signs and symptoms. Symptom terms for hypotension include 'Hypotension' or 'Blood pressure decreased,' and symptom terms for hypoxia include 'Hypoxia' or 'Oxygen Saturation decreased.'

The supportive therapies used to treat CRS events in the first cycle of treatment with cevostamab were effective. Tocilizumab used for treatment of CRS during the initial step-up dose(s) may reduce the severity of the treated CRS event as well as the incidence and severity of CRS in subsequent doses based on the pharmacokinetics and receptor occupancy of tocilizumab (Xu et al. 2021 ). Across all regimens, a consistent trend toward lower rates of all-grade and Grade >2 CRS at the first target dose was observed in patients who received tocilizumab during any prior step-up doses (e.g., see Table 12).

Table 12: Cytokine Release Syndrome Events at the First or Cycle 1 Target Dose(s) with or without Tocilizumab Usage in Prior Step-Up Doses Across Dosing Regimens in Safety-Evaluable

Population in Studies GO39775 and CO43476

SUD = step-up dose; TD = target dose; n/a = not applicable; CRS = cytokine release syndrome a Prior tocilizumab usage has only been determined for patients who were exposed to target dose. Patients who were not exposed to target dose for any reason are not included. b Percentage is based on the number of patients who were or were not given tocilizumab in any prior SUD(s), i.e., the n under the “Yes” or “No” columns, respectively.

Tocilizumab was used to treat CRS in 30.0% (9 of 30) patients receiving the selected

0.3/1 .2/3.6/160 mg triple step-up regimen, with 4 patients and another 4 patients receiving tocilizumab to treat Grade 1 and Grade 2 CRS events, respectively. Tocilizumab was given to treat CRS occurring after the three step-up doses in 3 patients (one patient each at each step-up dose), after the first target dose in 5 patients, and after the second target dose in 1 patient (FIG. 4A). One patient who received tocilizumab to treat Grade 2 CRS occurring after the first target dose in Cycle 1 experienced Grade 1 CRS events in Cycle 2, Cycle 3, and Cycle 6. The other 8 patients who received tocilizumab did not experience recurrence of CRS.

Tocilizumab was used to treat CRS in 36.7% (1 1 of 30) patients receiving the selected 0.3/3.3/7.2/160 mg triple step-up regimen, with 5 patients and 4 patients receiving tocilizumab to treat Grade 1 and Grade 2 CRS events, respectively (FIG. 4B). FIG. 57 provides similar data for single step-up and double step-up dosing regimens.

As observed in a Quantitative Systems Pharmacology (QSP) analysis (e.g., see Example 3), the triple step-up arms showed low overall CRS rates (FIG. 5), with Grade 2 and higher CRS rates appearing to decline with additional step-up doses. For example, triple step-up regimens (Arms H1 , H2, 11 , I2) show notable reduction in overall CRS rates compared to single step-up regimens. Moreover, Arm H1 exhibited low rate of overall CRS, Grade 2 CRS with tocilizumab use, as well as no Grade 3 or 4 CRS events. Despite extra priming doses, triple step-up arms had the lowest total number of CRS events normalized per patient. Neither regimen increased the number of patients experiencing multiple CRS events. Rates and grades of CRS are summarized in FIG. 6.

Across regimens, the majority of patients who experienced CRS had one event of CRS in Cycle 1 (Table 13). Recurrent CRS events in Cycle 1 were noted in all regimens, with the majority being Grade 1 . Recurrent Grade 2 events were infrequent at less than 5%.

Among 30 patients receiving the selected 0.3/1 .2/3.6/160 mg triple step-up regimen (Arm H1 ), 12 patients (40.0%) had one event of CRS in Cycle 1 . The recurrence of any-grade CRS events in Cycle 1 occurred in 5 patients (16.7%) who had 2 CRS events and 1 patient (3.3%) who had 4 CRS events. All recurrent events were Grade 1 . There were no recurrent Grade 2 events. These data indicate that an addition of a step-up dose does not increase the risk of CRS recurrence in Cycle 1 .

Table 13: Reoccurrence of Cytokine Release Syndrome Events in Cycle 1 by Grade Across Dosing Regimens in Safety-Evaluable Population in Studies GO39775 and CO43476

SUD = step-up dose; TD = target dose; CRS = Cytokine release syndrome

/'/. Macrophage Activation Syndrome and Hemophagocytic Lymphohistiocytosis

HLH/MAS is a rare condition characterized by inappropriate immune activation, often precipitated by factors such as infection including EBV, autoimmune disease, and malignancies, including, very rarely, MM. HLH/MAS has also been reported with T-cell engaging therapies such as bispecific antibodies and CAR T-cell therapies. Severe CRS and HLH/MAS can have overlapping presentations and symptoms. In addition, not all cases of HLH/MAS reported in clinical trials with cevostamab had preceding CRS. In general, patients in clinical trials with cevostamab who experienced HLH/MAS presented with fever, pancytopenia, elevated transaminases, and elevated ferritin levels.

Diagnostic, monitoring, and management guidelines for HLH/MAS are described below. Signs and symptoms may be nonspecific and onset may initially appear subtle. Once HLH/MAS was suspected, priority was placed on rapid evaluation for organ damage, with the goal of starting treatment as rapidly as possible once the diagnosis of HLH/MAS is made.

Traditionally, diagnosis of HLH/MAS has used the HLH-2004 criteria, which requires at least five of the following eight criteria to be met: (1 ) fever >38.5°C; (2) splenomegaly; (3) peripheral blood cytopenias affecting at least two cell lines (hemoglobin < 9 g/dL, platelets < 100,000/pL, and/or absolute neutrophil count < 1000/pL); (4) fasting triglyceride >265 mg/dL and/or fibrinogen < 150 mg/dL; (5) hemophagocytosis in bone marrow, spleen, lymph node, or liver; (6) low or absent NK cell activity; (7) ferritin > 500 ng/mL; (8) elevated soluble interleukin 2 (IL-2) receptor (soluble CD25) two standard deviations above laboratory-specific normal range.

While there is currently no universally accepted set of criteria for diagnosing HLH/MAS in this setting, guidelines have been proposed, which include elevated ferritin (>2x ULN or baseline, and/or rapidly rising), in the setting of a hyperinflammatory syndrome that is independent from CRS and immune effector cell-associated neurotoxicity syndrome (ICANS). Rather than using specific laboratory cutoffs, investigators were recommended to consider the above criteria in conjunction with a constellation of the following signs or symptoms presenting in patients, to make the diagnosis:

• Acute or unexplained rise in ferritin, particularly if accompanied by evidence of liver injury (significant increases in transaminases and/or bilirubin), new onset or marked worsening of cytopenias, and/or evidence of coagulopathy

• Signs of hyperinflammation (elevated CRP, ferritin, etc.) accompanying acute organ damage to the pulmonary, renal, neurologic, and/or other organ systems

• Signs and symptoms of severe sepsis

• Fever of unknown origin

• Grade >3 CRS at onset

• Late-onset CRS signs and symptoms, regardless of severity, that first present >72 hours following cevostamab administration

• CRS symptoms, regardless of severity, that persist >24 hours following initial management (as outlined in Table 9) and appear refractory to treatment

In all cases of suspected HLH/MAS, further dosing of cevostamab may be withheld. If HLH/MAS is confirmed, cevostamab may be discontinued. Table 14 includes recommended investigations, monitoring, and treatment guidelines for suspected or confirmed cases of HLH/MAS. The investigations, monitoring, and treatment recommendations within this guidance were non-mandatory. Therapy for HLH/MAS was individualized, based on the patient's clinical status, institutional practice, and available therapy and determined in consultation with the study investigator and a hematologist or other specialist with expertise in treating HLH/MAS.

Table 14: Guidelines for Investigation and Management of Suspected Hemophagocytic Lymphohistiocytosis / Macrophage Activation Syndrome a DNA tests such as PRF1 , MUNC13-4, STXBP2 as exploratory analysis can be considered. Additional virology: parvovirus, herpes simplex virus, varicella-zoster virus, measles virus, human herpesvirus 8, H1 N1 influenza virus, parechovirus can be considered. b Hayden et al., Ann. Oncol., 33:259-75, 2022. c Hines et al., Transplant Cell Then, S2666-6367:01 164-8, 2023. d Abou-el-Enein M, Gauthier J., Springer International Publishing, 231 -4, 2022. e Kennedy et al., Blood Adv., 5:5344-8, 2021 .

Hi. Neurologic Toxicity Neurologic toxicity has been reported frequently with blinatumomab and CAR-T cell therapy such as idecabtagene vicleucel; some of these events were life threatening or fatal. Reported symptoms have included headache, confusion, aphasia, encephalopathy, tremor, seizure, and other neurologic events. The etiology of toxicity in these settings is not known and may not be responsive to cytokine directed therapy such as tocilizumab but has generally improved with treatment discontinuations and corticosteroids. In patients with B-cell ALL who were treated with blinatumomab, neurologic toxicities were observed in approximately 50% of patients; Grade >3 neurological toxicity was observed in approximately 15% of patients. The majority of neurologic adverse events resolved following interruption of blinatumomab, with some patients requiring treatment discontinuation (BLINCYTO® USPI). Immune effector cell-associated neurotoxicity may manifest as delirium, encephalopathy, aphasia, lethargy, difficulty concentrating, agitation, tremor, seizures or, rarely, cerebral edema. Neurological symptoms may occur during or more commonly after CRS symptom onset (but rarely before CRS). Peak levels of IL-6, CRP, and ferritin are significantly higher in patients who develop immune- mediated neurotoxicity.

Neurologic toxicity was monitored during the trial. All patients were required to undergo a baseline complete neurologic examination prior to the first cevostamab infusion; the examination included an evaluation of mental status (e.g., Mini- Mental State Examination), cranial nerves, motor strength, sensation, and coordination. Results of the neurologic examination were documented in the patient's chart. A baseline brain MRI was also obtained in all patients unless medically contraindicated. Patients with a history of neurologic disease were excluded from this trial.

Patients were routinely assessed for any signs or symptoms of neurologic toxicity as part of the on-treatment clinical examination, including assessment of alertness and orientation. If new or worsening neurologic toxicity was suspected, the patient was referred to a neurologist for further evaluation of potential drug-related neurotoxicity. Treatable causes of neurologic dysfunction such as infection or hemorrhage were ruled out. Common manifestations of neurotoxicity can also be seen with infection, electrolyte imbalance, metabolic acidosis, uremia, concomitant medications (e.g., narcotics), and other medical conditions. Other causes for such symptoms were considered. Management of neurotoxicity is detailed in Table 15, shown below.

Table 15: Management Guidelines for Neurologic Toxicities

If immune-mediated mechanisms were suspected, corticosteroid treatment was administered per management guidelines for neurologic toxicities (Table 15).

Decisions on whether to continue or to hold cevostamab treatment for any Grade 1 neurotoxicity was at the discretion of the study investigator. For Grade >2 neurologic toxicity and Grade >1 seizure, treatment with cevostamab was held until the toxicity returned to baseline for at least 3 days without any medication. If restarting cevostamab following toxicity resolution, schedule modifications were considered. For Grade 3 neurologic toxicity lasting >3 days, the overall benefit-risk of continued treatment with cevostamab was assessed by a clinician. If Grade 3 neurologic toxicity recurred in any subsequent cycles, cevostamab was permanently discontinued. Cevostamab was permanently discontinued for Grade >3 seizures and all other Grade 4 neurologic toxicities.

Neurological events, including immune effector cell-associated neurotoxicity syndrome, are summarized in Table 16A. At the 160 mg target dose of a triple step-up regimen having a three-dose priming sequence (e.g., 0.3/1 .2/3.6 mg), 33.3% of patients experienced neurological adverse events, of which only 6.7% were >3 neurological adverse events.

Table 16A: Overview of Neurological Adverse Events Across Dosing Regimens in Safety-

Evaluable Population

AE = adverse event; PrD = progressive disease; SUD = step-up dose; TD = target dose.

One patient who received double step-up dosing regimen of 0.3/7.2/160 mg experienced completed suicide as a neurological AE with a fatal outcome. b One AE of spinal cord compression in a patient who received the selected triple step-up regimen 0.3/1 .2/3.6/160 mg was inadvertently reported as an AE leading to cevostamab withdrawal due to a data entry error. Following the clinical cutoff date, it was subsequently confirmed that the patient had discontinued from cevostamab treatment due to PrD.

Possible Immune Effector Cell-Associated Neurotoxicity Syndrome

Cases of possible immune effector cell-associated neurotoxicity syndrome (ICANS) were analyzed in Study GO39775. The methods of data collection in these studies are as follows:

• In Study GO39775, investigators were instructed to enter all neurological signs and symptoms that the investigator attributed to cytokine release syndrome (CRS) as signs and symptoms of CRS by using the CRS electronic Case Report Form (eCRF) because these signs and symptoms were thought to be immune effector cell associated.

• In Study GO39775, any neurological event not attributed to CRS was considered a separate event.

The investigator has analyzed possible ICAN events in a conservative fashion. For completeness, and to not miss any potential signals, all signs and symptoms captured in the CRS eCRF and all events captured in the AE eCRF were reviewed for neurological symptoms that would be consistent with ICANS as defined in the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus paper (e.g., see Lee et al., Biol Blood Marrow Transplant, 25(4): 625-638, 2019), the definition of which is bulleted below.

• High Level Group Term (HLGT): Deliria (including confusion)

• HLGT : Seizures (including subtypes)

• High Level Term (HLT): Cortical dysfunction not elsewhere classified (NEC)

• HLT: Disturbances in consciousness NEC • HLT: Encephalopathies NEC

• HLT: Memory loss (excluding dementia)

• HLT: Mental disorders NEC

• HLT : Mental impairment (excluding dementia and memory loss)

• HLT: Speech and language abnormalities

• HLT: Coma states

• HLT : Increased intracranial pressure disorders

• Preferred Term (PT): Agitation

• PT : Hyporesponsive to stimuli

• PT: Hypertonia

• PT : Slow response to stimuli

• PT : Unresponsive to stimuli

• PT: DAMP syndrome

• PT : Ganser syndrome

Analyses of Possible ICANS (e.g., see Table 16B and Table 16C) were done retrospectively with the data collected. Based on the method of data collection, one or more signs and symptoms of CRS (that were consistent with the definition of ICANS) were collected for a Possible ICANS event. Of note, neurological events, other than the MedDRA PT of Immune Effector Cell-Associated Neurotoxicity Syndrome that are consistent with the definition of ICANS may be due to other causes (e.g., underlying disease, concomitant medications, subdural hematoma). Because this study was initiated prior to the publication of the ASTCT consensus paper, investigators were not initially asked to identify signs and symptoms of CRS or AEs as ICANS. Thus, possible ICANS events were defined as those events that are consistent with ICANS definition outlined above and satisfy one of the following:

• Were captured as a sign and symptom of CRS on the CRS eCRF, or

• Were captured as an AE on the AE eCRF and have been assessed by the investigator as being related to cevostamab.

Table 16B: Overview of Possible ICANS AEs and Possible ICANS S/S of CRS Across Priming Regimens in Safety-Evaluable Population in Study GO39775

AE=adverse event; CCOD=clinical cutoff date; CRS=cytokine release syndrome; ICANS=immune effector cell-associated neurotoxicity syndrome;

NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; PT=Preferred Term; S/S=signs and symptoms; SUD-step-up dose; TD=target dose. Notes: Percentages are based on N in the column headings. All MedDRA PTs of AEs and S/S of CRS reported in this table were assessed by NCI-CTCAE grading criteria Version 4.0. For frequency counts by PT, multiple occurrences of the same AE or S/S of CRS in an individual are counted only once. The 'total' columns summarize the most severe NCI-CTCAE grade reported for each PT, regardless whether it was reported as a main AE outside of the context of CRS or as a S/S of CRS. All S/S of CRS are considered to be related to study drug. a One patient who received the selected triple-step regimen 0.3/1 .2/3.6/160 mg experienced a Possible ICANS reported as a S/S of CRS after the third SUD, which was reported as the PT of neurotoxicity at the time of CCOD due to a data entry error. Following the CCOD, the PT was subsequently updated to Grade 2 confusional state.

Table 16C: Frequency of Possible ICANS AEs and Possible ICANS S/S of CRS Across Priming

Regimens in Safety-Evaluable Population in Study GO39775 iv. Tumor Lysis Syndrome

Tumor lysis syndrome (TLS) is a known pharmacodynamic effect of anti-tumor therapy in hematologic malignancies including MM. TLS has been reported with blinatumomab (BLINCYTO® USPI), CAR-T cell therapy, and therapies for MM (VELCADE USPI; KYPROLIS® [carfilzomib] USPI). The inherent risk of TLS is dependent on the malignancy being treated and individual patient characteristics. There is a theoretical risk of TLS if treatment with cevostamab results in the rapid destruction of a large number of tumor cells.

Due to the potential risk of TLS following cevostamab administration, patients must have had serum creatinine < 2 mL/dL and a CrCI >30 mL/min to participate in this trial. Upon hospital admission for Cycle 1 cevostamab administration or hospitalization following dose escalation, the patient's serum chemistry and hematology laboratory samples were obtained and reviewed, and prophylactic measures were initiated according to the guidelines described below.

Laboratory results were reviewed and electrolyte values should not have demonstrated any clinically significant abnormalities prior to the infusion of cevostamab in Cycle 1 and beyond, otherwise the patient received additional prophylactic treatment and hydration prior to the initiation of dosing. Laboratory abnormalities suggestive of TLS prompted immediate action by the treating clinicians, and TLS was treated aggressively per institutional practice. Access to nephrologist and acute dialysis services were available in the event of clinically significant TLS.

Patients with elevated uric acid levels prior to cevostamab treatment or who were considered high risk for TLS received prophylaxis for TLS prior to each cevostamab infusion during Cycle 1 . Patients meeting any of the following criteria were considered at high risk for TLS:

• Prior history of TLS caused by previous MM therapy

• Preexisting renal insufficiency (serum creatinine >1 .5 mg/dL, or CrCI <60 mL/min) High tumor burden, defined as increased serum LDH (>2 x ULN), increased beta-2 microglobulin (>5.5 mg/dL), hypercalcemia (serum Ca >12 mg/dL), or per investigator’s clinical judgment (e.g., based on the magnitude of diffuse bone marrow disease and multiple lytic lesions)

Prophylaxis guidelines included the following:

• Hydration, consisting of a fluid intake of approximately 2-3 L/day starting 24-48 hours prior to the first dose of cevostamab; followed by IV hydration at a rate of 150-200 mL/hour beginning at the conclusion of Cycle 1 infusions of BFCR4503A and continued for at least 24 hours thereafter. Modification of fluid rate was considered for individuals with specific medical needs.

• Administration of an agent to reduce uric acid:

- Rasburicase (e.g., 0.2 mg/kg IV over 30 minutes prior to first dose cevostamab and daily for up to 5 days thereafter) was administered, unless contraindicated (ELITEK® [rasburicase] USPI).

- Treatment with rasburicase continued as specified above, or if laboratory evidence of TLS was observed until normalization of serum uric acid or other lab parameters.

• Note that uric acid measurement in the presence of rasburicase administration requires special handling (ELITEK® USPI).

• Telemetry was considered for patients at high risk for TLS. v. Infections

Due to its anticipated mode of action resulting in profound plasma-cell depletion and, potentially, B-cell depletion, cevostamab may be associated with hypogammaglobulinemia and an increased risk of infections. Serum Ig levels were monitored in this study. Administration of intravenous Ig was considered for patients with hypogammaglobulinemia who were considered to be at increased risk for infection. Infections have been reported in patients receiving CD20-directed therapies (RITUXAN® (rituximab) USPI; GAZYVA® USPI), CD38-directed therapy for MM (DARZALEX® USPI), as well as blinatumomab (BLINCYTO® USPI). In the single-dose PK/PD comparability study of cevostamab in male cynomolgus monkeys, severe gastrointestinal safety findings were consistent with those caused by proliferation of Shigella in the gastrointestinal tract, suggesting that cevostamab may contribute to the exacerbation of preexisting subclinical gastrointestinal infections.

Cevostamab was not administered in the presence of active severe infections. Careful consideration was taken regarding the use of cevostamab in patients with history of recurring or chronic infections or with underlying conditions that may predispose patients to infections. Signs and symptoms of infection resulted in prompt evaluation and appropriate samples for bacteriological investigation prior to starting antibiotic or other treatment.

Hepatitis B reactivation has been reported with B-cell-directed therapies. Patients with a history of chronic hepatitis B infection or positive test results for active or chronic HBV infection defined by HBsAg and/or positive total HBcAb and positive HBV PCR, or patients with HCV infection as assessed by PCR, were excluded from this trial. Patients who demonstrated evidence of hepatitis reactivation discontinued study treatment. Particular attention was given to patients who have had significant prior immunosuppressive treatment such as high-dose chemotherapy. Progressive multifocal leukoencephalopathy (PML) has been associated with treatment with B-cell-depleting therapies, including rituximab and obinutuzumab. The diagnosis of PML was considered in any patient that presented with new-onset neurological manifestations and consultation with a neurologist and diagnostic procedures including brain MRI and lumbar puncture were performed as clinically indicated. Note, however, that new-onset neurologic adverse events following initial doses of cevostamab were more likely due to acute effects of cevostamab, as PML associated with rituximab was generally following long-term exposure.

Patients with known or suspected chronic active EBV infection were excluded from this trial due to the risk of secondary MAS/HLH. vi. Tumor Inflammation/T umor Flare

Adverse events associated with tumor inflammation have been reported with T-cell engaging therapies and are consistent with the mechanism of action leading to influx of T cells into tumor sites. Events involving tumor inflammation, including tumor flare (if applicable), such as hypoxia and dyspnea, have been reported with, e.g., cibisatamab, a T-cell engaging therapy. These events tend to occur with a short time to onset following administration and present with varying degrees of severity. In addition, depending on tumor size and anatomic location, events associated with tumor inflammation may potentially result in mass effects on vital structures, including airways, major blood vessels, and/or major organs, or can present with organ dysfunction. Depending on the nature of the tumor inflammation, further medical and/or surgical management may have been necessary (e.g., anti-inflammatory agents, airway management, decompression, prolonged hospitalization). Patients with tumors involving critical anatomic locations were closely monitored for tumor inflammation, and prospective consideration for preventative or interventional measures was considered or planned prior to dosing. v/7. Neutropenia

Neutropenia and febrile neutropenia are associated with CD38-directed therapy for MM (DARZALEX® USPI). Similarly, neutropenia and febrile neutropenia are associated with therapies targeting B-cell malignancies, including blinatumomab (BLINCYTO® USPI), obinutuzumab (GAZYVA® USPI), and rituximab (RITUXAN® USPI).

In nonclinical testing of cevostamab in cynomolgus monkeys, the most pronounced cevostamab- related hematological changes were observed following the first and second weekly doses, including moderately to markedly decreased lymphocytes, decreased monocytes and basophils. These changes were reversible following a 5- week recovery. The risks of neutropenia and other types of hematological toxicities with cevostamab in humans are not known.

Patients who experienced Grade 3-4 neutropenia were closely monitored with more frequent assessments as applicable. v/77. Thrombocytopenia

Thrombocytopenia is associated with CD38-directed therapy for MM (daratumumab) and is associated with therapies targeting B-cell malignancies, including blinatumomab, obinutuzumab, and rituximab.

Patients were closely monitored for thrombocytopenia. Regular monitoring of platelet count was performed until the event resolves, and dose delays were considered in cases of severe or life-threatening thrombocytopenia. Transfusion of blood products (e.g., platelet transfusion) according to institutional practice was at the discretion of the treating physician. Use of all concomitant therapies, which could possibly worsen thrombocytopenia-related events such as platelet inhibitors and anticoagulants, were also considered. ix. Elevated Liver Enzymes

Elevated liver enzymes have been reported with blinatumomab (BLINCYTO® USPI), usually but not exclusively in the setting of CRS; Grade >3 liver enzyme elevations occurred in approximately 6% of patients outside the setting of CRS. Nearly all liver enzyme elevations resolved either with blinatumomab treatment interruption or while treatment continued.

In nonclinical testing with cevostamab in cynomolgus monkeys, increased values of aspartate transaminase (AST), alanine aminotransferase (ALT), and bilirubin along with increased c-reactive protein (CRP), fibrinogen, and triglycerides were observed following the first and second weekly doses, consistent with cevostamab-induced cytokine release and an acute phase protein response. These parameters were comparable or trending to baseline or control values by Day 29 and were all fully comparable to baseline or control values by Day 63 following a 5-week recovery, indicating reversibility.

Patients with elevated liver function tests (LFTs) at screening were excluded from this trial. LFTs will be assessed regularly during study and should be managed according to guidelines in Table 17 shown below.

Table 17: Management of Liver Function Test Abnormalities

I. Adverse Events

According to the ICH guideline for Good Clinical Practice, an adverse event is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. An adverse event was any of the following:

• Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product

• Any new disease or exacerbation of an existing disease (a worsening in the character, frequency, or severity of a known condition), except events that were clearly consistent with the expected pattern of progression of the underlying disease

• Recurrence of an intermittent medical condition (e.g., headache) not present at baseline

• Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that was associated with symptoms or led to a change in study treatment or concomitant treatment or discontinuation from study drug

• Adverse events that were related to a protocol-mandated intervention, including those that occurred prior to assignment of study treatment (e.g., screening invasive procedures such as biopsies)

The frequency of adverse events (excluding CRS) in safety-evaluable population at various selected target doses is shown in Table 18 below. The adverse events of interest showed no notable trend across target dose levels, except for a higher rate of Grade >3 infection that was observed at target doses >160 mg. Overall, the safety at 160 mg Q3W target dose is shown to be manageable and tolerable. Table 18: Frequency of Adverse Events Across Target Doses in Safety-Evaluable Population

Generally, the proportion of patients experiencing any adverse events at any grade was higher at the second step-up dose compared with the first step-up dose in all double step-up and triple step-up regimens (Table 19A). Irrespective of the number of step-up doses, the frequency of any-grade AEs at the first target dose was generally comparable across all regimens.

Table 19A: Distribution of Adverse Events (Excluding Progressive Disease) at Step-Up Doses and the First Target Dose by Grade Across Dosing Regimens in Safety-Evaluable Population in Studies GO39775 and CO43476

SUD = step-up dose; TD = target dose; AE = Adverse event; n/a = not applicable a One patient (3.3%) was reported with Grade 5 completed suicide. b One patient (3.3%) was reported with Grade 5 respiratory failure. c Three patients (2.4%) were reported with plasma cell myeloma as a Grade 5 PrD, 1 patient (0.8%) was reported with Grade 5 respiratory failure, and 1 patient (0.8%) was reported with Grade 5 pneumonia aspiration. d Three patients (10.0%) were reported with plasma cell myeloma as a Grade 5 PrD and 1 patient (3.3%) was reported with Grade 5 COVID-19.

All 30 patients enrolled at the selected 0.3/1 .2/3.6/160 mg triple step-up regimen received all 3 step-up doses and the first target dose of 160 mg in Cycle 1 , with 23.3% (all Grade 1 -2), 70.0% (Grade 1 - 4), 30.0% (Grade 1 -3), and 86.7% (Grade 1 -5) of patients experiencing at least one AE at the first step-up dose, the second step-up dose, the third step-up dose, and the first target dose, respectively. CRS was the most frequently reported AE in all of these doses, with only Grade 1 events in all three step-up doses and Grade 1 -2 events in the first target dose.

• At the first step-up dose, all PTs were reported in 1 -2 patients each. Those reported in 2 patients (6.7%) each were CRS, hypomagnesemia, and back pain (all Grade 1 ).

• At the second step-up dose, the most frequently reported PT was CRS (6 patients (20.0%); all Grade 1 ). The remaining PTs were reported in 1 -2 patients each.

• At the third step-up dose, CRS (3 patients (10.0%); all Grade 1 ) was the most frequently reported PT. The remaining PTs were reported in 1 -2 patients each.

• At the first target dose, CRS (15 patients (50.0%); 36.7% Grade 1 and 13.3% Grade 2) was also the most frequently reported PT, followed by back pain (4 patients (13.3%)), and anemia, cough, headache, and fatigue (3 patients (10.0%) each). Grade 5 AEs were reported in 4 patients due to disease progression (PT of plasma cell myeloma) in 3 patients (10.0%) and COVID-19 in 1 patient (3.3%).

/'. Serious Adverse Events

A serious adverse event is any adverse event that meets any of the following criteria:

• Was fatal (i.e. , the adverse event actually caused or led to death)

• Was life-threatening (i.e., the adverse event, in the view of the investigator, placed the patient at immediate risk of death)

This did not include any adverse event that, had it occurred in a more severe form or was allowed to continue, might have caused death.

• Required or prolonged inpatient hospitalization

• Resulted in persistent or significant disability/incapacity (i.e., the adverse event resulted in substantial disruption of the patient's ability to conduct normal life functions)

• Was a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug

• Was a significant medical event in the investigator's judgment (e.g., may have jeopardized the patient or may have required medical/surgical intervention to prevent one of the outcomes listed above)

The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE); the event itself may have been of relatively minor medical significance (such as severe headache without any further findings). Severity and seriousness were independently assessed for each adverse event.

/'/. Adverse Events of Special Interest

Adverse events of special interest were required to be reported immediately (i.e., no more than 24 hours after learning of the event). Adverse events of special interest for this study were as follows:

• Cases of potential drug-induced liver injury that included an elevated ALT or AST in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law

• Suspected transmission of an infectious agent by the study drug, as defined below:

Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent. A transmission of an infectious agent may be suspected from clinical symptoms or laboratory findings that indicate an infection in a patient exposed to a medicinal product. This term applies only when a contamination of the study drug is suspected.

• Adverse events of special interest specific to cevostamab

Grade >2 IRR

Grade >2 neurologic adverse event Grade >2 skin toxicities

Any grade CRS

- Any suspected MAS/HLH TLS (Grade >3 by definition)

Febrile neutropenia (Grade >3 by definition) Any grade disseminated intravascular coagulation (minimum Grade 2 by definition)

- Grade >3 AST, ALT, or total bilirubin elevation

In rare circumstances, it was acceptable to resume study drug, provided that any ECG abnormalities resolved, and the patient was appropriately monitored.

J. Clinical Pharmacodynamics

Elevations of circulating cytokines have been reported after administration of T-cell directed therapies. In Study GO38775, IL-6, a biomarker of CRS, was assessed as a primary pharmacodynamic biomarker by electrochemiluminescence-based plasma cytokine testing at baseline and following cevostamab administration up to the second target dose.

Cevostamab induced transient elevation of IL-6 in a time-dependent manner with the peak levels (e.g., concentrations) observed primarily after step-up dosing. Observed peak IL-6 levels after administration of the 3.3 mg or 3.6 mg step-up dose varied depending on the number of preceding step- up doses, as shown in FIG. 7. Median peak IL-6 following 3.6 mg as the first step-up dose was 213.5 ng/L (FIG. 7). In comparison, median peak IL-6 following 7.2 mg as the third step-up dose preceded by 0.3 mg (first step-up dose) and 3.3 mg (second step-up dose) was significantly lower at 70.52 ng/L (i.e. , 70.52 pg/mL) (FIG. 7), which suggests that triple step-up priming mitigated IL-6 release relative to single step- up and double step-up priming. This finding is consistent with observed CRS rates in triple step-up vs single and double step-up priming in Study GO39775 (e.g., see Table 11 A). Additionally, median peak IL- 6 following 3.6 mg as the third step-up dose preceded by 0.3 mg (first step-up dose) and 1 .2 mg (second step-up dose) was even lower at 18.01 ng/L (i.e., 18.01 pg/mL) (FIG. 7), further supporting triple step-up priming as a mitigator of IL-6 release and consistent with observed CRS rates (e.g., see Table 11 A). Administration of the second step-up dose of 3.3 mg or 3.6 mg on Day 2, Day 3, Day 4, or Day 8 resulted in peak IL-6 levels ranging from 38.31 -95.39 mg/L.

K. Conclusions

In this Example, 167 patients (median age: 66 years, range: 40-90 years; Eastern Cooperative Oncology Group Performance Status (ECOG PS): 0, 35%; 1 , 65%; median time from first MM therapy: 6.3 years, range: 0.3-21 .8 years) had received cevostamab at the 160 mg target dose level (single step- up: n=10; double step-up: n=97; and triple step-up: n=60); 28% of patients had extramedullary disease and 38% of patients with a conclusive assay result (38/100) had high-risk cytogenetics (t(4;14), t(14;16), or del( 17p)). The median number of prior lines of therapy was 6 (range: 2-18). Almost all patients (e.g., 95.8%) were triple-class refractory and 73.7% were penta-drug refractory (e.g., refractory to anti-CD38 monoclonal antibodies, bortezomib, lenalidomide, pomalidomide, and carfilzomib); 85.0% were refractory to their last prior therapy. A majority (57%) of patients had received >1 prior B-cell maturation antigen (BCMA)-targeted therapy. Twenty-four percent of patients had received >1 prior bispecific antibody.

Median observation time was 11 .3 months (range: 0.5-42.8 months). The ORR in all patients who received cevostamab at the 160 mg target dose level was 43.1% (72/167 patients); 6.6% achieved a sCR, 6.6% a CR, 12.6% a VGPR, and 17.4% a PR. The VGPR or better rate was 25.7%. Median time to first response (e.g., PR or better) was 1 .4 months (range: 0.6-4.6 months) and to best response was 2.4 months (range: 0.7-13.4 months). Median duration of response was 10.4 months (95% Cl: 6.8, 10.5). ORR was 30.2% (29/96) in patients with >1 prior BCMA-targeted therapy and 60.6% (43/71 ) in those without. ORR was 30.0% (12/40) in patients with >1 prior bispecific antibody, 33.3% (20/60) with >1 prior CAR T-cell, and 41 .2% (14/34) with >1 prior antibody-drug conjugate.

Common (>20%) AEs included CRS (74.3%; Grade 1 : 52.7% Grade 2: 19.8%; Grade 3: 1 .2%; Grade 4: 0.6%), neutropenia (31 .1 %; Grade 1 -2: 3.0%; Grade 3: 12.0%; Grade 4: 16.2%), cough (30.5%; Grade 1 -2: 29.9%; Grade 3: 0.6%), nausea (28.1%; Grade 1 -2: 27.5%; Grade 3: 0.6%), diarrhea (24.0%; all Grade 1 -2), anemia (23.4%; Grade 1 -2: 5.4%; Grade 3: 17.4%; Grade 4: 0.6%), and fatigue (21 .0%; Grade 1 -2: 19.8%; Grade 3: 1 .2%). Possible ICANS occurred in 13.2% of patients (Grade 1 : 6.0%; Grade 2: 5.4%; Grade 3: 1 .8%). Infections occurred in 53.9% of patients, with serious events and Grade >3 events in 22.2% and 19.2%, respectively. Treatment-related AEs leading to cevostamab discontinuation occurred in 11 patients (6.6%) and treatment-related Grade 5 (fatal) AEs in 3 patients (1 .8%; hemophagocytic lymphohistiocytosis, n=2; disseminated intravascular coagulation and pseudomonal sepsis, n=1 ). In the 0.3/1 .2/3.6/160 mg triple step-up dosing regimen, CRS occurred in 19/30 patients (63.3%) and was all Grade 1 (46.7%) or Grade 2 (16.7%). Patients with CRS were managed with tocilizumab (47.4%), steroids (21 .1%), or both agents (10.5%). No patients discontinued cevostamab due to CRS, and all events were resolved.

These results show that cevostamab provides clinically meaningful activity and manageable safety at the 160 mg target dose level in patients with heavily pretreated R/R MM. Moreover, the priming dosing of sequences was found to provide effective CRS mitigation. Therefore, cevostamab combination studies may use the 0.3/1 .2/3.6 mg triple step-up dosing regimen with a Q3W 160 mg target dose (or similar TD exposure).

Table 19B below summarizes some key areas the were considered and investigated during the GO39775 Study described herein.

Table 19B: Clinical Pharmacology (Dosing and Administration) Snapshot in Study GO39775

Example 2. Exposure-Response Analyses for Efficacy and Safety

Across the priming dose regimen tested, the nominal steady-state exposures for cevostamab target doses (e.g., Cavg, cycle s and Cmin, cycle s) were comparable at the same target dose levels tested. This supports a pooling strategy of a target dose exposure-response (ER) evaluation for the efficacy and safety endpoints of interest in single step-up, double step-up, and triple step-up dosing schedules. Pooling across multiple step-up dosing regimens may improve the precision of the response estimates given the increased sample size at each dose cohort for the pooled target doses following the administration of cevostamab every 3 weeks (Q3W) in the single step-up, double step-up, and triple step- up dosing schedules.

From a clinical efficacy perspective, the pooling strategy is further supported by a Population Pharmacokinetics-Tumor Growth Inhibition (PopPK-TGI) evaluation, which is described in further detail in Example 4. Briefly, based on the longitudinal modeling of paraprotein using a PopPK-TGI analysis, comparable (e.g., up to 5% difference) objective response rates (ORR) and very good partial response or better (>VGPR) rates were predicted for single step-up, double step-up, and triple step-up dosing regimens at the same target dose level, supporting the conclusion that target dose exposure, and not the exposure of a particular priming sequence of doses, drives clinical efficacy following cevostamab monotherapy administration. Therefore, all ER evaluations (e.g., efficacy and safety) for the target doses were conducted with the aforementioned pooling strategy across the step-up dosing regimens described in Study GO39775. i. Exposure-Efficacy Analyses

/'. Methodology

The exposure-efficacy analysis was performed using the ORR and >VGPR rates from 291 pharmacokinetic-evaluable and efficacy-evaluable patients from the single step-up, double step-up, and triple step-up cohorts described in Study GO39775 (e.g., see Example 1 and International Patent Application Publication No. WO/2022/076462, which is herein incorporated by reference in its entirety, for single step-up and double step-up regimens described in Study GO39775). The patient-specific pharmacokinetic exposure metrics, including cevostamab nominal exposures at steady-state (e.g., Cavg, cycle s and Cmin, cycle s) in the single step-up, double step-up, and triple step-up regimens were derived using a preliminary two-compartment PopPK model with linear and Michaelis- Menten clearance and additional time-dependent anti-drug antibody (ADA) clearance. The average cycle 3 concentrations were estimated using area under the curve at cycle 3 over a 21 -day period.

The relationship between ORR or >VGPR rate and the cevostamab exposure metrics at the steady-state (e.g., Cavg, cycle s and Cmin, cycle s) following the target dose administration of cevostamab were modeled using a logistic regression analysis. Specifically, a binary outcome was used (e.g., 0 for no ORR/>VGPR, and 1 for ORR/>VGPR).

A maximal effect (Emax) logistic regression model was used to evaluate the relationship between cevostamab nominal target dose exposure at steady-state (e.g., Cavg, cycle s and Cmin, cycle s) and the probability of having an event (e.g., ORR or >VGPR).

The Emax logistic regression model equation is as follows:

Equation 1 : log — = EO + i-y E ^E C^m S^a O^x + ^c C wherein C is the exposure variable for Cavg, cycle s and Cmin, cycle s, EO is the baseline estimate of efficacy, Emax is the maximal effect, EC50 is the half maximal effective concentrations, and Y is the probability of having an event (e.g., ORR or >VGPR).

/'/. Results

FIGS. 9-11 show the results of the logistic regression modeling for exposure-efficacy analysis using pooled data from the single step-up, double step-up and triple step-up dosing regimen for the ORR and >VGPR endpoints.

The exposure-efficacy analysis across the range of tested target doses (e.g., between 0.15-252 mg) indicated a statistically significant increase in the best clinical ORR and >VGPR rates with increasing cevostamab nominal exposures (e.g., Cavg, cycle s and Cmin, cycle s) using pooled data from the single step-up, double step-up, and triple step-up dosing regimens. ii. Exposu e-Safety Analyses

/'. Methodology

The exposure-safety relationships were analyzed in 316 pharmacokinetic- and safety-evaluable patients from the single step-up, double step-up, and triple step-up cohorts in Study GO39775.

The patient-specific PK exposure metrics, including cevostamab exposures in Cycle 1 (e.g., Cmax at ci Di and Cmax, cycle 1 target dose) and nominal steady-state exposures (e.g., Cavg, cycle 3 and Cmax, cycle 3) in the single step-up, double step-up, and triple step-up dosing regimens, were derived using a preliminary two-compartment PopPK model with linear and Michaelis-Menten clearance and additional time-dependent ADA clearance. The average cycle 3 concentrations were estimated using area under the curve at cycle 3 over a 21 -day period. /'/. Exposure-Safety Relationship of Cevostamab for Occurrence of

All-Grade and Grade >2 Cytokine Release Syndrome Events

Cytokine Release Syndrome (CRS) was the most frequently reported adverse event (AE) following cevostamab treatment. An exposure-safety analysis was conducted to evaluate the relationship between the occurrence of all-grade and Grade >2 CRS events and cevostamab exposures following the administration of step-up and target doses.

For the step-up doses, logistic regression analyses were performed to evaluate the relationship between (i) step-up dose exposures (CmaxatciDi) and (ii) the probability of all-grade and Grade >2 CRS events from the time of administration of the step-up dose on C1 D1 until the time of the administration of the subsequent step-up/target doses in Cycle 1 . Pooled data from the single step-up, double step-up and triple step-up dosing regimen was used.

Additionally, logistic regression analyses were conducted to evaluate the relationship between (i) the probability of all-grade and Grade >2 CRS events from the time of administration of the first target dose in Cycle 1 until the end of treatment and (ii) the target dose exposures (e.g., Cmax, cycle 1 target dose) on Day 8, Days 9-11 (e.g., Day 9, Day 10, or Day 11 ), or Day 15 in Cycle 1 . Pooled data from the single step-up, double step-up and triple step-up dosing regimen was used, which captured the majority of observed CRS events.

The Emax model (e.g., see Equation 1 ) was used to evaluate the relationship between step-up and target dose exposures and the probability of all-grade and Grade >2 CRS events. FIG. 12 and FIG. 13 show the results of the logistic regression modeling of all-grade and Grade >2 CRS events, respectively. As shown in the exposure-safety analyses, there was no evidence of an apparent relationship between the target dose exposures (e.g., Cmax, cycle 1 target dose) and the frequency of all-grade and Grade >2 CRS following the administration of the target doses on Day 8, Day 9-11 (e.g., Day 9, Day 10, or Day 11 ), or Day 15 in Cycle 1 until the end of treatment across the dose levels tested (e.g., 0.15- 252 mg) in the single step-up, double step-up and triple step-up dosing schedules.

However, statistically significant trends were observed between cevostamab C1 D1 step-up dose exposures (e.g., CmaxatciDi) and the frequency of the all-grade and Grade >2 CRS events across the range of tested step-up doses (0.05-3.6 mg) in the single step-up, double step-up, and triple step-up dosing schedules. These findings indicate that the step-up doses across the different step-up dosing regimens adequately cap the overall acute CRS risks while maximizing the safety margin to allow an escalation of the target doses of cevostamab up to 252 mg (e.g., 160 mg).

Hi. Exposure-Safety Relationship of Cevostamab for Occurrence of Key Non-Cytokine Release Syndrome Adverse Events

The exposure-safety analyses were conducted to evaluate the relationships between (i) the occurrence of Grade >3 cytopenias (e.g., neutropenia, anemia, lymphopenia, and thrombocytopenia), Grade >3 infections, Grade >3 any AEs, serious adverse events (SAEs), and AEs that led to any dose modifications (e.g., dose interruptions, dose reductions, and/or dose discontinuations), and (ii) cevostamab exposure following the administration of step-up and target doses. A linear logistic regression analysis using Equation 2 was performed to evaluate the relationship between (i) the occurrence of the aforementioned adverse events and (ii) cevostamab exposures following the C1 D1 step-up doses (e.g., Cmax atcycie 1 Day 1) from the time of administration of the step-up dose on C1 D1 until the time of the administration of the subsequent step-up/target dose in Cycle 1 using pooled data from the single step-up, double step-up and triple step-up dosing regimen; and at target doses using the nominal steady-state exposures (e.g., Cavg. cycles and Cmax, cycle s) in the single step-up, double step-up, and triple step-up dosing regimens from the time of administration of the first target dose on Day 8, Day 9-1 1 or Day 15 in Cycle 1 until the end of treatment for the single step-up, double step-up, and triple step-up dosing schedules.

The linear logistic regression equation is as follows:

Equation 2: log^ = po + pi ■ X wherein Y is the probability of having an AE and X represents the step dose exposures (e.g., CmaxatciDi) or the nominal steady-state exposures at the target doses (e.g., Cav . cycles or Cmax, cycles), po is the intercept, and /?1 is the slope of the cevostamab exposure variable.

Significant positive E-R trends across the C1 D1 step-up doses tested (e.g., 0.05-3.6 mg) were observed for Grade >3 cytopenia (e.g., neutropenia, thrombocytopenia, and lymphopenia), Grade >3 AEs, and SAEs; this suggests that 0.3 mg as an acceptable C1 D1 step-up dose, with this dose located at the bottom of the E-R curve (FIG. 14, FIG. 16, FIG. 17, FIG. 19, FIG. 20, and FIG. 21).

As shown in FIGS. 14-21 , no significant, positive E-R relationships were observed for Grade >3 cytopenia (e.g., neutropenia, anemia, thrombocytopenia, and lymphopenia) across the target doses tested (e.g., 0.15-252 mg). Grade >3 AEs were observed across the target doses tested (e.g., 0.15-252 mg). Significant, positive E-R trends were observed for Grade >3 infections, SAEs, and AEs leading to any dose modifications (e.g., dose interruptions, dose reductions, and dose discontinuations) across the pooled single step-up, double step-up, and triple step-up dosing schedules in the logistic regression analyses for the target doses.

Hi. Conclusion

The above E-R analyses demonstrate that increasing cevostamab exposure is significantly associated with higher ORR and >VGPR rates, which plateaued at the 160 mg Q3W dose across the pooled step-up dosing regimens tested in Study GO39775. This finding implies diminishing gains in efficacy beyond the target dose of 160 mg for the overall population of patients with a multiple myeloma (MM) (e.g., relapsed or refractory (R/R) MM).

While a significant E-R relationship was observed for all-grade CRS and Grade >2 CRS events at the range of C1 D1 step-up doses tested over 0.05 mg to 3.6 mg, no clear E-R trends following the administration of the target doses were observed for the frequency of all-grade CRS and Grade >2 CRS, despite the dose escalation up to 252 mg administered on Days 8, 9-1 1 , or 15 in Cycle 1 and Q3W thereafter in the single step-up, double step-up, and triple step-up dosing regimens. The E-R analyses continue to support the safety risk mitigation through the step-up dose approach, suggesting that a priming dose regimen adequately caps the overall acute safety risks (e.g., the risk of CRS) and maximizes the safety margin for target doses up to 252 mg (e.g., 160 mg). While the majority of the AEs did not show a strong correlation with target dose exposure (including Grades >1 and >2 CRS, Grades >3 cytopenias (e.g., neutropenia, anemia, lymphopenia, and thrombocytopenia), and Grade >3 any AEs), a significant E-R safety relationship was observed with Grade >3 infections, SAEs, and AEs leading to any dose modifications (e.g., dose interruptions, dose reductions, and/or discontinuations).

Taken together, these findings suggest that doses exceeding 160 mg Q3W do not offer a benefitrisk profile as favorable as compared with 160 mg Q3W in patients with MM (e.g., R/R MM). Therefore, in conclusion, the clinical data and clinical pharmacology analysis described herein support that the target dose of 160 mg Q3W provides a favorable benefit-risk for patients with MM (e.g., R/R MM).

Example 3. Quantitative Systems Pharmacology

As discussed in Example 1 , the recommended dose and administration schedules for the triple step-up dosing regimens described herein were informed by the evaluation of priming doses that mitigate CRS risk following target dosing, and target doses that impact the balance between efficacy and safety. Interleukin 6 (IL-6) is a biomarker correlated with CRS. Thus, an in silica evaluation of IL-6 dynamics using an exploratory Quantitative Systems Pharmacology (QSP) model was performed to guide dosage exploration strategies during cevostamab’s clinical development and to evaluate whether an alternative priming sequence of doses had the potential to mitigate peak IL-6 expression in patients. The QSP model was adapted from an established model previously developed for mosunetuzumab (e.g., see Hosseini et al., NPJ. Syst. Biol. Appl., 6(1 ):28, 2020; and Susilo et al., Clin. Transl. Sci., 16(7):1134-1148, 2023, each of which is incorporated herein in its entirety) and described the mechanism of action of cevostamab in a multiple myeloma (MM) population (e.g., a relapsed or refractory (RR) MM population). In particular, the model includes the activation of CD8+ T cells and subsequent target cell killing, as well as IL-6 release, with a bone marrow compartment modified to represent the bone marrow environment of patients with MM (e.g., R/R MM). Two mechanisms were implemented in the model for T-cell dependent bispecific antibody-induced IL-6 release: (1 ) target engagement, and (2) immune desensitization impacting systemic cytokine release upon repeated exposure to cevostamab.

The QSP model reasonably captured the IL-6 trends observed in Study GO39775 (e.g., FIGS. 28-31) and showed reasonable concordance with IL-6 data from priming sequences not used in model calibration. Notably, consistent with the observed data, the model predicted that peak IL-6 levels following a 3.6 mg step-up dose was lower when the 3.6 mg dose was administered as a third dose (e.g., Cycle 1 , Dose 3 (C1 D3)) and preceded by a first 0.3 mg dose and a second 1 .2 mg dose (FIG. 30), as compared to when the 3.6 mg dose was given as the first or second dose.

The QSP evaluation provides mechanistic support to the triple step-up priming sequence of doses of 0.3 mg, 1 .2 mg, and 3.6 mg (“0.3/1 .2/3.6 mg”) for reducing peak IL-6 compared to the single step-up and double step-up priming sequence of doses described in Study GO39775 (e.g., see the single step-up and double step-up regimens described in Example 1 and in International Patent Application Publication No. WQ/2022/076462, which is herein incorporated by reference in its entirety). Moreover, heatmap plots (FIG. 24) reveal that the selected cevostamab priming sequence of doses described herein serves as a basis for further drug development and is within a low IL-6 peak region. A. Data

IL-6 concentration was measured in patients enrolled in Study GO39775. Peak expression IL-6 after each dose in Cycle 1 (C1 ) was derived by finding the maximum concentration after the corresponding dose, but prior to any administration of tocilizumab. The dosing regimen schedules evaluated, include:

• Single step-up (SS) regimen:

• Step-up dose: Day 1 (D1 )

• First target dose: Day 8 (D8)

• Double step-up (DS) regimen:

• Schedule 1 (DS):

• Step-up doses: Day 1 and Day 8 (D1/D8)

• First target dose: Day 15 (D15)

• Schedule 2 (Compressed Double step-up (DScomp)):

• Step-up doses: Day 1 and Day 4 (D1/D4)

• First target dose: Day 8 (D8)

• Triple step-up (TS) regimen:

• Step-up doses: Day 1 , Day 2-4 (Day 2, Day 3, or Day 4) , and Day 8 (D1/D2-4/D8)

• First target dose: Day 9, Day 10, or Day 1 1 (D9-1 1 )

The number of subjects for the QSP model calibration and validation for each step-up dose level and regimen are listed in Table 20.

Table 20: Summary of Number of Subjects for QSP Model Virtual Population Generation and Validation

D = day; SS = single step-up; DS = double step-up; DSComp= Compressed double step-up; TS = triple step-up a Patients with incorrect dosing were censored. b Number of subjects with at least one IL-6 measurement after the first administration of cevostamab.

B. QSP Model Description and Development

The cevostamab QSP model structure generally follows the published mosunetuzumab QSP model structure (e.g., see Hosseini et al., NPJ. Syst. Biol. Appl., 6(1 ):28, 2020) but has additional mechanisms described below incorporated to support an in silico evaluation of peak IL-6 levels in different cevostamab priming sequences.

/'. T-cell Dependent Bispecific Antibody Mechanism of Action

The model structure from Hosseini et al., NPJ. Syst. Biol. Appl., 6(1 ):28, 2020 describes the in vivo dynamics of target cells and T cells and their interactions in the presence of a T-cell dependent bispecific antibody and was developed to enable simulation of biological measurements of processes of interest in a manner that is consistent with underlying biological mechanisms as well as preclinical and clinical measurements. For cevostamab, the target cells are FcRH5-expressing cells, which may include plasma cells and B cells. B cells and T cells may be represented in the blood and lymphoid tissues (e.g., bone marrow, lymph nodes, and the spleen), and plasma cells may be represented in the bone marrow. Without being bound by any theory, cevostamab may activate T cells in a target cell-dependent manner, which can then cause T cells to proliferate, kill target cells, and induce IL-6 production.

/'/. Multiple Myeloma Biology

The QSP model was modified to include biology that is relevant to the cevostamab mechanism of action in MM. The bone marrow environment of MM patients includes T cells, FcRH5-expressing plasma cells, and B cells. In MM, tumor dynamics are indirectly measured using paraproteins, such as M-protein and free light chains that are produced by malignant plasma cells. The measured paraproteins serve as biochemical tumor markers for response based on the International Myeloma Working Group criteria (e.g., see Kumar et al., Lancet Oncol., 17(8):e328-e346, 2016). The baseline T cells, plasma cells, and B cells in the bone marrow were parameters calibrated using the paraprotein time course data from R/R MM patients in Study GO39775 following a digital twin generation workflow (e.g., see Susilo et al., Clin. Transl. Sci., 16(7):1134-1148, 2023) and constrained by physiological ranges reported previously in the literature (e.g., see de Magalhaes et al., Haematologica, 98(1 ):79-86, 2013; Zelle-Rieser et al., J. Hematol. Oncol., 9(1 ):116, 2016; and Lee et al., Blood CanerJ., 7(2):e530, 2017). The baseline cell counts in the bone marrow environment are model inputs related to target engagement of cevostamab and are necessary to stimulate IL-6 kinetics.

Hi. Hypotheses of IL-6 Modulation

Without being bound by any theory, the following two mechanistic hypotheses may explain the exposure- and time-dependent pattern of IL-6 kinetics. The cevostamab QSP model includes representation of both hypotheses.

Mechanism 1: Target Engagement. The release of IL-6 is hypothesized to be associated with target cell engagement by the T cell-dependent bispecific (TDB) antibody. This mechanism is represented in the model’s TDB mechanism of action, which includes the T cell and target cell dynamics in the blood and lymphoid tissues, including T cell activation and proliferation, target cell killing, and IL-6 production.

Mechanism 2: The immune desensitization impacting system cytokine release upon repeated exposure to cevostamab. A representation of the immune desensitization was included in the model, where resting CD8+ T cells can be in a TDB-naive or a TDB-desensitize state. Prior to the start of TDB treatment, all resting T cells are in the TDB-naive state. TDB can induce T cell activation, which is a function of local drug concentration and the ratio between target cell and T cell. TDB-naive activated T cells proliferate, generate activated and post-activated progeny, kill target-expressing cells, induce cytokine production, and undergo apoptosis or transition to post-activated cells or TDB-desensitized resting cells. Post-activated T cells can undergo apoptosis, convert to TDB-desensitized resting T cells, or be reactivated to TDB-desensitized activated T cells. While both TDB-naive and TDB-desensitized activated T cells can kill target-expressing cells with equal potency, only TDB-naive activated T cells can induce cytokine release. The TDB-desensitized resting T cells can also convert back to the TDB-naive state over time. This representation of the immune desensitization mechanism is consistent with nonclinical data (e.g., see Li et al., Sci. Transl. Med., 11 (508):eaax8861 , 2019) where T cell activation and target cell killing were retained during repeated dosing of an anti-human epidermal growth factor receptor 2 (anti-HER2) TDB; however, IL-6 production was reduced at subsequent doses. The QSP model implementation assumed that only TDB-naive activated T cells can trigger downstream processes that lead to IL-6 production. In the presence of cevostamab, activated T cells induce IL-6 production as they kill local target cells.

During development of the model, an alternate hypothesis that only included mechanism 1 to explain the time- and concentration-dependent IL-6 peaks was considered. However, the objective function from the IL-6 peak calibration was improved when both mechanisms were combined to describe the IL-6 data. Additionally, when relying only on mechanism 1 , the model was only able to reproduce the time-dependent trend of IL-6 kinetics if most of the systemic IL-6 was produced from target engagement in the blood. Including both mechanisms allows for a similar contribution of IL-6 from both the bone marrow and blood. The model that incorporated mechanisms 1 and 2 described above provided the best overall fit for the IL-6 peak data and is consistent with the current biological understanding of IL-6 release and cevostamab mechanism of action.

C. QSP Model Calibration and Validation

The QSP model virtual population was calibrated and validated using cevostamab in vitro data (e.g., see Li et al., Sci. Transl. Med., 11 (508):eaax8861 , 2019), nonclinical data in cynomolgus monkey, and partial cevostamab clinical data in 84 R/R MM patients (e.g., see Table 20) from Study GO39775 (e.g., see International Patent Application Publication No. WO/2022/076462, which is herein incorporated by reference in its entirety). The calibration workflow (FIG. 26) closely followed the one presented in Hosseini et al., NPJ. Syst. Biol. Appl., 6(1 ):28, 2020, except as described herein. Briefly, a virtual cynomolgus cohort was generated to reproduce the dynamics of cytokines, B cells, and T cells in the peripheral blood and lymphoid tissues, and plasma cells in the bone marrow. The virtual cynomolgus cohort was then translated to healthy humans using the appropriate physiological volumes and cell numbers in circulation and lymphoid tissues.

Subsequently, an R/R MM virtual population was generated using a digital twin workflow (e.g., see Susilo et al., Clin. Transl. Sci., 16(7):1134-1148, 2023). The term digital twin refers to a virtual representation of a clinical patient that integrates patient-specific clinical data (e.g., pharmacokinetic and biomarker data) alongside the other in vitro/in vivo data within the established QSP model (e.g., see Susilo et al., Clin. Transl. Sci., 16(7):1134-1148, 2023). In the cevostamab digital twin workflow, 100 alternate parameter sets, or digital twins that best reproduced the time course of paraprotein were generated for each clinical patient using the patient’s time course of cevostamab concentrations, circulating B and T cells, and baseline paraprotein levels. The calibrated parameter set also included parameters describing the baseline tumor environment in the bone marrow (e.g., T cell, plasma cell, and B cell numbers). The virtual population (8,400 digital twins) included of digital twins derived from 84 patients (e.g., see Table 20) from Study GO39775 (e.g., see International Patent Application Publication No. WO/2022/076462).

For cevostamab pharmacokinetics, individual post-hoc population pharmacokinetics (PopPK) model estimates were used as a forcing function in the QSP model. The IL-6 production and immune desensitization parameters were calibrated using peak IL-6 data from a subset of R/R MM patients (N=84) in Study GO39775 treated in the SS dosing cohorts ranging from 0.05 mg/0.15 mg to 3.6 mg/132 mg (D1/D8 dosing) and DS dosing cohorts of 1 .2 mg/3.6 mg/60 mg and 1 .2 mg/3.6 mg/90 mg (Table 20). The IL-6 production rate and immune desensitization parameters were calibrated against the IL-6 peak in each cohort (FIG. 26). Model-based simulation of the IL-6 peaks after each dose in Cycle 1 was validated by evaluating the consistency of predicted IL-6 peak trends to the observed IL-6 peaks in cohorts not used in calibration (Table 20). D. QSP Model Simulations

Simulations of IL-6 time courses from the QSP model and virtual population (8,400 digital twins) were conducted:

• Using the planned doses of the various priming sequence evaluated in Study GO39775 (e.g., see International Patent Application Publication No. WO/2022/076462 and Table 20).

• Using alternative priming sequences not tested in the clinic to generate heatmap visualization to evaluate the effect of step-up dose levels to IL-6 peak, such as:

• Dosing regimens with two step-up doses and a target dose:

• Schedules evaluated: Day 1 , Day 8, and Day 15 (D1/D8/D15); Day 1 , Day 4, and Day 8 (D1/D4/D8); Day 1 , Day 3, and Day 8 (D1/D3/D8); and Day 1 , Day 2, and Day 8 (D1/D2/D8)

• Step doses varied: first and second step-up doses

• Fixed target dose at 160 mg

• Dosing regimens with three step-up doses and a target dose:

• Schedules evaluated: Day 1 , Day 4, Day 8, and Day 11 (D1/D4/D8/D11 );

Day 1 , Day 3, Day 8, and Day 10 (D1/D3/D8/D10); and Day 1 , Day 2, Day 8, and Day 9 (D1/D2/D8/D9)

• Step doses varied: second and third step-up doses

• Fixed first step-up dose at 0.3 mg

• Fixed target dose at 160 mg

The QSP model was developed and simulated in SimBiology and MATLAB R2019b (MathWorks, Natick, MA).

E. Assessment of Model Risk

The QSP model was planned to inform the cevostamab dosing regimen in order to evaluate peak IL-6 expression. An assessment of model risk, the weight of model predictions, and the potential of making an incorrect decision, including the rationale for the model risk level, are discussed below.

The QSP model was evaluated using a framework consistent with the American Society of Mechanical Engineer’s (ASMEs) verification and validation framework, as described in Kuemmel et al., CPT Pharmacometrics Syst. Pharmacol., 9(1 ):21 -28, 2020, and Viceconti et al., Methods, 185:120-127, 2020, as well as the QSP-specific context-dependent assessment framework (e.g., see Ramanujan et al., CPT Pharmacometrics Syst. Pharmacol., 8(6):340-343, 2019). The QSP model was used to evaluate IL-6 peaks for the cevostamab priming sequences, and to evaluate additional priming and target dose scenarios.

Based on the ASME’s verification and validation framework, model risk is determined by (1 ) the weight of the model in the totality of evidence to support the decision from the question of interest within the context of use (e.g., model influence) and (2) the potential consequence of an incorrect decision (e.g., decision consequence). Model Influence: In the totality of evidence to support the priming sequence selection, the QSP model was used in conjunction with the clinical data from Study GO39775. During dose finding, the model was used to simulate additional dosing regimens (e.g., double step-up and triple step-up dosing regimens with varying step-up dose levels) with the intention to identify and prioritize the testing of priming sequences in the clinic based on the extent of IL-6 peak reduction in Study GO39775. Based on the modeling outcomes, a few step-up dose levels and schedules were tested in the clinic, and this emerging clinical evidence was used to evaluate the model in a continuous learn-and-confirm cycle. Since the model was used as supportive evidence with available clinical data to inform the priming sequence decision, the weight of the model in the totality of evidence to support the priming sequence was considered medium.

Decision Consequence: Clinical data from Study GO39775 has demonstrated that step-up doses in double step-up and triple step-up dosing regimens reduced peak IL-6 when compared to single step-up dosing regimens. Furthermore, the dosing regimens tested in the clinic mitigated the dose/exposure dependency of target dose-related CRS. Clinical data has been generated for the selected priming sequences and, under the premise of the continuous learn-and-confirm paradigm, generation of additional clinical evidence for the selected priming sequence during the course of cevostamab development was anticipated.

Based on the model influence and decision consequence levels for the priming sequence of doses of cevostamab in R/R MM population, the QSP model risk was considered low-medium.

F. Establishing and Assessing Model Credibility

The verification and validation activities demonstrating QSP model credibility was consistent with assessment considerations outlined in the literature (e.g., Ramanujan et al., CPT Pharmacometrics Syst. Pharmacol., 8(6):340-343, 2019). Four assessment areas were followed.

1. Biological Relevance

The QSP model describes the mechanism of action of cevostamab in the R/R MM population, specifically, the activation of CD8+ T cells, the subsequent target cell killing, as well as IL-6 release, with a bone marrow compartment modified to represent the bone marrow environment of patients with R/R MM. Two mechanisms were implemented in the model for TDB-induced IL-6 release: (1 ) target engagement and (2) immune desensitization impacting systemic cytokine release upon repeated exposure to cevostamab.

2. Model Implementation

The goal of model assessment was to ensure that the model implementation was technically accurate and appropriate for the mechanisms represented in the model:

• The technical accuracy of the cevostamab QSP model was evaluated. The TDB mechanism of action implementation of the QSP model, including the full disclosure of the model file, has been published for TDB molecule mosunetuzumab (e.g., Hosseini et al., NPJ. Syst. Biol. Appl., 6(1 ):28, 2020). Furthermore, modifications of the model to include cevostamab had undergone internal technical reviews.

• The appropriateness of the representation of the model was evaluated by ensuring that the model was capable of generating the unique qualitative features observed in the clinic using model parameters within physiological range.

• The model code reproducibility was performed by repeating the model simulations and reproducing the table and plots in the report by an independent analyst.

3. Simulation Results Assessment

This assessment area determined the model’s qualitative and quantitative plausibility to capture the data and biological understanding. In other words, assessment included model calibration and validation:

• Calibration: The cevostamab QSP model was calibrated and validated using cevostamab in vitro data (e.g., see Li et al., Sci. Transl. Med., 1 1 (508):eaax8861 , 2019), nonclinical data in cynomolgus monkey, and cevostamab clinical data in R/R MM patients from Study GO39775 (e.g., see International Patent Application Publication No. WO/2022/076462). The model reasonably captured peak IL-6 expression after each dose in Cycle 1 (C1 ) in the calibration data set, as shown in FIG. 27.

• Validation: Data from cohorts not used in model calibration were used for model validation.

Notably, the model was able to capture IL-6 peak trends and showed reasonable consistency with the observed IL-6 data in the double step-up, compressed double step-up, and triple step- up regimen scenarios not used in model calibration (FIGs. 28-31). This increased the confidence in the predictive capability of the QSP model to project IL-6 peaks after treatment with cevostamab.

4. Robustness of Results

The assessment of robustness of results evaluates how the model captures variability or uncertainty, including biological and data variability, especially given that structural identifiability is typically challenging to assess in QSP models. In the cevostamab QSP model, the model parameters for the clinical virtual population were within physiological ranges either observed in the preclinical studies, clinical trial, or reported in literature. The model simulation for the virtual population also captured the observed ranges, notably for IL-6 peak expression in Cycle 1 (FIGS. 28-31). Furthermore, the digital twin workflow used to generate the virtual population addressed uncertainty by ensuring that each clinical patient was represented in the virtual population with a number of alternate model parameters sets (digital twins) which reasonably fit the data. G. Results

/'. Model Validation of Peak IL-6 Concentrations

The virtual population that was generated using the digital twin workflow captured the M-protein and free light chain dynamics from 84 clinical patients. The simulation results for IL-6 peaks of the digital twins from a cohort also captured the corresponding cohort-level IL-6 peaks reasonably well (FIG. 27).

Model validation was performed using clinical cevostamab data from Study GO39775. Model predictions reasonably described the observed data, supporting use of the QSP model for exploratory predictions of the dynamics expected in the time course of the systemic IL-6 profiles following the administration of cevostamab in Cycle 1 . FIGS. 28-31 show the overlay between the observed (Obs) IL-6 peak concentration and the model simulation. In general, the geometric mean of the observed IL-6 peak concentration in the validation dataset were within the population variability, and the observed IL-6 peak concentrations were generally within the 90% prediction interval of the QSP virtual population simulation. Notably, the trends of IL-6 peaks observed at different step-up dose levels and schedules tested in the clinical trial were well-captured by the model:

• The model captured the dose-dependent trend of IL-6 peak concentration post C1 D1 step-up dose (0.05-3.6 mg) (FIG. 28). This was consistent with the logistic regression exposure-CRS analysis for C1 D1 step-up dose described herein.

• Following the 3.6 mg step-up dose in single step-up dosing regimen, the IL-6 peak concentration was independent of the target dose (e.g., 10.8-252 mg) (FIG. 29). This was consistent with the logistic regression exposure-CRS analysis for target dose described herein. Even though IL-6 data from the dose cohorts with 160 mg to 252 mg target doses was not used in the model calibration, model simulation reasonably predicted the observed peak IL-6 levels.

• The IL-6 peak concentration following the administration of a 3.3-3.6 mg dose when it was administered as the third dose (e.g., in the triple step-up 0.3/1 .2/3.6 mg regimen) was trending lower compared to when the 3.6 mg dose was given as the first dose in the single step-up dosing regimen or as the second dose in the double step-up dosing regimen (FIG. 30).

• The model also captured the comparable IL-6 peak concentrations at the target dose in the single step-up, double step-up, compressed double step-up, and triple step-up regimens following the administration of the 3.6 mg dose (FIG. 31). This supported the pooling strategy for target dose CRS exposure-response evaluation described herein.

/'/. Model-Based Evaluation of the Impact of Step-

Up Dose Strategies on IL-6 Peak Expression

QSP virtual population simulations were performed for the following step-up dosing regimens evaluated in Study GO39775: single step-up (e.g., 3.6/160 mg of cevostamab administered on D1/D8), double step-up (e.g., 0.3/3.6/160 mg of cevostamab administered on D1/D8/D15), compressed double step-up (e.g., 0.3/3.6/160 mg of cevostamab administered on D1/D4/D8), triple step-up “low” (e.g., 0.3/1 .2/3.6/160 mg of cevostamab administered on D1 /D2-4/D8/D9-11 ), and triple step-up “high” (e.g., 0.3/3.3/7.2/160 mg of cevostamab administered on D1 /D2-4/D8/D9-1 1 ) dosing regimens. The simulation results shown in FIG. 32 suggest:

• The maximum cycle 1 IL-6 peak level in the single step-up dosing regimen occurred after the 3.6 mg D1 dose. In comparison to this IL-6 peak level, the other simulated dosing regimens were predicted to have lower maximum IL-6 peaks across 21 days (Cycle 1 ) based on the median trends of the simulated IL-6 profiles.

• Between the two triple step-up regimens simulated, the triple step-up “low” (e.g., 0.3/1 .2/3.6/160 mg) dosing regimen had a lower IL-6 peak at the second dose, while the triple step-up “high” (e.g., 0.3/3.3/7.2/160 mg) dosing regimen had a marginally lower IL-6 peak at the target dose.

Hi. Evaluation of Alternative Priming Sequences and Visualization

Using Heatmap Plots of Maximum Cycle 1 1L-6 Peaks

To evaluate whether alternative priming sequences had the potential to further reduce IL-6 compared to the single step-up priming sequences, an extensive range of levels for double and triple step-up priming sequences were simulated. The result of these simulations are summarized in heatmap plots (FIG. 24 and FIG. 25) based on the ratio of the maximum IL-6 peak concentrations from the tested regimen to the maximum IL-6 peak concentration of the single step-up dosing regimen (e.g., 3.6/160 mg of cevostamab administered on D1/D8), shown in Equation 3, below:

Equation 3:

The heatmaps in FIG. 25 show the maximum IL-6 peak ratio to single step-up for regimens with two step-up doses at different schedules. The x-axis shows the first dose level varying from 0.3-1 .2 mg. The y-axis shows the second dose level varying from 1 .2-60 mg. The target dose was fixed at 160 mg. The heatmaps show that the dose level of 0.3/3.6/160 mg with schedules of Day 1 , Day 8, and Day 15 (D1/D8/D15); Day 1 , Day 4, and Day 8 (D1/D4/D8); Day 1 , Day 3, and Day 8 (D1/D3/D8); and Day 1 , Day 2, and Day 8 (D1/D2/D8) were predicted to have a maximum IL-6 peak ratio between 0.21 and 0.39, relative to a single step-up dosing regimen

The heatmaps in FIG. 24 show the maximum IL-6 peak ratio to single step-up regimens with three step-up doses at different schedules. The x-axis shows the second dose level varying from 0.6-5.4 mg. The y-axis shows the third dose level varying from 1 .2-20 mg. The first dose on Day 1 (D1 ) was fixed at 0.3 mg and the target dose was fixed at 160 mg. The heatmaps show that the dose level of 0.3/1 .2/3.6/160 mg with schedules of Day 1 , Day 4, Day 8, and Day 1 1 (D1/D4/D8/D1 1 ); Day 1 , Day 3, Day 8, and Day 10 (D1/D3/D8/D10); and Day 1 , Day 2, Day 8, and Day 9 (D1/D2/D8/D9) were predicted to have a maximum IL-6 peak ratio between 0.21 and 0.23, relative to a single step-up dosing regimen.

Based on these data, the QSP evaluation provides mechanistic support for the triple step-up dosing regimens described herein (e.g., 0.3/1 .2/3.6/160 mg or 0.3/3.3/7.2/160 mg of cevostamab administered on D1/D2-4/D8/D9-1 1 ) to reduce peak IL-6 expression, as compared to single step-up and double step-up dosing regimens. iv. Conclusions

This Example describes a complementary model-informed drug development (MIDD) approach to characterize and decouple the pharmacological drivers for efficacy and CRS. This informed the selection of the priming sequence of doses (e.g., to mitigate CRS) and target dose (e.g., to maximize efficacy) of cevostamab’s recommended phase 2 dose (RP2D) in R/R MM patients. The QSP model evaluated the effect of various priming doses on the post-dose IL-6 dynamics following cevostamab administration and identified priming doses that mitigate CRS risk. The QSP model also explored a wide range of target doses (e.g., 0.15-252 mg) and identified target doses that would provide meaningful clinical benefit in patients with R/R MM. Increased cevostamab exposure was found to be associated with higher objective response rate (ORR) and very good partial response (VGPR) rate, with a plateau at the 160 mg every three weeks (Q3W) dose. This implied diminishing gains at doses beyond 160 mg Q3W. Taken together, the QSP model identified a suitable priming dose regimen that can mitigate CRS risk while enabling the delivery of higher, clinically meaningful target doses. For example, the 0.3/1 .2/3.6 mg priming doses and the Q3W 160 mg target dose was identified as a triple step-up dosing regimen with favorable benefit-risk for the R/R MM population.

Example 4. Population Pharmacokinetics and Tumor Growth Inhibition

A population pharmacokinetics (PopPK) model (to describe the serum concentration of cevostamab) and a concentration-driven tumor growth inhibition (TGI) model (to describe the patients’ corresponding paraprotein (e.g., M-protein and free light chain) dynamics) were developed for cevostamab in patients with R/R MM enrolled in the Study GO39775 (e.g., patients described in Example 1 and in International Patent Application Publication No. WQ/2022/076462, which is herein incorporated by reference in its entirety). The PopPK model was used to characterize cevostamab pharmacokinetics and generate individual time courses of cevostamab concentrations, which were subsequently used in an exposure-response (E-R) evaluation. The PopPK model was also used to support the development of the TGI model described herein and the Quantitative Systems Pharmacology (QSP) model described in Example 3. The TGI model characterized the dose E-R relationship of cevostamab and, in conjunction with a logistic regression E-R evaluation, evaluated the effect of priming sequence exposures on paraprotein reduction.

The PopPK model is a two-compartment model with linear and Michaelis-Menten clearance and an additional time-dependent anti-drug antibody (ADA) clearance. Overall, the PopPK model sufficiently described the cevostamab pharmacokinetics and demonstrated adequate predictive performance for use in cevostamab pharmacokinetic simulations. A preliminary covariant analysis showed that, among the identified covariates, baseline M-protein and body weight appeared to have the largest influence on cevostamab exposure (FIG. 33).

The TGI model was based on a reduced Gompertz tumor model (e.g., see Hokanson et al., Cancer, 39(3):1077-84, 1977; and Vaghi et al., PLoS Comput Biol., 16(2):e1007178, 2021 ) with a saturable, concentration-driven tumor killing effect (e.g., see Claret et al., J. Clin. Oncol., 25(4):4103-8, 2009). The model described a longitudinal time course of paraprotein concentrations and demonstrated a predictive capacity to capture the response rates shown in FIG. 39. A. Methodology

A model-based evaluation of the longitudinal time profiles of cevostamab’s pharmacokinetics and paraprotein (MPRO/FLC) levels was conducted as described herein. Analyses were performed using data collected from Study GO39775, including pharmacokinetic, anti-drug antibody, and paraprotein data. Pharmacokinetic data was available for 353 subjects, and paraprotein (e.g., M-protein and free light chain) data was available for 318 patients. Since this model relates the longitudinal time course of pharmacokinetic and paraprotein data using a population modeling approach, it can be leveraged to account for differences in dose levels and schedules on treatment response. Briefly, in Study GO39775, cevostamab was administered by intravenous infusion in a step-up dose approach implemented in the first 21 -day cycle. Several Arms of study GO39775 are as follows and are described further in Table 6A:

• Treatment Arm A: Single step-up dose fractionation (Day 1/Day 8) dose escalation stage, with dose level ranging from 0.05/0.15 mg to 3.6/252 mg

• Treatment Arm B: Multistep dose fractionation (Day 1/Day 8/Day 15) dose escalation stage

• Treatment Arm C: Single step-up dose fractionation dose expansion stage at 3.6/90 mg

• Treatment Arm D: Multistep dose fractionation dose expansion stage at 0.3/3.6/160 mg

• Treatment Arm E: Single step-up dose fractionation dose expansion stage at 3.6/90 mg with tocilizumab

• Treatment Arm F: Single step-up dose fractionation dose expansion stage at 3.6/252 mg

• Treatment Arm H & I: Triple step-up dose escalation stage at 0.3/1 .2/3.6/160 mg and 0.3/3.3/7.2/160 mg, respectively on (Day 1/Day 2-4/Day 8, Day 9-11 )

• Treatment Arm K: Compressed double step-up (DSComp) dose fractionation dose escalation stage at 0.3/3.3/160 mg (Day 1/Day 4/Day 8)

For PopPK model development, evaluable patients were those with pharmacokinetic data after cevostamab administration. For the PopPK-TGI model, evaluable patients included individuals with empirical Bayesian estimates (EBEs) of pharmacokinetic parameters from the PopPK model, baseline (e.g., prior to treatment initiation) paraprotein data, and at least one paraprotein assessment after commencement of treatment. Non-evaluable patients were excluded directly within the nonlinear mixed effects modelling software (NONMEM Version 7.5.1 ).

/'. Modeling and Simulation Approach

Model development was performed sequentially with an initial PopPK model development followed by the exposure driven TGI model development. Both models were developed using a population approach based on non-linear mixed effect modeling. This approach estimates the typical value of parameters (e.g., population mean) and their variances. Quantification of inter-individual variability (e.g., random effects on PK and TGI model parameters) and the residual variability is described in Equation 4:

Equation 4: wherein i denotes the i^,h patient, j denotes the j^,h observation of serum pharmacokinetics or tumor size, respectively. The model was implemented as a nonlinear mixed effect model in NONMEM Version 7.5.1 with a lognormal distribution for inter-individual variability on each of the model parameters 0 with patientlevel random effects q. Patient-level random effects q follows a normal distribution with mean 0 and variance w².

/'/. Covariate Identification

The following covariates were evaluated in the PopPK model development: age, weight, height, ethnicity, race, and baseline laboratory values (e.g., aspartate aminotransferase (AST), alanine aminotransferase (ALT), estimated glomerular filtration rate (eGFR), lactate dehydrogenase (LDH), C- reactive protein (CRP), albumin (ALB), ferritin (FERR), lymphocyte counts, neutrophil counts, platelet counts, soluble B cell maturation antigen (sBCMA), free light chain (FLC), M-protein (MPRO), ECOG status, high-risk cytogenetics, extramedullary disease status, number of prior lines of therapy, and history of bispecific therapy or CAR-T therapy). Covariates with significant levels of missingness (>25%) were not considered. Power functions on the log scale were applied to parameterize continuous covariates unless explicitly stated otherwise. Proportional changes on the log scale were used for categorical covariates.

The exploration of these covariates employed a stepwise methodology, whereby a machine learning (ML) procedure was initially applied for the preliminary screening of covariates. In this ML workflow, relationships between covariates and individual EBE parameters are learned, and statistical significance is established through a SHapley Additive exPlanations (SHAP)-based bootstrapping analysis. The significant covariates identified in this initial step guided the construction of a full model, which was subjected to a stepwise backward exclusion process. The selection criteria for this procedure relied on a change in the objective function value (AOFV) of 10.8 corresponding to a p-value threshold of 0.001 for 1 degree of freedom. This same procedure was applied to both the PopPK and PopPK-TGI models.

Hi. Software Details

Model development and parameter estimation were performed using the nonlinear mixed effect modeling software NONMEM Version 75.1 , supplemented with Perl-speaks-NONMEM (PsN) Version 4.9.0. R software (64-bit, Version 4.1 .0) for general scripting, data management, goodness-of-fit analyses, model evaluation, and model writing. The R package mrgsolve was used to generate exposure metrics from EBEs generated by the PopPK models used for the ER analyses and the pharmacokinetic- TGI model development and said R package was used to perform model-based simulations. The reproducibility of the code was verified by an independent analyst repeating the key model development steps and model-based simulations and reproducing the tables and figures.

B. Population Pharmacokinetic Modeling

The development of the PopPK model began by estimating the parameters of different structural models including a one-compartment and two compartment model. Additionally, non-linear forms of clearance were explored including Michaelis-Menten clearance and time-dependent clearance. To capture the wide dose and exposure range observed in Study GO39775, cevostamab PK was natural logarithm transformed. Additionally, the M3 method for handling observations below the limit of quantification (BLQ) was employed to better capture BLQ observations noted in ADA positive patients.

This initial structural model development was performed using censored post ADA onset observations. Subsequently, the inclusion of PK observations post ADA onset were included, and ADA mediated clearance were explored based on the observed cevostamab concentration in patients with ADA. The ADA effect to cevostamab clearance was further informed by the preliminary evaluation of the ADA effects on the observed minimum concentration (Cmin) (FIG. 34A) and maximum concentration (Cmax) (FIG. 34B). It was observed that ADA-mediated impact on pharmacokinetics were most apparent in patients with high ADA titers (e.g., titer >4).

Model refinement was driven by data and was based on various goodness-of-fit indicators, including visual inspection of diagnostic scatter plots (e.g., observed vs. predicted concentrations, conditional weighted residuals vs. concentration or time), precision of parameter estimates, the objective function value (OFV), the number of estimated parameters, and the pathophysiological plausibility of covariate relationships and prediction-corrected visual predictive checks (pcVPC).

/'. Model Evaluation and Qualification

Model evaluation and selection were based on the following:

• Standard statistical criteria of goodness-of-fit such as the log-likelihood difference between alternative models, e.g., a decrease in the minimum objective function value or in Akaike Information Criterion (AIC) (e.g., see Akaike et al., IEEE Transactions on Automatic Control, 19(6) :716-723, 1974)

• Successful model convergence

• Accuracy of parameter estimation (e.g., 95% confidence interval excluding 0 or relative standard error (RSE) <50%)

• Goodness-of-fit plots

• Observed dependent variable (DV) vs population predictions (PRED)

• DV vs individual predictions (IPRED)

• Conditional weighted residuals (CWRES) vs PRED, TIME and Time after dose (TAD)

• Normalized Prediction Distribution Errors (NPDE) vs PRED, TIME, TAD

• Estimation of shrinkage of the EBEs of the model parameters which reflects the degree of information

• pcVPC plots o Using history of dosing, sampling and covariates of the PopPK data set of Study GO39775, simulations from the model were used to generate 1000 concentration datasets. The observed concentrations and the simulated values were prediction corrected according to Equation 5 as follows:

Equation 5: \n(pcYij) = In(Tiy) + (\n(PREDbin) - \n(PREDij)) wherein Yij is the observation or prediction for the i^,h individual and j^,h time point, pcYij is the prediction-corrected observation or prediction, PREDij is the typical population prediction for the i^,h individual and j^,h time point, and PREDbin is the median of typical population predictions for the specific bin of the independent variable (time after dose). Bin values were values of time after dose rounded to 2 hours; bins with low representation were not shown. o For each dataset (observed and simulated) and each bin, 5^th, 50^th, and 95^th percentiles of prediction-corrected concentration values were calculated. For each of the calculated percentiles of the simulated values, the 90% confidence intervals were constructed by calculating 5th and 95th percentiles across 500 simulations. o The observed percentiles and confidence intervals for the simulated percentiles were plotted versus time after dose together with the prediction-corrected observed values.

/'/. Evaluation of Baseline Covariate Impact on Exposure

The effect of baseline covariates on cevostamab exposure were explored by simulating the marginal effect on steady-state exposure of a given covariate across the 5^th and 95^th percentile of the covariate relative to the typical covariate value. These simulations assumed nominal dosing of 160 mg Q3W dosing up to steady-state and summarized by forest plot. ill. Data Used for the PopPK Model Analyses

The number of subjects and data points available for development of the cevostamab PopPK model are summarized in Table 22 below. All data exclusions were performed in NONMEM so that no modifications were made. The final PopPK model was developed on 6,422 individual pharmacokinetic measurements collected in 352 patients.

Table 22: Summary of Number of Subjects and Data Points for Population Pharmacokinetic Model Estimation

BQL = below quantitation limit; MISS = missing observations (not BQL); OBS = observations; PopPK = population pharmacokinetics; SUBJ = subjects a Missing observations do not include those below quantitation limit.

C. Tumor Growth Inhibition Model

The TGI model describes the affected paraprotein, M-protein, or free light chain as a function of time and predicted cevostamab concentration. The drug effect was applied to the TGI model using serum concentrations of cevostamab that were predicted using the PopPK model described herein. Model estimation was performed sequentially, where the TGI parameters were separately estimated following the estimation of the PopPK model. At this stage, only the affected paraprotein was considered for dynamical modeling. For example, if a patient was an M-protein patient, only M-protein would be modeled; if a patient were a free light chain patient, then only the affected light chain would be considered.

/'. Model Development and Qualification

The development of the PK-TGI model started by exploring structural models to describe the dynamics of both M-protein and free light chain. The structural models that were considered included different single and multiple species ordinary differential equation systems (e.g., sensitive and resistant tumor populations and separate species for M-protein vs. free light chain). Additionally, different forms of growth, including exponential and Gompertz, linear, and saturable forms of exposure-driven tumor shrinkage effects were also explored.

Model refinement was driven by data and was based on various goodness-of-fit indicators, including visual inspection of diagnostic scatter plots (e.g., observed vs. predicted concentrations, conditional weighted residuals vs. concentration or time, among others), precision of parameter estimates, the objective function value, the number of estimated parameters, pathophysiological plausibility of covariate relationships, visual predictive checks (VPC), and posterior predictive checks (PPC).

Model evaluation and selection were based on the following:

• Standard statistical criteria of goodness-of-fit such as the log-likelihood difference between alternative models such as a decrease in the minimum objective function value or a decrease in AIC

• Successful model convergence

• Accuracy of parameter estimation (i.e., 95% confidence interval excluding 0 or RSE <50%)

• Goodness-of-fit plots

• VPC • VPC (Bergstrand et al. 2011 ) focusing on the ability of the model to reproduce the observed time course of M-protein or free light chain and associated variability was also performed.

• VPCs were stratified by diagnostic status (M-protein vs. free light chain).

• To reflect treatment discontinuation due to progressive disease observed in clinical practice. Simulated paraprotein data were censored if there was a 25% increase from nadir on an individual basis.

• PPC

• PPCs were performed to evaluate the ability of the TGI model to reproduce the chosen efficacy metric (i.e., the proportion of patients achieving at least 50% or 90% paraprotein reduction from baseline). Simulations of 500 replicates of the model development patient population were performed and accounted for I IV, residual variability, and uncertainty in TGI parameters implemented at the replicate level while having fixed the PopPK parameters to the individual EBE. To reflect treatment discontinuation due to progressive disease observed in clinical practice, simulated paraprotein data were censored if there was a 25% increase from nadir on an individual basis. For each replicate, the metric value was derived, and a 90% prediction interval was generated based on the 500 replicates. If the corresponding observed value from the model development dataset was included within the 90% prediction interval, the model was considered qualified.

• PPCs were stratified by target dose and priming dose regimens.

/'/. Population-Level Simulation to Support Cevostamab Dose Justification

For the clinical trial simulations, simulation of 500 replicates of 50 subject cohorts at each planned dose/schedule in Study GO39775 phase I clinical trial, where realistic baseline covariates were generated by sampling 50 subjects from the observed baseline patient characteristics in the clinical trial. Additional sources of variability in these clinical trial simulations included, between subject variability of the PopPK and TGI model parameters, residual variability, and uncertainty in the TGI parameters were included at the replicate level.

To characterize the dose/exposure-efficacy relationship, best ORR and >VGPR we used as efficacy metrics. Best ORR included partial response or better (>PR) and was defined as at least 50% reduction from baseline in paraprotein level at nadir, while >VGPR was defined as at least 90% reduction from baseline in paraprotein level at nadir. This definition is consistent with the response definition from the IMWG Uniform Response Criteria but does not consider additional components of response outside of M-protein or free light chain changes, such as urine M-protein levels and bone marrow plasma cell counts.

These efficacy metrics were derived using paraprotein simulation up to day 365 with a sampling frequency of 21 days to most closely reflect the clinical data and capture the best response which has been observed to occur in the first year of cevostamab treatment. To reflect treatment discontinuation due to progressive disease observed in clinical practice, simulated M-protein and free light chain data were censored if there was a 25% increase from baseline on an individual basis. ill. Data Used for the Tumor Growth Inhibition Model Analyses

The number of subjects and data points available to develop the cevostamab PopPK-TGI model are summarized in Table 24 below. All data exclusions were performed in NONMEM so that no modifications were made to the datasets.

Table 24: Summary of Number of Subjects and Data Points for PopPK-TGI Model Estimation iv. Model Development and Final Model

Based on initial exploratory analysis, it was determined that both affected M-protein and free light chain dynamics can be captured using the Gompertz growth model; however, some parameters need to be estimated separately to account for differences in units and dynamical behavior. Further evaluation of equations differentiating between sensitive and resistant tumor populations was unstable. A reduced Gompertz growth model with fixed carrying capacities for M-protein and free light chain significantly improved population predictions while having a negligible impact on the objective function value (OFV). The error model was best described by separate additive and proportional error models for M-protein and free light chain, respectively. The additive error was fixed to a small value to help handle predictions that were close to zero, resulting in a substantial reduction in OFV >1800 over an additive alone error model. A proportional only error model could not be successfully estimated. Evaluation of the drug effect started with a fixed drug effect that was independent of cevostamab exposure. The second step tested whether or not cevostamab exposure had an impact. Use of cevostamab concentration improved the model and was thus considered as the driver of the drug effect. Longitudinal exposure led to a stable model. Total cevostamab concentration (cumulative AUC) did not improve model fit and resulted in an increase in OFV. The third step tested the use of an effect compartment, and there was no improvement in AIC. The effect delay was very short, indicating little delay in drug effect. The final drug effect was explored with a saturable drug effect and resulted in a substantial reduction in OFV (>150). Ultimately, Equations 12 and 13, shown below, describe the final model structure.

Equation 12: = KG x M(t) x log - KS( )x M(t) Equation 13:

M is the paraprotein concentration used to define response, in which M-protein concentration is expressed as g/L, and free light chain concentration is expressed as mg/L. KG and KS are the estimated growth and shrinkage rates, respectively. The KS is time-dependent, and the parameters KSo and DecaynL are the initial value and decay half-life, respectively. KG and KSo were estimated separately for M-protein patients versus free light chain patients, as noted in the final parameter estimates shown in Table 25 below. The term log(^K^”^or) represents a reduced form of tumor carrying capacity with fixed species-specific carrying capacities. The observed baseline M-protein and free light chain values were used in model development to align simulations by linking these variables in the PopPK and/or the PopPK-TGI models.

Table 25: Final PK-TGI Model Parameter Estimates

MPRO: M-protein; FLC: free light chain; MPRO/FLC: M-protein or free light chain

The population estimates showed species-dependent differences (i.e., M-protein versus free light chain) in Kg, KS, and protein decay half-life (Decay-HL), in which free light chain patients had larger I IV, faster growth rate and shrinkage rates, and shorter Decay-HL, potentially suggesting worse responses in these patients at similar doses. Such estimates appear consistent with observed M-protein (FIG. 35A) and free light chain (FIG. 35B) dynamics. High I IV was noted for Decay-HL, which was consistent with the observed heterogeneity in M-protein and free light chain dynamics. Furthermore, a significant negative correlation was estimated between KG and Decay-HL.

Preliminary covariate evaluation identified statistically significant covariate relationships shown in the final parameter estimates shown in Table 25. There was a positive relationship between baseline paraprotein and KG; this theta was shared between the species. There was a negative relationship between baseline M-protein concentrations and Decay-HL. There was a significant relationship between higher baseline ferritin and higher baseline KG. Additionally, there was a relationship between higher baseline lymphocyte count and lower KG. There was a relationship identified between baseline IL-6 and Decay-HL, in which patients with baseline IL-6 >3 ng/mL had shorter Decay-HL than patients with IL-6 <3 ng/mL, wherein the threshold of 3 ng/mL represents the lower quartile of the observed IL-6, as shown in FIG. 36 and FIG. 37. Visual predictive check of M-protein or free light chain time profile demonstrates that the model captured the central tendency, extreme values, and the variability in the observed M-protein and free light chain levels (FIG. 38).

The PPC, which accounted for TGI model variabilities and parameter uncertainty after adjusting for individual patients’ pharmacokinetic characteristics, demonstrated the capability of the model to reproduce the observed ORR (at least 50% reduction of M-protein reduction at nadir) below 90 mg target dose, at 90 mg target dose, at the proposed target dose of 160 mg, and in cohorts which explored a target dose >160 mg for the model development patient population (FIG. 39). The model demonstrated reasonable predictive performance, the observed values in all four categories are within the prediction interval. The numerical values that correspond to the ORR (FIG. 39A) and VGPR+ (FIG. 39B) response rates are summarized in Table 27. PPCs for different dosing regimens with 160 mg target dose demonstrate that the model simulation reasonably captured the observed ORR (FIG. 40A) and >VGPR (FIG. 40B) rate for the cohort (Table 28). iv. Model Development and Final Model

Out of the evaluated model structures the best fitting structural model was found to be a two- compartment model with linear and Michalis-Menten clearance described by Equations 6-11 based on OFV, AIC, and overall goodness-of-fit. Based on preliminary evaluation, an apparent impact of high ADA titer (e.g., titer >4) on cevostamab exposures (Cmax and Cmin) was evident from Cycle 3 with maximal impact observed in Cycle 6 onwards, compared with patients with ADA negative or low ADA titer (e.g., titer<4) as shown in FIG. 34. To capture the post-ADA onset pharmacokinetics, a semi-mechanistic timedependent ADA effect to clearance was explored and was found to align closely with the observed ADA onset and characteristics. From this analysis, it was found that most pharmacokinetic loss occurs when ADA titer is greater than 4. As such, only patients with a maximum ADA titer >4 were considered to have additional ADA-mediated clearance characterized by the logistic function shown in Equation 8.

Equation 6:

Equation 7: Equation 8: wherein ADAi is 1 for a given subject if they are ADA+ and have a maximum titer >4 and 0 for subjects who are ADA- or ADA+ with a maximum titer <4. wherein ui is the amount of cevostamab in the central compartment, ui is the amount of cevostamab in a peripheral compartment, K12 = CLd/V1 , and K21 = CLd/V2 in Equation 10 and Equation 11 , respectively. Parameter descriptions are listed in Table 23, shown below.

Preliminary covariate evaluation identified several covariate relationships including body weight (bwt), beta-2-microblubulin, sBCMA and gender effects on central volume of distribution (V1 ); bwt, baseline M-protein levels on the linear clearance (CLss); bwt, baseline MPRO, baseline lymphocyte count gender on Maximum rate of elimination (Vmax); beta-2-microblubulin on C50; and bwt on peripheral volume of distribution (V2). The reduction in OFV of the final covariate model over the final structural model was 21OFV =-285.6 with an additional 12 degrees of freedom (p<0.001 ). The final model parameters estimates are shown in Table 23. All parameters except the maximum ADA mediated clearance (CLADA-MAX) were estimated with high precision based on the 95% confidence interval (Cl) and relative standard errors (RSE) <40%. The higher RSE and inter-individual (II V) observed on CLADA-MAX and T50 Z is likely reflective of the true parameter uncertainty, high between-subject variability, and small n supporting estimation of the ADA mediated clearance.

The effects of the identified covariates on steady-state exposure based on a 160 mg target dose are summarized in FIG. 33.

Table 23: Final Population Pharmacokinetic Model Parameter Estimates

Corr = correlation coefficient; Cl = confidence intervals (estimate ±1 .96 standard error); SE = standard error; RSE = relative standard error; I IV = inter-individual

Table 27: Summary of the Posterior Predictive Check of the Tumor Growth Inhibition Model by Target Dose Level

VGPR = very good partial response

Table 28: Summary of the Posterior Predictive Check of the Tumor Growth Inhibition Model for

Key Cohorts Treated with a 160 mg Target Dose Comp = Compressed; SS = single step-up; DS = double step-up; TS = triple step-up; VGPR = very good partial response

The PopPK-TGI model clinical trial simulations at target dose levels ranging from 0.15 to 252 mg shows an increase in the predicted ORR and >VGPR rates with an increase in target dose (FIG. 41). At the proposed target dose of 160 mg, both the ORR and >VGPR rate appear to approach a plateau.

Furthermore, the predicted ORR and >VGPR between differing step dosing regimen at the same target dose were within 5% median difference (FIG. 42 and Table 29, shown below). It is important to note that, unlike the PPC simulation described above, the clinical trial simulation accounts for the entire population variability from subjects included in the dataset used for model estimation detailed in the TGI data section (see, e.g., Section C(iii) above). Therefore, differences between the model prediction and observed data may be due to baseline patient characteristics for the given cohort.

Table 29: Summary of Simulated Response Across Tested 160 mg Target Dose Regimens

Comp = Compressed; SS = single step-up; DS = double step-up; TS = triple step-up; VGPR = very good partial response

D. Discussion and Conclusions

This example shows the development and qualification of PopPK and exposure-driven TGI models that characterize the pharmacokinetics and dose exposure-efficacy relationship of cevostamab by leveraging longitudinal pharmacokinetic and paraprotein data from Study GO39775. These models captured the variability, intrinsic, and extrinsic factors that influence cevostamab pharmacokinetics and paraprotein dynamics.

The PopPK model provides a robust depiction of cevostamab pharmacokinetics and accurately captured the concentration-time course for various dose levels and schedules. Additionally, the incorporation of a model structure describing the time-dependent ADA effect on clearance into the model captured the reduction in exposure in the small subset of patients (18/296 (6.1%)) of all ADA-evaluable patients with titers >4 (FIG. 34). The model parameter estimates (see Table 23) for the ADA-mediated clearance in patients with titers >4 was approximately 10 times the clearance of an ADA-negative patient.

Preliminary covariate evaluation identified several statistically significant covariate relationships including body weight, beta-2-microblubulin, sBCMA, and gender effects on central volume of distribution (V1 ); body weight and baseline M-protein levels on the linear clearance (CLss); body weight, baseline M- protein levels, baseline lymphocyte count, and gender on the maximum rate of elimination (Vmax); beta- 2-microblubulin on the concentration at which the rate of elimination is half-Vmax (C50); and body weight on peripheral volume distribution (V2). Several of these covariates, beta-2-microblubulin, sBMCA, baseline paraprotein levels, are associated with baseline disease state and suggest that patients with worse baseline disease may have lower cevostamab exposure. Baseline M-protein levels appeared to have the largest effect on steady-state Cmin and steady-state AUC, while body weight appeared to have the largest effect on steady state Cmax (FIG. 33).

The sequentially developed PopPK-TGI model reasonably captured the longitudinal serum paraprotein (M-protein and free light chain) dynamics in the tested population (FIG. 38). While this model only used M-protein and free light chain to define clinical response (e.g., objective response rate (ORR) and very good partial response (VGPR)) it captured the highly heterogeneous observed clinical responses in Study GO39775 across dose and cohort (FIG. 39 and FIG. 40).

Model-based clinical trial simulations demonstrated that response rates increased as a function of target dose up to target doses of 90 mg-160 mg (FIG. 41). Further model-based simulations predicted limited difference (<5%) in response rates between differing dosing regimen (single step-up, double step- up, triple step-up, compressed double step-up) at the same target dose (FIG. 42 and Table 29). The median (95% Cl) model predicted ORR at the proposed RP2D was 0.52 (0.4-0.64) with a model predicted VGPR rate of 0.42 (0.3-0.52).

The PopPK-TGI model with concentration-driven saturable drug effect adequately captured the paraprotein data and predicted response rates. Additionally, the model was able to explain some of the heterogeneity in observed response by accounting for patient factors and individual pharmacokinetics. Model-based simulation predicts an increase in ORR and very good partial response or better (>VGPR) rates with an increase in target dose up to 160 mg. At the target dose of 160 mg, the ORR and >VGPR rate appeared to approach a plateau. Comparable (<5% median difference) ORR and >VGPR rates were predicted for single step-up, double step-up, and triple step-up dosing regimens with the same target dose.

Example 5. Biomarker Correlates and Clinical Activity of Cevostamab in Patients with Refractory Multiple Myeloma

Proven salvage therapies for patients with triple-class refractory multiple myeloma (MM) who progress on B-cell maturation antigen (BCMA)-targeted therapies are lacking. Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed exclusively in the B-cell lineage. Cevostamab is a bispecific antibody that targets FcRH5 and CD3 and facilitates T cell-mediated killing of MM cells. In an initial Phase I study, (e.g., Study GO39775, e.g., see clinical trial identifier: NCT03275103), cevostamab monotherapy was clinically active and had manageable toxicity in patients with heavily pretreated relapsed/refractory MM. In Cohort A1 of a subsequent Phase l/ll study (e.g., Study CO43476, e.g., see clinical trial identifier: NCT05535244 and International Patent Application Publication No.

W02024/015897), cevostamab was highly active and had manageable safety at the 160 mg target dose (TD) level in patients with triple-class refractory MM who had received a prior BCMA-targeted antibodydrug conjugate (ADC; overall response rate (ORR): 60%, 6/10 patients) or chimeric antigen receptor T cell (CAR-T) therapy (ORR: 73%, 8/11 patients) but had not received a prior BCMA-targeted bispecific antibody (BsAb). The present Example provides the initial results from Cohort A2 of Studt CO43476, which enrolled patients with triple-class refractory MM who had received prior BCMA-targeted therapies, including >1 BCMA-targeted BsAb.

/'. Methodology

Cevostamab was initiated with step dosing of 0.3 mg on Day 1 and 3.3 mg on Day 2, Day 3, or Day 4, depending on the emergence of cytokine release syndrome (CRS) after the initial 0.3 mg administration. A 160 mg target dose was administered on Day 8 and continuously administered on Day 1 of each subsequent 21 -day cycle until disease progression (PD) or unacceptable toxicity. Cytokine, tumor antigen, T cell function or activation, and inhibitory immune checkpoint expression were assessed in blood and tumor samples collected at baseline and during treatment.

/'/. Results

Twenty-one patients (median age: 64 years, range: 46-84) were enrolled in Cohort A2. Seven patients (33%) had extramedullary disease and 5/12 patients (42%) with a conclusive assay result had high-risk cytogenetics (t(4; 14), t(14;16), or del ( 17p)). All patients were heavily pretreated (median prior lines of therapy: 8, range: 5-14); 62% had received >2 prior BCMA-targeted therapies (median time since last: 122 days, range: 68-558 days), and 33% had received >2 prior bispecific antibodies (median time since last: 139 days, range: 68782 days). Most patients (86%) were refractory to their last line of therapy; 62% were penta-drug refractory. The median follow-up was 173 days (range: 20-360 days).

Grade 3-4 adverse events (AEs) occurred in 71 % of patients (15/21 ). Grade 3-4 AEs in >3 patients were neutropenia, anemia, thrombocytopenia (38% each), and infections (29%). CRS occurred in 76% of patients (16/21 ) and was mainly Grade 1 (43%) or Grade 2 (29%); one patient had Grade 3 CRS. One treatment-related Grade 5 (fatal) AE of pneumonia was reported in the context of PD. No treatment-related AEs leading to cevostamab discontinuation occurred.

Objective responses (i.e., partial response (PR) or better) were observed in 2/21 patients (ORR: 10%). Both patients achieved a very good PR and had ongoing responses at cut-off. Stable disease was observed in 10 patients (48%).

Patients in the prior bispecific antibody group had received more prior lines of therapy than those in the prior ADC and CAR-T groups (median 8 vs 5 and 6 respectively) and more prior BCMA-targeted therapies (median 2 vs 1 and 1 ). The percentage of patients with low levels (<4.5 ng/mL) of soluble BCMA in plasma was also higher in the prior bispecific antibody group (47% vs 0% and 18%). At baseline, inhibitory immune checkpoint expression across T cell subsets was more common in the prior bispecific antibody group. Notably, the median frequency of PD1 +CD8+ Tnaive and TIGIT+CD8+ Tnaive cells in blood was higher in the prior bispecific antibody group (21 % and 29% respectively) than in the prior ADC (3% and 6%) and CAR-T groups (4% each). Peak median IL-6 and IFN-y levels were delayed until the first TD in the prior bispecific antibody group, suggesting a different pharmacodynamic profile. ill. Conclusions

Cevostamab has manageable safety in patients with triple-class refractory MM who have received prior BCMA-targeted therapies, including >1 BCMA-targeted bispecific antibodies. Clinical responses were less frequent in the prior bispecific antibody group than in the prior ADC and CAR-T groups, which could be explained by the higher number of prior lines of therapy and T cell exhaustion due to multiple prior exposures to bispecific antibodies. Notably, the high frequency of CD8+ T cell subsets expressing inhibitory immune checkpoints in the prior bispecific antibody group suggests a level of T cell dysfunction that could prevent effective T cell activation.

Example 6. Cevostamab in Patients with Heavily Pretreated Relapsed/Refractory Multiple Myeloma: Updated Results from an Ongoing Phase I Study Demonstrate Clinically Meaningful Activity and Manageable Safety and Inform the Doses and Regimen for Combination Studies

There is an unmet need for additional treatments of multiple myeloma (MM), particularly ones that can achieve a favorable benefit-risk profile. Unfortunately, there has been an emergence of triple-class refractory MM patients using early lines of treatment, as well as resistance to B-cell maturation antigen (BCMA)-targeting and G-protein coupled receptor, family C, group 5, subtype D (GPRC5D)-targeting agents. Morbidity and mortality associated with progressive disease (PD) and infection are also prevalent.

The present example summarizes results of an ongoing Phase I study of cevostamab monotherapy (GO39775; Clinical Trial Identifier: NCT03275103) after another data cut-off (August 22, 2024). In brief, this study used a fixed-duration of treatment in patients who were heavily pre-treated for their relapsed or refractory (R/R) MM. Patients treated with prior BCMA-targeting and GPRC5D-targeting agents were also included in the study with increased exposure during enrollment (e.g., from 2017-2023). The present example further describes safety and efficacy data at a 160-mg target-dose (TD) level, as well as patient cytokine release syndrome (CRS) data with a 0.3 mg/1 .2 mg/3.6 mg triple-step (TS) dosing and 160-mg TD regimen.

Schematic diagrams showing the possible single-step (SS), double-step (DS), and triple-step (TS) dosing regimens from GO39775 are shown in FIG. 43. Briefly, a total of 324 patients were enrolled in a cevostamab monotherapy study (FIG. 43A), 167 patients were enrolled in a 160-mg target dose (TD) study (FIG. 43B), and 30 patients were enrolled in a cycle 1 (C1 ) 0.3mg/1 .2 mg/3.6 mg triple step-up plus 160-mg TD study (FIG. 43C) (e.g., see GO39775; Clinical Trial Identifier: NCT03275103). The baseline characteristics of these patients are summarized in FIG. 44. Notably, most patients enrolled had heavily pretreated and highly refractory disease, while more than 50% of patients had received a prior BCMA- targeted therapy. At data cut-off (Aug 22, 2024), 81/167 patients remained ongoing in the GO39775 study. Those patients that completed treatment, discontinued treatment (e.g., due to progressive disease (PD) and adverse event (AE) or other), or are ongoing are described in FIG. 45. For patients that had an AE, most were grade (Gr) 3-4 and were reversible cytopenias. Almost all CRS events were Grade 1 -2, with the CRS profile influenced by the step-dosing regimen.

FIG. 46 is a table (left) and graph (right) characterizing adverse effects that were observed in the GO39775 Phase I dose-escalation study. * = includes time after completion and/or discontinuation of treatment when AE reporting was limited to 90 days after the last dose of study drug or until initiation of another anti-cancer therapy, whichever occurred first, and to treatment-related SAEs thereafter; f = excludes 16 patients with Gr 5 AE of PD; $ = HLH (n=2) and pseudomonal sepsis in the context of DIC (n=1); §group term: neutropenia, neutrophil count decreased and febrile neutropenia; fl = group term: thrombocytopenia and platelet count decreased; data cut-off: Aug 22, 2024; ALT, alanine transaminase; DIC, disseminated intravascular coagulation; Gr, Grade; HLH, hemophagocytic lymphohistiocytosis; PT, Preferred Term; SAE, serious AE. A summary of AEs in the 167 patients that were enrolled in the 160-mg target dose (TD) study is shown in FIG. 47. Notably, 29.3% of patients had a medical history of hypogammaglobulinemia; 32.9% received IV immunoglobulin. The majority of infections observed were Grade 1 -2. Infections leading to treatment discontinuation were uncommon in this study.

Thirty patients were enrolled in the cycle 1 (C1 ) 0.3mg/1 .2 mg/3.6 mg triple step-up plus 160-mg TD study (e.g., see FIG. 43C). Notably, there were no Grade 3+ CRS events in these patients and the majority of CRS events were Grade 1 (FIG. 48). This shows that the triple step-up dosing regimen provides for a safe and tolerable administration of cevostamab.

At the 160-mg target dose (TD) level in GO39775, overall response rate (ORR) was measured (FIG. 49). Notably, responses occurred early. The median time to first response (PR+) was 1 .4 months (range: 0.5-4.6). Responses deepened over time with a median time to best response being 2.6 months (range: 0.5-13.4). Minimal residual disease (MRD) negativity was achieved in 11/18 patients evaluated. Durability of response over 42 months was also measured (FIG. 50). Taken together, this data shows that the 160-mg TD can induce durable responses, especially in patients who achieve VGPR or better. The durability of response after completion of cevostamab treatment in patients administered the 160-mg target dose (TD) of cevostamab is shown in FIG. 51. A total of 28 patients completed 17 cycles of treatment at the 160-mg TD level; 9 patients had responses >6 months from completion (8/9 in CR/sCR at completion); 6 patients had ongoing responses of <6 months; and 1 patient in sCR withdrew from study. These data show that response to cevostamab continued after the completion of treatment, especially in patients who achieve CR/sCR.

In summary, cevostamab monotherapy has a manageable safety profile. At the 160-mg TD level, most Grade 3-4 AEs were reversible cytopenias. Infections leading to treatment discontinuation were uncommon. When initiated with C1 TS dosing, the majority of CRS was Gr 1 . Most notable, there were no Gr 3+ CRS or any CRS leading to discontinuation. The example shows that cevostamab is clinically active in patients with heavily pretreated and highly refractory disease. Such patients experienced an ORR of 44.3% (32.3% with prior BCMA-targeted therapy; 60.6% without) and an mDoR of 10.4 months in PR+ (21 .2 months in VGPR+*). Taken together, these data show that there were durable responses to cevostamab after the completion of fixed-duration treatment, especially in CR/sCR. These data highlight a role for FcRH5 as a unique and novel target in the evolving MM treatment landscape and support the continued development of cevostamab with Q3W 160-mg TD and with C1 0.3/1 .2/3.6/160mg TS dosing.

Example 7. Cevostamab, a FcRH5xCD3 bispecific antibody, in relapsed/refractory multiple myeloma

This example describes Study GO39775 (ClinicalTrials.gov Identifier: NCT03275103), a phase 1 study evaluating fixed-duration cevostamab in late-line relapsed/refractory multiple myeloma (MM). FcRH5 is a membrane protein that is ubiquitously expressed on myeloma cells. Cevostamab, a first-inclass, FcRH5xCD3 bispecific antibody, induces T cell-mediated killing of myeloma cells. In brief, cevostamab was initiated with step-up dosing and continued at target dose once every 3 weeks for 17 cycles (e.g., about 12 months) unless disease progression or unacceptable toxicity occurred. Prior T cell-redirecting therapy was allowed in this study. The primary objectives of this study were to evaluate safety of cevostamab and identify a recommended phase 2 dose and schedule. As of August 22, 2024, 324 patients had been enrolled, including 167 patients that received a 160 mg target dose (TD) of cevostamab; many of these patients were heavily pretreated with a prior therapy (e.g., 95.8% were tripleclass refractory, and 57.5% received a prior BCMA-targeted therapy). In these patients, reversible cytopenias were the most common Grade 3 or 4 events, which did not result in discontinuation of treatment, and Grade 3 or 4 infections occurred in 15.6% of patients. Cytokine release syndrome (CRS) was only Grade 1 or Grade 2 in the cohort receiving the 0.3 mg/1 .2 mg/3.6 mg triple step-up doses of cevostamab (i.e., the triple step-up “low” priming sequence). At the 160 mg TD, the objective response rate (ORR) and very good partial response rate (VGPR) or better (VGPR+) was 44.3% and 25.7% in all patients, respectively, and 60.6% and 39.4% in BCMA-naive patients, respectively. The median duration of response was 10.4 months in all patients and 15.5 months in BCMA-naTve patients, with durable responses maintained after the completion of treatment. Additional details are described further below.

A. METHODS

Patients

Eligible patients were those with measurable disease for whom no established therapy was available or appropriate. Prior chimeric antigen receptor (CAR) T-cells >12 weeks before cevostamab initiation, and antibody-drug conjugates (ADCs) or bispecific antibodies >4 weeks before cevostamab initiation were allowed. The trial was conducted in accordance with International Conference on Harmonization guidelines for Good Clinical Practice. The protocol was approved by the ethics committee at each participating center. Patients provided written informed consent.

Treatment

An intravenous (IV) infusion of cevostamab was initiated with a step-up dosing regimen to mitigate CRS and continued at target dose once every 3 weeks (Q3W) for 17 cycles, unless disease progression or unacceptable toxicity occurred (FIG. 2 and FIG. 43A). In the dose-escalation stage, escalating step-up and target doses, and alternative step-up schedules, were evaluated in a standard 3+3 design. In the dose-expansion stage, dosing regimens showing promising safety and were selected for further evaluation. Corticosteroid, acetaminophen, and diphenhydramine premedications were utilized for mitigating CRS.

Objectives and endpoints

The primary objectives of this study were to evaluate safety, including characterization of doselimiting toxicities (DLTs) and determination of maximum-tolerated dose (MTD), and to identify a recommended phase 2 dose (RP2D) and schedule. Secondary objectives were to evaluate the pharmacokinetics (PK), immunogenicity, and activity of cevostamab. Safety was assessed by evaluating the incidence and severity of adverse events, as graded by National Cancer Institute criteria (e.g., see National Cancer Institute - Division of Cancer Treatment & Diagnostics. National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. Available at: dctd.cancer.gov/). CRS was initially graded by the criteria established in Lee et al. (Blood, 124: 188-195, 2014) and was subsequently graded by the criteria established by the American Society of Transplantation and Cellular Therapy (e.g., see Lee et al., Biol Blood Marrow Transplant, 25(4): 625-638, 2019), and is reported according to the latter. Pharmacokinetics and immunogenicity were assessed by measuring the concentration of cevostamab and anti-drug antibodies in serum samples. Activity assessments included the rate, depth, and duration of response (DoR), as determined by investigators according to International Myeloma Working Group (IMWG) criteria (e.g., see Kumar et al. Lancet Oncol., 2016; 17:e328-46). Progression-free survival (PFS) was assessed in a post-hoc analysis. FcRH5 expression on myeloma cells collected at baseline by bone marrow aspiration was assessed by flow cytometry (FC).

Treatment assignment and statistical methods

Patients were assigned to open study cohorts in the order they were enrolled. Planned enrollment was about 180 patients in the dose-escalation stage and >30 patients per dosing regimen in the doseexpansion stage. Descriptive statistics were used to describe and summarize the data in patients who received >1 dose of cevostamab. Patients with missing or no response assessment were classified as non-responders.

Corticosteroid, acetaminophen, and diphenhydramine premedication

Initially, corticosteroid premedication (e.g., 20 mg dexamethasone intravenous or 80 mg methylprednisolone intravenous) was included as a premedication prior to each administration of cevostamab in Cycle 1 and Cycle 2, with the option to discontinue corticosteroid premedication from Cycle 3 onwards, e.g., in patients who do not experience CRS with their previous administration. Premedication with acetaminophen or paracetamol (e.g., about 500 mg to about 1000 mg, oral) and diphenhydramine (e.g., about 25 to about 50 mg, oral) may also be administered prior to each administration.

Study assessments

DoR was defined as time from first partial response (PR) or better to disease progression or death from any cause (whichever occurs first). PFS was defined as time from first exposure to treatment to disease progression or death.

B. RESULTS

Patients

Between September 19, 2017, and July 18, 2023, 324 patients were enrolled into the monotherapy cohorts at 17 centers in the United States, Canada, Spain, and Australia; all received >1 dose of cevostamab. As of August 22, 2024, 48 patients completed treatment and 276 discontinued treatment (FIG. 53). The most common reason for discontinuation was disease progression (65.1%). Twenty-two dose-escalation cohorts were opened (FIG. 2 and FIG. 43A). Six were expanded and one additional expansion cohort was opened. Dosing regimens included those assessing single step-up, double step-up, and triple step-up dosing, along with 0.15 mg to 252 mg target doses.

Among the 324 patients enrolled, the median age was 65 years (range: 33 to 90 years old), 55.6% of patients were male and 75.9% of patients were white. High-risk cytogenetics (e.g., t(4;14), t(14;16), or del ( 17p)) were present in 34.7% of patients with a conclusive assay result, while 1 q21 gain or amplification was present in 52.4% of patients. Extramedullary disease was present in 26.2% of patients. The median number of prior lines of therapy was 6 (range: 2 to 21 ); 47.5% of patients had received a prior BCMA-targeted therapy (e.g., CAR T-cell: 28.1%; ADC: 17.6%; and bispecific antibody: 10.8%). Triple-class refractory disease was present in 89.5% of patients and penta-drug refractory disease in 72.5% of patients; 87.0% of patients had myeloma that was refractory to their last prior therapy.

Safety

DLT occurred in one patient in the 3.6 mg/90 mg single step-up cohort (e.g., due to Grade 3 pneumonia) and one patient in the 3.6 mg/198 mg single step-up cohort (e.g., due to Grade 1 CRS, which was initially graded as Grade 3 CRS by the older criteria established in Lee et al., Blood, 124: 188-195, 2014). The condition of both patients resolved. MTD was not reached. Based on a comprehensive assessment of cumulative safety and efficacy and a quantitative clinical pharmacology evaluation, Q3W dosing at the 160 mg TD and triple step-up dosing at the 0.3 mg/1 .2 mg/3.6 mg dose level (e.g., triple step-up “low”) was found to have an acceptable benefit-risk profile and was selected for future development.

A total of 167 patients were enrolled at the 160 mg TD. Baseline characteristics were generally comparable with those in all patients. Median follow-up was 14.8 months (range: 0.5 to 48.8).

The most common (e.g., >20%) adverse events of any grade at the 160 mg TD level were CRS (74.3%), neutropenia (31.7%), cough (30.5%), nausea (28.1%), diarrhea (24.0%), anemia (23.4%), and fatigue (21 .6%). Grade 3 or 4 adverse events and serious adverse events (SAE) occurred in 96 patients each (57.5%). Grade 5 (fatal) events excluding disease progression occurred in 10 patients (6.0%); events in 3 patients (1 .8%) were considered treatment-related (e.g., hemophagocytic lymphohistiocystosis (HLH) in 2 patients, disseminated intravascular coagulation in the context of pseudomonal sepsis in 1 patient. AEs leading to cevostamab discontinuation excluding plasma cell myeloma progression occurred in 29 patients (17.4%); events in 13 patients (7.8%) were considered treatment-related.

Grade 3 or 4 neutropenia occurred in 48 patients (28.7%) and Grade 3 or 4 febrile neutropenia in 8 patients (4.8%) at the 160 mg TD level. Thirty-seven (22.2%) patients received colony stimulating factors and 19 (11 .4%) received dose modifications or interruptions for any grade neutropenia. Grade 3 or 4 thrombocytopenia occurred in 18 patients (10.8%). No neutropenia or thrombocytopenia leading to cevostamab discontinuation was reported.

Infections occurred in 91 patients (54.5%) at the 160 mg TD level. Infections observed in >5% of patients include pneumonia (9.6%), upper respiratory tract infection (8.4%), urinary tract infection (7.2%), and rhinovirus infection (5.4%). Grade 3 or 4 infections occurred in 26 patients (15.6%) and Grade 5 infections in 6 patients (3.6%). Infections leading to treatment discontinuation were uncommon (e.g., 10 patients, 6.0%). Forty-nine patients (29.3%) had a reported medical history of any hypogammaglobulinemia, while 13 patients (7.8%) had >1 treatment-emergent AE of hypogammaglobulinemia. Fifty-five patients (32.9%) received intravenous immunoglobulin during treatment.

Possible immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 23 patients (13.8%; 11 patients with Grade 1 , 6.6%; 9 patients with Grade 2, 5.4%; and 3 patients with Grade 3, 1 .8%) at the 160 mg target-dose level. Possible ICANS events were defined as neurologic/psychiatric adverse events that were consistent with ICANS as described by the American Society of Transplantation and Cellular Therapy (e.g., see Lee et al., Biol Blood Marrow Transplant, 25(4): 625-638, 2019) and satisfied either: (1 ) neurologic/psychiatric AEs that presented as a symptom of CRS, or (2) neurologic/psychiatric AEs that were considered treatment related by a clinician. Infusion-related reactions (IRR) occurred in 12 patients (7.2%; all Grade 1 or 2). No cases of tumor lysis syndrome were reported. Grade 3 HLH occurred in one additional patient who discontinued treatment.

CRS occurred in 19 of 30 patients (63.3%) who received the 0.3 mg/1 .2 mg/3.6 mg triple step-up dosing schedule. CRS was Grade 1 in 14 (46.7%) and Grade 2 in 5 (16.7%). No Grade 3 or 4 events or events leading to treatment discontinuation occurred. Most CRS events occurred in Cycle 1 (FIG. 48). Median time to CRS onset from last end of infusion was 13.1 hours (min to max: 0 to 57.1 ) and median time to resolution was 1 day (min to max: 0 to 5 days). CRS was managed with tocilizumab in 9 patients (30.0%), steroids in 4 (13.3%), and both agents in 2 (6.7%). All events resolved.

Pharmacokinetics and immunogenicity

Cevostamab pharmacokinetics and immunogenicity were assessed with a data cut-off of August 2023. Systemic exposure increased in a dose-proportional manner over the tested dose range. Serum concentrations peaked at end of infusion and declined in a multi-phasic fashion (FIG. 54). At the 160 mg TD, the estimated median half-life was about 13 days. In patients with >1 post-baseline result at the 160 mg TD, anti-drug antibodies were detected in 29 of 148 patients (19.6%) and neutralizing antibodies in 5 of 142 patients (3.5%). As the sample size for neutralizing antibodies was limited (n = 5), no conclusive characterization could be carried out to assess their impact on pharmacokinetics, efficacy, or safety.

Anti-tumor activity

At the 160 mg TD level, the ORR was 44.3% and the VGPR or better rate was 25.7% (FIG. 52A). Median time to first response was 1 .4 months (min to max: 0.5 to 4.6 months) and to best response was 2.6 months (min to max: 0.5 to 13.4 months). Median duration of response was 10.4 months (95% confidence interval (Cl), 6.2, 15.0) among patients in partial response or better (n=74) and 21 .2 months (95% Cl, 15.0, 36.4) among those in VGPR or better (n=43) (FIG. 52B). Minimal residual disease (MRD) negativity at the <10^-5 level by next generation sequencing (NGS) was achieved in 11/18 patients who achieved a VGPR or better and were evaluated. Response was independent of baseline FcRH5 expression level (FIG. 55). Median PFS was 2.8 months (95% Cl, 2.1 , 4.2), and the 12-month PFS rate was 23.1% (95% Cl, 16.6, 29.6) (FIG. 56). At the 160 mg TD, baseline characteristics were generally comparable between patients with and without prior exposure to BCMA-targeted therapies, although the median number of prior lines of therapy appeared lower and the percentage of patients with high-risk cytogenetics and who were refractory to their last prior line appeared higher in those without prior exposure. The ORR was 60.6% in patients without a prior BCMA-targeted therapy versus 36.2% in patients with >1 BCMA-targeted CAR T-cell, 17.2% in patients with >1 BCMA-targeted bispecific antibody, and 43.8% in patients with >1 BCMA- targeted ADC (FIG. 52A). Median DoR (e.g., partial or better) was 15.5 months (95% Cl, 10.0, 25.5) in patients without prior BCMA-targeted therapy (n=71 ) versus 7.1 months (95% Cl, 4.2, 15.0) in patients with >1 BCMA-targeted CAR-T cell (n=58), 3.8 months (95% Cl, 1 .6, not evaluable) in patients with >1 BCMA-targeted bispecific antibody (n=29), and 5.5 months (95% Cl, 3.4, 14.0) in patients with >1 BCMA- targeted ADC (n=32). Median PFS was 5.2 months (95% Cl, 2.6, 1 1 .1 ; n=71 ) in patients without a prior BCMA-targeted therapy and 2.1 months (95% Cl, 1 .4, 3.0; n=96) in patients with a prior BCMA-targeted therapy.

The ORR was 46.5% (20/43 patients) in patients with a 1 q21 gain or amplification at baseline and 36.2% (17/47 patients) in patients with extramedullary disease.

Twenty-seven patients completed the planned 17 cycles of treatment in partial response or better (FIG. 51 ). Sixteen had ongoing responses off-treatment at the data cut-off, including four with responses lasting >30 months after treatment initiation. Nine of 12 patients with responses lasting >6 months after completion were in complete response (CR) or better at end of treatment.

C. DISCUSSION

The safety, pharmacokinetics, immunogenicity, and activity of cevostamab, was evaluated in Study GO39775, a first-in-class, FcRH5-targeted bispecific antibody, in late-line multiple myeloma. Notably, the population in this phase 1 study was heavily pretreated; at the 160 mg TD of cevostamab, patients had received a median of six prior lines of therapy, 95.8% of patients were triple-class refractory, 73.7% of patients were penta-drug refractory, and 57.5% of patients had received prior BCMA-targeted therapy.

The most frequent Grade 3 or 4 events at the 160 mg TD of cevostamab were reversible neutropenia (28.7%), anemia (18.0%), and thrombocytopenia (10.8%), with no Grade 5 events or events leading to discontinuation reported.

Grade 3 or 4 infections occurred in 15.6% of patients at the 160 mg TD of cevostamab. Grade 5 infections occurred with a low frequency (e.g., 3.6% of patients) in all studies. Notably, anti-infective prophylaxis was not mandated in the current study, which may influence the infection rate. Cevostamab did not cause substantial dysgeusia, weight loss, nail changes, desquamation, or ataxia, toxicities.

In this study, extensive efforts were made to mitigate CRS. At the 160 mg TD of cevostamab, treatment initiation with the 0.3 mg/1 .2 mg/3.6 mg triple step-up dosing (i.e., the triple step-up “low” priming sequence) had a favorable CRS profile. Among 30 patients who received this schedule, CRS primarily occurred in Cycle 1 , and was only Grade 1 or 2. No events leading to treatment discontinuation were reported, and all events had resolved. At the 160 mg TD, cevostamab was associated with an (ORR) of 44.3% and a VGPR or better of 25.7%. Responses were durable, especially in patients in VGPR or better. These data are compelling, given that FcRH5 is a novel myeloma target, the population was highly refractory, and >50% had received prior BCMA-targeted therapy. Notably, the ORR in patients without prior BCMA-targeted therapy (60.6%) was higher than in those with prior exposure (17.2% to 43.8%). Response rates in patients with prior BCMA-targeted CAR T-cell (36.2%) and ADC (43.8%) exposure were also clinically meaningful, supporting exploration of cevostamab as a non-BCMA-targeted option for patients relapsing after these therapies.

The short median PFS observed at the 160 mg TD of cevostamab was largely driven by the high proportion of BCMA therapy-exposed, penta-drug refractory patients in this cohort, and was relatively similar to that reported with other T cell-redirecting therapies when used after prior BCMA-targeted therapies. The relatively short wash-out period in this trial (>12 weeks for CAR T-cells, and >4 weeks for bispecific antibodies) may also have played a role, as recent reports suggest that a shorter interval between T cell-redirecting therapies may be associated with poorer T-cell function and worse outcomes.

In this study, a fixed duration of treatment of about 12 months was evaluated. At the 160 mg TD level of cevostamab, 27 patients completed treatment with a PR or better, with 16 having ongoing responses off-treatment at data cut-off. Most durable responders were in CR or better at end of treatment, suggesting that, in patients who achieve a CR to cevostamab, it may be possible to achieve an extended treatment-free interval that could help to alleviate cumulative toxicities, improve quality of life, and avoid resistance.

Collectively, these data validate FcRH5 as a novel therapeutic target for myeloma and demonstrate that fixed-duration cevostamab has manageable safety and induces durable remissions in patients with late-line disease. These data support the continued development of cevostamab alone or in combination with standard of care or novel agents.

Other Embodiments

All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.

While the methods of the present disclosure have been described in connection with specific embodiments thereof, it will be understood that such methods are capable of further modifications, and this application is intended to cover any variations, uses, or adaptations following, in general, the principles and including such departures from the disclosed methods that come within known or customary practice within the art to which the disclosed methods pertain and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

Other embodiments are within the claims.

Claims

WHAT IS CLAIMED IS:

1 . A method of reducing the likelihood of cytokine release syndrome (CRS) in a subject having multiple myeloma (MM) and being administered an effective amount of cevostamab, wherein, prior to a first administration to the subject of the effective amount of cevostamab, the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg, and the C1 D3 is between about 3.6 mg to about 7.2 mg.

2. A method of reducing the likelihood of CRS in a subject having MM and being administered an effective amount of cevostamab, wherein, prior to a first administration to the subject of the effective amount of cevostamab, the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; and the C1 D3 is about 3.6 mg.

3. A method of reducing the likelihood of CRS in a subject having MM and being administered an effective amount of cevostamab, wherein, prior to a first administration to the subject of the effective amount of cevostamab, the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 3.3 mg; and the C1 D3 is about 7.2 mg.

4. A method of achieving a median peak IL-6 level of less than about 30 pg/mL in a population of subjects having MM and being administered an effective amount of cevostamab, the method comprising administering to a subject in the population, prior to being administered the effective amount of cevostamab, a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg, and the C1 D3 is between about 3.6 mg to about 7.2 mg.

5. The method of claim 4, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; and the C1 D3 is about 3.6 mg.

6. The method of claim 4 or 5, wherein the median peak IL-6 level is about 18 pg/mL following administration of the effective amount of cevostamab.

7. A method of achieving a peak IL-6 level of less than about 30 pg/mL in a subject having MM and being administered an effective amount of cevostamab, the method comprising administering to the subject, prior to being administered the effective amount of cevostamab, a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3, the C1 D2 is between about 1 .2 mg to about 3.3 mg, and the C1 D3 is between about 3.6 mg to about 7.2 mg.

8. The method of claim 7, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; and the C1 D3 is about 3.6 mg.

9. The method of claim 7 or 8, wherein the peak IL-6 level is about 18 pg/mL following administration of cevostamab.

10. A method of reducing the occurrence of CRS events in a subject being treated for MM with a target dose of cevostamab, the method comprising administering to the subject, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.03 mg, the C1 D2 is between about 1 .2 mg to about 3.3 mg, and the C1 D3 is between about 3.6 mg to about 7.2 mg.

11 . A method of reducing the occurrence of CRS events in a subject being treated for MM with a target dose of cevostamab, the method comprising administering to the subject, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), (i) a first dose

(C1 D1 ) of about 0.3 mg, (ii) a second dose (C1 D2) of about 1 .2 mg, and (iii) a third dose (C1 D3) of about 3.6 mg of cevostamab.

12. A method of reducing the occurrence of CRS events in a subject being treated for MM with a target dose of cevostamab, the method comprising administering to the subject, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), (i) a first dose (C1 D1 ) of about 0.3 mg, (ii) a second dose (C1 D2) of about 3.3 mg, and (ii) a third dose (C1 D3) of about 7.2 mg of cevostamab.

13. The method of any one of claims 10-12, wherein the C1 is 21 days in length, and wherein:

(i) the C1 D1 is administered on Day 1 of the C1 ;

(ii) the C1 D2 is administered on Day 2, Day 3, or Day 4 of the C1 ; and

(iii) the C1 D3 is administered on Day 8 of the C1 .

14. The method of any one of claims 10-13, wherein the target dose is greater than the C1 D3.

15. The method of claim 14, wherein the target dose is between about 20 mg to about 252 mg.

16. The method of any one of claims 1 -15, wherein the method further comprises administering to the subject an additional dose of cevostamab, wherein the additional dose of cevostamab is greater than the C1 D3.

17. The method of claim 16, wherein the additional dose of cevostamab is administered during the C1 after the C1 D3 as a fourth dose (C1 D4) of cevostamab, wherein the C1 D4 is an effective amount of cevostamab.

18. A method of treating a subject having MM, wherein the method comprises administering to the subject an effective amount of cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, wherein the C1 D1 is about 0.3 mg, the C1 D2 is about 1 .2 mg to about 3.3 mg, the C1 D3 is about 3.6 mg to about 7.2 mg, and the C1 D4 is between about 20 mg to about 252 mg.

19. The method of claim 18, wherein the C1 D4 is an effective amount of cevostamab.

20. The method of claim 18 or 19, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; and the C1 D3 is about 3.6 mg.

21 . The method of claim 18 or 19, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 3.3 mg; and the C1 D3 is about 7.2 mg.

22. A method of treating a subject having MM, wherein the method comprises administering to the subject an effective amount of cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, wherein the C1 D1 is about 0.3 mg; the C1 D2 is about 1 .2 mg; the C1 D3 is about 3.6 mg; and the C1 D4 is about 160 mg.

23. A method of treating a subject having MM, wherein the method comprises administering to the subject an effective amount of cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, the C1 D1 is about 0.3 mg; the C1 D2 is about 3.3 mg; the C1 D3 is about 7.2 mg; and the C1 D4 is about 160 mg.

24. The method of any one of claims 1 -23, wherein the length of the C1 is 21 days.

25. The method of claim 24, wherein the method comprises administering to the subject:

(a) the C1 D1 on or about Day 1 of the C1 ;

(b) the C1 D2 on or about Day 2, Day 3, or Day 4 of the C1 ; and

(c) the C1 D3 on or about Day 8 of the C1 .

26. The method of any one of claims 17-25, wherein the method comprises administering to the subject the C1 D4 on or about Day 9, Day 10, or Day 11 of the C1 .

27. The method of any one of claims 17-26, wherein the method comprises administering to the subject the C1 D4 about 1 day, 2 days, or 3 days after the C1 D3 of the C1 .

28. The method of any one of claims 1 -27, wherein the dosing regimen further comprises a second dosing cycle (C2) comprising a single dose (C2D1 ) of cevostamab, wherein the C2D1 is an effective amount of cevostamab that is equal to or greater than the last administered dose of cevostamab and is between about 20 mg to about 252 mg.

29. The method of claim 28, wherein the C2D1 is about 160 mg.

30. The method of claim 28 or 29, wherein the length of the C2 is 21 days.

31 . The method of claim 30, wherein the method comprises administering to the subject the C2D1 on Day 1 of the C2.

32. The method of any one of claims 28-31 , wherein the dosing regimen further comprises one or more additional dosing cycles.

33. The method of claim 32, wherein the dosing regimen comprises one to 15 additional dosing cycles.

34. The method of claim 32 or 33, wherein the length of each of the one or more additional dosing cycles is 21 days.

35. The method of any one of claims 32-34, wherein each of the one or more additional dosing cycles comprises a single effective dose of cevostamab.

36. The method of claim 35, wherein the method comprises administering to the subject the single effective dose of cevostamab on Day 1 of the one or more additional dosing cycles.

37. The method of claim 36, wherein the single dose is between about 20 mg to about 252 mg.

38. The method of claim 37, wherein the single dose is about 160 mg.

39. The method of any one of claims 18-23, wherein a median peak IL-6 level in a population of subjects treated according to the method does not exceed 80 pg/mL between the C1 D1 and the C1 D2.

40. The method of any one of claims 4-6 and 39, wherein the median peak IL-6 level in the population of subjects treated according to the method does not exceed 30 pg/mL between the C1 D1 and the C1 D2.

41 . The method of any one of claims 18-23, 39, and 40, wherein a median peak IL-6 level in a population of subjects treated according to the method does not exceed 80 pg/mL between the C1 D2 and the C1 D3.

42. The method of any one of claims 4-6, 40, and 41 , wherein the median peak IL-6 level in the population of subjects treated according to the method does not exceed 30 pg/mL between the C1 D2 and the C1 D3.

43. The method of any one of claims 4-6, wherein the method further comprises administering to the subject a fourth dose (C1 D4) of cevostamab during the C1 , wherein the C1 D4 is between about 20 mg to about 252 mg, and wherein the median peak IL-6 level in a population of subjects treated according to the method does not exceed 30 pg/mL between the C1 D3 and the C1 D4.

44. The method of any one of claims 18-23 and 39-42, wherein a median peak IL-6 level in a population of subjects treated according to the method does not exceed 30 pg/mL between the C1 D3 and the C1 D4.

45. The method of any one of claims 18-23, wherein a peak IL-6 level in the subject does not exceed 80 pg/mL between the C1 D1 and the C1 D2.

46. The method of any one of claims 7-9 and 45, wherein the peak IL-6 level in the subject does not exceed 30 pg/mL between the C1 D1 and the C1 D2.

47. The method of any one of claims 18-23, 45, and 46, wherein a peak IL-6 level in the subject does not exceed 80 pg/mL between the C1 D2 and the C1 D3.

48. The method of any one of claims 7-9, 46, and 47, wherein the peak IL-6 level in the subject does not exceed 30 pg/mL between the C1 D2 and the C1 D3.

49. The method of any one of claims 7-9, wherein the method further comprises administering to the subject a fourth dose (C1 D4) of cevostamab during the C1 , wherein the C1 D4 is between about 20 mg to about 252 mg, and wherein the peak IL-6 level in the subject does not exceed 30 pg/mL between the C1 D3 and the C1 D4.

50. The method of any one of claims 18-23 and 45-48, wherein a peak IL-6 level in the subject does not exceed 30 pg/mL between the C1 D3 and the C1 D4.

51 . The method of any one of claims 1 -50, wherein a peak level of CD8+ T cell activation in the subject in the C1 occurs between administration of the C1 D1 and the C1 D2.

52. The method of any one of claims 1 -50, wherein a peak level of CD8+ T cell activation in the subject in the C1 occurs between administration of the C1 D2 and the C1 D3.

53. The method of any one of claims 1 -50, wherein a peak level of CD8+ T cell activation in the subject in the C1 occurs between administration of the C1 D3 and the C1 D4.

54. The method of any one of claims 51 -53, wherein the peak level of CD8+ T cell activation in the subject in the C1 occurs within 24 hours after administration of cevostamab.

55. The method of any one of claims 1 -54, wherein the method further comprises evaluating CRS after at least one of the C1 D1 , the C1 D2, and/or the C1 D3.

56. The method of claim 55, wherein the method further comprises measuring CRS after each of the C1 D1 , the C1 D2, and the C1 D3.

57. The method of claim 55 or 56, wherein, after administration of at least one of the C1 D1 , the C1 D2, and/or the C1 D3 (i) no CRS event has occurred, or (ii) CRS signs and symptoms from the previous dose have resolved, and the subject is administered the next dose of cevostamab.

58. The method of any one of claims 55-57, wherein the subject is not administered the next dose of cevostamab unless (i) no CRS event has occurred from administration of at least one of the C1 D1 , the C1 D2, and/or the C1 D3, or (ii) CRS signs and symptoms have resolved after administration of at least one of the C1 D1 , the C1 D2, and/or the C1 D3.

59. The method of claim 57, wherein the subject is administered the next dose of cevostamab no earlier than 20 hours from administration of the previous dose.

60. The method of any one of claims 55-59, wherein the method reduces the likelihood of the subject experiencing a CRS event.

61 . The method of any one of claims 55-60, wherein the method reduces the likelihood of the subject experiencing Grade >1 CRS.

62. The method of any one of claims 55-61 , wherein the method reduces the likelihood of the subject experiencing Grade >2 CRS.

63. The method of any one of claim 55-62, wherein the method reduces the likelihood of the subject experiencing Grade >3 CRS.

64. The method of claim 60, wherein the likelihood of the subject experiencing Grade 1 CRS after the C1 D1 is less than 10%.

65. The method of claim 60, wherein the likelihood of the subject experiencing Grade 1 CRS after the C1 D2 is less than 25%.

66. The method of claim 60, wherein the likelihood of the subject experiencing Grade 1 CRS after the C1 D3 is less than 15%.

67. The method of claim 62, wherein the likelihood of the subject experiencing Grade 2 CRS after the C1 D1 is less than 10%.

68. The method of claim 62, wherein the likelihood of the subject experiencing Grade 2 CRS after the C1 D2 is less than 25%.

69. The method of claim 62, wherein the likelihood of the subject experiencing Grade 2 CRS after the C1 D3 is less than 15%.

70. The method of any one of claims 55-69, wherein the likelihood of the subject experiencing at least one Grade 1 or Grade 2 CRS event after the first administration of the C1 D4 is less than 65%.

71 . The method of any one of claims 1 -70, wherein the dosing regimen results in a CRS event in less than about 90% of a population of subjects having MM.

72. The method of claim 71 , wherein the dosing regimen results in the CRS event in about 58% to about 90% of the population of subjects having MM.

73. The method of claim 72, wherein the dosing regimen results in the CRS event in about 58% to about 68% of the population of subjects having MM.

74. The method of claim 73, wherein the dosing regimen results in the CRS event in about 63% of the population of subjects having MM.

75. The method of any one of claims 1 -74, wherein the dosing regimen results in a grade >2 CRS event in less than about 50% of a population of subjects having MM.

76. The method of claim 75, wherein the dosing regimen results in the grade >2 CRS event in about 10% to about 25% of the population of subjects having MM.

77. The method of claim 75 or 76, wherein the dosing regimen results in the grade >2 CRS event in about 17% of the population of subjects having MM.

78. The method of any one of claims 1 -77, wherein the dosing regimen results in a grade >3 CRS event in less than about 10% of a population of subjects having MM.

79. The method of claim 78, wherein the dosing regimen results in the grade >3 CRS event in about 0% to about 5% of the population of subjects having MM.

80. The method of claim 78 or 79, wherein the dosing regimen does not result in any grade >3 CRS event in the population of subjects having MM.

81 . The method of any one of claims 1 -80, wherein cevostamab is administered to the subject as a monotherapy.

82. The method of any one of claims 1 -80, wherein cevostamab is administered to the subject as a combination therapy.

83. The method of claim 82, wherein cevostamab is administered to the subject concurrently with one or more additional therapeutic agents.

84. The method of claim 83, wherein cevostamab is administered to the subject prior to the administration of one or more additional therapeutic agents.

85. The method of claim 83, wherein cevostamab is administered to the subject subsequent to the administration of one or more additional therapeutic agents.

86. The method of any one of claims 83-85, wherein the one or more additional therapeutic agents comprise an effective amount of tocilizumab.

87. The method of claim 86, wherein tocilizumab is administered to the subject by intravenous infusion.

88. The method of claim 86 or 87, wherein:

(a) the subject weighs > 100 kg, and tocilizumab is administered to the subject at a dose of 800 mg;

(b) the subject weighs > 30 kg and < 100 kg, and tocilizumab is administered to the subject at a dose of 8 mg/kg; or

(c) the subject weighs < 30 kg, and tocilizumab is administered to the subject at a dose of 12 mg/kg.

89. The method of any one of claims 86-88, wherein tocilizumab is administered to the subject 2 hours before administration of cevostamab.

90. The method of any one of claims 1 -89, wherein cevostamab is administered to the subject by intravenous infusion.

91 . The method of any one of claims 1 -89, wherein cevostamab is administered to the subject subcutaneously.

92. The method of any one of claims 1 -91 , wherein the subject experiences a CRS event, and treatment with cevostamab is suspended as a result of the CRS event to enable treatment of the CRS event.

93. The method of claim 92, wherein the method further comprises administering to the subject an effective amount of tocilizumab to treat the CRS event.

94. The method of any one of claims 1 -93, wherein the subject has received prior treatment for MM.

95. The method of claim 94, wherein the prior treatment for MM is selected from one or more of a proteasome inhibitor, an I MiD, an anti-CD38 therapeutic agent, an anti-SLAMF7 therapeutic agent, a nuclear export inhibitor, a histone deacetylase (HDAC) inhibitor, an autologous stem cell transplant (ASCT), a bispecific antibody, an antibody-drug conjugate (ADC), a CAR-T cell therapy, and a BCMA- directed therapy.

96. The method of claim 94 or 95, wherein the subject has received a standard of care treatment for MM prior to being administered the C1 D1 .

97. The method of claim 96, wherein the standard of care treatment comprises a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-cluster of differentiation 38 (CD38) monoclonal antibody (mAb).

98. The method of any one of claims 94-97, wherein the subject has received at least three prior lines of treatment for the MM.

99. The method of claim 98, wherein the subject has received at least four prior lines of treatment for the MM.

100. The method of any one of claims 96-99, wherein the subject has relapsed or become refractory to the standard of care treatment for MM.

101 . The method of any one of claims 1 -100, wherein the MM is relapsed or refractory (R/R) MM.

102. A method of treating a subject having R/R MM, wherein the method comprises administering to the subject an effective amount of cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 of C1 ; the C1 D2 is about 1 .2 mg and is administered on Day 2, Day 3, or Day 4 of C1 ; the C1 D3 is about 3.6 mg and is administered on Day 8 of C1 ; and the C1 D4 is the effective amount of cevostamab and is administered on Day 9, Day 10, or Day 11 of C1 .

103. A method of treating a subject having R/R MM, wherein the method comprises administering to the subject an effective amount of cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), a third dose (C1 D3), and a fourth dose (C1 D4) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 of C1 ; the C1 D2 is about 3.3 mg and is administered on Day 2, Day 3, or Day 4 of C1 ; the C1 D3 is about 7.2 mg and is administered on Day 8; and the C1 D4 is the effective amount of cevostamab and is administered on Day 9, Day 10, or Day 11 of C1 .

104. A method of reducing the likelihood of CRS in a subject having R/R MM and being administered an effective amount of cevostamab, wherein, prior to a first administration to the subject of the effective amount of cevostamab, the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 of C1 ; the C1 D2 is about 1 .2 mg and is administered on Day 2, Day 3, or Day 4 of C1 ; and the C1 D3 is about 3.6 mg and is administered on Day 8 of C1.

105. A method of reducing the likelihood of CRS in a subject having R/R MM and being administered an effective amount of cevostamab, wherein, prior to a first administration to the subject of the effective amount of cevostamab, the method comprises administering to the subject cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 of C1 ; the C1 D2 is about 3.3 mg and is administered on Day 2, Day 3, or Day 4 C1 ; and the C1 D3 is about 7.2 mg and is administered on Day 8 C1.

106. A method of achieving a median peak IL-6 level of less than about 30 pg/mL in a population of subjects having R/R MM and being administered an effective amount of cevostamab, the method comprising administering to each subject in the population, prior to being administered the effective amount of cevostamab, a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 of C1 ; the C1 D2 is about 1 .2 mg and is administered on Day 2, Day 3, or Day 4 of C1 ; and the C1 D3 is about 3.6 mg and is administered on Day 8 of C1 .

107. A method of treating a subject having R/R MM, wherein the method comprises administering to the subject an effective amount of cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 3.3 mg and is administered on Day 2, Day 3, or Day 4; the C1 D3 is about 160 mg and is administered on Day 8, and wherein an effective amount of tocilizumab is administered to the subject about 2 hours prior to administering the first dose of cevostamab.

108. A method of treating a subject having R/R MM, wherein the method comprises administering to the subject an effective amount of cevostamab in a dosing regimen comprising at least a first dosing cycle (C1 ), wherein the length of the C1 is 21 days, wherein the C1 comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3), wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 3.3 mg and is administered on Day 4; and the C1 D3 is about 160 mg and is administered on Day 8.

109. The method of any one of claims 102-108, wherein the dosing regimen further comprises a second dosing cycle (C2) comprising a single dose (C2D1 ) of cevostamab, wherein the length of the C2 is 21 days, and wherein the C2D1 is an effective amount of cevostamab and is administered to the subject on Day 1 of the second dosing cycle.

110. The method of claim 109, wherein the dosing regimen comprises one or more additional dosing cycles, wherein the length of each of the one or more additional dosing cycles is 21 days, wherein each of the one or more additional dosing cycles comprises a single dose of the effective amount of cevostamab administered to the subject on Day 1 of each of the one or more additional dosing cycles.

111 . A method of reducing the occurrence of CRS events in a subject being treated for R/R MM with a target dose of cevostamab, the method comprising administering to the subject, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 1 .2 mg and is administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 3.6 mg and is administered on Day 8, wherein the length of the C1 is 21 days.

112. A method of reducing the occurrence of CRS events in a subject being treated for R/R MM with a target dose of cevostamab, the method comprising administering to the subject, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D1 is about 0.3 mg and is administered on Day 1 ; the C1 D2 is about 3.3 mg and is administered on Day 2, Day 3, or Day 4; and the C1 D3 is about 7.2 mg and is administered on Day 8, wherein the length of the C1 is 21 days.

113. A method of reducing the occurrence of CRS events in a subject being treated for R/R MM with a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ), (ii) a second dose (TS-C1 D2), and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering such target dose to a first plurality of such subjects results in a reduction in the number of subjects experiencing a CRS event after first administration of the target dose, as compared to a second plurality of subjects (e.g., human subjects) being treated for R/R MM with a target dose of cevostamab and administered such target dose after administration of a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), with no third dose of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

114. The method of claim 113, wherein administering such target dose to the first plurality of such subjects results in at least a 10% reduction in the number of subjects experiencing a CRS event after first administration of the target dose.

115. The method of claim 113 or 114, wherein administering such target dose to the first plurality of such subjects results in a 15% reduction in the number of subjects experiencing a CRS event after first administration of the target dose.

116. A method of reducing the occurrence of CRS events in a subject being treated for R/R MM with a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ), (ii) a second dose (TS-C1 D2), and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering such target dose to a first plurality of such subjects results in a reduction in the number of subjects experiencing a CRS event during the C1 , as compared to a second plurality of subjects (e.g., human subjects) being treated for R/R MM with a target dose of cevostamab and administered such target dose after administration of a first dose (DS-C1 D1 ) and a second dose (DS-

C1 D2), with no third dose of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

117. The method of claim 116, wherein administering such target dose to the first plurality of such subjects results in at least a 10% reduction in the number of subjects experiencing a CRS event during the C1 .

118. The method of claim 116 or 117, wherein administering such target dose to the first plurality of such subjects results in a 14% reduction in the number of subjects experiencing a CRS event during the C1.

119. A method of reducing the occurrence of CRS events in a subject being treated for R/R MM at an target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of CRS events experienced by each subject during the C1 , as compared to a second plurality of subjects administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

120. The method of claim 119, wherein administering cevostamab in the C1 to the first plurality of such subjects results in at least a 30% reduction in the number of CRS events experienced by each subject during the C1 .

121 . A method of reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein, prior to first administration of the target dose to the subject in a first treatment cycle (C1 ), the subject is administered cevostamab at (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3), wherein administering cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of subjects requiring tocilizumab treatment for CRS during the C1 , as compared to a second plurality of subjects being treated for MM and administered a target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , and the TS- C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

122. The method of claim 121 , wherein administering cevostamab in the C1 to the first plurality of such subjects results in at least a 10% reduction in the number of subjects requiring tocilizumab treatment for CRS during the C1 .

123. A method of pre-treating a subject for receiving a target dose of cevostamab, wherein the method comprises administering to the subject (i) a first dose (C1 D1 ), (ii) a second dose (C1 D2), and (iii) a third dose (C1 D3) of cevostamab, wherein the C1 D2 is greater than the C1 D1 , and the C1 D3 is greater than the C1 D2, wherein the risk of CRS events in the subject, after administration of the C1 D1 , C1 D2, and

C1 D3 to the subject, is at a level that is safe for the subject to receive the target dose of cevostamab.

124. The method of claim 123, wherein, following administration of the C1 D1 , C1 D2, and C1 D3 to the subject, the subject achieves a peak IL-6 level of less than about 80 pg/mL, thereby indicating that the risk of CRS events in the subject is at a level that is safe for the subject to receive the target dose of cevostamab.

125. The method of claim 124, wherein the subject achieves a peak IL-6 level of less than about 30 pg/mL prior to the administration of the target dose of cevostamab.

126. The method of claim 124 or 125, wherein the method further comprises administering to the pretreated subject a target dose of cevostamab.

127. A method of reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering cevostamab in the C1 to a first plurality of such human subjects results in a reduction in the number of CRS events experienced by each subject during the C1 , as compared to a second plurality of subjects being treated for R/R MM and administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose (DS-C1 D3) of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

128. The method of claim 127, wherein administering cevostamab in the C1 to the first plurality of such subjects results in at least a 25% reduction in the number of CRS events experienced by each subject during the C1 .

129. A method of reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering cevostamab in the C1 to a first plurality of such subjects results in an increase in the number of subjects experiencing no CRS event during the C1 , as compared to a second plurality of subjects being treated for R/R MM and administered the target dose of cevostamab after a first dose (DS- C1 D1 ) and a second dose (DS-C1 D2), but not a third dose of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1.

130. The method of claim 129, wherein administering cevostamab in the C1 to the first plurality of such subjects results in at least a 50% increase in the number of subjects experiencing no CRS event during the C1 .

131 . A method of reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of subjects experiencing Grade >2 CRS events during the C1 , as compared to a second plurality of subjects being treated for R/R MM and administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

132. The method of claim 131 , wherein administering cevostamab in the C1 to the first plurality of such subjects results in at least a 35% reduction in the number of subjects experiencing Grade >2 CRS events during the C1 .

133. A method of reducing the occurrence of CRS events in a subject being treated for R/R MM at a target dose of cevostamab, wherein, prior to a first administration of the target dose to the subject in a dosing regimen comprising a first dosing cycle (C1 ), the method comprises administering to the subject (i) a first dose (TS-C1 D1 ); (ii) a second dose (TS-C1 D2); and (iii) a third dose (TS-C1 D3) of cevostamab, wherein administering cevostamab in the C1 to a first plurality of such subjects results in a reduction in the number of subjects experiencing at least two CRS events during the C1 , as compared to a second plurality of subjects being treated for R/R MM and administered the target dose of cevostamab after a first dose (DS-C1 D1 ) and a second dose (DS-C1 D2), but not a third dose of cevostamab, and wherein the TS-D1 D2 is greater than the TS-C1 D1 , the TS-C1 D3 is greater than the TS-C1 D2, and the DS-C1 D2 is greater than the DS-C1 D1 .

134. The method of claim 133, wherein administering cevostamab in the C1 to the first plurality of such subjects results in at least a 50% reduction in the number of subjects experiencing at least two CRS events during the C1 .

135. The method of any one of claims 1 -134, wherein the subject is a human subject.