Methods of Treating Multiple Myeloma

Abstract

Provided herein are methods of treating multiple myeloma (MM) using specific doses of anti-B cell migration antigen (BCMA) antibodies and nirogacestat and, optionally, dexamethasone. TIFF2024534602000026.tif63170

Description

[Technical field]

[0001] Claiming priority This application claims the benefit of U.S. Provisional Application No. 63 / 247,637, filed September 23, 2021. The disclosure of the prior application is incorporated herein by reference in its entirety.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically as an XML file titled "49223-0060WO1_SL_ST26.XML". The XML file, created on September 13, 2022, is 19,519 bytes in size. The contents of the XML file are incorporated herein by reference in their entirety. [Background technology]

[0003] background Multiple myeloma (MM) is a neoplastic disease of clonally proliferating plasma cells in the bone marrow, peripheral blood or other extramedullary sites. Malignant plasma cells exert direct pathological effects on the bone marrow microenvironment and adjacent skeletal bone, leading to anemia, osteolytic bone lesions and hypercalcemia. In most cases, malignant plasma cells also produce abnormal monoclonal immunoglobulins known as M-proteins, but in a minority of subjects, myeloma cells only produce monoclonal free light chains (FLCs). Abnormal levels of either M protein or FLC can contribute to a clinical spectrum of disease, including renal failure and increased susceptibility to infection (Kumar et al., Nat. Rev. Dis. Primers 3:17046, 2017; Palumbo et al., N. Engl. J. Med. 364(11):1046-1060, 2011; Rollig et al., Lancet 385(9983):2197-2208, 2015).

[0004] Standard treatments for MM include combination chemotherapy regimens containing proteasome inhibitors (PIs) such as bortezomib and carfilzomib, and ixazomib, and / or immunomodulatory drugs (IMiDs) such as lenalidomide and pomalidomide. Alkylating agents such as melphalan and cyclophosphamide are also active in MM. Eligible patients without significant comorbidities are often treated with myeloablative chemotherapy and / or radiation followed by autologous stem cell transplantation (ASCT) (Rollig et al., Lancet. 385(9983):2197-208, 2015; and Rajkumar et al., Mayo Clin Proc. 91(1):101-19, 2016). More recently, daratumumab, a monoclonal antibody targeting the CD38 antigen, has been approved for the treatment of RRMM as a monotherapy in the fourth line.

[0005] To date, multiple myeloma is considered an incurable disease that is generally managed only with sequential treatments with shorter periods of disease control after each subsequent relapse (Kumar et al., Mayo Clin. Proc. 79(7):867-874, 2004). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Kumar et al., Nat. Rev. Dis. Primers 3:17046, 2017 [Non-Patent Document 2] Palumbo et al., N. Engl. J. Med. 364(11):1046-1060, 2011 [Non-Patent Document 3] Rollig et al., Lancet 385(9983):2197-2208, 2015 [Non-Patent Document 4] Rajkumar et al., Mayo Clin Proc. 91(1):101-19, 2016 [Non-Patent Document 5] Kumar et al., Mayo Clin. Proc. 79(7):867-874, 2004 Summary of the Invention

[0007] overview This application is based on evidence demonstrating the efficacy of combinations of certain BCMA therapeutics, such as BCMA antibodies (including non-fucosylated antibodies), with a variety of other therapeutic agents for treating cancers such as MM. Therapeutic agents found to be successful in combination with such BCMA agents (e.g., non-fucosylated antibodies) include nirogacestat and / or dexamethasone.

[0008] In another aspect, the present application is based in part on the identification of various BCMA antibody dosing regimens, including standard and intensive dosing regimens (defined in more detail below) that have been shown to be therapeutically effective in combination therapy, including in combination with nirogacestat and / or dexamethasone. These results were unexpected given that relatively high levels of BCMA antibodies as described herein can be administered while maintaining a manageable safety profile, including when the BCMA antibodies are administered as part of a combination therapy.

[0009] Accordingly, provided herein is a method of treating a subject having multiple myeloma (MM), comprising administering to the subject (i) one or more doses of an antibody or antigen-binding fragment thereof that specifically binds to B-cell maturation antigen (BCMA) and (ii) one or more doses of nirogacestat, wherein the one or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject at about 100 mg of the antibody or antigen-binding fragment thereof to about 2,000 mg of the antibody or antigen-binding fragment thereof, and the one or more doses of nirogacestat are independently administered to the subject at about 80 mg to about 120 mg of nirogacestat.

[0010] In some embodiments of any of the methods described herein, the antibody or antigen-binding fragment thereof is a non-fucosylated antibody or antigen-binding fragment thereof.

[0011] In some embodiments of any of the methods described herein, a composition comprising an antibody or antigen-binding fragment thereof is administered to a subject, and about or at least 95%, 97%, 98% or 99% of the antibody or antigen-binding fragment thereof in the composition is defucosylated.

[0012] In some embodiments of any of the methods described herein, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising CDR1 comprising SEQ ID NO:1, CDR2 comprising SEQ ID NO:2, and CDR3 comprising SEQ ID NO:3, and a light chain variable domain comprising CDR1 comprising SEQ ID NO:5, CDR2 comprising SEQ ID NO:6, and CDR3 comprising SEQ ID NO:7.

[0013] In some embodiments of any of the methods described herein, the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising an amino acid sequence that is at least 80% identical to SEQ ID NO:4 and a light chain variable domain comprising an amino acid sequence that is at least 80% identical to SEQ ID NO:8.

[0014] In some embodiments of any of the methods described herein, the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to SEQ ID NO:4 and a light chain variable domain comprising an amino acid sequence that is at least 90% identical to SEQ ID NO:8.

[0015] In some embodiments of any of the methods described herein, the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:4 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:8.

[0016] In some aspects of any of the methods described herein, the antibody or antigen-binding fragment thereof is humanized.

[0017] In some embodiments of any of the methods described herein, the antibody is an IgG1 antibody.

[0018] In some embodiments of any of the methods described herein, the antibody or antigen-binding fragment thereof is not a bispecific antibody, a bispecific T cell engager (BiTE), a chimeric antigen receptor (CAR), and an antibody drug conjugate (ADC), or a portion thereof.

[0019] In some embodiments of any of the methods described herein, one or more doses of the antibody or antigen-binding fragment thereof are independently administered to a subject from about 200 mg of the antibody or antigen-binding fragment thereof to about 1600 mg of the antibody or antigen-binding fragment thereof.

[0020] In some embodiments of any of the methods described herein, one or more doses of the antibody or antigen-binding fragment thereof are independently administered to a subject from about 200 mg of the antibody or antigen-binding fragment thereof to about 800 mg of the antibody or antigen-binding fragment thereof.

[0021] In some embodiments of any of the methods described herein, one or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject from about 400 mg of the antibody or antigen-binding fragment thereof to about 800 mg of the antibody or antigen-binding fragment thereof.

[0022] In some embodiments of any of the methods described herein, one or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject from about 100 mg of the antibody or antigen-binding fragment thereof to about 400 mg of the antibody or antigen-binding fragment thereof.

[0023] In some embodiments of any of the methods described herein, one or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject from about 800 mg of the antibody or antigen-binding fragment thereof to about 2,000 mg of the antibody or antigen-binding fragment thereof.

[0024] In some embodiments of any of the methods described herein, one or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject from about 1,200 mg of the antibody or antigen-binding fragment thereof to about 2,000 mg of the antibody or antigen-binding fragment thereof.

[0025] In some embodiments of any of the methods described herein, one or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject from about 1,400 mg of the antibody or antigen-binding fragment thereof to about 1,800 mg of the antibody or antigen-binding fragment thereof.

[0026] In some embodiments of any of the methods described herein, one or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject at about 100 mg of the antibody or antigen-binding fragment thereof.

[0027] In some embodiments of any of the methods described herein, one or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject at about 200 mg of the antibody or antigen-binding fragment thereof.

[0028] In some embodiments of any of the methods described herein, one or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject at about 400 mg of the antibody or antigen-binding fragment thereof.

[0029] In some embodiments of any of the methods described herein, one or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject at about 800 mg of the antibody or antigen-binding fragment thereof.

[0030] In some embodiments of any of the methods described herein, the one or more doses of the antibody or antigen-binding fragment thereof are administered to the subject at about 1,600 mg of the antibody or antigen-binding fragment thereof.

[0031] In some embodiments of any of the methods described herein, a single dose of the antibody or antigen-binding fragment thereof is administered to the subject.

[0032] In some embodiments of any of the methods described herein, two or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject.

[0033] In some embodiments of any of the methods described herein, two or more doses of the antibody or antigen-binding fragment thereof are independently administered to a subject at a frequency ranging from about once per week to about once every four weeks.

[0034] In some embodiments of any of the methods described herein, two or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject at a frequency of about once per week.

[0035] In some embodiments of any of the methods described herein, two or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject at a frequency of about once every two weeks.

[0036] In some embodiments of any of the methods described herein, two or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject at a frequency of about once every three weeks.

[0037] In some embodiments of any of the methods described herein, two or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject at a frequency of about once every four weeks.

[0038] In some embodiments of any of the methods described herein, each dose of the antibody or antigen-binding fragment thereof contains about 100 mg of the antibody or antigen-binding fragment thereof and is independently administered to the subject about once a week or about once every two weeks.

[0039] In some embodiments of any of the methods described herein, each dose of the antibody or antigen-binding fragment thereof contains about 200 mg of the antibody or antigen-binding fragment thereof and is independently administered to the subject about once a week or about once every two weeks.

[0040] In some embodiments of any of the methods described herein, each dose of the antibody or antigen-binding fragment thereof contains about 400 mg of the antibody or antigen-binding fragment thereof and is independently administered to the subject about once a week or about once every two weeks.

[0041] In some embodiments of any of the methods described herein, each dose of the antibody or antigen-binding fragment thereof contains about 800 mg of the antibody or antigen-binding fragment thereof and is independently administered to the subject about once a week or about once every two weeks.

[0042] In some embodiments of any of the methods described herein, each dose of the antibody or antigen-binding fragment thereof contains about 1600 mg of the antibody or antigen-binding fragment thereof and is independently administered to the subject about once a week or about once every two weeks.

[0043] In some embodiments of any of the methods described herein, individual doses of the antibody or antigen-binding fragment thereof are administered independently to the subject on days 1 and 15 of a 28-day cycle.

[0044] In some embodiments of any of the methods described herein, individual doses of the antibody or antigen-binding fragment thereof are administered independently to a subject on days 1, 8, 15, and 22 of a 28-day cycle.

[0045] In some embodiments of any of the methods described herein, individual doses of the antibody or antigen-binding fragment thereof are administered independently to the subject in multiple 28-day cycles.

[0046] In some embodiments of any of the methods described herein, the two or more doses of the antibody or antigen-binding fragment thereof include (1) one or more induction doses administered independently to the subject during an induction phase, and (2) one or more maintenance doses of the antibody or antigen-binding fragment thereof administered independently to the subject during a maintenance phase after the induction phase.

[0047] In some aspects of any of the methods described herein, a single induction dose is administered to the subject.

[0048] In some embodiments of any of the methods described herein, two or more induction doses are administered independently to a subject.

[0049] In some embodiments of any of the methods described herein, each of the two or more induction doses is independently administered to the subject about once per week for about 1-10 weeks.

[0050] In some embodiments of any of the methods described herein, each of the two or more induction doses is independently administered to the subject once per week for eight weeks.

[0051] In some embodiments of any of the methods described herein, the induction dose is administered to the subject four independent times within a single 28-day cycle.

[0052] In some embodiments of any of the methods described herein, the induction dose is administered to the subject eight independent times within two 28-day cycles.

[0053] In some embodiments of any of the methods described herein, separate induction doses are administered to the subject independently on days 1, 8, 15, and 22 of each of two 28-day cycles.

[0054] In some embodiments of any of the methods described herein, each of the induction doses comprises about 100, about 200, about 400, about 800, or about 1600 mg of the antibody or antigen-binding fragment thereof.

[0055] In some embodiments of any of the methods described herein, each induction dose comprises about 800 mg of the antibody or antigen-binding fragment thereof.

[0056] In some embodiments of any of the methods described herein, each induction dose comprises about 1600 mg of the antibody or antigen-binding fragment thereof.

[0057] In some embodiments of any of the methods described herein, a single maintenance dose is administered to the subject.

[0058] In some embodiments of any of the methods described herein, two or more maintenance doses are independently administered to the subject.

[0059] In some embodiments of any of the methods described herein, each of the two or more maintenance doses is independently administered to the subject once every 1-4 weeks.

[0060] In some embodiments of any of the methods described herein, each of the two or more maintenance doses is independently administered to the subject once every two weeks.

[0061] In some embodiments of any of the methods described herein, a separate maintenance dose is administered to the subject independently on days 1 and 15 of a 28-day cycle.

[0062] In some embodiments of any of the methods described herein, each maintenance dose comprises about 100, about 200, about 400, about 800, or about 1600 mg of the antibody or antigen-binding fragment thereof.

[0063] In some embodiments of any of the methods described herein, each maintenance dose comprises about 800 mg of the antibody or antigen-binding fragment thereof.

[0064] In some embodiments of any of the methods described herein, each maintenance dose comprises about 1600 mg of the antibody or antigen-binding fragment thereof.

[0065] In some embodiments of any of the methods described herein, the antibody or antigen-binding fragment thereof is dosed q1wk during the induction phase for a total of eight induction phase doses, and q2wk during the maintenance phase.

[0066] In some embodiments of any of the methods described herein, each induction dose comprises about 100, about 200, about 400, about 800, or about 1600 mg of the antibody or antigen-binding fragment thereof; each maintenance dose comprises about 100, about 200, about 400, about 800, or about 1600 mg of the antibody or antigen-binding fragment thereof; a separate induction dose is administered independently to the subject on each of days 1, 8, 15, and 22 for each of two 28-day cycles for a total of eight induction doses during the induction phase; and a separate maintenance dose is administered independently to the subject on each of days 1 and 15 of each of one or more subsequent 28-day cycles.

[0067] In some embodiments of any of the methods described herein, each induction dose and each maintenance dose comprises about 800 or about 1600 mg of the antibody or antigen-binding fragment thereof.

[0068] In some embodiments of any of the methods described herein, each induction dose and each maintenance dose comprises about 1600 mg of the antibody or antigen-binding fragment thereof.

[0069] In some embodiments of any of the methods described herein, the dose of the antibody or antigen-binding fragment thereof is administered to the subject intravenously.

[0070] In some embodiments of any of the methods described herein, a single dose of nirogacestat is administered to the subject.

[0071] In some embodiments of any of the methods described herein, two or more doses of nirogacestat are independently administered to the subject.

[0072] In some embodiments of any of the methods described herein, each dose of nirogacestat contains about 100 mg of nirogacestat.

[0073] In some embodiments of any of the methods described herein, two or more doses of nirogacestat are independently administered to a subject at a frequency of about once per day to about four times per day.

[0074] In some embodiments of any of the methods described herein, two or more doses of nirogacestat are independently administered to the subject at a frequency of about twice daily.

[0075] In some embodiments of any of the methods described herein, each of the two or more doses of nirogacestat comprises about 100 mg of nirogacestat, and the two or more doses of nirogacestat are independently administered to the subject at a frequency of about twice per day on each day of one or more 28-day cycles.

[0076] In some embodiments of any of the methods described herein, the dose of nirogacestat is administered orally to the subject.

[0077] In some embodiments of any of the methods described herein, the method further includes independently administering to the subject one or more doses of dexamethasone.

[0078] In some embodiments of any of the methods described herein, the method includes administering a single dose of dexamethasone to the subject.

[0079] In some embodiments of any of the methods described herein, the method further comprises independently administering to the subject two or more doses of dexamethasone.

[0080] In some embodiments of any of the methods described herein, the two or more doses of dexamethasone are independently administered to the subject at a frequency of about once per week.

[0081] In some embodiments of any of the methods described herein, each dose of dexamethasone contains from about 30 mg to about 50 mg of dexamethasone.

[0082] In some embodiments of any of the methods described herein, each dose of dexamethasone contains about 40 mg of dexamethasone.

[0083] In some embodiments of any of the methods described herein, each dose of dexamethasone is administered intravenously to the subject.

[0084] In some embodiments of any of the methods described herein, when the dose of dexamethasone and the dose of the antibody or antigen-binding fragment thereof are administered to the subject on the same day, the dose of dexamethasone is administered to the subject about 1 to about 3 hours before the dose of the antibody or antigen-binding fragment thereof is administered to the subject.

[0085] In some embodiments of any of the methods described herein, each of the two or more doses of the antibody or antigen-binding fragment thereof is independently administered to the subject about once every 1-4 weeks; each of the two or more doses of nirogacestat is independently administered to the subject about once per day to about 4 times per day; and each of the two or more doses of dexamethasone is independently administered to the subject about once every 1-4 weeks.

[0086] In some embodiments of any of the methods described herein, each of the two or more doses of the antibody or antigen-binding fragment thereof is independently administered to the subject about once every two weeks; each of the two or more doses of nirogacestat is independently administered to the subject twice daily; and each of the two or more doses of dexamethasone is independently administered to the subject about once a week.

[0087] In some embodiments of any of the methods described herein, each of the two or more doses of the antibody or antigen-binding fragment thereof is independently administered to the subject on each of days 1 and 15 of one or more 28-day cycles; each of the two or more doses of nirogacestat is independently administered to the subject on each of days 1-28 of one or more 28-day cycles; and each of the two or more doses of dexamethasone is independently administered to the subject on each of days 1, 8, 15, and 22 of one or more 28-day cycles.

[0088] In some embodiments of any of the methods described herein, each of the two or more doses of the antibody or antigen-binding fragment comprises about 400 to about 1,600 mg of the antibody or antigen-binding fragment, each of the two or more doses of nirogacestat comprises about 100 mg of nirogacestat, and each of the two or more doses of dexamethasone comprises about 40 mg of dexamethasone.

[0089] In some embodiments of any of the methods described herein, each of the two or more doses of the antibody or antigen-binding fragment comprises about 400 mg of the antibody or antibody or antigen-binding fragment thereof, each of the two or more doses of nirogacestat comprises about 100 mg of nirogacestat, and each of the two or more doses of dexamethasone comprises about 40 mg of dexamethasone.

[0090] In some embodiments of any of the methods described herein, each of the two or more doses of the antibody or antigen-binding fragment comprises about 800 mg of the antibody or antibody or antigen-binding fragment thereof, each of the two or more doses of nirogacestat comprises about 100 mg of nirogacestat, and each of the two or more doses of dexamethasone comprises about 40 mg of dexamethasone.

[0091] In some embodiments of any of the methods described herein, each of the two or more doses of the antibody or antigen-binding fragment comprises about 1,600 mg of the antibody or antibody or antigen-binding fragment thereof, each of the two or more doses of nirogacestat comprises about 100 mg of nirogacestat, and each of the two or more doses of dexamethasone comprises about 40 mg of dexamethasone.

[0092] In some embodiments of any of the methods described herein, two or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject about once per week during the induction phase, and two or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject about once every two weeks during a subsequent maintenance phase; two or more doses of nirogacestat are independently administered to the subject about twice per day during one or both of the induction and maintenance phases; and two or more doses of dexamethasone are independently administered to the subject about once per week during one or both of the induction and maintenance phases.

[0093] In some embodiments of any of the methods described herein, the induction phase is about 8 weeks.

[0094] In some embodiments of any of the methods described herein, two or more doses of the antibody or antigen-binding fragment thereof are administered to the subject independently on days 1, 8, 15, and 22 of each of two 28-day cycles of the induction phase, then on days 1 and 15 of each of a subsequent 28-day cycle of the maintenance phase; two or more doses of nirogacestat are administered to the subject independently on days 1-28 of each of two 28-day cycles of the induction phase and each of a subsequent 28-day cycle of the maintenance phase; and two or more doses of dexamethasone are administered to the subject independently on days 1, 8, 15, and 22 of each of two 28-day cycles of the induction phase and each of a subsequent 28-day cycle of the maintenance phase.

[0095] In some embodiments of any of the methods described herein, the two or more doses of antibody or antigen-binding fragment administered independently to the subject on each of days 1, 8, 15, and 22 of each of two 28-day cycles of the induction phase comprise about 100 mg, about 200 mg, about 400 mg, about 800 mg, or about 1600 mg of the antibody or antigen-binding fragment; the two or more doses of antigen or antigen-binding fragment administered independently to the subject on each of days 1 and 15 of each of the 28-day cycles of the subsequent maintenance phase comprise about 100, about 200, about 400, about 800, or about 1600 mg of the antibody or antigen-binding fragment; 00, or about 1600 mg; the two or more doses of nirogacestat administered independently to the subject on days 1 through 28 of each of two 28 day cycles of the induction phase and each subsequent 28 day cycle of the maintenance phase comprise from about 80 mg to about 120 mg of nirogacestat; and the two or more doses of dexamethasone administered independently to the subject on days 1, 8, 15, and 22 of each of two 28 day cycles of the induction phase and each subsequent 28 day cycle of the maintenance phase comprise from about 20 mg to about 60 mg of dexamethasone.

[0096] In some embodiments of any of the methods described herein, the two or more doses of the antibody or antigen-binding fragment thereof administered independently to the subject on days 1, 8, 15, and 22 of each of two 28-day cycles of the induction phase comprise about 800 mg of the antibody or antigen-binding fragment thereof.

[0097] In some embodiments of any of the methods described herein, the two or more doses of the antibody or antigen-binding fragment thereof administered independently to the subject on days 1, 8, 15, and 22 of each of two 28-day cycles of the induction phase comprise about 1,600 mg of the antibody or antigen-binding fragment thereof.

[0098] In some embodiments of any of the methods described herein, the two or more doses of nirogacestat administered independently to the subject on each of days 1 through 28 of each of two 28 day cycles of the induction phase and each subsequent 28 day cycle of the maintenance phase comprise about 100 mg of nirogacestat.

[0099] In some embodiments of any of the methods described herein, the two or more doses of dexamethasone administered independently to the subject on each of days 1, 8, 15, and 22 of each of two 28-day cycles of the induction phase and each subsequent 28-day cycle of the maintenance phase comprise about 20 mg of dexamethasone.

[0100] In some embodiments of any of the methods described herein, the two or more doses of dexamethasone administered independently to the subject on each of days 1, 8, 15, and 22 of each of two 28-day cycles of the induction phase and each subsequent 28-day cycle of the maintenance phase comprise about 40 mg of dexamethasone.

[0101] In some embodiments of any of the methods described herein, the two or more doses of antibody or antigen-binding fragment administered independently to the subject on each of days 1, 8, 15, and 22 of each of two 28-day cycles of the induction phase comprise about 1600 mg of antibody or antigen-binding fragment; the two or more doses of antigen or antigen-binding fragment administered independently to the subject on each of days 1 and 15 of each of two 28-day cycles of the subsequent maintenance phase comprise about 1600 mg; The two or more doses of nirogacestat, independently administered twice daily to the subject on days 1 through 28 of each of the two 28 day cycles of the induction phase and on days 1 through 28 of each of the subsequent 28 day cycles of the maintenance phase, comprise about 100 mg of nirogacestat; and the two or more doses of dexamethasone, independently administered to the subject on days 1, 8, 15, and 22 of each of the two 28 day cycles of the induction phase and on days 1, 8, 15, and 22 of each of the subsequent 28 day cycles of the maintenance phase, comprise about 40 mg of dexamethasone.

[0102] In some embodiments of any of the methods described herein, the two or more doses of the antibody or antigen-binding fragment administered independently to the subject on each of days 1, 8, 15, and 22 of each of two 28-day cycles of the induction phase comprise about 800 mg of the antibody or antigen-binding fragment; the two or more doses of the antigen or antigen-binding fragment administered independently to the subject on each of days 1 and 15 of each of two 28-day cycles of the subsequent maintenance phase comprise about 800 mg; the two or more doses of nirogacestat independently administered twice daily to the subject on each of days 1 through 28 of each of the two 28 day cycles of the induction phase and each of the subsequent 28 day cycles of the maintenance phase comprise about 100 mg of nirogacestat; and the two or more doses of dexamethasone independently administered to the subject on each of days 1, 8, 15, and 22 of each of the two 28 day cycles of the induction phase and each of the subsequent 28 day cycles of the maintenance phase comprise about 40 mg of dexamethasone.

[0103] In some embodiments of any of the methods described herein, the two or more doses of dexamethasone are administered to the subject by intravenous administration.

[0104] In some embodiments of any of the methods described herein, two or more doses of the antibody or antigen-binding fragment thereof are administered to the subject by intravenous administration.

[0105] In some embodiments of any of the methods described herein, at least the first of the two or more doses of the antibody or antigen-binding fragment thereof is administered to the subject using gradual infusions.

[0106] In some embodiments of any of the methods described herein, the gradual infusion is performed using an infusion rate of about 50 mg / hour to about 400 mg / hour.

[0107] In some embodiments of any of the methods described herein, during the gradual infusion, the infusion rate is increased every 30 minutes.

[0108] In some embodiments of any of the methods described herein, during the gradual infusion, the infusion rate is increased by no more than 2-fold every 30 minutes.

[0109] In some embodiments of any of the methods described herein, the two or more doses of nirogacestat are administered to the subject by oral administration.

[0110] In some aspects of any of the methods described herein, the subject is a human subject.

[0111] In some embodiments of any of the methods described herein, the subject has previously been diagnosed with multiple myeloma.

[0112] In some embodiments of any of the methods described herein, the subject has relapsed or refractory multiple myeloma.

[0113] In some embodiments of any of the methods described herein, the subject has previously been administered one or more therapeutic agents or treatments for multiple myeloma.

[0114] In some embodiments of any of the methods described herein, one or more previously administered therapeutic agents or treatments for multiple myeloma have been unsuccessful.

[0115] In some embodiments of any of the methods described herein, the subject has previously been administered at least one of a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody, or is unable to tolerate any of the foregoing.

[0116] In some embodiments of any of the methods described herein, the subject has previously received therapies including all three of a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody, or is unable to tolerate any of the foregoing.

[0117] In some embodiments of any of the methods described herein, the subject has previously received at least three prior lines of anti-multiple myeloma therapy and is refractory to at least one therapeutic agent from each of the following classes: proteasome inhibitors, immunomodulatory agents, and anti-CD38 antibodies.

[0118] In some embodiments of any of the methods described herein, the subject has previously been treated with a BCMA-directed myeloma therapy other than the antibody or antigen-binding fragment thereof.

[0119] In some embodiments of any of the methods described herein, the subject meets one, two, or all three of the following criteria prior to initiating treatment: (1) serum monoclonal paraprotein (M-protein) level ≧0.5 g / dL, urinary M-protein level ≧200 mg / 24 hours, (2) serum immunoglobulin free light chain ≧10 mg / dL, and / or (3) an abnormal serum immunoglobulin kappa lambda free light chain ratio.

[0120] In some embodiments of any of the methods described herein, the method results in a steady state concentration of the antibody or antigen-binding fragment thereof in the subject's serum of about 1 μg / mL to about 200 μg / mL.

[0121] In some embodiments of any of the methods described herein, the method results in a steady state concentration of free light chain (FLC) in the subject's serum of less than 50 mg / dL.

[0122] In some embodiments of any of the methods described herein, the subject has received at least two prior lines of anti-multiple myeloma therapy and / or has documented progression per IMWG (International Myeloma Working Group) at or within 60 days of completing two prior lines of anti-myeloma therapy.

[0123] In some embodiments of any of the methods described herein, the one or more therapeutic effects in the subject are improved compared to baseline after administration of a dose of the antibody or antigen-binding fragment thereof, a dose of nirogacestat, and optionally a dose of dexamethasone.

[0124] In some embodiments of any of the methods described herein, the one or more therapeutic effects are selected from the group consisting of objective response rate, complete response rate, duration of response, duration of complete response, time to response, progression-free survival, and overall survival of the subject.

[0125] In some embodiments of any of the methods described herein, the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%.

[0126] In some embodiments of any of the methods described herein, the subject exhibits progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years.

[0127] In some embodiments of any of the methods described herein, the subject exhibits an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years.

[0128] In some embodiments of any of the methods described herein, the duration of response or complete response to administration is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years.

[0129] Kits may also be provided that include: (a) one or more doses of a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to B-cell maturation antigen (BCMA), wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR1 comprising SEQ ID NO:1, a CDR2 comprising SEQ ID NO:2, and a CDR3 comprising SEQ ID NO:3, and a light chain variable domain comprising a CDR1 comprising SEQ ID NO:5, a CDR2 comprising SEQ ID NO:6, and a CDR3 comprising SEQ ID NO:7; and (b) instructions for performing any of the methods described herein.

[0130] In some embodiments of any of the kits described herein, the kit further comprises one or more doses of a pharmaceutical composition comprising nirogacestat. In some embodiments of any of the kits described herein, the kit further comprises one or more doses of a pharmaceutical composition comprising dexamethasone.

[0131] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention belongs. Methods and materials are described herein for use in the present invention, but other suitable methods and materials known in the art can also be used. Materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0132] Other features and advantages of the invention will become apparent from the following detailed description and drawings, and from the claims. [Brief description of the drawings]

[0133] Description of the drawings [Figure 1] FIG. 1 is a schematic diagram showing continuation or discontinuation of treatment with nirogacestat. [Diagram 2] Figure 2A. NCI-H929 cells exhibited increased BCMA expression upon DAPT treatment. Light grey: isotype control; medium grey: untreated cells; dark grey: DAPT-treated cells. Figure 2B. Molp-8 cells exhibited increased BCMA expression upon DAPT treatment. Light grey: isotype control; medium grey: untreated cells; dark grey: DAPT-treated cells. Figure 2C. Fold over background of NFAT signaling due to FcγRIII engagement. DAPT(GSI)-treated NCI-H929 cells compared to untreated cells (N=3). Figure 2D. Fold over background of NFAT signaling due to FcγRIII engagement. DAPT(GSI)-treated Molp-8 cells compared to untreated cells (N=3). [Diagram 3]Figure 3A. Overnight treatment of multiple myeloma cells with nirogacestat induced BCMA expression in target cells. Figure 3B. Increased multiple myeloma target cell lysis mediated by isolated primary natural killer (NK) cells (MOLP-8 cells incubated with high affinity FcγRIII V / V genotype donor cells and U266 cells incubated with low affinity FcγRIII V / F genotype donor cells). [Figure 4A] Molp-8 cells exhibited increased BCMA expression following nirogacestat treatment. Dark grey: isotype control; medium grey: untreated cells; light grey: nirogacestat-treated cells. [Figure 4B] Maximal target cell lysis of nirogacestat treated cells compared to untreated cells (N=3). hIgG1k is a non-binding antibody control. [Diagram 5] p65 activation in NCI-H929 cells in the presence or absence of nirogacestat, treated and untreated with APRIL, and bound and unbound with SEA-BCMA. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0134] Detailed Description Provided herein are methods of treating a subject with multiple myeloma (MM), comprising administering to the subject (i) one or more doses of an antibody or antigen-binding fragment thereof that binds to B-cell maturation antigen (BCMA) and (ii) one or more doses of nirogacestat, wherein the one or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject at about 100 mg of the antibody or antigen-binding fragment thereof to about 2,000 mg of the antibody or antigen-binding fragment thereof, and the one or more doses of nirogacestat are independently administered to the subject at about 80 mg to about 120 mg of nirogacestat. In some embodiments, the method further comprises administering one or more doses of dexamethasone.

[0135] In some embodiments, the antibody is an IgG1 antibody. In some embodiments, the antibody is a defucosylated antibody. In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising CDR1 comprising SEQ ID NO:1, CDR2 comprising SEQ ID NO:2, and CDR3 comprising SEQ ID NO:3, and a light chain variable domain comprising CDR1 comprising SEQ ID NO:5, CDR2 comprising SEQ ID NO:6, and CDR3 comprising SEQ ID NO:7. In some embodiments, one or more doses of 1600 mg of the antibody or antigen-binding fragment thereof are independently administered to the subject every two weeks. In some embodiments, one or more doses of 800 mg of the antibody or antigen-binding fragment thereof are independently administered to the subject every week. In some embodiments, about one to two induction doses of 1600 mg of the antibody or antigen-binding fragment thereof are independently administered to the subject as frequently as every week, followed by one or more maintenance doses of 1600 mg of the antibody or antigen-binding fragment thereof, independently administered to the subject as frequently as every two weeks. In some embodiments, about one to two induction doses of 800 mg of the antibody or antigen-binding fragment thereof are independently administered to the subject as frequently as every week, followed by one or more maintenance doses of 1600 mg of the antibody or antigen-binding fragment thereof, independently administered to the subject as frequently as every two weeks.

[0136] In some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma (RRMM). In some embodiments, the subject has previously been administered one or more therapeutic agents or treatments for multiple myeloma. The one or more previously administered therapeutic agents or treatments for multiple myeloma include, but are not limited to, proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and anti-CD38 antibodies. In some embodiments, the subject has previously been administered at least one BCMA-directed myeloma therapy selected from the group consisting of ADCs, CAR-T cell therapy and bispecific antibodies. In some embodiments, the one or more previously administered therapeutic agents or treatments are ineffective in treating multiple myeloma. In some embodiments, the subject has one or more (e.g., two, three, or four) of the following: serum monoclonal paraprotein (M protein) level ≧0.5 g / dL, urinary M protein level ≧200 mg / 24 hours, serum immunoglobulin free light chain ≧10 mg / dL, and / or an abnormal serum immunoglobulin kappa to lambda free light chain ratio.

[0137] In some embodiments, these methods result in, for example, one or more of a therapeutically desirable steady state concentration of an anti-BCMA antibody in the subject's serum, a therapeutically desirable reduction in steady state levels of free light chain in the subject's serum, and a therapeutically desirable saturation of BCMA in the subject.

[0138] Initial results from clinical trials conducted with defucosylated anti-BCMA antibodies, such as the SEA-BCMA antibodies described herein, indicate that the SEA-BCMA antibodies can be administered at high doses (e.g., 800 mg or 1600 mg per dose) while maintaining a tolerable safety profile. These initial results indicate that such antibodies may be able to be administered in flexible dosing regimens, including standard or intensive dosing regimens. The ability to dosing at high levels also indicates that the antibody is a good candidate for dosing in combination with other therapeutic agents, including, for example, nirogacestat and / or dexamethasone.

[0139] Multiple myeloma Multiple myeloma (MM) is a neoplastic disease of clonally proliferating plasma cells in the bone marrow, peripheral blood or other extramedullary sites. The diagnosis of MM, which requires systemic therapy, is defined by the International Myeloma Working Group (IMWG) 2014 criteria (Kumar 2016). Malignant plasma cells exert direct pathological effects on the bone marrow microenvironment and adjacent skeletal bone, leading to anemia, osteolytic bone lesions and hypercalcemia. In most cases, malignant plasma cells also produce abnormal monoclonal immunoglobulins known as M-proteins, but in a minority of patients, myeloma cells produce only monoclonal free light chains (FLCs). Abnormal levels of either M-proteins or FLCs can contribute to the clinical spectrum of the disease, including renal failure and increased susceptibility to infections.

[0140] Standard treatment for multiple myeloma includes combination chemotherapy regimens containing proteasome inhibitors (PIs) such as bortezomib and carfilzomib, and / or immunomodulatory drugs (IMiDs) such as lenalidomide and pomalidomide, together with corticosteroids. Alkylating agents such as melphalan and cyclophosphamide are also active in multiple myeloma. Eligible patients without significant comorbidities are often treated with myeloablative chemotherapy and / or radiation. More recently, daratumumab, a monoclonal antibody targeting the CD38 antigen, has been approved for the treatment of RRMM based on significant clinical efficacy as a monotherapy in the fourth line and in combination with bortezomib, lenalidomide, or pomalidomide plus dexamethasone in early lines of therapy. Subsequently, in 2018-2019, daratumumab received U.S. Food and Drug Administration approval in combination with several standard of care (SOC) regimens (bortezomib + melphalan + prednisone, and lenalidomide + dexamethasone for transplant-ineligible patients, and bortezomib + thalidomide + dexamethasone in transplant-eligible patients) for subjects with newly diagnosed multiple myeloma.

[0141] Conventional therapies for multiple myeloma (MM), such as combination chemotherapy regimens, are not curative and ultimately result in progression in the majority of patients. In addition, some patients do not respond to initial treatment.

[0142] Duration of early disease response remains one of the strongest prognostic factors in MM, especially after autologous stem cell transplantation (ASCT). Early relapse (<24 months) after upfront ASCT strongly predicts poorer overall survival (OS), and despite all the progress over the last two decades, the natural history of the disease remains largely unchanged, with the rate of early relapse remaining stable at around 35-38% (see Kumar et al., Leukemia 32:986-95, 2018). These relapses are usually of fulminant type, with similar poor outcomes from refractory disease, and are defined as progression under treatment or within 60 days after cessation of treatment. Early relapses may also preclude adequate patient recovery from initial treatment, significantly limiting treatment options.

[0143] Almost all, if not all, myeloma patients will eventually relapse, but early relapses are usually fulminant and poor, while late relapses (>24 months) generally follow a more indolent course. In addition, patients will usually have a longer recovery time, but with little residual toxicity from previous interventions, allowing for a more aggressive approach. There is a special unmet need in later lines of therapy. The unmet need is particularly prevalent in patients who are refractory to prior PI, IMiD, and anti-CD38 antibody treatment ("triple-class" refractory subjects).

[0144] Provided herein is a method of treating a subject with multiple myeloma (MM). In some embodiments, the multiple myeloma is selected from the group consisting of myeloma precursor, multiple myeloma cancer producing kappa-type light chain and / or lambda-type light chain, fulminant multiple myeloma, refractory multiple myeloma, and drug-resistant multiple myeloma. In some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma (RRMM). In some embodiments, the subject has one or more (e.g., two, three, or four) of serum monoclonal paraprotein (M protein) level ≧0.5 g / dL, urinary M protein level ≧200 mg / 24 hours, serum immunoglobulin free light chain ≧10 mg / dL, and / or abnormal serum immunoglobulin kappa to lambda free light chain ratio.

[0145] Methods for assessing the effectiveness of treatment in a subject with multiple myeloma include measuring the levels of free light chains, M protein, hypercalcemia, and the relative numbers of myeloma cells in the subject.

[0146] BCMA B-cell maturation antigen (BCMA or BCM), also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17), is a protein encoded by the TNFRSF17 gene in humans. BCMA is a protein specific to established plasmablasts and plasma cells that mediates cell proliferation and survival. BCMA is expressed at moderate to low levels on the majority of tumor cells in MM patients (Novak et al., Blood 103(2):689-694, 2004;Seckinger et al., Cancer Cell 31(3):396-410, 2017). The ligands APRIL and BAFF bind to BCMA and mediate pro-survival cell signals (Moreaux et al., Blood 103(8):3148-3157, 2004; Novak et al., Blood 103(2):689-694, 2004; O'Connor et al., J. Exp. Med. 199(1):91-8, 2004).

[0147] Unless otherwise indicated, BCMA refers to human BCMA. Exemplary sequences for wild-type human BCMA protein and wild-type human BCMA cDNA are shown below.

[0148] Wild-type mature human BCMA protein (SEQ ID NO:9) TIFF2024534602000002.tif18170

[0149] Wild-type human BCMA cDNA (SEQ ID NO:10) TIFF2024534602000003.tif74151

[0150] Unless otherwise clear from the context, reference to BMCA refers to at least the extracellular domain of the BCMA protein. An exemplary extracellular domain of a human BCMA protein includes amino acids 1-54 of SEQ ID NO:9. In some embodiments, the anti-BCMA antibodies or antigen-binding fragments described herein can specifically bind to BCMA expressed on the surface of a cancer cell (e.g., a myeloma cell).

[0151] Antibodies and antigen-binding fragments The term "antibody" is used herein in its broadest sense and includes proteins (e.g., single or multi-chain polypeptides) that contain one or more antigen-binding domains that specifically bind to an antigen or epitope. An intact antibody usually contains four polypeptides, i.e., two heavy chains and two light chains connected to form a "Y" shaped molecule. The amino acid sequence at the end of the "Y" varies widely among different antibodies. This variable region (e.g., consisting of 110-130 amino acids) gives the antibody its specificity for binding to the antigen. The variable region includes the ends of the light and heavy chains. This region can be cleaved by treating the antibody with a protease, resulting in a Fab or antigen-binding fragment that contains the variable end of the antibody. The regions in the variable region that directly contact a portion of the surface of the antigen are the complementarity determining regions (CDRs). The light chain variable region (VL) and the heavy chain variable region (VH) each contain three CDRs, i.e., CDR1, CDR2, and CDR3. The constant regions determine the mechanism used to destroy the antigen. Antibodies are classified into five major classes, IgM, IgG, IgA, IgD and IgE, based on their constant region structures and immune functions.

[0152] In some embodiments, antibodies specifically include, for example, intact antibodies (e.g., intact immunoglobulins, e.g., human IgG (e.g., human IgG1, human IgG2, human IgG3, human IgG4)) and antigen-binding antibody fragments. In some embodiments, the antibody is a humanized IgG1 antibody. One example of an antigen-binding domain is the antigen-binding domain formed by a VH-VL dimer. Further examples of antibodies are described herein. Further examples of antibodies are known in the art.

[0153] As used herein, the term "antigen-binding domain" or "antigen-binding fragment" refers to one or more protein domains (e.g., formed from amino acids from a single polypeptide or formed from amino acids from two or more polypeptides (e.g., the same or different polypeptides)) capable of specifically binding to one or more different antigens. In some examples, an antigen-binding domain can bind to an antigen or epitope with specificity and affinity similar to that of a naturally occurring antibody. In some embodiments, an antigen-binding domain can include an alternative scaffold. Non-limiting examples of antigen-binding domains are described herein. Further examples of antigen-binding domains are known in the art. In some examples, an antigen-binding domain can bind to a single antigen. In some embodiments, an antibody or antigen-binding fragment used in the methods described herein specifically binds to B-cell maturation antigen (BCMA).

[0154] The antibodies or antigen-binding fragments thereof described herein can be a single polypeptide or can comprise 2, 3, 4, 5, 6, 7, 8, 9, or 10 (the same or different) polypeptides. In some embodiments where the antibody or antigen-binding fragment thereof is a single polypeptide, the antibody or antigen-binding fragment can comprise a single antigen-binding domain or two antigen-binding domains. In some embodiments where the antibody or antigen-binding fragment is a single polypeptide and comprises two antigen-binding domains, the first and second antigen-binding domains can be the same or different from each other (and can specifically bind to the same or different antigens or epitopes).

[0155] In some embodiments where the antibody or antigen-binding fragment is a single polypeptide, the first antigen-binding domain and the second antigen-binding domain (if present) can each be independently selected from the group of VH domain, VHH domain, VNAR domain, and scFv. In some embodiments where the antibody or antigen-binding fragment is a single polypeptide, the antibody or antigen-binding fragment can be BiTe, (scFv)2, nanobody, nanobody-HSA, DART, TandAb, sc diabody, sc diabody-CH3, scFv-CH-CL-scFv, HSAbody, sc diabody-HAS, tandem-scFv, adnectin, DARPin, fibronectin, and DEP conjugate. Further examples of antigen-binding domains that can be used when the antibody or antigen-binding fragment is a single polypeptide are known in the art.

[0156] VHH domains are single monomeric variable antibody domains that can be found in camelids. NAR The VHH domain is a single monomeric variable antibody domain that can be found in cartilaginous fish. NARSee also Cromie et al., Curr. Top. Med. Chem. 15:2543-2557, 2016;De Genst et al., Dev. Comp. Immunol. 30:187-198, 2006;De Meyer et al., Trends Biotechnol. 32:263-270, 2014;Kijanka et al., Nanomedicine 10:161-174, 2015;Kovaleva et al., Expert. Opinion. Biol. Ther. 14:1527-1539, 2014;Krah et al., Immunopharmacol. Immunotoxicol. 38:21-28, 2016;Mujic-Delic et al., Trends Pharmacol. Sci. 35:247-255, 2014;Muyldermans, J. Biotechnol. 74:277-302, 2001;Muyldermans et al., Trends Biochem. Sci. 26:230-235, 2001;Muyldermans, Ann. Rev. Biochem. 82:775-797, 2013;Rahbarizadeh et al., Immunol. Invest. 40:299-338, 2011;Van Audenhove et al., EBioMedicine 8:40-48, 2016;Van Bockstaele et al., Curr. Opinion. Investigate. Drugs 10:1212-1224, 2009;Vincke et al., Methods Mol. Biol. 911:15-26, 2012;および Wesolowski et al., Med. Microbiol. Immunol. 198:157-174,

[0157] In some embodiments where the antibody or antigen-binding fragment is a single polypeptide and comprises two antigen-binding domains, the first and second antigen-binding domains can both be VHH domains or at least one antigen-binding domain can be a VHH domain. In some embodiments where the antibody or antigen-binding fragment is a single polypeptide and comprises two antigen-binding domains, the first and second antigen-binding domains can both be VHH domains. NAR domain or at least one antigen-binding domain is V NAR In some embodiments where the antibody or antigen-binding domain is a single polypeptide, the first antigen-binding domain is an scFv domain. In some embodiments where the antibody or antigen-binding fragment is a single polypeptide and comprises two antigen-binding domains, the first antigen-binding domain and the second antigen-binding domain can both be scFv domains or at least one antigen-binding domain can be an scFv domain.

[0158] In some embodiments, an antibody or antigen-binding fragment can comprise two or more polypeptides (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 polypeptides). In some embodiments in which an antibody or antigen-binding fragment comprises two or more polypeptides, two, three, four, five, or six of the polypeptides of the two or more polypeptides can be identical.

[0159] In some embodiments, where an antibody or antigen-binding fragment comprises two or more polypeptides (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 polypeptides), two or more of the polypeptides of the antibody or antigen-binding fragment may be assembled (e.g., non-covalently assembled) to form one or more antigen-binding domains, such as an antigen-binding fragment of an antibody (e.g., any of the antigen-binding fragments of an antibody described herein), a VHH-scAb, a VHH-Fab, a dual scFab, a F(ab')2, a diabody, a cross-linked antibody, a cross-linked Fab ... Mab, DAF (two in one), DAF (four in one), DutaMab, DT-IgG, knob-in-hole common light chain, knob-in-hole assembly, charge pair, Fab arm exchange, SEED body, LUZ-Y, Fcab, κλ-body, orthogonal Fab, DVD-IgG, IgG(H)-scFv, scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zy-body, DVI-IgG, diabody-CH3, triple body, mini-antibody, minibody, TriBi minibody, scFv-CH3 KIH, Fab-scFv, F(ab')2-scFv2, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, sc diabody-Fc, diabody-Fc, tandem scFv-Fc, VHH-Fc, tandem VHH-Fc, VHH-Fc KiH, Fab-VHH-Fc, intrabody, dock and lock, ImmTAC, IgG-IgG conjugates, Cov-X-body, scFv1-PEG-scFv2, adnectin, DARPin, fibronectin, and DEP conjugates can be formed. See, e.g., Spiess et al., Mol. Immunol. 67:95-106, 2015, which is incorporated herein in its entirety for a description of these elements. Non-limiting examples of antigen-binding fragments of antibodies include Fv fragments, Fab fragments, F(ab')2 fragments, and Fab' fragments.Further examples of antigen-binding fragments of antibodies are antigen-binding fragments of IgG (e.g., antigen-binding fragments of IgG1, IgG2, IgG3, or IgG4) (e.g., antigen-binding fragments of human or humanized IgG, e.g., human or humanized IgG1, IgG2, IgG3, or IgG4); antigen-binding fragments of IgA (e.g., antigen-binding fragments of IgA1 or IgA2) (e.g., antigen-binding fragments of human or humanized IgA, e.g., human or humanized IgA1 or IgA2); antigen-binding fragments of IgD (e.g., antigen-binding fragments of human or humanized IgD); antigen-binding fragments of IgE (e.g., antigen-binding fragments of human or humanized IgE); or antigen-binding fragments of IgM (e.g., antigen-binding fragments of human or humanized IgM).

[0160] An "Fv" fragment comprises a non-covalently linked dimer of one heavy- and one light-chain variable domain.

[0161] A "Fab" fragment contains the heavy and light chain variable domains of the Fv fragment as well as the constant domain of the light chain and the first constant domain of the heavy chain (C H1 ).

[0162] An "F(ab')2" fragment contains two Fab fragments connected by disulfide bonds near the hinge region.

[0163] "Dual variable domain immunoglobulin" or "DVD-Ig" refers to a multivalent and multispecific binding protein, e.g., as described in DiGiammarino et al., Methods Mol. Biol. 899:145-156, 2012; Jakob et al., MABs 5:358-363, 2013; and U.S. Pat. Nos. 7,612,181; 8,258,268; 8,586,714; 8,716,450; 8,722,855; 8,735,546; and 8,822,645 (each of which is incorporated by reference in its entirety).

[0164] DART is described, for example, in Garber, Nature Reviews Drug Discovery 13:799-801, 2014.

[0165] Defucosylated or non-fucosylated monoclonal antibodies are monoclonal antibodies that have been engineered such that the oligosaccharides in the Fc region of the antibody do not have any fucose sugar units. In some embodiments, defucosylation of the antibody increases effects such as antibody-dependent cellular cytotoxicity (ADCC). As described in more detail below, in some embodiments, the antibody used in the methods described herein is a defucosylated antibody.

[0166] In some embodiments, an antibody described herein can be an IgG1 (e.g., human or humanized IgG1), IgG2 (e.g., human or humanized IgG2), IgG3 (e.g., human or humanized IgG3), IgG4 (e.g., human or humanized IgG4), IgA1 (e.g., human or humanized IgA1), IgA2 (e.g., human or humanized IgA2), IgD (e.g., human or humanized IgD), IgE (e.g., human or humanized IgE), or IgM (e.g., human or humanized IgM).

[0167] A humanized antibody is a genetically engineered antibody in which CDRs from a non-human "donor" antibody are grafted onto human "acceptor" antibody sequences (see, e.g., U.S. Patent Nos. 5,530,101 and 5,585,089 to Queen; U.S. Patent No. 5,225,539 to Winter; U.S. Patent No. 6,407,213 to Carter; U.S. Patent No. 5,859,205 to Adair; and U.S. Patent No. 6,881,557 to Foote). The acceptor antibody sequence can be, for example, a mature human antibody sequence, a composite of such sequences, a consensus sequence of human antibody sequences, or a germline region sequence. For humanization, an exemplary acceptor sequence for the heavy chain is the germline VH exon VH1-2, and for the J exon (JH), exon JH-3. For the light chain, an exemplary acceptor sequence is exon VL1-12 and J exon JK5.

[0168] Thus, a humanized antibody is an antibody that has at least four CDRs that are entirely or substantially derived from a non-human donor antibody and variable region framework sequences and constant regions, if present, entirely or substantially derived from human antibody sequences.Similarly, a humanized heavy chain has at least two, and usually all three CDRs that are entirely or substantially derived from a donor antibody heavy chain and heavy chain variable region framework sequences and heavy chain constant regions, if present, essentially derived from human heavy chain variable region framework and constant region sequences.Similarly, a humanized light chain has at least two, and usually all three CDRs that are entirely or substantially derived from a donor antibody light chain and light chain variable region framework sequences and light chain constant regions, if present, essentially derived from human light chain variable region framework and constant region sequences.Besides nanobodies and dAbs, humanized antibodies include humanized heavy chains and humanized light chains. A CDR in a humanized or human antibody is substantially derived from or substantially identical to a corresponding CDR in a non-human antibody if at least 60%, 85%, 90%, 95% or 100% of the corresponding residues (as defined by Kabat) are identical between the respective CDRs. A variable region framework sequence of an antibody chain or a constant region of an antibody chain is substantially derived from a human variable region framework sequence or human constant region, respectively, if at least 70%, 80%, 85%, 90%, 95% or 100% of the corresponding residues as defined by Kabat are identical.

[0169] Humanized antibodies often incorporate all six CDRs (as defined by Kabat) from a murine antibody, although they can also be made with less than all of the CDRs from the murine antibody (e.g., at least four or five CDRs) (e.g., Pascalis et al., J. Immunol. 169:3076, 2002; Vajdos et al., J. Mol. Biol. 320:415-428, 2002; Iwahashi et al., Mol. Immunol. 36:1079-1091, 1999; Tamura et al., J. Immunol. 164:1432-1441, 2000).

[0170] Certain amino acids from the human variable region framework residues can be selected for substitution based on their possible influence on CDR conformation and / or binding to antigen, which may be explored by modeling, by examination of the characteristics of the amino acid at a particular position, or by empirical observation of the effects of substitution or mutagenesis of a particular amino acid.

[0171] For example, if an amino acid differs between the murine variable region framework residue and a selected human variable region framework residue, the human framework amino acid can be replaced by the equivalent framework amino acid from the murine antibody if it can be reasonably assumed that that amino acid is: (1) Direct non-covalent binding to antigens; (2) adjacent to the CDR region, (3) otherwise interacts with the CDR regions (e.g., is within about 6 Å of the CDR regions); or (4) Mediates the interaction between heavy and light chains.

[0172] In some embodiments of any of the antibodies or antigen-binding fragments described herein, the antibody or antigen-binding fragment can comprise a heavy chain variable region comprising CDR1 comprising DYYIH (SEQ ID NO:1), CDR2 comprising YINPNSGYTNYAQKFQG (SEQ ID NO:2), and CDR3 comprising YMWERVTGFFDF (SEQ ID NO:3), and a light chain variable region comprising CDR1 comprising LASEDISDDLA (SEQ ID NO:5), CDR2 comprising TTSSLQS (SEQ ID NO:6), and CDR3 comprising QQTYKFPPT (SEQ ID NO:7).

[0173] In some embodiments of any of the antibodies or antigen-binding fragments described herein, the antibody or antigen-binding fragment can comprise a heavy chain variable region comprising a sequence that is at least 80% identical (e.g., at least 82% identical, at least 84% identical, at least 86% identical, at least 88% identical, at least 90% identical, at least 92% identical, at least 94% identical, at least 96% identical, at least 98% identical, at least 99% identical, or 100% identical) to SEQ ID NO:4, and / or a light chain variable domain comprising a sequence that is at least 80% identical (e.g., at least 82% identical, at least 84% identical, at least 86% identical, at least 88% identical, at least 90% identical, at least 92% identical, at least 94% identical, at least 96% identical, at least 98% identical, at least 99% identical, or 100% identical) to SEQ ID NO:8.

[0174] In some embodiments of any of the antibodies or antigen-binding fragments described herein, the antibody or antigen-binding fragment can comprise a heavy chain variable region encoded by a nucleic acid comprising a sequence that is at least 80% identical (e.g., at least 82% identical, at least 84% identical, at least 86% identical, at least 88% identical, at least 90% identical, at least 92% identical, at least 94% identical, at least 96% identical, at least 98% identical, at least 99% identical, or 100% identical) to SEQ ID NO:11, and / or a light chain variable domain encoded by a nucleic acid comprising a sequence that is at least 80% identical (e.g., at least 82% identical, at least 84% identical, at least 86% identical, at least 88% identical, at least 90% identical, at least 92% identical, at least 94% identical, at least 96% identical, at least 98% identical, at least 99% identical, or 100% identical) to SEQ ID NO:12.

[0175] Exemplary Heavy Chain Variable Domains (SEQ ID NO:4) TIFF2024534602000004.tif18164

[0176] DNA encoding an exemplary heavy chain variable domain (SEQ ID NO:11) TIFF2024534602000005.tif54137

[0177] Exemplary Light Chain Variable Domain (SEQ ID NO:8) TIFF2024534602000006.tif11165

[0178] DNA encoding an exemplary light chain variable domain (SEQ ID NO:12) TIFF2024534602000007.tif47137

[0179] In some embodiments of any of the antibodies or antigen-binding fragments described herein, the antibody or antigen-binding fragment can comprise a heavy chain comprising a sequence at least 80% identical (e.g., at least 82% identical, at least 84% identical, at least 86% identical, at least 88% identical, at least 90% identical, at least 92% identical, at least 94% identical, at least 96% identical, at least 98% identical, at least 99% identical, or 100% identical) to SEQ ID NO:13, and / or a light chain comprising a sequence at least 80% identical (e.g., at least 82% identical, at least 84% identical, at least 86% identical, at least 88% identical, at least 90% identical, at least 92% identical, at least 94% identical, at least 96% identical, at least 98% identical, at least 99% identical, or 100% identical) to SEQ ID NO:15.

[0180] In some embodiments of any of the antibodies or antigen-binding fragments described herein, the antibody or antigen-binding fragment can comprise a heavy chain encoded by a nucleic acid comprising a sequence at least 80% identical (e.g., at least 82% identical, at least 84% identical, at least 86% identical, at least 88% identical, at least 90% identical, at least 92% identical, at least 94% identical, at least 96% identical, at least 98% identical, at least 99% identical, or 100% identical) to SEQ ID NO:14, and / or a light chain encoded by a nucleic acid comprising a sequence at least 80% identical (e.g., at least 82% identical, at least 84% identical, at least 86% identical, at least 88% identical, at least 90% identical, at least 92% identical, at least 94% identical, at least 96% identical, at least 98% identical, at least 99% identical, or 100% identical) to SEQ ID NO:16.

[0181] Exemplary Heavy Chain (SEQ ID NO:13) TIFF2024534602000008.tif55165

[0182] DNA encoding an exemplary heavy chain (SEQ ID NO:14) TIFF2024534602000009.tif191147

[0183] Exemplary Light Chain (SEQ ID NO:15) TIFF2024534602000010.tif26165

[0184] DNA encoding an exemplary light chain (SEQ ID NO:16) TIFF2024534602000011.tif90137

[0185] In some embodiments of any of the antibodies or antigen-binding fragments described herein, the antibody is as described in US 2017 / 0233484 (see also WO 2017 / 143069). In one such embodiment, the antibody or antigen-binding fragment includes an hSG16.17 VH3 antibody comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 corresponding to SEQ ID NOs:60-62, respectively, as listed in US 2017 / 0233484 and WO 2017 / 143069, and a light chain variable domain comprising CDR1, CDR2, and CDR3 corresponding to SEQ ID NOs:90-92, respectively, as listed in US 2017 / 0233484 and WO 2017 / 143069. The VH and VL domains of hSG16.17 VH3 correspond to SEQ ID NOs:13 and 19, respectively, as listed in US 2017 / 0233484 and WO 2017 / 143069.

[0186] The heavy and light chain variable regions of the humanized antibody can be linked to at least a portion of a human constant region. The choice of constant region depends in part on whether antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis and / or complement-dependent cytotoxicity are desired. For example, human isotopes IgG1 and IgG3 have strong complement-dependent cytotoxicity, human isotype IgG2 has weak complement-dependent cytotoxicity, and human IgG4 lacks complement-dependent cytotoxicity. Human IgG1 and IgG3 also induce stronger cell-mediated effector functions than human IgG2 and IgG4. The light chain constant region can be lambda or kappa. Antibodies can be expressed as tetramers containing two light chains and two heavy chains, as separate heavy and light chains, as Fab, Fab', F(ab')2, and Fv, or as single chain antibodies in which the heavy and light chain variable domains are linked through a spacer.

[0187] One or several amino acids at the amino or carboxy termini of the light and / or heavy chains, such as the C-terminal lysine of the heavy chain, may be missing or derivatized in part or all of the molecule. Substitutions may be made in the constant region to reduce or increase effector functions such as complement-mediated cytotoxicity or ADCC (see, e.g., Winter et al., U.S. Pat. No. 5,624,821; Tso et al., U.S. Pat. No. 5,834,597; and Lazar et al., Proc. Natl. Acad. Sci. USA 103:4005, 2006) or to extend half-life in humans (see, e.g., Hinton et al., J. Biol. Chem. 279:6213, 2004).

[0188] Exemplary substitutions include substitutions of the native amino acid at amino acid position 234, 235, 237, 239, 267, 298, 299, 326, 330 or 332 with a cysteine ​​residue, preferably the S239C mutation in the human IgG1 heavy chain (numbering according to the EU index (Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md., 1987 and 1991)); US Pat. No. 5,399,413, which is incorporated herein by reference). 20100158909). The heavy chain can contain an S239C substitution with and without a C-terminal lysine. The presence of an additional cysteine ​​residue allows for the formation of interchain disulfide bonds. Such interchain disulfide bond formation can cause steric hindrance, thereby reducing the affinity of the Fc region-FcγR binding interaction. Cysteine ​​residues introduced into or adjacent to the Fc region of the IgG constant region can also serve as sites for conjugation to therapeutic agents (i.e., coupling of cytotoxic drugs using thiol-specific reagents such as maleimide derivatives of the drug). The presence of a therapeutic agent causes steric hindrance, thereby further reducing the affinity of the Fc region-FcγR binding interaction. Other substitutions at any of the heavy chain amino acid positions 234, 235, 236 and / or 237 reduce the affinity to Fcγ receptors, especially the FcγRI receptor (see, e.g., U.S. Patent No. 6,624,821, U.S. Patent No. 5,624,821). A preferred combination of heavy chain amino acid substitutions is S239D, A330L and 1332E, which increases the affinity of the Fc domain to FcγRIIIA, thereby increasing ADCC.

[0189] The in vivo half-life of an antibody can also affect its effector function. The half-life of an antibody can be increased or decreased to modify its therapeutic activity. FcRn is a receptor similar in structure to MHC class I antigens that non-covalently associates with β2-microglobulin. FcRn regulates the catabolism of IgG and their transcytosis across tissues (Ghetie and Ward, Annu. Rev. Immunol. 18:739-766, 2000;Ghetie and Ward, Immunol. Res. 25:97-113, 2002). IgG-FcRn interaction occurs at pH 6.0 (pH of intracellular vesicles) but not at pH 7.4 (pH of blood); this interaction allows IgG to be recycled back into the circulation (Ghetie and Ward, Ann. Rev. Immunol. 18:739-766, 2000;Ghetie and Ward, Immunol. Res. 25:97-113, 2002). The region on human IgG1 involved in FcRn binding has been mapped (Shields et al., J. Biol. Chem. 276:6591-604, 2001). Alanine substitutions at amino acid positions Pro238, Thr256, Thr307, Gln311, Asp312, Glu380, Glu382, or Asn434 of the heavy chain of human IgG1 enhance FcRn binding (Shields et al., J. Biol. Chem. 276:6591-604, 2001). IgG1 molecules carrying these substitutions have a longer serum half-life. As a result, these modified IgG1 molecules can perform their effector functions and exert their therapeutic effects for a longer period of time compared to unmodified IgG1. Other exemplary substitutions in the heavy chain to increase binding to FcRn include the introduction of Gln at amino acid position 250 and / or Leu at amino acid position 428. EU numbering is used for all positions in the constant region.

[0190] The oligosaccharide covalently attached to the conserved Asn297 is responsible for the ability of the Fc region of IgG to bind to FcγR (Lund et al., J. Immunol. 157:4963-69, 1996;Wright and Morrison, Trends Biotechnol. 15:26-31, 1997). Manipulation of this glycan structure on IgG can significantly improve IgG-mediated ADCC. Addition of bisecting N-acetylglucosamine modifications to this glycan structure (Umana et al., Nat. Biotechnol. 17:176-180, 1999; Davies et al., Biotech. Bioeng. 74:288-94, 2001) or removal of fucose from this glycan structure (Shields et al., J. Biol. Chem. 277:26733-40, 2002; Shinkawa et al., J. Biol. Chem. 278:6591-604, 2003; Niwa et al., Cancer Res. 64:2127-33, 2004) are two examples of IgG Fc engineering that enhances Ig-mediated ADCC activity by improving the binding between IgG Fc and FcγR.

[0191] Systematic substitution of solvent-exposed amino acids in the human IgG1 Fc region generated IgG variants with altered FcγR binding affinity (Shields et al., J. Biol. Chem. 276:6591-604, 2001). A subset of these variants with Ala substitutions at Thr256 / Ser298, Ser298 / Glu333, Ser298 / Lys334, or Ser298 / Glu333 / Lys334 compared to the parent IgG1 show increases in both binding affinity to FcγR and ADCC activity (Shields et al., J. Biol. Chem. 276:6591-604, 2001; Okazaki et al., J. Mol. Biol. 336:1239-49, 2004).

[0192] The complement fixation activity (both C1q binding and CDC activity) of antibodies can be improved by substitutions at Lys326 and Glu333 (Idusogie et al., J. Immunol. 166:2571-2575, 2001). The same substitutions on a human IgG2 backbone can convert an antibody isotype that binds poorly to C1q and has a large loss of complement activation activity into one that can both bind C1q and mediate CDC (Idusogie et al., J. Immunol. 166:2571-75, 2001). Several other methods have also been applied to improve the complement fixation activity of antibodies. For example, grafting an 18 amino acid carboxyl-terminal tail piece of IgM onto the carboxyl terminus of IgG greatly enhances its CDC activity. This is observed even with IgG4, which normally has no detectable CDC activity (Smith et al., J. Immunol. 154:2226-36, 1995). Also, replacement of Ser444, located near the carboxy terminus of the IgG1 heavy chain, with Cys induced tail-to-tail dimerization of IgG1, which increased CDC activity 200-fold over monomeric IgG1 (Shopes et al., J. Immunol. 148:2918-22, 1992). In addition, bispecific diabody constructs with specificity for C1q also confer CDC activity (Kontermann et al., Nat. Biotech. 15:629-31, 1997).

[0193] Complement activity can be reduced by mutating at least one of amino acid residues 318, 320, and 322 of the heavy chain to a residue with a different side chain, such as Ala. Other alkyl-substituted non-ionic residues, such as Gly, Ile, Leu, or Val, or aromatic non-polar residues, such as Phe, Tyr, Trp, and Pro, in place of any one of the three residues also reduce or abolish C1q binding. Ser, Thr, Cys, and Met can be used at residues 320 and 322, but not 318, to reduce or abolish C1q binding activity. Replacement of residue 318 (Glu) by a polar residue can modify but not abolish C1q binding activity. Replacement of residue 297 (Asn) with Ala results in the elimination of lytic activity but only slightly reduces affinity for C1q (approximately 3-fold weaker). This change destroys the glycosylation site and the presence of carbohydrates required for complement activation. Any other substitution at this site also destroys the glycosylation site. The following heavy chain substitutions and any combination thereof also reduce C1q binding: D270A, K322A, P329A, and P311S (see WO 06 / 036291).

[0194] Reference to a human constant region includes constant regions with any naturally occurring allotype or any permutation of residues occupying polymorphic positions in the naturally occurring allotypes, and may have up to 1, 2, 5, or 10 mutations as set forth above relative to a native human constant region to reduce Fcγ receptor binding or increase binding to FcRN.

[0195] Nonfucosylated antibodies or antigen-binding fragments In some embodiments, any antibody or antigen-binding fragment as described herein has reduced fucosylation or is non-fucosylated and can be utilized in the provided methods. For example, in some embodiments, the antibody or antigen-binding fragment has reduced core fucosylation. "Core fucosylation" refers to the addition of fucose to N-acetylglucosamine ("GlcNAc") at the reducing end of an N-linked glycan ("fucosylation").

[0196] A "complex N-glycoside-linked glycan" is typically attached to asparagine 297 (according to Kabat numbering). As used herein, a complex N-glycoside-linked glycan is primarily of the following structure: TIFF2024534602000012.tif41156, where ± indicates that a sugar molecule may or may not be present, and the numbers indicate the position of the linkage between the sugar molecules. In the above structure, the sugar chain end that is bound to asparagine is called the reducing end (right) and the opposite end is called the non-reducing end. Fucose is usually bound to N-acetylglucosamine ("GlcNAc") at the reducing end, typically by an α1,6 bond (position 6 of GlcNAc is linked to position 1 of fucose). "Gal" refers to galactose and "Man" refers to mannose.

[0197] "Complex N-glycoside-linked glycans" include 1) complex types in which the non-reducing end of the core structure has one or more galactose-N-acetylglucosamine (also referred to as "gal-GlcNAc") branches, and the non-reducing end of Gal-GlcNAc optionally has sialic acid, bisecting N-acetylglucosamine, etc.; or 2) hybrid types in which the non-reducing end of the core structure has both high mannose N-glycoside-linked glycans and complex N-glycoside-linked glycans. In some embodiments, "complex N-glycoside-linked glycans" include complex types in which the non-reducing end of the core structure has zero, one or more galactose-N-acetylglucosamine (also referred to as "gal-GlcNAc") branches, and the non-reducing end of Gal-GlcNAc optionally further has structures such as sialic acid, bisecting N-acetylglucosamine, etc.

[0198] In certain embodiments, typically only small amounts of fucose are incorporated into the complex N-glycoside-linked glycans of the antibodies or antigen-binding fragments disclosed herein. For example, in various embodiments, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 3% of the molecules of the antibody have core fucosylation with fucose. In some embodiments, about 2% of the molecules of the antibody have core fucosylation with fucose.

[0199] In some embodiments, only a small amount of fucose analog (or metabolite or product of fucose analog) is incorporated into complex N-glycoside-linked glycans. For example, in various embodiments, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 3% of the antibodies or antigen-binding fragments have core fucosylation with fucose analog or metabolite or product of fucose analog. In some embodiments, about 2% of the antibodies or antigen-binding fragments have core fucosylation with fucose analog or metabolite or product of fucose analog.

[0200] In some of any of the embodiments disclosed herein, the antibody is a defucosylated antibody, meaning that the antibody does not contain fucose at position N297 (EU numbering), or a population of such antibodies collectively have no fucose at this position or only a very low level of fucosylation. For example, in certain embodiments, the antibody is >90%, or >95% defucosylated. In some embodiments, the antibody is at least 95-98% defucosylated, or at least 98-99% defucosylated.

[0201] A method for making non-fucosylated antibodies by incubating antibody-producing cells with a fucose analog is described, for example, in WO2009 / 135181. Briefly, cells engineered to express an antibody or an antigen-binding fragment are incubated in the presence of a fucose analog or an intracellular metabolite or product of the fucose analog. The intracellular metabolite can be, for example, a GDP-modified analog or a fully or partially deesterified analog. The product can be, for example, a fully or partially deesterified analog. In some embodiments, the fucose analog can inhibit an enzyme in the fucose salvage pathway. For example, the fucose analog (or an intracellular metabolite or product of the fucose analog) can inhibit the activity of fucokinase, or GDP-fucose-pyrophosphorylase. In some embodiments, the fucose analog (or an intracellular metabolite or product of the fucose analog) inhibits fucosyltransferase (preferably 1,6-fucosyltransferase, for example, FUT8 protein). In some embodiments, the fucose analog (or an intracellular metabolite or product of the fucose analog) can inhibit the activity of an enzyme in the de novo synthesis pathway of fucose. For example, the fucose analog (or an intracellular metabolite or product of the fucose analog) can inhibit the activity of GDP-mannose 4,6-dehydratase or / and GDP-fucose synthetase. In some embodiments, the fucose analog (or an intracellular metabolite or product of the fucose analog) can inhibit a fucose transporter (e.g., a GDP-fucose transporter).

[0202] In certain embodiments, the fucose analog is 2-flurofucose. Methods of using fucose analogs in growth media and other fucose analogs are described, for example, in WO / 2009 / 135181.

[0203] Other methods for engineering cell lines to reduce core fucosylation have included gene knockout, gene knockin and RNA interference (RNAi). In gene knockout, the gene encoding FUT8 (alpha 1,6-fucosyltransferase enzyme) is inactivated. FUT8 catalyzes the transfer of a fucosyl residue from GDP-fucose to the 6-position of the Asn-linked (N-linked) GlcNac of N-glycans. FUT8 has been reported to be the only enzyme responsible for fucose addition to N-linked biantennary carbohydrates at Asn297. Gene knockin adds genes encoding enzymes such as GNTIII or Golgi alpha mannosidase II. Increasing the levels of such enzymes in the cells diverts monoclonal antibodies from the fucosylation pathway (leading to reduced core fucosylation) and increases the amount of bisecting N-acetylglucosamine. RNAi also typically targets FUT8 gene expression, leading to reduced mRNA transcription levels or knocking out gene expression completely. Either of these methods can be used to generate cell lines that would be capable of producing nonfucosylated antibodies.

[0204] Many methods are available for determining the amount of fucosylation on an antibody, including, for example, LC-MS via PLRP-S chromatography and electrospray ionization quadrupole TOF MS.

[0205] Production of antibodies and antigen-binding fragments Antibodies and antigen-binding fragments are typically produced by recombinant expression. Recombinant polynucleotide constructs typically contain expression control sequences operably linked to the coding sequences of antibody chains, including naturally associated or heterologous promoter regions. Preferably, the expression control sequences are eukaryotic promoter systems in vectors capable of transforming or transfecting eukaryotic host cells. Once the vector is incorporated into a suitable host, the host is maintained under conditions suitable for high-level expression of the nucleotide sequence, and collection and purification of the produced antibody or antigen-binding fragment.

[0206] Mammalian cells are the preferred host for expressing nucleotide segments encoding antibodies and antigen-binding fragments. See Winnacker, From Genes to Clones, (VCH Publishers, NY, 1987). A number of suitable host cell lines capable of secreting intact heterologous proteins have been developed in the art, including CHO cell lines (e.g., DG44), various COS cell lines, HeLa cells, HEK293 cells, L cells, and non-antibody producing myelomas including Sp2 / 0 and NS0. Preferably, the cells are non-human. Expression vectors for these cells can include expression control sequences, such as origins of replication, promoters, enhancers (Queen et al., Immunol. Rev. 89:49, 1986), and necessary processing information sites such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcription terminator sequences. Preferred expression control sequences are promoters derived from endogenous genes, cytomegalovirus, SV40, adenovirus, bovine papilloma virus, etc. See Co et al., J. Immunol. 148:1149, 1992.

[0207] Once expressed, antibodies and antigen-binding fragments can be purified according to standard procedures in the art, including HPLC purification, column chromatography, gel electrophoresis, and the like (see generally, Scopes, Protein Purification (Springer-Verlag, NY, 1982)).

[0208] Nirogacestat Nirogacestat is a selective, reversible, non-competitive inhibitor of gamma-secretase. In some embodiments of any of the methods described herein, nirogacestat ((S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide) (PF-03084014) is a compound I: The compound has the structure shown in TIFF2024534602000013.tif37139 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is a hydrobromide salt (e.g., nirogacestat hydrobromide salt). In other embodiments, the pharmaceutically acceptable salt is a dihydrobromide salt (e.g., nirogacestat dihydrobromide salt). Known carriers, such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate, and glycine, can be included in the formulation for oral administration of nirogacestat together with disintegrants (e.g., starch (e.g., corn, potato, or tapioca starch)), methylcellulose, alginic acid, and certain complex silicates, granule binders (e.g., polyvinylpyrrolidone, sucrose, gelatin, and acacia), lubricants (e.g., magnesium stearate, sodium lauryl sulfate, and talc). In some embodiments, nirogacestat is combined with various sweetening and / or flavoring agents, coloring dyes.

[0209] Pharmaceutical Compositions A pharmaceutical composition used in any of the methods described herein comprises an antibody or antigen-binding fragment thereof that specifically binds to B-cell maturation antigen (BCMA) (e.g., any of the exemplary antibodies or antigen-binding fragments described herein) and / or dexamethasone. Another pharmaceutical composition used in any of the methods described herein comprises nirogacestat.

[0210] The pharmaceutical composition comprising the antibody or antigen-binding fragment and / or dexamethasone can be formulated for systemic (e.g., intravenous) administration. The pharmaceutical composition comprising nirogacestat can be formulated for oral administration.

[0211] Methods for producing pharmaceutical compositions are known in the art, see, for example, Remington: The Science and Practice of Pharmacy, 21st ed., 2005; and the books in the series Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, solutions or suspensions used for parenteral (e.g., intravenous), intradermal or subcutaneous application can contain the following components: sterile diluents, such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, or phosphates; and agents for adjusting osmolarity, such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

[0212] Pharmaceutical compositions suitable for injectable use can include sterile aqueous solutions (if water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate buffered saline (PBS). In some embodiments, the pharma-ceutically acceptable carrier is a sodium chloride solution. In all cases, the composition must be sterile. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In some embodiments, the composition can include isotonic agents, such as sugars, polyalcohols, such as mannitol, sorbitol, and sodium chloride, in the composition. Prolonged absorption of the injectable composition can be achieved by including in the composition an agent that delays absorption, such as aluminum monostearate and gelatin.

[0213] Sterile injectable solutions can be prepared by incorporating the required amount of active compound in a suitable solvent, optionally with one or combination of the above-listed components, followed by filtration sterilization.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle that contains a basic dispersion medium and other components required from above-listed.In the case of sterile powder for preparing sterile injectable solutions, the preparation method can include using vacuum drying and freeze-drying to produce powder of active ingredient plus any additional desired components from its solution that has been previously sterilized and filtered.

[0214] In some embodiments, the therapeutic compounds are prepared with carriers that protect the therapeutic compounds from rapid elimination from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using standard techniques or can be obtained commercially, for example, from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions can also be used as pharmaceutically acceptable carriers, including liposomes targeted to selected cells with monoclonal antibodies against cellular antigens. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0215] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0216] One or more doses of a pharmaceutical composition comprising nirogacestat ((S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide) (PF-03084014) can be formulated for oral administration (e.g., any of the pharma- ceutically acceptable salt forms of nirogacestat described herein or known in the art, e.g., nirogacestat hydrobromide or nirogacestat dihydrobromide). In some embodiments, one or more doses of a pharmaceutical composition comprising nirogacestat or a pharma- ceutically acceptable salt thereof are formulated as a tablet, capsule, or aqueous suspension. Non-limiting examples of carriers that may be present in pharmaceutical compositions containing nirogacestat include microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate, and glycine. Non-limiting examples of disintegrants that may be present in pharmaceutical compositions containing nirogacestat include starch (preferably corn, potato, or tapioca starch), methylcellulose, alginic acid, and certain complex silicates. Non-limiting examples of granule binders that may be present in pharmaceutical compositions containing nirogacestat include polyvinylpyrrolidone, sucrose, gelatin, and acacia. Lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often useful for tableting. Similar types of solid compositions may also be used as fillers in gelatin capsules. Preferred materials in this regard include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with diluents such as water, ethanol, glycerin, and various similar combinations thereof, along with various sweetening or flavoring agents, coloring substances or dyes, and, if desired, with emulsifying and / or suspending agents.

[0217] Treatment Method Provided herein are methods of treating a subject with multiple myeloma (MM), comprising administering to the subject one or more doses of an antibody or antigen-binding fragment thereof (e.g., any of the exemplary antibodies or antigen-binding fragments described herein) that specifically binds to B-cell maturation antigen (BCMA) and one or more doses of nirogacestat (e.g., nirogacestat dihydrobromide or nirogacestat hydrobromide).

[0218] Also provided herein is a method of treating a subject having multiple myeloma (MM), comprising administering to the subject one or more doses of an antibody or antigen-binding fragment thereof (e.g., any of the exemplary antibodies or antigen-binding fragments described herein) that specifically binds to B-cell maturation antigen (BCMA), one or more doses of nirogacestat (e.g., nirogacestat dihydrobromide, nirogacestat hydrobromide), and one or more doses of dexamethasone.

[0219] As used herein, "subject" typically refers to a human subject, e.g., a human patient, with multiple myeloma (MM). In some embodiments, the subject is identified or diagnosed as having myeloma precursor, multiple myeloma cancer producing kappa-type light chain and / or lambda-type light chain, fulminant multiple myeloma, refractory multiple myeloma, or drug-resistant multiple myeloma. In some embodiments, the subject is identified or diagnosed as having relapsed or refractory multiple myeloma (RRMM). The diagnosis of MM requiring systemic therapy is defined by the International Myeloma Working Group (IMWG) 2014 criteria (Rajkumar, et al. (2014) Lancet Oncol, 15(12):e538-48).

[0220] In some embodiments, the subject is evaluated to determine whether the subject has a small nucleotide polymorphism of FcγRII and / or FcγRIII. In some embodiments, the small nucleotide polymorphism of FcγRII and FcγRIII can be determined, for example, by testing for the polymorphism of FCGRIIIA-158V / F and / or FCGRIIA-131H / R. Thus, in some embodiments, the subject has a small nucleotide polymorphism of FcγRII and / or FcγRIII.

[0221] In some embodiments, the subject has previously been administered one or more therapeutic agents or treatments for multiple myeloma. The previously administered one or more therapeutic agents or treatments for multiple myeloma include, but are not limited to, proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and anti-CD38 antibodies. In some embodiments, the previously administered one or more (e.g., one, two or three) therapeutic agents or treatments (e.g., one or more of PIs, IMiDs and anti-CD38 antibodies) were ineffective in treating multiple myeloma in the subject. In some embodiments, the subject has previously been administered BCMA-directed myeloma therapy other than at least one of proteasome inhibitors, immunomodulatory agents and anti-CD38 antibodies, or is intolerant to any of the above. In some embodiments, the subject has previously been administered at least one BCMA-directed myeloma therapy selected from the group consisting of ADCs, CAR-T cell therapy and bispecific antibodies that target human BCMA.

[0222] In some embodiments, the subject has one or more of: a serum monoclonal paraprotein (M protein) level > 0.5 g / dL, a urinary M protein level > 200 mg / 24 hours, a serum immunoglobulin free light chain level > 10 mg / dL, and / or an abnormal serum immunoglobulin kappa to lambda free light chain ratio.

[0223] In some embodiments, cancer cells in a subject with MM exhibit detectable levels of BCMA measured either at the protein level (e.g., by immunoassay using one of the exemplified antibodies) or at the mRNA level. In some embodiments, cancer cells in a subject with MM exhibit elevated levels of BCMA compared to non-cancerous tissue of the same type (e.g., from the same or similar patient). Exemplary BCMA levels on cancer cells can be 5,000-150,000 BCMA molecules per cell. Optionally, BCMA levels in cancer cells from a subject can be measured prior to administering treatment. In some embodiments, the methods described herein can further include selecting a subject with multiple myeloma. In some embodiments, certain criteria are applied to select the subject (e.g., any of the selection criteria described herein). Such criteria include subject characteristics such as age, sex, type and stage of disease, prior treatment history, and other medical conditions. In some embodiments, the methods described herein can further include terminating treatment due to the subject's condition (e.g., using any of the termination criteria described herein).

[0224] A. Combination therapy with nirogacestat Provided herein are methods of treating a subject with multiple myeloma (MM), comprising administering to the subject one or more doses of an antibody or antigen-binding fragment thereof (e.g., any of the exemplary antibodies or antigen-binding fragments described herein) that specifically binds to B-cell maturation antigen (BCMA) and one or more doses of nirogacestat (e.g., nirogacestat dihydrobromide or nirogacestat hydrobromide).

[0225] In some embodiments, the antibody or antigen-binding fragment thereof is a non-fucosylated antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof is administered to a subject, and about or at least 95%, 97%, 98% or 99% of the antibody or antigen-binding fragment thereof in the composition is non-fucosylated. In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR1 comprising SEQ ID NO:1, a CDR2 comprising SEQ ID NO:2, and a CDR3 comprising SEQ ID NO:3, and a light chain variable domain comprising a CDR1 comprising SEQ ID NO:5, a CDR2 comprising SEQ ID NO:6, and a CDR3 comprising SEQ ID NO:7.

[0226] In some embodiments of any of the methods described herein, the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising an amino acid sequence that is at least 80% identical to SEQ ID NO:4 and a light chain variable domain comprising an amino acid sequence that is at least 80% identical to SEQ ID NO:8.

[0227] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to SEQ ID NO:4 and a light chain variable domain comprising an amino acid sequence that is at least 90% identical to SEQ ID NO:8. In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:4 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:8.

[0228] In some embodiments of any of the methods described herein, the antibody or antigen-binding fragment thereof is humanized. In some embodiments of any of the methods described herein, the antibody is an IgG1 antibody. In some embodiments of any of the methods described herein, the antibody or antigen-binding fragment thereof is not a bispecific antibody, a bispecific T cell engager (BiTE), a chimeric antigen receptor (CAR), and an antibody drug conjugate (ADC), and is not a part thereof.

[0229] General dosing of BCMA antibodies or antigen fragments and nirogacestat In some embodiments of any of the methods described herein, one or more doses of the antibody or antigen-binding fragment thereof may be administered to a subject in the form of about 100 mg of the antibody or antigen-binding fragment thereof to about 2000 mg of the antibody or antigen-binding fragment thereof (e.g., about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 100 mg to about 200 mg, about 200 mg to about 2000 mg). g, approx. 200mg ~ approx. 1800mg, approx. 200mg ~ approx. 1600mg, approx. 200mg ~ approx. 1400mg, approx. 200mg ~ approx. 1200mg, approx. 200mg ~ approx. 1000mg, approx. ~2000mg, 400mg~1800mg, 400mg~1600mg, 400mg~1400mg, 400mg~1200mg, 400mg~1000mg, 400mg~800mg, 400mg~600mg, 600mg~2000m g, approx. 600 mg ~ approx. 1800 mg, approx. 600 mg ~ approx. 1600 mg, approx. 600 mg ~ approx. 1400 mg, approx. 600 mg ~ approx. 1200 mg, approx. 600 mg ~ approx. 1000 mg, approx. mg ~ about 1600mg, about 800mg - about 1400mg, about 800mg - about 1200mg, about 800mg - about 1000mg, about 1000mg - about 2000mg, about 1000mg - about 1800mg, about 1000mg - about 1600mg, about 1000mg - about 1400mg, about 1000 mg ~ approx. 1200 mg, approx. 1200 mg ~ approx. 2000 mg, approx. 1200 mg ~ approx. 1800 mg, approx. 1200 mg ~ approx. 1600 mg, approx. 600mg to about 2000mg, about 1600mg to about 1800mg, about 1800mg to about 2000mg, about 100mg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg,about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg.

[0230] In some embodiments, one or more doses of the antibody or antigen-binding fragment are administered to a subject in the range of about 100 mg of the antibody or antigen-binding fragment to about 2,000 mg of the antibody or antigen-binding fragment (e.g., about 100 mg to about 1,950 mg, about 100 mg to about 1,900 mg, about 100 mg to about 1,850 mg, about 100 mg to about 1,800 mg, about 100 mg to about 1,750 mg, about 100 mg to about 1,700 mg, about 100 mg to about 1,650 mg, about 100 mg to about 1,600 mg, about 100 mg to about 1,550 mg, about 100 mg to about 1,500 mg, about 100 mg to about 1,500 mg, about 100 mg to about 1,650 mg, about 100 mg to about 1,600 mg, about 100 mg to about 1,5 ... mg ~ approx. 1,450 mg, approx. 100 mg ~ approx. 1,400 mg, approx. 100 mg ~ approx. 1,350 mg, approx. 100 mg ~ approx. 1,300 mg, approx. , approx. 100mg to approx. 1,050mg, approx. g ~ about 700mg, about 100mg - about 650mg, about 100mg - about 600mg, about 100mg - about 550mg, about 100mg - about 500mg, about 100mg - about 450mg, about 100mg - about 400mg, about 100mg - about 350mg, about 100mg - about 300mg, about 1 00mg to about 250mg, about 100mg to about 200mg, about 100mg to about 150mg, about 200mg to about 2,000mg, about 200mg to about 1,950mg, about 200mg to about 1,900mg, about 200mg to about 1,850mg, about 200mg to about 1,800mg, about 20 0mg to about 1,750mg, about 200mg to about 1,700mg, about 200mg to about 1,650mg, about 200mg to about 1,600mg, about 200mg to about 1,550mg, about 200mg to about 1,500mg, about 200mg to about 1,450mg, about 200mg to about 1,400m g, approx. 200mg to approx. 1,350mg, approx. 200mg to approx. 1,300mg, approx. 200mg to approx. 1,250mg, approx. 200mg to approx. 1,200mg, approx.050 mg, about 200 mg to about 1000 mg, about 200 mg to about 950 mg, about 200 mg to about 900 mg, about 200 mg to about 850 mg, about 200 mg to about 800 mg, about 200 mg to about 750 mg, about 200 mg to about 700 mg, about 200 mg to about 650 mg, about 200 mg to about 600 mg, about 200 mg to about 550 mg, about 200 mg to about 500 mg, about 200 mg to about 450 mg, about 200 mg to about 400 mg, about 200 mg to about 350 mg, about 200 mg to about 300 mg, about 200 mg to about 250 mg, about 300 mg to about 2,000 mg, about 300 mg to about 1,950 mg, about 300 mg to about 1,900 mg, about 300 mg to about 1,850 mg, about 300 mg to about 1,800 mg, about 300 mg to about 1,750 mg, about 300 mg to about 1,700 mg, about 300 mg to about 1,650 mg, about 300 mg to about 1,600 mg, about 300 mg to about 1,550 mg, about 300 mg to about 1,500 mg, about 300 mg to about 1,450 mg, about 300 mg to about 1,400 mg, about 300 mg to about 1,350 mg, about 300 mg to about 1,300 mg, about 300 mg to about 1,250 mg, about 300 mg to about 1,200 mg, about 300 mg to about 1,150 mg, about 300 mg to about 1,100 mg, about 300 mg to about 1,050 mg, about 300 mg to about 1,050 mg, about 300 mg to about 1000 mg, about 300 mg to about 950 mg, about 300 mg to about 900 mg, about 300 mg to about 850 mg, about 300 mg to about 800 mg, about 300 mg to about 750 mg, about 300 mg to about 700 mg, about 300 mg to about 650 mg, about 300 mg to about 600 mg, about 300 mg to about 550 mg, about 300 mg to about 500 mg, about 300 mg to about 450 mg, about 300 mg to about 400 mg, about 300 mg to about 350 mg, about 400 mg to about 2,000 mg, about 400 mg to about 1,950 mg, about 400 mg to about 1,900 mg, about 400 mg to about 1,850 mg, about 400 mg to about 1,800 mg, about 400 mg to about 1,750 mg, about 400 mg to about 1,700 mg, about 400 mg to about 1,650 mg, about 400 mg to about 1,600 mg, about 400 mg to about 1,550 mg, about 400 mg to about 1,500 mg, about 400 mg to about 1,450 mg, about 400 mg to about 1,400 mg, about 400 mg to about 1,350 mg, about 400 mg to about 1,300 mg, about 400 mg to about 1,250 mg, about 400 mg to about 1,200 mg, about 400 mg to about 1,150 mg, about 400 mg to about 1,100 mg, about 400 mg to about 1,050 mg, about 400 mg to about 1,000 mg, about 400 mg to about 950 mg, about 400 mg to about 900 mg, about 400 mg to about 900 mg, about 400 mg to about 850 mg, about 400 mg to about 800 mg, about 400 mg to about 750 mg, about 400 mg to about 700 mg, about 400 mg to about 650 mg, about 400 mg to about 600 mg, about 400 mg to about 550 mg, about 400 mg to about 500 mg, about 400 mg to about 450 mg, about 500 mg to about 2,000 mg, about 500 mg to about 1,950 mg, about 500 mg to about 1,900 mg, about 500 mg to about 1,850 mg, about 500 mg to about 1,800 mg, about 500 mg to about 1,750 mg, about 500 mg to about 1,700 mg, about 500 mg to about 1,650 mg, about 500 mg to about 1,600 mg, about 500 mg to about 1,550 mg, about 500 mg to about 1,500 mg, about 500 mg to about 1,450 mg, about 500 mg to about 1,400 mg, about 500 mg to about 1,350 mg, about 500 mg to about 1,300 mg, about 500 mg to about 1,250 mg, about 500 mg to about 1,200 mg, about 500 mg to about 1,150 mg, about 500 mg to about 1,100 mg, about 500 mg to about 1,050 mg, about 500 mg to about 1,000 mg, about 500 mg to about 950 mg, about 500 mg to about 900 mg, about 500 mg to about 900 mg, about 500 mg to about 850 mg, about 500 mg to about 800 mg, about 500 mg to about 750 mg, about 500 mg to about 700 mg, about 500 mg to about 650 mg, about 500 mg to about 600 mg, about 500 mg to about 550 mg, about 600 mg to about 2,000 mg, about 600 mg to about 1,950 mg, about 600 mg to about 1,900 mg, about 600 mg to about 1,850 mg, about 600 mg to about 1,800 mg, about 600 mg to about 1,750 mg, about 600 mg to about 1,700 mg, about 600 mg to about 1,650 mg, about 600 mg to about 1,600 mg, about 600 mg to about 1,550 mg, about 600 mg to about 1,500 mg, about 600 mg to about 1,450 mg, about 600 mg to about 1,400 mg, about 600 mg to about 1,350 mg, about 600 mg to about 1,300 mg, about 600 mg to about 1,250 mg, about 600 mg to about 1,200 mg, about 600 mg to about 1,150 mg, about 600 mg to about 1,100 mg, about 600 mg to about 1,050 mg, about 600 mg to about 1,000 mg, about 600 mg to about 950 mg, about 600 mg to about 900 mg, about 600 mg to about 900 mg, about 600 mg to about 850 mg, about 600 mg to about 800 mg, about 600 mg to about 750 mg, about 600 mg to about 700 mg, about 600 mg to about 650 mg, about 700 mg to about 2,000 mg, about 700 mg to about 1,950 mg, about 700 mg to about 1,900 mg, about 700 mg to about 1,850 mg, about 700 mg to about 1,800 mg, about 700 mg to about 1,750 mg, about 700 mg to about 1,700 mg, about 700 mg to about 1,650 mg, about 700 mg to about 1,600 mg, about 700 mg to about 1,550 mg, about 700 mg to about 1,500 mg, about 700 mg to about 1,450 mg, about 700 mg to about 1,400 mg, about 700 mg to about 1,350 mg, about 700 mg to about 1,300 mg, about 700 mg to about 1,250 mg, about 700 mg to about 1,200 mg, about 700 mg to about 1,150 mg, about 700 mg to about 1,100 mg, about 700 mg to about 1,050 mg, about 700 mg to about 1,000 mg, about 700 mg to about 950 mg, about 700 mg to about 900 mg, about 700 mg to about 900 mg, about 700 mg to about 850 mg, about 700 mg to about 800 mg, about 700 mg to about 750 mg, about 800 mg to about 2,000 mg, about 800 mg to about 1,950 mg, about 800 mg to about 1,900 mg, about 800 mg to about 1,850 mg, about 800 mg to about 1,800 mg, about 800 mg to about 1,750 mg, about 800 mg to about 1,700 mg, about 800 mg to about 1,650 mg, about 800 mg to about 1,600 mg, about 800 mg to about 1,550 mg, about 800 mg to about 1,500 mg, about 800 mg to about 1,450 mg, about 800 mg to about 1,400 mg, about 800 mg to about 1,350 mg, about 800 mg to about 1,300 mg, about 800 mg to about 1,250 mg, about 800 mg to about 1,200 mg, about 800 mg to about 1,150 mg, about 800 mg to about 1,100 mg, about 800 mg to about 1,050 mg, about 800 mg to about 1,000mg, about 800mg to about 950mg, about 800mg to about 900mg, about 800mg to about 900mg, about 800mg to about 850mg, about 900mg to about 2,000mg, about 900mg to about 1,950mg, about 900mg to about 1,900mg, about 900mg to about 1,850mg, about 900mg to about 1,800mg, about 900mg to about 1,750mg, about 900mg to about 1,700mg, about 900mg to about 1,650mg, about 900mg to about 1,600mg, about 900mg to about 1,550mg, about 900mg to about 1,500mg, about 900mg to about 1,45 0 mg, about 900 mg to about 1,400 mg, about 900 mg to about 1,350 mg, about 900 mg to about 1,300 mg, about 900 mg to about 1,250 mg, about 900 mg to about 1,200 mg, about 900 mg to about 1,150 mg, about 900 mg to about 1,100 mg, about 900 mg to about 1,050 mg, about 900 mg to about 1,000 mg, about 900 mg to about 950 mg, about 1,000 mg to about 2,000 mg, about 1,000 mg to about 1,950 mg, about 1,000 mg to about 1,900 mg, about 1,000 mg to about 1,850 mg, about 1,000 mg to about 1,800 mg g, approx. 1,000mg ~ approx. 1,750mg, approx. 1,000mg ~ approx. 1,700mg, approx. 1,000mg ~ approx. 1,650mg, approx. 1,000mg ~ approx. 1,600mg, approx. mg, approx. 1,000mg to approx. 1,400mg, approx. 1,000mg to approx. 1,350mg, approx. 1,000mg to approx. 1,300mg, approx. 1,000mg to approx. 1,250mg, approx. 1,000mg to approx. 0mg, about 1,000mg to about 1,050mg, about 1,100mg to about 2,000mg, about 1,100mg to about 1,950mg, about 1,100mg to about 1,900mg, about 1,100mg to about 1,850mg, about 1,100mg to about 1,800mg, about 1,100mg to about 1,7 50mg, about 1,100mg to about 1,700mg, about 1,100mg to about 1,650mg, about 1,100mg to about 1,600mg, about 1,100mg to about 1,550mg, about 1,100mg to about 1,500mg, about 1,100mg to about 1,450mg, about 1,100mg to about 1,400 mg, about 1,100 mg to about 1,350 mg, about 1,100 mg to about 1,300 mg, about 1,100 mg to about 1,250 mg, about 1,100 mg to about 1,200 mg, about 1,100 mg to about 1,150 mg, about 1,200 mg to about 2,000 mg, about 1,200 mg to about 1,950 mg, about 1,200 mg to about 1,900 mg, about 1,200 mg to about 1,850 mg, about 1,200 mg to about 1,800 mg, about 1,200 mg to about 1,750 mg, about 1,200 mg to about 1,700 mg, about 1,200 mg to about 1,650 mg, about 1,200 mg to about 1,600 mg, about 1,200 mg to about 1,550 mg, about 1,200 mg to about 1,500 mg, about 1,200 mg to about 1,450 mg, about 1,200 mg to about 1,400 mg, about 1,200 mg to about 1,350 mg, about 1,200 mg to about 1,300 mg, about 1,200 mg to about 1,250 mg, about 1,300 mg to about 2,000 mg, about 1,300 mg to about 1,950 mg, about 1,300 mg to about 1,900 mg, about 1,300 mg to about 1,850 mg, about 1,300 mg to about 1,800 mg, about 1,300 mg to about 1,750 mg, about 1,300 mg to about 1,700 mg, about 1,300 mg to about 1,650 mg, about 1,300 mg to about 1,600 mg, about 1,300 mg to about 1,550 mg, about 1,300 mg to about 1,500 mg, about 1,300 mg to about 1,450 mg, about 1,300 mg to about 1,400 mg, about 1,300 mg to about 1,350 mg, about 1,400 mg to about 2,000 mg, about 1,400 mg to about 1,950 mg, about 1,400 mg to about 1,900 mg, about 1,400 mg to about 1,850 mg, about 1,400 mg to about 1,800 mg, about 1,400 mg to about 1,750 mg, about 1,400 mg to about 1,700 mg, about 1,400 mg to about 1,650 mg, about 1,400 mg to about 1,600 mg, about 1,400 mg to about 1,550 mg, about 1,400 mg to about 1,500 mg, about 1,400 mg to about 1,450 mg, about 1,500 mg to about 2,000 mg, about 1,500 mg to about 1,950 mg, about 1,500 mg to about 1,900 mg, about 1,500 mg to about 1,850 mg, about 1,500 mg to about 1,800 mg, about 1,500 mg to about 1,750 mg, about 1,500 mg to about 1,700 mg, about 1,500 mg to about 1,650 mg, about 1,500mg to about 1,600mg, about 1,500mg to about 1,550mg, about 1,600mg to about 2,000mg, about 1,600mg to about 1,950mg, about 1,600mg to about 1,900mg, about 1,600mg to about 1,85 0mg, about 1,600mg to about 1,800mg, about 1,600mg to about 1,750mg, about 1,600mg to about 1,700mg, about 1,600mg to about 1,650mg, about 1,700mg to about 2,000mg, about 1,700mg about 1,700 mg to about 1,900 mg, about 1,700 mg to about 1,850 mg, about 1,700 mg to about 1,800 mg, about 1,700 mg to about 1,750 mg, about 1,800 mg to about 2,000 mg, about 1,800 mg to about 1,950 mg, about 1,800 mg to about 1,900 mg, about 1,800 mg to about 1,850 mg, about 1,900 mg to about 2,000 mg, or about 1,900 mg to about 1,950 mg.

[0231] In some embodiments, one or more doses of nirogacestat (e.g., nirogacestat dihydrobromide or nirogacestat hydrobromide) are independently administered to the subject at about 80 mg to about 120 mg of nirogacestat (e.g., nirogacestat dihydrobromide or nirogacestat hydrobromide) (e.g., about 80 mg to about 100 mg, about 80 mg to about 90 mg, about 90 mg to about 120 mg, about 90 mg to about 100 mg, about 100 mg to about 120 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg). In some embodiments, one or more doses of nirogacestat (e.g., nirogacestat dihydrobromide or nirogacestat hydrobromide) are independently administered to a subject at about 100 mg of nirogacestat (e.g., nirogacestat dihydrobromide or nirogacestat hydrobromide). In some embodiments, two or more doses of about 100 mg of nirogacestat (e.g., nirogacestat dihydrobromide or nirogacestat hydrobromide) are independently administered (e.g., orally administered) to a subject twice daily.

[0232] Induction and maintenance dosing of BCMA antibodies and antigen-binding fragments thereof and nirogacestat In some embodiments, the methods described herein include administering to the subject one or more induction doses of an antibody or antigen-binding fragment described herein. In some embodiments, the methods described herein further include administering to the subject one or more maintenance doses of an antibody or antigen-binding fragment described herein.

[0233] In some embodiments, the one or more induction doses are independently administered to the subject at about 100, 200, 400, 800, or 1600 mg of antibody or antigen-binding fragment, and each dose of nirogacestat is administered to the subject at about 100 mg of nirogacestat. In some embodiments, the one or more induction doses are 800 mg of antibody or antigen-binding fragment, and each dose of nirogacestat is administered to the subject at about 100 mg of nirogacestat. In further embodiments, the one or more induction doses are 1600 mg of antibody or antigen-binding fragment, and each dose of nirogacestat is administered to the subject at about 100 mg of nirogacestat.

[0234] In some embodiments of any of the methods described herein, two or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject at a frequency ranging from about once per week to about once every four weeks. In some embodiments, two or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject at a frequency ranging from about once per week to about once per week. In some embodiments, two or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject at a frequency of about once per two weeks, about once per three weeks, or about once per four weeks.

[0235] In some embodiments, each dose of the antibody or antigen-binding fragment thereof comprises about 100 mg, about 200 mg, about 400 mg, about 800 mg, or about 1600 mg of the antibody or antigen-binding fragment thereof, and is independently administered to a subject about once per week or about once every two weeks.

[0236] In some embodiments of any of the methods described herein, individual doses of the antibody or antigen-binding fragment thereof are administered independently to the subject on days 1 and 15 of a 28-day cycle. In some embodiments of any of the methods described herein, individual doses of the antibody or antigen-binding fragment thereof are administered independently to the subject on days 1, 8, 15, and 22 of a 28-day cycle. In some embodiments of any of the methods described herein, individual doses of the antibody or antigen-binding fragment thereof are administered independently to the subject in multiple 28-day cycles.

[0237] In some embodiments, the two or more doses of the antibody or antigen-binding fragment thereof include (1) one or more induction doses administered independently to the subject during an induction phase, and (2) one or more maintenance doses of the antibody or antigen-binding fragment thereof administered independently to the subject during a maintenance phase following the induction phase. In some embodiments, a single induction dose is administered to the subject. In some embodiments, two or more induction doses are administered independently to the subject. In some embodiments, each of the two or more induction doses is independently administered to the subject about once per week for about 1-10 weeks. In some embodiments, each of the two or more induction doses is independently administered to the subject about once per week for 8 weeks. In some embodiments, the induction doses are independently administered to the subject four times within one 28-day cycle.

[0238] In some embodiments, the induction dose is administered to the subject eight independent times within two 28-day cycles. In some embodiments, a separate induction dose is administered to the subject independently on days 1, 8, 15, and 22 of each of the two 28-day cycles. In some embodiments of any of the methods described herein, each induction dose comprises about 100, about 200, about 400, about 800, or about 1600 mg of the antibody or antigen-binding fragment thereof.

[0239] In some embodiments of any of the methods described herein, each induction dose comprises about 100, about 200, about 400, about 800, or about 1600 mg of the antibody or antigen-binding fragment thereof; each maintenance dose comprises about 100, about 200, about 400, about 800, or about 1600 mg of the antibody or antigen-binding fragment thereof; a separate induction dose is administered independently to the subject on each of days 1, 8, 15, and 22 for each of two 28-day cycles for a total of eight induction doses during the induction phase; and a separate maintenance dose is administered independently to the subject on each of days 1 and 15 of each of one or more subsequent 28-day cycles.

[0240] In some embodiments of any of the methods described herein, a dose of the antibody or antigen-binding fragment thereof is administered intravenously to the subject. In some embodiments of any of the methods described herein, a single dose of nirogacestat is administered to the subject. In some embodiments of any of the methods described herein, two or more doses of nirogacestat are administered independently to the subject. In some embodiments of any of the methods described herein, each dose of nirogacestat comprises about 100 mg of nirogacestat. In some embodiments of any of the methods described herein, two or more doses of nirogacestat are administered independently to the subject at a frequency of about once a day to about four times a day. In some embodiments of any of the methods described herein, two or more doses of nirogacestat are administered independently to the subject at a frequency of about twice a day. In some embodiments, each dose of nirogacestat comprises about 100 mg of nirogacestat, and two or more doses of nirogacestat are independently administered to a subject about twice a day on each day of a 28-day cycle. In some embodiments of any of the methods described herein, the doses of nirogacestat are orally administered to the subject.

[0241] B. Combination therapy with nirogacestat and dexamethasone Also provided herein is a method of treating a subject having multiple myeloma (MM), comprising administering to the subject one or more doses of an antibody or antigen-binding fragment thereof (e.g., any of the exemplary antibodies or antigen-binding fragments described herein) that specifically binds to B-cell maturation antigen (BCMA), one or more doses of nirogacestat (e.g., nirogacestat dihydrobromide, nirogacestat hydrobromide), and one or more doses of dexamethasone.

[0242] General dosing of BCMA antibody or antigen fragment thereof, nirogacestat and dexamethasone In some embodiments, one or more doses may be administered to a subject in the form of about 100 mg of the antibody or antigen-binding fragment to about 2,000 mg of the antibody or antigen-binding fragment (e.g., about 100 mg to about 2,000 mg, about 100 mg to about 1,950 mg, about 100 mg to about 1,900 mg, about 100 mg to about 1,850 mg, about 100 mg to about 1,800 mg, about 100 mg to about 1,750 mg, about 100 mg to about 1,700 mg, about 100 mg to about 1,650 mg, about 100 mg to about 1,600 mg, about 100 mg to about 1,550 mg, about 100 mg to about 1,500 mg, or about 1,500 mg). mg, approx. 100mg to approx. 1,450mg, approx. 100mg to approx. 1,400mg, approx. 100mg to approx. 1,350mg, approx. 100mg to approx. 1,300mg, approx. Approximately 1,100mg, approximately 100mg to approximately 1,050mg, approximately 100mg to approximately 1,000mg, approximately 100mg to approximately 950mg, approximately 100mg to approximately 900mg, approximately 100mg to approximately 850mg, approximately 100mg to approximately 800mg, approximately 100mg to approximately 750mg, approximately 100mg to approximately 700 mg, approx. 100mg to approx. 650mg, approx. 100mg to approx. 600mg, approx. 100mg to approx. 550mg, approx. 100mg to approx. 500mg, approx. 100mg to approx. 450mg, approx. ~250mg, 100mg~200mg, 100mg~150mg, 200mg~2,000mg, 200mg~1,950mg, 200mg~1,900mg, 200mg~1,850mg, 200mg~1,800mg, 200mg ~1,750mg, 200mg~1,700mg, 200mg~1,650mg, 200mg~1,600mg, 200mg~1,550mg, 200mg~1,500mg, 200mg~1,450mg, 200mg~1,400mg, Approx. 200mg to approx. 1,350mg, approx. 200mg to approx. 1,300mg, approx. 200mg to approx. 1,250mg, approx. 200mg to approx. 1,200mg, approx.000 mg, about 200 mg to about 950 mg, about 200 mg to about 900 mg, about 200 mg to about 850 mg, about 200 mg to about 800 mg, about 200 mg to about 750 mg, about 200 mg to about 700 mg, about 200 mg to about 650 mg, about 200 mg to about 600 mg, about 200 mg to about 550 mg, about 200 mg to about 500 mg, about 200 mg to about 450 mg, about 200 mg to about 400 mg, about 200 mg to about 350 mg, about 200 mg to about 300 mg, about 200 mg to about 250 mg, about 300 mg to about 2,000 mg, about 300 mg to about 1,950 mg, about 300 mg to about 1,900 mg, about 300 mg to about 1,850 mg, about 300 mg to about 1,800 mg, about 300 mg to about 1,750 mg, about 300 mg to about 1,700 mg, about 300 mg to about 1,650 mg, about 300 mg to about 1,600 mg, about 300 mg to about 1,550 mg, about 300 mg to about 1,500 mg, about 300 mg to about 1,450 mg, about 300 mg to about 1,400 mg, about 300 mg to about 1,350 mg, about 300 mg to about 1,300 mg, about 300 mg to about 1,250 mg, about 300 mg to about 1,200 mg, about 300 mg to about 1,150 mg, about 300 mg to about 1,100 mg, about 300 mg to about 1,050 mg, about 300 mg to about 1,000 mg, about 300 mg to about 950 mg, about 300 mg to about 900 mg, about 300 mg to about 850 mg, about 300 mg to about 800 mg, about 300 mg to about 750 mg, about 300 mg to about 700 mg, about 300 mg to about 650 mg, about 300 mg to about 600 mg, about 300 mg to about 550 mg, about 300 mg to about 500 mg, about 300 mg to about 450 mg, about 300 mg to about 400 mg, about 300 mg to about 350 mg, about 400 mg to about 2,000 mg, about 400 mg to about 1,950 mg, about 400 mg to about 1,900 mg, about 400 mg to about 1,850 mg, about 400 mg to about 1,800 mg, about 400 mg to about 1,750 mg, about 400 mg to about 1,700 mg, about 400 mg to about 1,650 mg, about 400 mg to about 1,600 mg, about 400 mg to about 1,550 mg, about 400 mg to about 1,500 mg, about 400 mg to about 1,450 mg, about 400 mg to about 1,400 mg, about 400 mg to about 1,350 mg, about 400 mg to about 1,300 mg, about 400 mg to about 1,250 mg, about 400 mg to about 1,200 mg, about 400 mg to about 1,150 mg, about 400 mg to about 1,100 mg, about 400 mg to about 1,050 mg, about 400 mg to about 1,000 mg, about 400 mg to about 950 mg, about 400 mg to about 900 mg, about 400 mg to about 900 mg, about 400 mg to about 850 mg, about 400 mg to about 800 mg, about 400 mg to about 750 mg, about 400 mg to about 700 mg, about 400 mg to about 650 mg, about 400 mg to about 600 mg, about 400 mg to about 550 mg, about 400 mg to about 500 mg, about 400 mg to about 450 mg, about 500 mg to about 2,000 mg, about 500 mg to about 1,950 mg, about 500 mg to about 1,900 mg, about 500 mg to about 1,850 mg, about 500 mg to about 1,800 mg, about 500 mg to about 1,750 mg, about 500 mg to about 1,700 mg, about 500 mg to about 1,650 mg, about 500 mg to about 1,600 mg, about 500 mg to about 1,550 mg, about 500 mg to about 1,500 mg, about 500 mg to about 1,450 mg, about 500 mg to about 1,400 mg, about 500 mg to about 1,350 mg, about 500 mg to about 1,300 mg, about 500 mg to about 1,250 mg, about 500 mg to about 1,200 mg, about 500 mg to about 1,150 mg, about 500 mg to about 1,100 mg, about 500 mg to about 1,050 mg, about 500 mg to about 1,000 mg, about 500 mg to about 950 mg, about 500 mg to about 900 mg, about 500 mg to about 900 mg, about 500 mg to about 850 mg, about 500 mg to about 800 mg, about 500 mg to about 750 mg, about 500 mg to about 700 mg, about 500 mg to about 650 mg, about 500 mg to about 600 mg, about 500 mg to about 550 mg, about 600 mg to about 2,000 mg, about 600 mg to about 1,950 mg, about 600 mg to about 1,900 mg, about 600 mg to about 1,850 mg, about 600 mg to about 1,800 mg, about 600 mg to about 1,750 mg, about 600 mg to about 1,700 mg, about 600 mg to about 1,650 mg, about 600 mg to about 1,600 mg, about 600 mg to about 1,550 mg, about 600 mg to about 1,500 mg, about 600 mg to about 1,450 mg, about 600 mg to about 1,400 mg, about 600 mg to about 1,350 mg, about 600 mg to about 1,300 mg, about 600 mg to about 1,250 mg, about 600 mg to about 1,200 mg, about 600 mg to about 1,150 mg, about 600 mg to about 1,100 mg, about 600 mg to about 1,050 mg, about 600 mg to about 1,000 mg, about 600 mg to about 950 mg, about 600 mg to about 900 mg, about 600 mg to about 900 mg, about 600 mg to about 850 mg, about 600 mg to about 800 mg, about 600 mg to about 750 mg, about 600 mg to about 700 mg, about 600 mg to about 650 mg, about 700 mg to about 2,000 mg, about 700 mg to about 1,950 mg, about 700 mg to about 1,900 mg, about 700 mg to about 1,850 mg, about 700 mg to about 1,800 mg, about 700 mg to about 1,750 mg, about 700 mg to about 1,700 mg, about 700 mg to about 1,650 mg, about 700 mg to about 1,600 mg, about 700 mg to about 1,550 mg, about 700 mg to about 1,500 mg, about 700 mg to about 1,450 mg, about 700 mg to about 1,400 mg, about 700 mg to about 1,350 mg, about 700 mg to about 1,300 mg, about 700 mg to about 1,250 mg, about 700 mg to about 1,200 mg, about 700 mg to about 1,150 mg, about 700 mg to about 1,100 mg, about 700 mg to about 1,050 mg, about 700 mg to about 1,000 mg, about 700 mg to about 950 mg, about 700 mg to about 900 mg, about 700 mg to about 900 mg, about 700 mg to about 850 mg, about 700 mg to about 800 mg, about 700 mg to about 750 mg, about 800 mg to about 2,000 mg, about 800 mg to about 1,950 mg, about 800 mg to about 1,900 mg, about 800 mg to about 1,850 mg, about 800 mg to about 1,800 mg, about 800 mg to about 1,750 mg, about 800 mg to about 1,700 mg, about 800 mg to about 1,650 mg, about 800 mg to about 1,600 mg, about 800 mg to about 1,550 mg, about 800 mg to about 1,500 mg, about 800 mg to about 1,450 mg, about 800 mg to about 1,400 mg, about 800 mg to about 1,350 mg, about 800 mg to about 1,300 mg, about 800 mg to about 1,250 mg, about 800 mg to about 1,200 mg, about 800 mg to about 1,150 mg, about 800 mg to about 1,100 mg, about 800 mg to about 1,050 mg, about 800 mg to about 1,000 mg, about 800 mg to about 950 mg, about 800 mg to about 900 mg, about 800 mg to about 900 mg, about 800 mg to about 850 mg, about 900 mg to about 2,000mg, about 900mg to about 1,950mg, about 900mg to about 1,900mg, about 900mg to about 1,850mg, about 900mg to about 1,800mg, about 900mg to about 1,750mg, about 900mg to about 1,700mg, about 900mg to about 1,650mg, about 900mg to about 1,600mg, about 900mg to about 1,550mg, about 900mg to about 1,500mg, about 900mg to about 1,450mg, about 900mg to about 1,400mg, about 900mg to about 1,350mg, about 900mg to about 1,300mg, about 900mg to about 1,250mg, about 900 mg~1,200mg, 900mg~1,150mg, 900mg~1,100mg, 900mg~1,050mg, 900mg~1,000mg, 900mg~950mg, 1,000mg~2,000mg, 1,000mg~1,950mg , about 1,000mg to about 1,900mg, about 1,000mg to about 1,850mg, about 1,000mg to about 1,800mg, about 1,000mg to about 1,750mg, about 1,000mg to about 1,700mg, about 1,000mg to about 1,650mg, about 1,000mg to about 1,600m g, approx. 1,000mg to approx. 1,550mg, approx. 1,000mg to approx. 1,500mg, approx. 1,000mg to approx. 1,450mg, approx. 1,000mg to approx. 1,400mg, approx. mg, about 1,000mg to about 1,200mg, about 1,000mg to about 1,150mg, about 1,000mg to about 1,100mg, about 1,000mg to about 1,050mg, about 1,100mg to about 2,000mg, about 1,100mg to about 1,950mg, about 1,100mg to about 1,90 0mg, about 1,100mg to about 1,850mg, about 1,100mg to about 1,800mg, about 1,100mg to about 1,750mg, about 1,100mg to about 1,700mg, about 1,100mg to about 1,650mg, about 1,100mg to about 1,600mg, about 1,100mg to about 1,5 50mg, about 1,100mg to about 1,500mg, about 1,100mg to about 1,450mg, about 1,100mg to about 1,400mg, about 1,100mg to about 1,350mg, about 1,100mg to about 1,300mg, about 1,100mg to about 1,250mg, about 1,100mg to about 1,200 mg, about 1,100 mg to about 1,150 mg, about 1,200 mg to about 2,000 mg, about 1,200 mg to about 1,950 mg, about 1,200 mg to about 1,900 mg, about 1,200 mg to about 1,850 mg, about 1,200 mg to about 1,800 mg, about 1,200 mg to about 1,750 mg, about 1,200 mg to about 1,700 mg, about 1,200 mg to about 1,650 mg, about 1,200 mg to about 1,600 mg, about 1,200 mg to about 1,550 mg, about 1,200 mg to about 1,500 mg, about 1,200 mg to about 1,450 mg, about 1,200 mg to about 1,400 mg, about 1,200 mg to about 1,350 mg, about 1,200 mg to about 1,300 mg, about 1,200 mg to about 1,250 mg, about 1,300 mg to about 2,000 mg, about 1,300 mg to about 1,950 mg, about 1,300 mg to about 1,900 mg, about 1,300 mg to about 1,850 mg, about 1,300 mg to about 1,800 mg, about 1,300 mg to about 1,750 mg, about 1,300 mg to about 1,700 mg, about 1,300 mg to about 1,650 mg, about 1,300 mg to about 1,600 mg, about 1,300 mg to about 1,550 mg, about 1,300 mg to about 1,500 mg, about 1,300 mg to about 1,450 mg, about 1,300 mg to about 1,400 mg, about 1,300 mg to about 1,350 mg, about 1,400 mg to about 2,000 mg, about 1,400 mg to about 1,950 mg, about 1,400 mg to about 1,900 mg, about 1,400 mg to about 1,850 mg, about 1,400 mg to about 1,800 mg, about 1,400 mg to about 1,750 mg, about 1,400 mg to about 1,700 mg, about 1,400 mg to about 1,650 mg, about 1,400 mg to about 1,600 mg, about 1,400 mg to about 1,550 mg, about 1,400 mg to about 1,500 mg, about 1,400 mg to about 1,450 mg, about 1,500 mg to about 2,000 mg, about 1,500 mg to about 1,950 mg, about 1,500 mg to about 1,900 mg, about 1,500 mg to about 1,850 mg, about 1,500 mg to about 1,800 mg, about 1,500 mg to about 1,750 mg, about 1,500 mg to about 1,700 mg, about 1,500 mg to about 1,650 mg, about 1,500 mg to about 1,600 mg, about 1,500 mg to about 1,550 mg, about 1,600 mg to about 2,000 mg, about 1,600 mg to about 1,950 mg, about 1,600mg to about 1,900mg, about 1,600mg to about 1,850mg, about 1,600mg to about 1,800mg, about 1,600mg to about 1,750mg, about 1,600mg to about 1,70 0mg, about 1,600mg to about 1,650mg, about 1,700mg to about 2,000mg, about 1,700mg to about 1,950mg, about 1,700mg to about 1,900mg, about 1,700mg about 1,850 mg, about 1,700 mg to about 1,800 mg, about 1,700 mg to about 1,750 mg, about 1,800 mg to about 2,000 mg, about 1,800 mg to about 1,950 mg, about 1,800 mg to about 1,900 mg, about 1,800 mg to about 1,850 mg, about 1,900 mg to about 2,000 mg, or about 1,900 mg to about 1,950 mg.

[0243] In some embodiments, one or more doses of nirogacestat (e.g., nirogacestat dihydrobromide or nirogacestat hydrobromide) are independently administered to the subject at about 80 mg to about 120 mg (e.g., about 80 mg to about 100 mg, about 80 mg to about 90 mg, about 90 mg to about 120 mg, about 90 mg to about 100 mg, about 100 mg to about 120 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg) of nirogacestat. In some embodiments, one or more doses of nirogacestat (e.g., nirogacestat dihydrobromide or nirogacestat hydrobromide) are independently administered to the subject at about 100 mg of nirogacestat (e.g., nirogacestat dihydrobromide or nirogacestat hydrobromide). In some embodiments, two or more doses of about 100 mg of nirogacestat (e.g., nirogacestat dihydrobromide or nirogacestat hydrobromide) are independently administered (e.g., orally administered) to a subject twice daily.

[0244] In some embodiments, one or more doses of dexamethasone are administered to a subject in the range of about 5 mg to about 200 mg (e.g., about 5 mg to about 150 mg, about 5 mg to about 100 mg, about 5 mg to about 90 mg, about 5 mg to about 80 mg, about 5 mg to about 70 mg, about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg to about 40 mg, about 5 mg to about 30 mg, about 5 mg to about 20 mg, about 10 mg to about 200 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 10 mg to about 90 mg, about 10 mg to about 80mg, about 10mg to about 70mg, about 10mg to about 60mg, about 10mg to about 50mg, about 10mg to about 40mg, about 10mg to about 30mg, about 10mg to about 20mg, about 20mg to about 200mg, about 20mg to about 150mg, about 20mg to about 100mg, about 20mg to about 90mg, about 20mg to about 80mg, about 20mg to about 70mg, about 20mg to about 60mg, about 20mg to about 50mg, about 20mg to about 40mg, about 20mg to about 30mg, about 30mg to about 200mg, about 30mg to about 1 50mg, about 30mg to about 100mg, about 30mg to about 90mg, about 30mg to about 80mg, about 30mg to about 70mg, about 30mg to about 60mg, about 30mg to about 50mg, about 30mg to about 40mg, about 40mg to about 200mg, about 40mg to about 150mg, about 40mg to about 100mg, about 40mg to about 80mg, about 40mg to about 60mg, about 40mg to about 50mg, about 50mg to about 200mg, about 50mg to about 150mg, about 50mg to about 100mg, about 50mg to about 90mg, about 50m and the like.

[0245] Induction and maintenance dosing of BCMA antibodies and antigen-binding fragments thereof, nirogacestat and dexamethasone In some embodiments, each of the two or more doses of the antibody or antigen-binding fragment thereof is independently administered to the subject about once every 1-4 weeks; each dose of nirogacestat is independently administered to the subject once per day to about 4 times per day; and each dose of dexamethasone is independently administered to the subject about once every 1-4 weeks.

[0246] In some embodiments, each dose of the antibody or antigen-binding fragment thereof is independently administered to the subject about once every two weeks; each dose of nirogacestat is independently administered to the subject twice daily; and each dose of dexamethasone is independently administered to the subject about once a week.

[0247] In some embodiments, each dose of the antibody or antigen-binding fragment thereof is administered independently to the subject on each of days 1 and 15 of one or more 28 day cycles; each dose of nirogacestat is administered independently to the subject on each of days 1-28 of one or more 28 day cycles; and each dose of dexamethasone is administered independently to the subject on each of days 1, 8, 15, and 22 of one or more 28 day cycles.

[0248] In some embodiments, each dose of the antibody or antigen-binding fragment comprises about 400-1600 mg (or any of the subranges of this range described herein) of the antibody or antigen-binding fragment, each dose of nirogacestat comprises about 100 mg of nirogacestat, and each dose of dexamethasone comprises about 40 mg of dexamethasone.

[0249] In some embodiments, each dose of the antibody or antigen-binding fragment comprises about 400 mg of the antibody or antigen-binding fragment, each dose of nirogacestat comprises about 100 mg of nirogacestat, and each dose of dexamethasone comprises about 40 mg of dexamethasone.

[0250] In some embodiments, each dose of the antibody or antigen-binding fragment comprises about 800 mg of the antibody or antigen-binding fragment, each dose of nirogacestat comprises about 100 mg of nirogacestat, and each dose of dexamethasone comprises about 40 mg of dexamethasone.

[0251] In some embodiments, each dose of the antibody or antigen-binding fragment comprises about 1600 mg of the antibody or antigen-binding fragment, each dose of nirogacestat comprises about 100 mg of nirogacestat, and each dose of dexamethasone comprises about 40 mg of dexamethasone.

[0252] In some embodiments, two or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject about once per week during the induction phase, and two or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject about once every two weeks during the subsequent maintenance phase; two or more doses of nirogacestat are independently administered to the subject about twice per day during one or both of the induction and maintenance phases; and two or more doses of dexamethasone are independently administered to the subject about once per week during one or both of the induction and maintenance phases. In some embodiments, the induction phase is about 8 weeks.

[0253] In some embodiments, two or more doses of the antibody or antigen-binding fragment thereof are administered to the subject independently on days 1, 8, 15, and 22 of each of two 28-day cycles of the induction phase, followed by days 1 and 15 of each of a subsequent 28-day cycle of the maintenance phase; two or more doses of nirogacestat are administered to the subject independently on days 1-28 of each of two 28-day cycles of the induction phase and each of a subsequent 28-day cycle of the maintenance phase; and two or more doses of dexamethasone are administered to the subject independently on days 1, 8, 15, and 22 of each of two 28-day cycles of the induction phase and each of a subsequent 28-day cycle of the maintenance phase.

[0254] In some embodiments, the two or more doses of an antibody or antigen-binding fragment administered independently to a subject on days 1, 8, 15, and 22 of each of two 28-day cycles of the induction phase comprise about 100 mg, about 200 mg, about 400 mg, about 800 mg, or about 1600 mg of an antibody or antigen-binding fragment thereof; and the two or more doses of an antigen or antigen-binding fragment administered independently to a subject on days 1 and 15 of each of two 28-day cycles of the subsequent maintenance phase comprise about 100, about 200, about 400, about 800, or about 1600 mg of an antibody or antigen-binding fragment thereof. 600 mg; the two or more doses of nirogacestat administered independently to the subject on days 1 through 28 of each of two 28 day cycles of the induction phase and each subsequent 28 day cycle of the maintenance phase comprise from about 80 mg to about 120 mg of nirogacestat; and the two or more doses of dexamethasone administered independently to the subject on days 1, 8, 15, and 22 of each of two 28 day cycles of the induction phase and each subsequent 28 day cycle of the maintenance phase comprise from about 20 mg to about 60 mg of dexamethasone.

[0255] In some embodiments, the two or more doses of the antibody or antigen-binding fragment thereof administered independently to the subject on days 1, 8, 15, and 22 of each of two 28-day cycles of the induction phase comprise about 800 mg of the antibody or antigen-binding fragment thereof.

[0256] In some embodiments, the two or more doses of the antibody or antigen-binding fragment thereof administered independently to the subject on days 1, 8, 15, and 22 of each of two 28-day cycles of the induction phase comprise about 1,600 mg of the antibody or antigen-binding fragment thereof.

[0257] In some embodiments of any of the methods described herein, the two or more doses of nirogacestat administered independently to the subject on each of days 1 through 28 of each of two 28 day cycles of the induction phase and each subsequent 28 day cycle of the maintenance phase comprise about 100 mg of nirogacestat.

[0258] In some embodiments of any of the methods described herein, the two or more doses of dexamethasone administered independently to the subject on each of days 1, 8, 15, and 22 of each of two 28-day cycles of the induction phase and each subsequent 28-day cycle of the maintenance phase comprise about 20 mg of dexamethasone.

[0259] In some embodiments of any of the methods described herein, the two or more doses of dexamethasone administered independently to the subject on each of days 1, 8, 15, and 22 of each of two 28-day cycles of the induction phase and each subsequent 28-day cycle of the maintenance phase comprise about 40 mg of dexamethasone.

[0260] In some embodiments, the two or more doses of the antibody or antigen-binding fragment independently administered to the subject on each of days 1, 8, 15, and 22 of each of two 28 day cycles of the induction phase comprise about 1600 mg of the antibody or antigen-binding fragment; the two or more doses of the antibody or antigen-binding fragment independently administered to the subject on each of days 1 and 15 of each of the subsequent 28 day cycles of the maintenance phase comprise about 1600 mg; the two or more doses of nirogacestat independently administered to the subject on each of days 1-28 of each of the 28 day cycles of the induction phase and each of the subsequent 28 day cycles of the maintenance phase comprise about 100 mg of nirogacestat; and the two or more doses of dexamethasone independently administered to the subject on each of days 1, 8, 15, and 22 of each of the two 28 day cycles of the induction phase and each of the subsequent 28 day cycles of the maintenance phase comprise about 40 mg of dexamethasone.

[0261] In some embodiments of any of the methods described herein, the two or more doses of the antibody or antigen-binding fragment independently administered to the subject on each of days 1, 8, 15, and 22 of each of two 28 day cycles of the induction phase comprise about 800 mg of the antibody or antigen-binding fragment; the two or more doses of the antibody or antigen-binding fragment independently administered to the subject on each of days 1 and 15 of each of the subsequent 28 day cycles of the maintenance phase comprise about 800 mg; the two or more doses of nirogacestat independently administered to the subject on each of days 1-28 of each of the 28 day cycles of the induction phase and each of the subsequent 28 day cycles of the maintenance phase comprise about 100 mg of nirogacestat; and the two or more doses of dexamethasone independently administered to the subject on each of days 1, 8, 15, and 22 of each of the two 28 day cycles of the induction phase and each of the subsequent 28 day cycles of the maintenance phase comprise about 40 mg of dexamethasone.

[0262] In some embodiments, dexamethasone is administered within about 10 minutes to about 5 hours (e.g., about 5 minutes to about 4.5 hours, about 5 minutes to about 4 hours, about 5 minutes to about 3.5 hours, about 5 minutes to about 3 hours, about 5 minutes to about 2.5 hours, about 5 minutes to about 2 hours, about 5 minutes to about 1.5 hours, about 5 minutes to about 1 hour, about 5 minutes to about 45 minutes, about 5 minutes to about 40 minutes, about 5 minutes to about 35 minutes, about 5 minutes to about 30 minutes, about 5 minutes to about 25 minutes, about 5 minutes to about 20 minutes) of administration of each dose of a pharmaceutical composition described herein (e.g., comprising any of the antibodies or antigen-binding fragments described herein). , about 5 minutes to about 15 minutes, about 5 minutes to about 10 minutes, about 30 minutes to about 5 hours, about 30 minutes to about 4.5 hours, about 30 minutes to about 4 hours, about 30 minutes to about 3.5 hours, about 30 minutes to about 3 hours, about 30 minutes to about 2.5 hours, about 30 minutes to about 2 hours, about 30 minutes to about 1.5 hours, about 30 minutes to about 1 hour, about 30 minutes to about 45 minutes, about 1 hour to about 5 hours, about 1 hour to about 4.5 hours, about 1 hour to about 4 hours, about 1 hour to about 3.5 hours, about 1 hour to about 3 hours, about 1 hour to about 2.5 hours, about 1 hour to about 2 hours, about 1 hour to about 1.5 hours

[0263] In some embodiments, dexamethasone is administered within about 10 minutes to about 5 hours (e.g., about 5 minutes to about 4.5 hours, about 5 minutes to about 4 hours, about 5 minutes to about 3.5 hours, about 5 minutes to about 3 hours, about 5 minutes to about 2.5 hours, about 5 minutes to about 2 hours, about 5 minutes to about 1.5 hours, about 5 minutes to about 1 hour, about 5 minutes to about 45 minutes, about 5 minutes to about 40 minutes, about 5 minutes to about 35 minutes, about 5 minutes to about 30 minutes, about 5 minutes to about 25 minutes, about 5 minutes to about 20 minutes) of administration of each dose of a pharmaceutical composition described herein (e.g., comprising any of the antibodies or antigen-binding fragments described herein). , about 5 minutes to about 15 minutes, about 5 minutes to about 10 minutes, about 30 minutes to about 5 hours, about 30 minutes to about 4.5 hours, about 30 minutes to about 4 hours, about 30 minutes to about 3.5 hours, about 30 minutes to about 3 hours, about 30 minutes to about 2.5 hours, about 30 minutes to about 2 hours, about 30 minutes to about 1.5 hours, about 30 minutes to about 1 hour, about 30 minutes to about 45 minutes, about 1 hour to about 5 hours, about 1 hour to about 4.5 hours, about 1 hour to about 4 hours, about 1 hour to about 3.5 hours, about 1 hour to about 3 hours, about 1 hour to about 2.5 hours, about 1 hour to about 2 hours, about 1 hour to about 1.5 hours

[0264] In some embodiments, a dose of about 40 mg of dexamethasone is administered to the subject about 1 to about 3 hours prior to each dose of a pharmaceutical composition described herein (e.g., comprising any of the antibodies or antigen-binding fragments described herein).

[0265] C. Treatment Duration In some embodiments, the treatment period is from about 1 week to about 5 years (e.g., from about 1 week to about 4.5 years, from about 1 week to about 4 years, from about 1 week to about 3.5 years, from about 1 week to about 3 years, from about 1 week to about 2.5 years, from about 1 week to about 2 years, from about 1 week to about 1.5 years, from about 1 week to about 1 year, from about 1 week to about 10 months, from about 1 week to about 8 months, from about 1 week to about 6 months, from about 1 week to about 4 months, from about 1 week to about 2 months, from about 1 week to about 1 month, from about 1 week to about 2 weeks, from about 2 weeks to about 5 years, from about 2 weeks to about 4.5 years, from about 2 weeks to about 4 years, from about 2 weeks to about 3.5 years, from about 2 weeks to about 3 years, about 2 weeks to about 2.5 years, about 2 weeks to about 2 years, about 2 weeks to about 1.5 years, about 2 weeks to about 1 year, about 2 weeks to about 10 months, about 2 weeks to about 8 months, about 2 weeks to about 6 months, about 2 weeks to about 4 months, about 2 weeks to about 2 months, about 2 weeks to about 1 month, about 1 month to about 5 years, about 1 month to about 4.5 years, about 1 month to about 4 years, about 1 month to about 3.5 years, about 1 month to about 3 years, about 1 month to about 2.5 years, about 1 month to about 2 years, about 1 month to about 1.5 years, about 1 month to about 1 year, about 1 month to about 10 months, about 1 month to about 8 months 1 month to 6 months, 1 month to 4 months, 1 month to 2 months, 2 months to 5 years, 2 months to 4.5 years, 2 months to 4 years, 2 months to 3.5 years, 2 months to 3 years, 2 months to 2.5 years, 2 months to 2 years, 2 months to 1.5 years, 2 months to 1 year, 2 months to 10 months, 2 months to 8 months, 2 months to 6 months, 2 months to 4 months, 4 months to 5 years, 4 months to 4.5 years, 4 months to 4 years, 4 months to 3.5 years, 4 months to 3 years months to about 3 years, about 4 months to about 2.5 years, about 4 months to about 2 years, about 4 months to about 1.5 years, about 4 months to about 1 year, about 4 months to about 10 months, about 4 months to about 8 months, about 4 months to about 6 months, about 6 months to about 5 years, about 6 months to about 4.5 years, about 6 months to about 4 years, about 6 months to about 3.5 years, about 6 months to about 3 years, about 6 months to about 2.5 years, about 6 months to about 2 years, about 6 months to about 1.5 years, about 6 months to about 1 year, about 6 months to about 10 months, about 6 months to about 8 months, about 8 months to about 5 years, about 8 months to about 4.5 years, about 8 months to about 4 years, about 8 months to about 3.5 years, about 8 months to about 3 years, about 8 months to about 2.5 years, about 8 months to about 2 years, about 8 months to about 1.5 years, about 8 months to about 1 year, about 8 months to about 10 months, about 10 months to about 5 years, about 10 months to about 4.5 years, about 10 months to about 4 years, about 10 months to about 3.5 years, about 10 months to about 3 years , about 10 months to about 2.5 years, about 10 months to about 2 years, about 10 months to about 1.5 years, about 10 months to about 1 year, about 1 year to about 5 years, about 1 year to about 4.5 years, about 1 year to about 4 years, about 1 year to about 3.5 years, about 1 year to about 3 years, about 1 year to about 2.5 years, about 1 year to about 2 years, about 1 year to about 1.5 years, about 1.5 years to about 5 years, about 1.5 years to about 4. 5 years, about 1.5 years to about 4 years, about 1.5 years to about 3.5 years, about 1.5 years to about 3 years, about 1.5 years to about 2.5 years, about 1.5 years to about 2 years, about 2 years to about 5 years, about 2 years to about 4.5 years, about 2 years to about 4 years, about 2 years to about 3.5 years, about 2 years to about 3 years, about 2 years to about 2.5 years, about 2.5 years to about 5 years, about 2.5 years to about 4.5 years, about 2. 5 years to about 4 years, about 2 / 5 years to about 3.5 years, about 2.5 years to about 3 years, about 3 years to about 5 years, about 3 years to about 4.5 years, about 3 years to about 4 years, about 3 years to about 3.5 years, about 3.5 years to about 5 years, about 3.5 years to about 4.5 years, about 3.5 years to about 4 years, about 4 years to about 5 years, about 4 years to about 4.5 years, or about 4.5 years to about 5 years.

[0266] Effective treatment of multiple myeloma in subject means one or more of the following: reduction in the disease severity of multiple myeloma in subject, reduction in incidence, and / or reduction in the number, frequency, severity and / or duration of one or more symptoms.In some cases, therapeutic efficacy can be observed in subject compared to historical control or past experience of the same subject.In other cases, therapeutic efficacy can be demonstrated in a population of treated subjects in preclinical or clinical trials compared to a control population of untreated or placebo-treated subjects.

[0267] In some embodiments, the pharmaceutical composition comprising any of the antibodies or antigen-binding fragments described herein is administered at a frequency of once every two weeks. In some embodiments, the pharmaceutical composition comprising any of the antibodies or antigen-binding fragments described herein is administered at a fixed dose of 1600 mg once a week. In some embodiments, the pharmaceutical composition comprising any of the antibodies or antigen-binding fragments described herein is administered at a fixed dose of 1600 mg once every two weeks. In some embodiments, the pharmaceutical composition comprising any of the antibodies or antigen-binding fragments described herein is administered at a fixed dose of 800 mg once a week. In some embodiments, the pharmaceutical composition comprising any of the antibodies or antigen-binding fragments described herein is administered at a fixed dose of 800 mg once every two weeks.

[0268] In some embodiments, provided herein is a method of treating a subject with multiple myeloma, comprising administering to the subject (i) one or more doses of a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to B-cell maturation antigen (BCMA), and (ii) one or more doses of a pharmaceutical composition comprising nirogacestat, and optionally (iii) one or more doses of a pharmaceutical composition comprising dexamethasone. In some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma (RRMM). In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising CDR1 comprising SEQ ID NO:1, CDR2 comprising SEQ ID NO:2, and CDR3 comprising SEQ ID NO:3, and a light chain variable domain comprising CDR1 comprising SEQ ID NO:5, CDR2 comprising SEQ ID NO:6, and CDR3 comprising SEQ ID NO:7. In some embodiments, the antibody is an IgG1 antibody.

[0269] In some embodiments, one or more doses of 1600 mg of the antibody or antigen-binding fragment thereof are independently administered to the subject every two weeks. In some embodiments, one or more doses of 800 mg of the antibody or antigen-binding fragment thereof are independently administered to the subject every week. In some embodiments, about one to two induction doses of 1600 mg of the antibody or antigen-binding fragment thereof are independently administered to the subject every week, followed by one or more maintenance doses of 1600 mg of the antibody or antigen-binding fragment thereof, independently administered to the subject every two weeks. In some embodiments, about one to two induction doses of 800 mg of the antibody or antigen-binding fragment thereof are independently administered to the subject every week, followed by one or more maintenance doses of 1600 mg of the antibody or antigen-binding fragment thereof, independently administered to the subject every two weeks.

[0270] In some embodiments, the subject has previously been administered one or more therapeutic agents or treatments for multiple myeloma. The one or more therapeutic agents or treatments for multiple myeloma previously administered include, but are not limited to, proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and anti-CD38 antibodies. In some embodiments, the subject has previously been administered BCMA-directed myeloma therapy other than at least one of proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies, or is intolerant to any of the above.

[0271] Specifically, proteasome inhibitors are agents whose mechanism of action is to inhibit the proteasome. Exemplary proteasome inhibitors include, but are not limited to, bortezomib, carfilzomib, and ixazomib. Immunomodulatory drugs (IMiDs) are thalidomide analogs that possess pleiotropic antimyeloma properties, including immunomodulatory, antiangiogenic, anti-inflammatory, and antiproliferative effects. Immunomodulatory imide drugs (IMiDs) are immunomodulators that contain an "imide" group. Exemplary IMiDs include, but are not limited to, lenalidomide, pomalidomide, thalidomide, and ivedomide (CC-220, Celgene). Exemplary anti-CD38 antibodies include, but are not limited to, daratumumab and isatuximab.

[0272] In some embodiments, one or more previously administered therapeutic agents or treatments have been ineffective in treating multiple myeloma. In some embodiments, the subject has one or more measurable disease including serum monoclonal paraprotein (M protein) level > 0.5 g / dL, urinary M protein level > 200 mg / 24 hr, serum immunoglobulin free light chain > 10 mg / dL, and / or abnormal serum immunoglobulin kappa to lambda free light chain ratio.

[0273] D. Route of Administration Administration of a pharmaceutical composition (e.g., any of the exemplary pharmaceutical compositions described herein comprising any of the antibodies or antigen-binding fragments described herein, or any of the exemplary pharmaceutical compositions described herein comprising dexamethasone) can be parenteral. In some aspects, administration of a pharmaceutical composition (e.g., any of the exemplary pharmaceutical compositions described herein comprising any of the antibodies or antigen-binding fragments described herein, or any of the exemplary pharmaceutical compositions described herein comprising dexamethasone) can be intravenous, subcutaneous, intraarterial, intracranial, intrathecal, intraperitoneal, or intramuscular. Administration can also be localized directly within the tumor. Administration to the systemic circulation by intravenous or subcutaneous administration. In some aspects, administration of a pharmaceutical composition (e.g., any of the exemplary pharmaceutical compositions described herein comprising any of the antibodies or antigen-binding fragments described herein, or any of the exemplary pharmaceutical compositions described herein comprising dexamethasone) is systemic. In some aspects, systemic administration of a pharmaceutical composition (e.g., any of the exemplary pharmaceutical compositions described herein comprising any of the antibodies or antigen-binding fragments described herein, or any of the exemplary pharmaceutical compositions described herein comprising dexamethasone) is intravenous administration.

[0274] Intravenous administration can be performed, for example, by stepwise infusion or single bolus injection. In some embodiments, stepwise infusion can be performed at a rate of about 20 mg / hour to about 500 mg / hour (e.g., about 20 mg / hour to about 450 mg / hour, about 20 mg / hour to about 400 mg / hour, about 20 mg / hour to about 350 mg / hour, about 20 mg / hour to about 300 mg / hour, about 20 mg / hour to about 250 mg / hour, about 20 mg / hour to about 200 mg / hour, about 20 mg / hour to about 180 mg / hour, about 20 mg / hour to about 160 mg / hour, about 20 mg / hour to about 140 mg / hour, about 20 mg / hour to about 12 ...50 mg / hour, about 20 mg / hour to about 250 mg / hour, about 20 mg / hour to about 250 mg / hour, about 20 mg / hour to / hour to about 100mg / hour, about 20mg / hour to about 80mg / hour, about 20mg / hour to about 60mg / hour, about 20mg / hour to about 50mg / hour, about 20mg / hour to about 40mg / hour, about 40mg / hour to about 500mg / hour, about 40mg / hour to about 450mg / hour, about 40mg / hour to about 400mg / hour, about 40mg / hour to about 350mg / hour, about 40mg / hour to about 300mg / hour, about 40mg / hour to about 250mg / hour, about 40mg / hour to about 200mg / hour, about 40mg / hour to about 180mg / hour between about 40 mg / hour and about 160 mg / hour, between about 40 mg / hour and about 140 mg / hour, between about 40 mg / hour and about 120 mg / hour, between about 40 mg / hour and about 100 mg / hour, between about 40 mg / hour and about 80 mg / hour, between about 40 mg / hour and about 60 mg / hour, between about 40 mg / hour and about 50 mg / hour, between about 50 mg / hour and about 500 mg / hour, between about 50 mg / hour and about 450 mg / hour, between about 50 mg / hour and about 400 mg / hour, between about 50 mg / hour and about 350 mg / hour, between about 50 mg / hour and about 300 mg / hour, between about 50 mg / hour and about 50 mg / hour about 250 mg / hour, about 50 mg / hour to about 200 mg / hour, about 50 mg / hour to about 180 mg / hour, about 50 mg / hour to about 160 mg / hour, about 50 mg / hour to about 140 mg / hour, about 50 mg / hour to about 120 mg / hour, about 50 mg / hour to about 100 mg / hour, about 50 mg / hour to about 80 mg / hour, about 50 mg / hour to about 60 mg / hour, about 60 mg / hour to about 500 mg / hour, about 60 mg / hour to about 450 mg / hour, about 60 mg / hour to about 400 mg / hour, about 60 mg / hour to about 350 mg / hour,about 60mg / hour to about 300mg / hour, about 60mg / hour to about 250mg / hour, about 60mg / hour to about 200mg / hour, about 60mg / hour to about 180mg / hour, about 60mg / hour to about 160mg / hour, about 60mg / hour to about 140mg / hour, about 60mg / hour to about 120mg / hour, about 60mg / hour to about 100mg / hour, about 60mg / hour to about 80mg / hour, about 80mg / hour to about 500mg / hour, about 80mg / hour to about 450mg / hour, about 80mg / hour to about 400mg / hour, about 80mg / hour to about 350mg / hour, about 80 mg / hour~about 300mg / hour, about 80mg / hour~about 250mg / hour, about 80mg / hour~about 200mg / hour, about 80mg / hour~about 180mg / hour, about 80mg / hour~about 160mg / hour, about 80mg / hour~about 140mg / hour, about 80mg / hour~about 120m g / hour, approx. 80mg / hour ~ approx. 100mg / hour, approx. 100mg / hour ~ approx. 500mg / hour, approx. 100mg / hour ~ approx. 450mg / hour, approx. 100mg / hour ~ approx. 400mg / hour, approx. 100mg / hour~about 250mg / hour, about 100mg / hour~about 200mg / hour, about 100mg / hour~about 180mg / hour, about 100mg / hour~about 160mg / hour, about 100mg / hour~about 140mg / hour, about 100mg / hour~about 120mg / hour, about 120m g / hour~about 500mg / hour, about 120mg / hour~about 450mg / hour, about 120mg / hour~about 400mg / hour, about 120mg / hour~about 350mg / hour, about 120mg / hour~about 300mg / hour, about 120mg / hour~about 250mg / hour, about 120mg / hour~ Approximately 200mg / hour, approximately 120mg / hour ~ approximately 180mg / hour, approximately 120mg / hour ~ approximately 160mg / hour, approximately 120mg / hour ~ approximately 140mg / hour, approximately 140mg / hour ~ approximately 500mg / hour, approximately 140mg / hour ~ approximately 450mg / hour, approximately 140mg / hour ~ approximately 400m g / hour, about 140mg / hour to about 350mg / hour, about 140mg / hour to about 300mg / hour, about 140mg / hour to about 250mg / hour, about 140mg / hour to about 200mg / hour, about 140mg / hour to about 180mg / hour, about 140mg / hour to about 160mg / hour,Approx. 160mg / hour ~ approx. 500mg / hour, approx. 160mg / hour ~ approx. 450mg / hour, approx. 160mg / hour ~ approx. 400mg / hour, approx. 160mg / hour ~ approx. 350mg / hour, approx. 160mg / hour ~ approx. 3 00mg / hour, about 160mg / hour~about 250mg / hour, about 160mg / hour~about 200mg / hour, about 160mg / hour~about 180mg / hour, about 180mg / hour~about 500mg / hour, about 180 mg / hour~about 450mg / hour, about 180mg / hour~about 400mg / hour, about 180mg / hour~about 350mg / hour, about 180mg / hour~about 300mg / hour, about 180mg / hour~about 250mg / hour, about 180mg / hour~about 200mg / hour, about 200mg / hour~about 500mg / hour, about 200mg / hour~about 450mg / hour, about 200mg / hour~about 400mg / hour, about 200mg / hour ~350mg / hour, approx. 200mg / hour ~ approx. 300mg / hour, approx. 200mg / hour ~ approx. 250mg / hour, approx. 250mg / hour ~ approx. 500mg / hour, approx. 250mg / hour~about 400mg / hour, about 250mg / hour~about 350mg / hour, about 250mg / hour~about 300mg / hour, about 300mg / hour~about 500mg / hour, about 300mg / hour~about 45 The infusion rate is about 0 mg / hour, about 300 mg / hour to about 400 mg / hour, about 300 mg / hour to about 350 mg / hour, about 350 mg / hour to about 500 mg / hour, about 350 mg / hour to about 450 mg / hour, about 350 mg / hour to about 400 mg / hour, about 400 mg / hour to about 500 mg / hour, about 400 mg / hour to about 450 mg / hour, or about 450 mg / hour to about 500 mg / hour.

[0275] In some embodiments, the stepwise infusion rate is increased about every 10 minutes. In some embodiments, the stepwise infusion rate is increased about every 20 minutes. In some embodiments, the stepwise infusion rate is increased about every 30 minutes. In some embodiments, the stepwise infusion rate is increased about every 40 minutes. In some embodiments, the stepwise infusion rate is increased about every 50 minutes. In some embodiments, the stepwise infusion rate is increased about every 60 minutes. In some embodiments, during the stepwise infusion, the infusion rate is increased by no more than about a factor of 2 every 30 minutes.

[0276] In some embodiments, the administration of the pharmaceutical composition comprising nirogacestat can be oral administration. In such embodiments, the pharmaceutical composition comprising nirogacestat can be formulated as a tablet, capsule, or aqueous suspension.

[0277] E. Pharmacokinetic Effects In some embodiments, administration of a pharmaceutical composition described herein using any of the methods described herein results in a steady state concentration of an antibody or antigen-binding fragment thereof in the subject's serum that is capable of binding to at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the BCMA expressed on the surface of tumor cells in the subject.

[0278] In certain embodiments, the antibody or antigen-binding fragment is administered at a dose and infusion rate such that the half-life of the antibody or antigen-binding fragment is at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In other embodiments, the half-life is at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks.

[0279] Some embodiments of these methods include administering a concentration of from about 1 μg / mL to about 200 μg / mL (e.g., from about 1 μg / mL to about 180 μg / mL, from about 1 μg / mL to about 160 μg / mL, from about 1 μg / mL to about 140 μg / mL, from about 1 μg / mL to about 120 μg / mL, from about 1 μg / mL to about 100 μg / mL, from about 1 μg / mL to about 90 μg / mL, from about 1 μg / mL to about 80 μg / mL, from about 1 μg / mL to about 70 μg / mL, from about 1 μg / mL to about 60 μg / mL, from about 1 μg / mL to about 50 μg / mL, from about 1 μg / mL to about 40 μg / mL, from about 1 μg / mL to about 30 μg / mL, from about 1 μg / mL to about 50 μg / mL, from about 1 μg / mL to about 60 μg / mL, from about 1 μg / mL to about 70 μg / mL, from about 1 μg / mL to about 80 μg / mL, from about 1 μg / mL to about 90 μg / mL, from about 1 μg / mL to about 100 μg / mL, from about 1 μg / mL to about 120 μg / mL, from about 1 μg / mL to about 140 μg / mL, from about 1 μg / mL to about 150 μg / mL, from about 1 μg / mL to about 160 μg / mL, from about 1 μg / mL to about 170 μg / mL, from about 1 μg / mL to about 180 μg / mL, from about 1 μg / mL to about 190 μg / mL, from about 1 μg / mL to about 20 g / mL~about 20μg / mL, about 1μg / mL~about 10μg / mL, about 10μg / mL~about 200μg / mL, about 10μg / mL~about 180μg / mL, about 10μg / mL~about 160μg / mL, about 10μg / mL~about 140μg / mL, about 10μg / mL~about 120μg / mL , about 10μg / mL to about 100μg / mL, about 10μg / mL to about 90μg / mL, about 10μg / mL to about 80μg / mL, about 10μg / mL to about 70μg / mL, about 10μg / mL to about 60μg / mL, about 10μg / mL to about 50μg / mL, about 10μg / mL to about 40μg / mL mL, about 10μg / mL to about 30μg / mL, about 10μg / mL to about 20μg / mL, about 20μg / mL to about 200μg / mL, about 20μg / mL to about 180μg / mL, about 20μg / mL to about 160μg / mL, about 20μg / mL to about 140μg / mL, about 20μg / mL to about 120μg / mL, about 20μg / mL to about 100μg / mL, about 20μg / mL to about 90μg / mL, about 20μg / mL to about 80μg / mL, about 20μg / mL to about 70μg / mL, about 20μg / mL to about 60μg / mL, about 20μg / mL to about 50μg / mL, about 20μg / m L ~ approx. 40 μg / mL, approx. 20 μg / mL ~ approx. 30 μg / mL, approx. 30 μg / mL ~ approx. 200 μg / mL, approx. 30 μg / mL ~ approx. 180 μg / mL, approx. 30μg / mL to approximately 100μg / mL, approximately 30μg / mL to approximately 90μg / mL, approximately 30μg / mL to approximately 80μg / mL, approximately 30μg / mL to approximately 70μg / mL, approximately 30μg / mL to approximately 60μg / mL, approximately 30μg / mL to approximately 50μg / mL, approximately 30μg / mL to approximately 40μg / mL,About 40 μg / mL to about 200 μg / mL, about 40 μg / mL to about 180 μg / mL, about 40 μg / mL to about 160 μg / mL, about 40 μg / mL to about 140 μg / mL, about 40 μg / mL to about 120 μg / mL, about 40 μg / mL to about 100 μg / mL, about 40 μg / mL to about 90 μg / mL, about 40 μg / mL to about 80 μg / mL, about 40 μg / mL to about 70 μg / mL, about 40 μg / mL to about 60 μg / mL, about 40 μg / mL to about 50 μg / mL, about 50 μg / mL to about 200 μg / mL, about 50 μg / mL to about 180 μg / mL, about 50 μg / mL to about 160 μg / mL, about 50 μg / mL to about 140 μg / mL, about 50 μg / mL to about 120 μg / mL, about 50 μg / mL to about 100 μg / mL, about 50 μg / mL to about 90 μg / mL, about 50 μg / mL to about 80 μg / mL, about 50 μg / mL to about 70 μg / mL, about 50 μg / mL to about 60 μg / mL, about 60 μg / mL to about 200 μg / mL, about 60 μg / mL to about 180 μg / mL, about 60 μg / mL to about 160 μg / mL, about 60 μg / mL to about 140 μg / mL, about 60 μg / mL to about 120 μg / mL, about 60 μg / mL to about 100 μg / mL, about 60 μg / mL to about 90 μg / mL, about 60 μg / mL to about 80 μg / mL, about 60 μg / mL to about 70 μg / mL, about 70 μg / mL to about 200 μg / mL, about 70 μg / mL to about 180 μg / mL, about 70 μg / mL to about 160 μg / mL, about 70 μg / mL to about 140 μg / mL, about 70 μg / mL to about 120 μg / mL, about 70 μg / mL to about 100 μg / mL, about 70 μg / mL to about 90 μg / mL, about 70 μg / mL to about 80 μg / mL, about 80 μg / mL to about 200 μg / mL, about 80 μg / mL to about 180 μg / mL, about 80 μg / mL to about 160 μg / mL, about 80 μg / mL to about 140 μg / mL, about 80 μg / mL to about 120 μg / mL, about 80 μg / mL to about 100 μg / mL, about 80 μg / mL to about 90 μg / mL, about 90 μg / mL to about 200 μg / mL, about 90 μg / mL to about 180 μg / mL, about 90 μg / mL to about 160 μg / mL, about 90 μg / mL to about 140 μg / mL, about 90 μg / mL to about 120 μg / mL, about 90 μg / mL to about 100 μg / mL, about 100 μg / mL to about 200 μg / mL, about 100 μg / mL to about 180 μg / mL,About 100μg / mL to about 160μg / mL, about 100μg / mL to about 140μg / mL, about 100μg / mL to about 120μg / mL, about 120μg / mL to about 200μg / mL, about 120μg / mL to about 180μg / mL, about 120μg / mL to about 160μg / mL, about 120μg / mL to about 140μg / mL, about 140μg / mL to about 200μg / mL, about 140μg / mL to about 180μg / mL, about 140μg / mL to about 160μg / mL, about 160μg / mL to about 200μg / mL, about 160μg / mL to about 180μg / mL, or about 180μg / mL or about 6 hours to about 1 year (e.g., about 6 hours to about 11.5 months, about 6 hours to about 11.0 months, about 6 hours to about 10.5 months, about 6 hours to about 10.0 months, about 6 hours to about 9.5 months, about 6 hours to about 9.0 months, about 6 hours to about 8.5 months, about 6 hours to about 8.0 months, about 6 hours to about 7.5 months, about 6 hours to about 7.0 months, about 6 hours to about 6.5 months, about 6 hours to about 6.0 months) after administration of the initial dose of the antibody or antigen-binding fragment. , about 6 hours to about 5.5 months, about 6 hours to about 5.0 months, about 6 hours to about 4.5 months, about 6 hours to about 4.0 months, about 6 hours to about 3.5 months, about 6 hours to about 3.0 months, about 6 hours to about 2.5 months, about 6 hours to about 2.0 months, about 6 hours to about 1.5 months, about 6 hours to about 5 weeks, about 6 hours to about 4 weeks, about 6 hours to about 3 weeks, about 6 hours to about 2 weeks, about 6 hours to about 1 week, about 6 hours to about 5 days, about 6 hours to about 3 days, about 6 hours to about 1 day, about 6 hours to about 18 hours, about 6 hours to about 12 hours, about 12 hours to about 1 year, about 12 hours to about 11.5 months, about 12 hours to About 11.0 months, about 12 hours to about 10.5 months, about 12 hours to about 10.0 months, about 12 hours to about 9.5 months, about 12 hours to about 9.0 months, about 12 hours to about 8.5 months, about 12 hours to about 8.0 months, about 12 hours to about 7.5 months, about 12 hours to about 7.0 months, about 12 hours to about 6.5 months, about 12 hours to about 6.0 months, about 12 hours to about 5.5 months, about 12 hours to about 5.0 months, about 12 hours to about 4.5 months, about 12 hours to about 4.0 months, about 12 hours to about 3.5 months, about 12 hours to about 3.0 months, about 12 hours to about 2.5 months,About 12 hours to about 2.0 months, About 12 hours to about 1.5 months, About 12 hours to about 5 weeks, About 12 hours to about 4 weeks, About 12 hours to about 3 weeks, About 12 hours to about 2 weeks, About 12 hours to about 1 week, About 12 hours to about 5 days, About 12 hours to about 3 days, About 12 hours to about 1 day, About 12 hours to about 18 hours, About 18 hours to about 1 year, About 18 hours to about 11.5 months, About 18 hours to about 11.0 months, About 18 hours to about 10.5 months, About 18 hours to about 10.0 months, About 18 hours to about 9.5 months, About 18 hours to about 9.0 months, About 18 hours to about 8.5 months, About 18 hours to about 8. 0 months, about 18 hours to about 7.5 months, about 18 hours to about 7.0 months, about 18 hours to about 6.5 months, about 18 hours to about 6.0 months, about 18 hours to about 5.5 months, about 18 hours to about 5.0 months, about 18 hours to about 4.5 months, about 18 hours to about 4.0 months, about 18 hours to about 3.5 months, about 18 hours to about 3.0 months, about 18 hours to about 2.5 months, about 18 hours to about 2.0 months, about 18 hours to about 1.5 months, about 18 hours to about 5 weeks, about 18 hours to about 4 weeks, about 18 hours to about 3 weeks, about 18 hours to about 2 weeks, about 18 hours to about 1 week, about 18 hours to about 5 days, about 18 hours to about 3 days, about 18 hours to about 1 day, about 1 day to about 1 year, about 1 day to about 11.5 months, about 1 day to about 11.0 months, about 1 day to about 10.5 months, about 1 day to about 10.0 months, about 1 day to about 9.5 months, about 1 day to about 9.0 months, about 1 day to about 8.5 months, about 1 day to about 8.0 months, about 1 day to about 7.5 months, about 1 day to about 7.0 months, about 1 day to about 6.5 months, about 1 day to about 6.0 months, about 1 day to about 5.5 months, about 1 day to about 5.0 months, about 1 day to about 4.5 months, about 1 day to about 4.0 months, about 1 day to about 3.5 months, about 1 day to about 3 .0 months, about 1 day to about 2.5 months, about 1 day to about 2.0 months, about 1 day to about 1.5 months, about 1 day to about 5 weeks, about 1 day to about 4 weeks, about 1 day to about 3 weeks, about 1 day to about 2 weeks, about 1 day to about 1 week, about 1 day to about 5 days, about 1 day to about 3 days, about 3 days to about 1 year, about 3 days to about 11.5 months, about 3 days to about 11.0 months, about 3 days to about 10.5 months, about 3 days to about 10.0 months, about 3 days to about 9.5 months, about 3 days to about 9.0 months, about 3 days to about 8.5 months, about 3 days to about 8.0 months, about 3 days to about 7.5 months, about 3 days to about 7.0 months, about 3 days to about 6.5 months,about 3 days to about 6.0 months, about 3 days to about 5.5 months, about 3 days to about 5.0 months, about 3 days to about 4.5 months, about 3 days to about 4.0 months, about 3 days to about 3.5 months, about 3 days to about 3.0 months, about 3 days to about 2.5 months, about 3 days to about 2.0 months, about 3 days to about 1.5 months, about 3 days to about 5 weeks, about 3 days to about 4 weeks, about 3 days to about 3 weeks, about 3 days to about 2 weeks, about 3 days to about 1 week, about 3 days to about 5 days, about 5 days to about 1 year, about 5 days to about 11.5 months, about 5 days to about 11.0 months, about 5 days to about 10.5 months, about 5 days to about 10.0 months, about 5 days to about 9.5 months, about 5 days to about 9.0 months, about 5 days to about 8.5 months, about 5 days to about 8.0 months, about 5 days to about 7.5 months, about 5 days to about 7.0 months, about 5 days to about 6.5 months, about 5 days to about 6.0 months, about 5 days to about 5.5 months, about 5 days to about 5.0 months, about 5 days to about 4.5 months, about 5 days to about 4.0 months, about 5 days to about 3.5 months, about 5 days to about 3.0 months, about 5 days to about 2.5 months, about 5 days to about 2.0 months, about 5 days to about 1.5 months, about 5 days to about 5 weeks, about 5 days to about 4 weeks, about 5 days to about 3 weeks, about 5 days to about 2 weeks, about 5 days to about 1 week, about 1 week to about 1 year, about 1 week 1 week to about 11.5 months, about 1 week to about 11.0 months, about 1 week to about 10.5 months, about 1 week to about 10.0 months, about 1 week to about 9.5 months, about 1 week to about 9.0 months, about 1 week to about 8.5 months, about 1 week to about 8.0 months, about 1 week to about 7.5 months, about 1 week to about 7.0 months, about 1 week to about 6.5 months, about 1 week to about 6.0 months, about 1 week to about 5.5 months, about 1 week to about 5.0 months, about 1 week to about 4.5 months, about 1 week to about 4.0 months, about 1 week to about 3.5 months, about 1 week to about 3.0 months, about 1 week to about 2.5 months, about 1 week to about 2.0 months, about 1 week to about 1.5 months, about 1 week to about 5 weeks, about 1 week to about 4 weeks, about 1 week to about 3 weeks, about 1 week to about 2 weeks, about 2 weeks to about 1 year, about 2 weeks to about 11.5 months, about 2 weeks to about 11.0 months, about 2 weeks to about 10.5 months, about 2 weeks to about 10.0 months, about 2 weeks to about 9.5 months, about 2 weeks to about 9.0 months, about 2 weeks to about 8.5 months, about 2 weeks to about 8.0 months, about 2 weeks to about 7.5 months, about 2 weeks to about 7.0 months, about 2 weeks to about 6.5 months, about 2 weeks to about 6.0 months, about 2 weeks to about 5.5 months,About 2 weeks to about 5.0 months, About 2 weeks to about 4.5 months, About 2 weeks to about 4.0 months, About 2 weeks to about 3.5 months, About 2 weeks to about 3.0 months, About 2 weeks to about 2.5 months, About 2 weeks to about 2.0 months, About 2 weeks to about 1.5 months, About 2 weeks to about 5 weeks, About 2 weeks to about 4 weeks, About 2 weeks to about 3 weeks, About 3 weeks to about 1 year, About 3 weeks to about 11.5 months, About 3 weeks to about 11.0 months, About 3 weeks to about 10.5 months, About 3 weeks to about 10.0 months, About 3 weeks to about 9.5 months, About 3 weeks to about 9.0 months, About 3 weeks to about 8.5 months, About 3 weeks to about 8.0 months months, about 3 weeks to about 7.5 months, about 3 weeks to about 7.0 months, about 3 weeks to about 6.5 months, about 3 weeks to about 6.0 months, about 3 weeks to about 5.5 months, about 3 weeks to about 5.0 months, about 3 weeks to about 4.5 months, about 3 weeks to about 4.0 months, about 3 weeks to about 3.5 months, about 3 weeks to about 3.0 months, about 3 weeks to about 2.5 months, about 3 weeks to about 2.0 months, about 3 weeks to about 1.5 months, about 3 weeks to about 5 weeks, about 3 weeks to about 4 weeks, about 4 weeks to about 1 year, about 4 weeks to about 11.5 months, about 4 weeks to about 11.0 months, about 4 weeks to about 10.5 months, about 4 weeks to about 10.0 months, about 4 weeks to about 9.5 months, about 4 weeks to about 9.0 months, about 4 weeks to about 8.5 months, about 4 weeks to about 8.0 months, about 4 weeks to about 7.5 months, about 4 weeks to about 7.0 months, about 4 weeks to about 6.5 months, about 4 weeks to about 6.0 months, about 4 weeks to about 5.5 months, about 4 weeks to about 5.0 months, about 4 weeks to about 4.5 months, about 4 weeks to about 4.0 months, about 4 weeks to about 3.5 months, about 4 weeks to about 3.0 months, about 4 weeks to about 2.5 months, about 4 weeks to about 2.0 months, about 4 weeks to about 1.5 months, about 4 weeks to about 5 weeks, about 5 weeks to about 1 year, about 5 weeks to about 11.5 months, about 5 weeks to about 11.0 months, about 5 weeks to about 10.5 months, about 5 weeks to about 10.0 months, about 5 weeks to about 9.5 months, about 5 weeks to about 9.0 months, about 5 weeks to about 8.5 months, about 5 weeks to about 8.0 months, about 5 weeks to about 7.5 months, about 5 weeks to about 7.0 months, about 5 weeks to about 6.5 months, about 5 weeks to about 6.0 months, about 5 weeks to about 5.5 months, about 5 weeks to about 5.0 months, about 5 weeks to about 4.5 months, about 5 weeks to about 4.0 months, about 5 weeks to about 3.5 months, about 5 weeks to about 3.0 months, about 5 weeks to about 2.5 months,About 5 weeks to about 2.0 months, about 5 weeks to about 1.5 months, About 1.5 months to about 1 year, About 1.5 months to about 11.5 months, About 1.5 months to about 11.0 months, About 1.5 months to about 10.5 months, About 1.5 months to about 10.0 months, About 1.5 months to about 9.5 months, About 1.5 months to about 9.0 months, About 1.5 months to about 8.5 months, About 1.5 months to about 8.0 months, About 1.5 months to about 7.5 months, About 1.5 months to about 7.0 months, About 1.5 months to about 6.5 months, About 1.5 months to about 6.0 months, About 1.5 months to about 5.5 months, About 1.5 months to about 5.0 months, About 1.5 months to About 4.5 months, about 1.5 months to about 4.0 months, about 1.5 months to about 3.5 months, about 1.5 months to about 3.0 months, about 1.5 months to about 2.5 months, about 1.5 months to about 2.0 months, about 2.0 months to about 1 year, about 2.0 months to about 11.5 months, about 2.0 months to about 11.0 months, about 2.0 months to about 10.5 months, about 2.0 months to about 10.0 months, about 2.0 months to about 9.5 months, about 2.0 months to about 9.0 months, about 2.0 months to about 8.5 months, about 2.0 months to about 8.0 months, about 2.0 months to about 7.5 months, About 2.0 months to about 7.0 months, About 2.0 months to about 6.5 months, About 2.0 months to about 6.0 months, About 2.0 months to about 5.5 months, About 2.0 months to about 5.0 months, About 2.0 months to about 4.5 months, About 2.0 months to about 4.0 months, About 2.0 months to about 3.5 months, About 2.0 months to about 3.0 months, About 2.0 months to about 2.5 months, About 2.5 months to about 1 year, About 2.5 months to about 11.5 months, About 2.5 months to about 11.0 months, About 2.5 months to about 10.5 months, About 2.5 months to about 10.0 months, About 2.5 months to About 9.5 months, about 2.5 months to about 9.0 months, about 2.5 months to about 8.5 months, about 2.5 months to about 8.0 months, about 2.5 months to about 7.5 months, about 2.5 months to about 7.0 months, about 2.5 months to about 6.5 months, about 2.5 months to about 6.0 months, about 2.5 months to about 5.5 months, about 2.5 months to about 5.0 months, about 2.5 months to about 4.5 months, about 2.5 months to about 4.0 months, about 2.5 months to about 3.5 months, about 2.5 months to about 3.0 months, about 3.0 months to about 1 year, about 3.0 months to about 11.5 months, about 3.0 months to about 11.0 months, about 3.0 months to about 10.5 months, about 3.0 months to about 10.0 months, about 3.0 months to about 9.5 months, about 3.0 months to about 9.0 months, about 3.0 months to about 8.5 months, about 3.0 months to about 8.0 months, about 3.0 months to about 7.5 months, about 3.0 months to about 7.0 months, about 3.0 months to about 6.5 months, about 3.0 months to about 6.0 months, about 3.0 months to about 5.5 months, about 3.0 months to about 5.0 months, about 3.0 months to about 4.5 months, about 3.0 months to about 4.0 months, about 3.0 months to about 3.5 months, about 3.5 months to about 1 year, about 3.5 months to about 11.5 months, about 3.5 months to about 11.0 months, about 3.5 months to about 10.5 months, about 3.5 months to about 10.0 months, about 3.5 months to about 9.5 months, about 3.5 months to about 9.0 months, about 3.5 months to about 8.5 months, about 3.5 months to about 8.0 months, about 3.5 months to about 7.5 months, about 3.5 months to about 7.0 months, about 3.5 months to about 6.5 months, about 3.5 months to about 6.0 months, about 3.5 months to about 5.5 months, about 3.5 months to about 5.0 months, about 3 .5 months to about 4.5 months, about 3.5 months to about 4.0 months, about 4.0 months to about 1 year, about 4.0 months to about 11.5 months, about 4.0 months to about 11.0 months, about 4.0 months to about 10.5 months, about 4.0 months to about 10.0 months, about 4.0 months to about 9.5 months, about 4.0 months to about 9.0 months, about 4.0 months to about 8.5 months, about 4.0 months to about 8.0 months, about 4.0 months to about 7.5 months, about 4.0 months to about 7.0 months, about 4.0 months to about 6.5 months, about 4.0 months to about 6.0 months, about 4.0 months to about 5 .5 months, about 4.0 months to about 5.0 months, about 4.0 months to about 4.5 months, about 4.5 months to about 1 year, about 4.5 months to about 11.5 months, about 4.5 months to about 11.0 months, about 4.5 months to about 10.5 months, about 4.5 months to about 10.0 months, about 4.5 months to about 9.5 months, about 4.5 months to about 9.0 months, about 4.5 months to about 8.5 months, about 4.5 months to about 8.0 months, about 4.5 months to about 7.5 months, about 4.5 months to about 7.0 months, about 4.5 months to about 6.5 months, about 4.5 months to about 6.0 months, about 4.5 months to about 5.5 months, about 4.5 months to about 5.0 months, about 5.0 months to about 1 year, about 5.0 months to about 11.5 months, about 5.0 months to about 11.0 months, about 5.0 months to about 10.5 months, about 5.0 months to about 10.0 months, about 5.0 months to about 9.5 months, about 5.0 months to about 9.0 months, about 5.0 months to about 8.5 months, about 5.0 months to about 8.0 months, about 5.0 months to about 7.5 months, about 5.0 months to about 7.0 months, about 5.0 months to about 6.5 months, about 5.0 months to about 6.0 months, about 5.0 months to about 5. 5 months, about 5.5 months to about 1 year, about 5.5 months to about 11.5 months, about 5.5 months to about 11.0 months, about 5.5 months to about 10.5 months, about 5.5 months to about 10.0 months, about 5.5 months to about 9.5 months, about 5.5 months to about 9.0 months, about 5.5 months to about 8.5 months, about 5.5 months to about 8.0 months, about 5.5 months to about 7.5 months, about 5.5 months to about 7.0 months, about 5.5 months to about 6.5 months, about 5.5 months to about 6.0 months, about 6.0 months to about 1 year, about 6.0 months to about 11.5 months, about 6.0 months months to about 11.0 months, about 6.0 months to about 10.5 months, about 6.0 months to about 10.0 months, about 6.0 months to about 9.5 months, about 6.0 months to about 9.0 months, about 6.0 months to about 8.5 months, about 6.0 months to about 8.0 months, about 6.0 months to about 7.5 months, about 6.0 months to about 7.0 months, about 6.0 months to about 6.5 months, about 6.5 months to about 1 year, about 6.5 months to about 11.5 months, about 6.5 months to about 11.0 months, about 6.5 months to about 10.5 months, about 6.5 months to about 10.0 months, about 6.5 months to about 9 .5 months, about 6.5 months to about 9.0 months, about 6.5 months to about 8.5 months, about 6.5 months to about 8.0 months, about 6.5 months to about 7.5 months, about 6.5 months to about 7.0 months, about 7.0 months to about 1 year, about 7.0 months to about 11.5 months, about 7.0 months to about 11.0 months, about 7.0 months to about 10.5 months, about 7.0 months to about 10.0 months, about 7.0 months to about 9.5 months, about 7.0 months to about 9.0 months, about 7.0 months to about 8.5 months, about 7.0 months to about 8.0 months, about 7.0 months to about 7.5 months, about 7.5 months to about 1 year, about 7.5 months to about 11.5 months, about 7.5 months to about 11.0 months, about 7.5 months to about 10.5 months, about 7.5 months to about 10.0 months, about 7.5 months to about 9.5 months, about 7.5 months to about 9.0 months, about 7.5 months to about 8.5 months, about 7.5 months to about 8.0 months, about 8.0 months to about 1 year, about 8.0 months to about 11.5 months, about 8.0 months to about 1 1.0 months, about 8.0 months to about 10.5 months, about 8.0 months to about 10.0 months, about 8.0 months to about 9.5 months, about 8.0 months to about 9.0 months, about 8.0 months to about 8.5 months, about 8.5 months to about 1 year, about 8.5 months to about 11.5 months, about 8.5 months to about 11.0 months, about 8.5 months to about 10.5 months, about 8.5 months to about 10.0 months, about 8.5 months to about 9.5 months months, about 8.5 months to about 9.0 months, about 9.0 months to about 1 year, about 9.0 months to about 11.5 months, about 9.0 months to about 11.0 months, about 9.0 months to about 10.5 months, about 9.0 months to about 10.0 months, about 9.0 months to about 9.5 months, about 9.5 months to about 1 year, about 9.5 months to about 11.5 months, about 9.5 months to about 11.0 months, about 9.5 months to about 10.5 months, about 9. 5 months to about 10.0 months, about 10.0 months to about 1 year, about 10.0 months to about 11.5 months, about 10.0 months to about 11.0 months, about 10.0 months to about 10.5 months, about 10.5 months to about 1 year, about 10.5 months to about 11.5 months, about 10.5 months to about 11.0 months, about 11.0 months to about 1 year, about 11.0 months to about 11.5 months, or about 11.5 months to about 1 year).

[0280] Some embodiments of these methods result in a steady state concentration of free light chain (FLC) in the subject's serum of less than about 50 mg / dL, less than about 45 mg / dL, less than about 40 mg / dL, less than about 35 mg / dL, less than about 30 mg / dL, less than about 25 mg / dL, less than about 20 mg / dL, less than about 18 mg / dL, less than about 16 mg / dL, less than about 14 mg / dL, less than about 12 mg / dL, less than about 10 mg / dL, less than about 8 mg / dL, less than about 6 mg / dL, less than about 4 mg / dL, less than about 2 mg / dL, or less than about 1 mg / dL (e.g., from about 6 hours to about 1 year, or any subrange of this range, following administration of a first dose of antibody or antigen-binding fragment and a first dose of nirogacestat to the subject).

[0281] Some embodiments of these methods include administering a serotonin concentration of about 0.1 mg / dL to about 50 mg / dL (e.g., about 0.1 mg / dL to about 48 mg / dL, about 0.1 mg / dL to about 45 mg / dL, about 0.1 mg / dL to about 40 mg / dL, about 0.1 mg / dL to about 35 mg / dL, about 0.1 mg / dL to about 30 mg / dL, about 0.1 mg / dL to about 25 mg / dL, about 0.1 mg / dL to about 20 mg / dL, about 0.1 mg / dL to about 18 mg / dL, about 0.1 mg / dL to about 16 mg / dL, about 0.1 mg / dL to about 14 mg / dL, about 0.1 mg / dL to about 12 mg / dL, or about 0.1 mg / dL to about 16 mg / dL. L, approximately 0.1 mg / dL ~ approximately 10 mg / dL, approximately 0.1 mg / dL ~ approximately 8 mg / dL, approximately 0.1 mg / dL ~ approximately 6 mg / dL, approximately 0.1 mg / dL ~ approximately 4 mg / dL, approximately 0.1 mg / dL ~ approximately 2 mg / dL, approximately 0.1 mg / dL ~ approximately 1.0 mg / dL, approximately 0.1 mg / dL ~ Approximately 0.5 mg / dL, approximately 0.1 mg / dL ~ approximately 0.2 mg / dL, approximately 0.2 mg / dL ~ approximately 50 mg / dL, approximately 0.2 mg / dL ~ approximately 48 mg / dL, approximately 0.2 mg / dL ~ approximately 45 mg / dL, approximately 0.2 mg / dL ~ approximately 40 mg / dL, approximately 0.2 mg / dL ~ approximately 35 mg / dL , about 0.2 mg / dL to about 30 mg / dL, about 0.2 mg / dL to about 25 mg / dL, about 0.2 mg / dL to about 20 mg / dL, about 0.2 mg / dL to about 18 mg / dL, about 0.2 mg / dL to about 16 mg / dL, about 0.2 mg / dL to about 14 mg / dL, about 0.2 mg / d L ~ about 12mg / dL, about 0.2mg / dL - about 10mg / dL, about 0.2mg / dL - about 8mg / dL, about 0.2mg / dL - about 6mg / dL, about 0.2mg / dL - about 4mg / dL, about 0.2mg / dL - about 2mg / dL, about 0.2mg / dL - about 1.0mg / dL, about 0.2mg / dL~about 0.5mg / dL, about 0.5mg / dL~about 50mg / dL, about 0.5mg / dL~about 48mg / dL, about 0.5mg / dL~about 45mg / dL, about 0.5mg / dL~about 40mg / dL, about 0.5mg / dL~about 35mg / dL, about 0.5mg / dL ~30mg / dL, 0.5mg / dL~25mg / dL, 0.5mg / dL~20mg / dL, 0.5mg / dL~18mg / dL, 0.5mg / dL~16mg / dL, 0.5mg / dL~14mg / dL, 0.5mg / dL~12mg / dL,About 0.5 mg / dL to about 10 mg / dL, about 0.5 mg / dL to about 8 mg / dL, about 0.5 mg / dL to about 6 mg / dL, about 0.5 mg / dL to about 4 mg / dL, about 0.5 mg / dL to about 2 mg / dL, about 0.5 mg / dL to about 1.0 mg / dL, about 1.0 mg / dL to about 50 mg / dL, about 1.0 mg / dL to about 48 mg / dL, about 1.0 mg / dL to about 45 mg / dL, about 1.0 mg / dL to about 40 mg / dL, about 1.0 mg / dL to about 35 mg / dL, about 1.0 mg / dL to about 30 mg / dL, about 1.0 mg / dL to about 25 mg / dL, about 1.0 mg / dL to about 20 mg / dL, about 1.0 mg / dL to about 18 mg / dL, about 1.0 mg / dL to about 16 mg / dL, about 1.0 mg / dL to about 14 mg / dL, about 1.0 mg / dL to about 12 mg / dL, about 1.0 mg / dL to about 10 mg / dL, about 1.0 mg / dL to about 8 mg / dL, about 1.0 mg / dL to about 6 mg / dL, about 1.0 mg / dL to about 4 mg / dL, about 1.0 mg / dL to about 2 mg / dL, about 2 mg / dL to about 50 mg / dL, about 2 mg / dL to about 48 mg / dL, about 2 mg / dL to about 45 mg / dL, about 2 mg / dL to about 40 mg / dL, about 2 mg / dL to about 35 mg / dL, about 2 mg / dL to about 30 mg / dL, about 2 mg / dL to about 25 mg / dL, about 2 mg / dL to about 20 mg / dL, about 2 mg / dL to about 18 mg / dL, about 2 mg / dL to about 16 mg / dL, about 2 mg / dL to about 14 mg / dL, about 2 mg / dL to about 12 mg / dL, about 2 mg / dL to about 10 mg / dL, about 2 mg / dL to about 8 mg / dL, about 2 mg / dL to about 6 mg / dL, about 2 mg / dL to about 4 mg / dL, about 4 mg / dL to about 50 mg / dL, about 4 mg / dL to about 48 mg / dL, about 4 mg / dL to about 45 mg / dL, about 4 mg / dL to about 40 mg / dL, about 4 mg / dL to about 35 mg / dL, about 4 mg / dL to about 30 mg / dL, about 4 mg / dL to about 25 mg / dL, about 4 mg / dL to about 20 mg / dL, about 4 mg / dL to about 18 mg / dL, about 4 mg / dL to about 16 mg / dL, about 4 mg / dL to about 14 mg / dL, about 4 mg / dL to about 12 mg / dL, about 4 mg / dL to about 10 mg / dL, about 4 mg / dL to about 8 mg / dL, about 4 mg / dL to about 6 mg / dL, about 6 mg / dL to about 50 mg / dL, about 6 mg / dL to about 48 mg / dL,About 6 mg / dL to about 45 mg / dL, about 6 mg / dL to about 40 mg / dL, about 6 mg / dL to about 35 mg / dL, about 6 mg / dL to about 30 mg / dL, about 6 mg / dL to about 25 mg / dL, about 6 mg / dL to about 20 mg / dL, about 6 mg / dL to about 18 mg / dL, about 6 mg / dL to about 16 mg / dL, about 6 mg / dL to about 14 mg / dL, about 6 mg / dL to about 12 mg / dL, about 6 mg / dL to about 10 mg / dL, about 6 mg / dL to about 8 mg / dL, about 8 mg / dL to about 50 mg / dL, about 8 mg / dL to about 48 mg / dL, about 8 mg / dL to about 45 mg / dL, about 8 mg / dL to about 40 mg / dL, about 8 mg / dL to about 35 mg / dL, about 8 mg / dL to about 30 mg / dL, about 8 mg / dL to about 25 mg / dL, about 8 mg / dL to about 20 mg / dL, about 8 mg / dL to about 18 mg / dL, about 8 mg / dL to about 16 mg / dL, about 8 mg / dL to about 14 mg / dL, about 8 mg / dL to about 12 mg / dL, about 8 mg / dL to about 10 mg / dL, about 10 mg / dL to about 50 mg / dL, about 10 mg / dL to about 48 mg / dL, about 10 mg / dL to about 45 mg / dL, about 10 mg / dL to about 40 mg / dL, about 10 mg / dL to about 35 mg / dL, about 10 mg / dL to about 30 mg / dL, about 10 mg / dL to about 25 mg / dL, about 10 mg / dL to about 20 mg / dL, about 10 mg / dL to about 18 mg / dL, about 10 mg / dL to about 16 mg / dL, about 10 mg / dL to about 14 mg / dL, about 10 mg / dL to about 12 mg / dL, about 12 mg / dL to about 50 mg / dL, about 12 mg / dL to about 48 mg / dL, about 12 mg / dL to about 45 mg / dL, about 12 mg / dL to about 40 mg / dL, about 12 mg / dL to about 35 mg / dL, about 12 mg / dL to about 30 mg / dL, about 12 mg / dL to about 25 mg / dL, about 12 mg / dL to about 20 mg / dL, about 12 mg / dL to about 18 mg / dL, about 12 mg / dL to about 16 mg / dL, about 12 mg / dL to about 14 mg / dL, about 14 mg / dL to about 50 mg / dL, about 14 mg / dL to about 48 mg / dL, about 14 mg / dL to about 45 mg / dL, about 14 mg / dL to about 40 mg / dL, about 14 mg / dL to about 35 mg / dL, about 14 mg / dL to about 30 mg / dL, about 14 mg / dL to about 25 mg / dL, about 14 mg / dL to about 20 mg / dL, about 14 mg / dL to about 18 mg / dLApproximately 14 mg / dL to approximately 16 mg / dL, approximately 16 mg / dL to approximately 50 mg / dL, approximately 16 mg / dL to approximately 48 mg / dL, approximately 16 mg / dL to approximately 45 mg / dL, approximately 16 mg / dL to approximately 40 mg / dL, approximately 16 mg / dL to approximately 35 mg / dL, approximately 16 mg / dL to Approx. 30 mg / dL, Approx. 16 mg / dL ~ Approx. 25 mg / dL, Approx. 16 mg / dL ~ Approx. 20 mg / dL, Approx. 16 mg / dL ~ Approx. 18 mg / dL, Approx. 18 mg / dL ~ Approx. 50 mg / dL, Approx. 18 mg / dL ~ Approx. Approx. 18 mg / dL ~ approx. 40 mg / dL, approx. 18 mg / dL ~ approx. 35 mg / dL, approx. 18 mg / dL ~ approx. 30 mg / dL, approx. 18 mg / dL ~ approx. 25 mg / dL, approx. 18 mg / dL ~ approx. 20 mg / dL, approx. Approximately 48 mg / dL, approximately 20 mg / dL to approximately 45 mg / dL, approximately 20 mg / dL to approximately 40 mg / dL, approximately 20 mg / dL to approximately 35 mg / dL, approximately 20 mg / dL to approximately 30 mg / dL, approximately 20 mg / dL to approximately 25 mg / dL, approximately 25 mg / dL to approximately 50 mg / dL, Approximately 25 mg / dL to approximately 48 mg / dL, approximately 25 mg / dL to approximately 45 mg / dL, approximately 25 mg / dL to approximately 40 mg / dL, approximately 25 mg / dL to approximately 35 mg / dL, approximately 25 mg / dL to approximately 30 mg / dL, approximately 30 mg / dL to approximately 50 mg / dL, approximately 30 mg / dL to Approximately 48 mg / dL, approximately 30 mg / dL to approximately 45 mg / dL, approximately 30 mg / dL to approximately 40 mg / dL, approximately 30 mg / dL to approximately 35 mg / dL, approximately 35 mg / dL to approximately 50 mg / dL, approximately 35 mg / dL to approximately 48 mg / dL, approximately 35 mg / dL to approximately 45 mg / dL, resulting in a steady state concentration of free light chain (FLC) in the subject's serum of about 35 mg / dL to about 40 mg / dL, about 40 mg / dL to about 50 mg / dL, about 40 mg / dL to about 48 mg / dL, about 40 mg / dL to about 45 mg / dL, about 45 mg / dL to about 50 mg / dL, about 45 mg / dL to about 48 mg / dL, or about 48 mg / dL to about 50 mg / dL) (e.g., about 6 hours to about 1 year, or any subrange of this range, following administration of the first dose of antibody or antigen-binding fragment and the first dose of nirogacestat to the subject).

[0282] G. Therapeutic Efficacy The therapeutic effect of the methods described herein can be evaluated by the expression level of one or more biomarkers in patient samples.Exemplary biomarker evaluations include testing the level of serum free light chain and improved serum protein electrophoresis (SPEP), peripheral blood immunophenotyping, including but not limited to flow cytometry measurements to characterize NK cells, monocytes, T cells and B cells, evaluation of the levels of circulating soluble BCMA (sBCMA), proliferation-inducing ligand (APRIL) and B cell activating factor (BAFF), retrospective analysis of cellular and circulating biomarkers, characterization of tumor tissue, bone marrow immunotyping, baseline and treatment-related changes in gene expression profiles in tumor and tumor microenvironment evaluated by RNA sequencing in tumor and non-tumor cells, and evaluation of the levels of soluble targets, ligands and / or cytokines / chemokines in bone marrow plasma.

[0283] The therapeutic effect achieved by the methods described herein can also include, for example, a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease-free periods, an increase in life span, disease remission, or prevention of functional impairment or disability due to disease affliction.For example, for the treatment of multiple myeloma, fulminant and / or drug-resistant and / or refractory multiple myeloma, the methods described herein inhibit cell growth or tumor growth by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% compared to untreated subjects or subjects receiving a different treatment.In addition, the methods described herein can result in at least stable disease, partial response, or complete response as assessed by WHO or RECIST tumor response criteria (Natl. Cancer. Inst. 91:523-8, 1999; and Cancer 47:207-14, 1981). In some embodiments, efficacy of treatment is determined based on objective response, objective response rate, complete response, complete response rate, duration of response, duration of complete response, progression-free survival, and overall survival.

[0284] The methods described herein can reduce tumor size or cancer burden, or otherwise ameliorate symptoms in a subject, or otherwise support partial or complete disease stability and / or partial or complete response, as determined above.

[0285] Treatment with any of the pharmaceutical compositions described herein (e.g., comprising any of the antibodies or antigen-binding fragments described herein), optionally in combination with any of the other therapeutic agents or treatments described herein, may increase the median progression-free survival or overall survival of patients with cancer, especially relapsed or refractory cancer, by at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%, compared to the same treatment (e.g., chemotherapy) but without administration of any of the pharmaceutical compositions comprising any of the anti-BCMA antibodies or antigen-binding fragments described herein. Additionally or alternatively, a treatment (e.g., standard chemotherapy) comprising administration of any of the pharmaceutical compositions comprising any of the anti-BCMA antibodies or antigen-binding fragments described herein may increase the complete response rate, partial response rate or objective response rate (complete + partial) in a patient with a tumor by at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to the same treatment (e.g., chemotherapy) but without administration of any of the pharmaceutical compositions comprising any of the anti-BCMA antibodies or antigen-binding fragments described herein.

[0286] Typically, in a clinical trial (e.g., a Phase II, Phase II / III or Phase III trial), the aforementioned increase in median progression-free survival and / or response rate of patients treated with standard therapy plus any of the pharmaceutical compositions comprising any of the anti-BCMA antibodies or antigen-binding fragments described herein, compared to a control group of patients receiving standard therapy alone (or plus placebo) is statistically significant, e.g., at the level of p=0.05, 0.01 or 0.001. Complete and partial response rates are determined by objective criteria commonly used in cancer clinical trials, e.g., as set forth or approved by the National Cancer Center and / or the Food and Drug Administration in the United States.

[0287] Patients are deemed to have an objective response (OR) if they achieve stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) based on the 2016 IMWG Uniform Response Criteria. Objective response rate (ORR) is defined as the proportion of patients with OR by the investigator. Patients whose disease response cannot be assessed by the 2016 IMWG Uniform Response Criteria are scored as Not Evaluable for calculation of ORR. Patients who do not have a post-baseline response assessment or whose response is not evaluable by IMWG criteria are counted as non-responders in the calculation of ORR. Objective response (OR) can be assessed by imaging studies, clinical laboratory evaluations or physical examinations; or by SD in disease-related symptoms and clinical response by the investigator.

[0288] In one embodiment of any of the methods described herein, the objective response rate (ORR) is at least 5%, at least 10%, at least 15%, at least 20%, 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 96%, at least 97%, at least 98%, at least 99% after administration of an antibody or antigen-binding fragment described herein.

[0289] Patients are considered to have a complete response (CR) if they achieve sCR or CR based on the 2016 IMWG Uniform Response Criteria. CR rate is defined as the proportion of patients with CR by the investigator. Patients whose disease response cannot be assessed by the IMWG Uniform Response Criteria are scored as non-evaluable for the calculation of CR rate.

[0290] In one embodiment of any of the methods described herein, the complete response rate (CRR) is at least 5%, at least 10%, at least 15%, at least 20%, 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 96%, at least 97%, at least 98%, at least 99% after administration of an antibody or antigen-binding fragment described herein.

[0291] Duration of OR is defined as the time from first documentation of OR (sCR, CR, VGPR, or PR) to first documentation of progression or death from any cause, whichever occurs first. Progression includes tumor progression (based on serum, urine, or bone marrow assessment) and / or objective evidence of clinical progression by the investigator. Duration of response is calculated only for the subgroup of patients achieving sCR, CR, VGPR, or PR.

[0292] In one embodiment of any of the methods described herein, the duration of objective response or complete response to treatment is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years.

[0293] Progression-free survival (PFS) is defined as the time from the start of treatment to the first documented progression or death from any cause, whichever occurs first. Progression includes tumor progression (based on serum, urine, or bone marrow assessment) and / or objective evidence of clinical progression by the investigator. PFS is censored at the date of last disease assessment with confirmed absence of disease progression (PD) for patients who do not have progression and are still on study at the time of analysis or who are removed from the study before confirmation of tumor progression. Patients who start a new antitumor treatment before confirmation of PD are censored at the time of last disease assessment before initiation of the new treatment. Patients missing an assessment of tumor response after the first dose are censored at event time of 1 day.

[0294] In one embodiment of any of the methods described herein, the subject exhibits progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years.

[0295] Overall survival (OS) is defined as the time from the start of any study treatment to the date of death from any cause. OS = date of death - date of first administration of any study treatment + 1.

[0296] In one embodiment of any of the methods described herein, the subject exhibits an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years.

[0297] H. Exemplary Monotherapy and Combination Therapies In certain embodiments, subjects receive a dose of a pharmaceutical composition comprising either an antibody or antigen-binding fragment that specifically binds to BCMA once every two weeks (q2wk) according to a standard dosing regimen. In some standard dosing regimens, each dose contains 800 mg of an anti-BCMA antibody or antigen-binding fragment described herein. In other standard dosing regimens, each dose administered to a subject contains 1600 mg of an anti-BCMA antibody or antigen-binding fragment described herein.

[0298] In some embodiments of any of the methods described herein, consolidation dosing of an anti-BCMA antibody or antigen-binding fragment thereof is performed. In certain embodiments, the consolidation dosing includes weekly induction dosing (q1wk) of 8 doses of any of the anti-BCMA antibodies or antigen-binding fragments described herein during the first two cycles of therapy (i.e., cycle 1 and cycle 2). Assuming that the patient has not experienced a confirmed progression, the subject is administered any of the anti-BCMA antibodies or antigen-binding fragments described herein, dosed q2wk from cycle 3 onwards during the maintenance phase. Dosing during the maintenance phase is typically at standard dosing levels, i.e., dosing at either 800mg or 1600mg of the antibody or antigen-binding fragment.

[0299] Thus, in some embodiments, consolidation dosing of an anti-BCMA antibody or antigen-binding fragment thereof comprises administering 800 or 1600 mg of an anti-BCMA antibody or antigen-binding fragment described herein on days 1, 8, 15 and 22 of cycle 1 and cycle 2, and on days 1 and 15 of the subsequent cycle.

[0300] In some embodiments, nirogacestat is combined with a standard or enhanced anti-BCMA antibody or antigen-binding fragment thereof regimen as part of a combination therapy. In some embodiments of such combination treatment, nirogacestat is administered as a 100 mg dose and is administered twice daily. Thus, for example, some combination therapy embodiments include standard dosing combination therapy, in which nirogacestat is administered in combination with a standard dosing regimen of an anti-BCMA antibody or antigen-binding fragment as described herein, in which the antibody or antigen-binding fragment is administered q2wk. For example, in some standard dosing combination treatments, an anti-BCMA antibody or antigen-binding fragment as described herein is administered on days 1 and 15 of each 28-day cycle (i.e., according to a standard dosing regimen), and nirogacestat is administered twice each day of each 28-day cycle. In some of these standard dosing combination embodiments, each dose of the antibody or antigen-binding fragment is administered as an 800 mg dose, and each dose of nirogacestat is administered as a 100 mg dose. In other embodiments of the standard dosing combination treatment, each dose of the antibody or antigen-binding fragment is administered as a 1600 mg dose and each dose of nirogacestat is administered as a 100 mg dose.

[0301] In some embodiments, dexamethasone is combined with a standard or enhanced anti-BCMA antibody or antigen-binding fragment thereof regimen and nirogacestat as part of a combination therapy. In some embodiments of such combination treatment, dexamethasone is administered as a 40 mg dose and is administered once a week (i.e., q1wk). Thus, for example, some combination therapy embodiments include standard dosing combination therapy in which dexamethasone is administered in combination with a standard dosing regimen of an anti-BCMA antibody or antigen-binding fragment described herein, in which the antibody or antigen-binding fragment is administered q2wk and nirogacestat (e.g., 100 mg of nirogacestat) is administered twice each day. For example, in some standard dosing combination treatments, an anti-BCMA antibody or antigen-binding fragment as described herein is administered on days 1 and 15 of each 28 day cycle (i.e., according to a standard dosing regimen), nirogacestat is administered as a 100 mg dose twice each day of each 28 day cycle, and dexamethasone is administered on days 1, 8, 15, and 22 of each 28 day cycle. In some of these standard dosing combination embodiments, each dose of the antibody or antigen-binding fragment is administered as an 800 mg dose, nirogacestat is administered as a 100 mg dose twice each day of each 28 day cycle, and each dose of dexamethasone is administered as a 40 mg dose. In another embodiment of the standard dosing combination treatment, each dose of the antibody or antigen-binding fragment is administered as a 1600 mg dose, each dose of nirogacestat is administered as a 100 mg dose, and each dose of dexamethasone is administered as a 40 mg dose.

[0302] Other examples of combination therapy embodiments include intensive dosing combination therapy in which nirogacestat and dexamethasone are administered in combination with an intensive dosing regimen of any of the anti-BCMA antibodies or antigen-binding fragments described herein in which the antibody or antigen-binding fragment is administered q1wk followed by q2wk for 8 weeks. For example, in some intensive dosing combinations, an anti-BCMA antibody or antigen-binding fragment as described herein is administered on days 1, 8, 15, and 22 of cycles 1 and 2, and on days 1 and 15 of subsequent cycles (i.e., according to the intensive dosing regimen), nirogacestat is administered twice daily on days 1-28 of each 28 day cycle, and dexamethasone is administered on days 1, 8, 15, and 22 of each 28 day cycle. In some embodiments of these boosted dosing combinations, each dose of antibody or antigen-binding fragment is administered as an 800 mg dose, each dose of nirogacestat is administered as a 100 mg dose, and each dose of dexamethasone is administered as a 40 mg dose, while in other of these embodiments, each dose of antibody or antigen-binding fragment is administered as a 1600 mg dose, each dose of nirogacestat is administered as a 100 mg dose, and each dose of dexamethasone is administered as a 40 mg dose.

[0303] In any one of the exemplary combination therapies, when the anti-BCMA antibody or antigen-binding fragment and dexamethasone are both administered on the same day, the dexamethasone is administered 1-3 hours prior to the SEA BCMA infusion.

[0304] In some embodiments, an anti-BCMA antibody or antigen-binding fragment described herein is administered to a subject once every two weeks (e.g., on days 1 and 15 of each 28 day cycle), dexamethasone is administered once every week (e.g., on days 1, 8, 15 and 22 of each 28 day cycle), and nirogacestat is administered to a subject twice daily on days 1-28 of each 28 day cycle. In some embodiments, 1600 mg of an anti-BCMA antibody (e.g., SEA-BCMA) is administered to a subject once every two weeks (e.g., on days 1 and 15 of each 28 day cycle), 40 mg of dexamethasone is administered once every week (e.g., on days 1, 8, 15 and 22 of each 28 day cycle), and 100 mg of nirogacestat is administered to a subject twice daily on days 1-28 of each 28 day cycle.

[0305] In some embodiments, an anti-BCMA antibody or antigen-binding fragment described herein is administered to a subject once weekly for about 8 weeks, then once every two weeks (e.g., on days 1, 8, 15, and 22 of two 28 day cycles, and on days 1 and 15 of a subsequent 28 day cycle), dexamethasone is administered once weekly (e.g., on days 1, 8, 15, and 22 of each 28 day cycle), and nirogacestat is administered to a subject twice daily, on days 1 through 28 of each 28 day cycle.

[0306] In some embodiments, 1600 mg of an anti-BCMA antibody (e.g., SEA-BCMA) is administered to a subject once weekly for about 8 weeks, then once every two weeks (e.g., on days 1, 8, 15, and 22 of two 28 day cycles, and on days 1 and 15 of a subsequent 28 day cycle), 40 mg of dexamethasone is administered once weekly (e.g., on days 1, 8, 15, and 22 of each 28 day cycle), and 100 mg of nirogacestat is administered to a subject twice daily, days 1-28 of each 28 day cycle.

[0307] In some embodiments, 800 mg of an anti-BCMA antibody (e.g., SEA-BCMA) is administered to a subject once weekly for about 8 weeks, then once every two weeks (e.g., on days 1, 8, 15, and 22 of two 28 day cycles, and on days 1 and 15 of a subsequent 28 day cycle), 40 mg of dexamethasone is administered once weekly (e.g., on days 1, 8, 15, and 22 of each 28 day cycle), and 100 mg of nirogacestat is administered to a subject twice daily, on days 1-28 of each 28 day cycle.

[0308] In some embodiments, 800 mg of an anti-BCMA antibody (e.g., SEA-BCMA) is administered to the subject on days 1, 8, 15, and 22 of two 28 day cycles, and 1600 mg of an anti-BCMA antibody (e.g., SEA-BCMA) is administered to the subject on days 1 and 15 of a subsequent 28 day cycle of the maintenance phase, 40 mg of dexamethasone is administered to the subject on each of days 1, 8, 15, and 22 of each 28 day cycle, and 100 mg of nirogacestat is administered to the subject twice daily on days 1-28 of each 28 day cycle.

[0309] In some embodiments, 400 mg of an anti-BCMA antibody (e.g., SEA-BCMA) is administered to the subject on days 1, 8, 15, and 22 of two 28 day cycles, and 800 mg of an anti-BCMA antibody (e.g., SEA-BCMA) is administered to the subject on days 1 and 15 of a subsequent 28 day cycle of the maintenance phase, 40 mg of dexamethasone is administered to the subject on each of days 1, 8, 15, and 22 of each 28 day cycle, and 100 mg of nirogacestat is administered to the subject twice daily on days 1-28 of each 28 day cycle.

[0310] In some embodiments, 400 mg of an anti-BCMA antibody (e.g., SEA-BCMA) is administered to the subject on days 1, 8, 15, and 22 of two 28 day cycles, and 400 mg of an anti-BCMA antibody (e.g., SEA-BCMA) is administered to the subject on days 1 and 15 of a subsequent 28 day cycle of the maintenance phase, 40 mg of dexamethasone is administered to the subject on each of days 1, 8, 15, and 22 of each 28 day cycle, and 100 mg of nirogacestat is administered to the subject twice daily on days 1-28 of each 28 day cycle.

[0311] I. Patient Selection for Different Dosing Regimens and Combination Therapies A diagnosis of multiple myeloma (MM) requiring systemic therapy can be based on the International Myeloma Working Group (IMWG) 2014 criteria. Measurable disease can be defined by one or more of the following: a) Serum monoclonal paraprotein (M protein) level ≥ 0.5 g / dL; in patients with IgA or IgD myeloma, serum IgA or serum IgD ≥ 0.5 g / dL is acceptable b) Urinary M-protein level ≥ 200 mg / 24 hours c) Serum immunoglobulin FLC ≥ 10 mg / dL and abnormal serum immunoglobulin kappa lambda FLC ratio

[0312] In some embodiments, an ECOG performance status score of 0 or 1 is required prior to undergoing treatment as described herein.

[0313] In some embodiments, hematological criteria must be met in the absence of growth factor or platelet transfusion support: a) Estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Renal Disease (MDRD) equation ≥ 30 mL / min / 1.73 m 2 b) Absolute neutrophil count ≥ 1000 / μL c) Platelet count ≥75,000 / μL.

[0314] Patients can be selected for different dosing regimens or combination therapy. For example, standard dosing (e.g., q2wk, day 1 and day 15 of each 28-day cycle) can be administered to certain patients. In some embodiments, these patients are required to have no access to other treatment options known to provide clinical benefit in MM. In some embodiments, the patient's prior therapy line must include at least a proteasome inhibitor (PI), an immunomodulatory drug (IMiD) and an anti-CD38 antibody in any order during the course of treatment. In some embodiments, the subject has previously received at least one BCMA-directed myeloma therapy selected from the group consisting of ADC, CAR-T cell therapy and bispecific antibody that target human BCMA.

[0315] Intensive dosing (e.g., q1wk for the first two 28-day cycles, then q2wk for the subsequent 28-day cycles) or combination therapy with dexamethasone can be administered to certain patients. In some embodiments, these patients are required to have no other treatment options known to provide clinical benefit in MM. In some embodiments, these patients must have received at least three prior lines of anti-myeloma therapy and must be refractory to at least one agent from each of the following classes: PI, IMiD, and anti-CD38 antibody. In some embodiments, the subject has previously received at least one BCMA-directed myeloma therapy selected from the group consisting of ADC, CAR-T cell therapy, and bispecific antibody. When combination therapy with dexamethasone is administered to the patient, the antibody or antigen-binding fragment thereof as described herein can be administered under either a standard dosing schedule or an intensive dosing schedule.

[0316] In some embodiments, combination therapy with dexamethasone and IMiD can be administered to certain patients. In some embodiments, these patients must have received at least two prior lines of anti-myeloma therapy, including at least two consecutive cycles of lenalidomide and a proteosome inhibitor (given separately or in combination), and must have confirmed progression based on IMWG during or within 60 days after the end of their last treatment. Patients with a history of autologous SCT (stem cell transplant) are eligible if the transplant date was at least 12 weeks prior to the start of SEA-BCMA treatment.

[0317] Assay The physical condition of the subject treated by the method described herein can be measured by any suitable assay known in the art.Non-limiting assays include immunohistochemistry assay, radioactive imaging assay, in vivo imaging, positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), ultrasound, optical imaging, computed tomography, radioimmunoassay (RIA), ELISA (enzyme-linked immunosorbent assay), slot blot, competitive binding assay, fluorescent imaging assay, Western blot, FACS, etc.

[0318] In some embodiments, biological samples are collected from subjects for assay.Biological samples include, but are not limited to, blood, serum, urine, plasma, respiratory, intestinal and genitourinary tract external secretions, cerebrospinal fluid, peritoneal fluid, pleural fluid, cyst fluid, bronchoalveolar lavage fluid, any other body part or body system washings, and any organ sample containing isolated cells or tissues (wherein cells or tissues can be obtained from organs selected from, but not limited to, lung, colon, kidney, pancreas, ovary, prostate, liver, skin, bone marrow, lymph node, breast and / or blood tissue); fecal or tissue samples, or any combination thereof.Before performing the assay, the sample can be optionally diluted with a suitable diluent.In some embodiments, the cells obtained from the sample are cultured in vitro before performing the assay.

[0319] In some embodiments, the steady state concentration of anti-BCMA antibodies can be measured in the subject's serum.

[0320] One exemplary in vitro cell binding assay for estimating free anti-BCMA antibodies in patient serum involves pelleting a suspension of cultured MM1R cells and then resuspending the pellet in serum from the subject's peripheral blood collected at different times during treatment. After 0.5 hours of incubation at room temperature, the cells are washed and stained with a saturating amount of one of the anti-BCMA antibodies described herein conjugated to a fluorescent dye. After 0.5 hours of incubation at 4°C in the dark, the cells are washed and fixed. The stained cells are analyzed on an Invitrogen Attune NxT flow cytometer. Viable cells are gated and median fluorescence intensity (MFI) is recorded using FlowJo V10 software. GraphPad Prism 8 is used for analysis.

[0321] One exemplary method of measuring BCMA expression and its ligand binding by anti-BCMA antibodies as described herein involves collecting bone marrow aspirates from a subject at baseline and after or during treatment, then testing the samples by flow cytometry within one day of collection. Detection of MM cells can be performed using extracellular biomarker stains, such as CD138, CD38, CD45, CD56 and CD28 stains, as well as intracellular kappa and lambda light chain stains. Profiling of BCMA expression can be performed, for example, using two anti-BCMA antibodies: BCMA available for binding to the anti-BCMA antibody is detected using a reference anti-BCMA antibody (e.g., one of the antibodies or antigen-binding fragments described herein, such as the SEA-BCMA antibody described in the Examples) and a labeled anti-BCMA antibody that binds to BCMA in a competitive manner with the BCMA ligand (such as APRIL), while total extracellular BCMA is detected using a reference antibody and a differently labeled anti-BCMA antibody that binds to BCMA without competing with the BCMA ligand. Detection of APRIL bound to BCMA on the surface of MM cells can also be performed. Split each sample into three aliquots: one aliquot is stained with the MM gating antigen only and no anti-BCMA or anti-APRIL antibodies (gating control), one aliquot is stained with the MM gating antigen and both labeled anti-BCMA antibodies, and one is incubated with spiked BCMA (e.g., 100 μg / mL spiked BCMA) for 2 hours at 37 °C before staining with the MM gating antigen, APRIL, and labeled anti-BCMA antibodies that detect total extracellular BCMA. After staining, wash and fix the cells in 2% paraformaldehyde and analyze the cells on a flow cytometer.

[0322] kit Also provided herein are kits comprising (a) one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 doses) of a pharmaceutical composition (e.g., any of the pharmaceutical compositions described herein) comprising any of the antibodies or antigen-binding fragments thereof described herein that specifically bind to BCMA, and (b) instructions or directions for carrying out any one of the methods described herein. In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR1 comprising SEQ ID NO:1, a CDR2 comprising SEQ ID NO:2, and a CDR3 comprising SEQ ID NO:3, and a light chain variable domain comprising a CDR1 comprising SEQ ID NO:5, a CDR2 comprising SEQ ID NO:6, and a CDR3 comprising SEQ ID NO:7. In some embodiments of any of the kits described herein, the kit further comprises one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 doses) of a pharmaceutical composition comprising nirogacestat. In some embodiments of any of the kits described herein, the kit further comprises one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 doses) of a pharmaceutical composition comprising dexamethasone.

[0323] In some embodiments, one or more doses of a pharmaceutical composition comprising any of the antibodies or antigen-binding fragments described herein that specifically bind to BCMA and / or dexamethasone can be provided in an infusion device (e.g., a pre-pressurized infusion device). In some embodiments, one or more doses of a pharmaceutical composition comprising any of the antibodies or antigen-binding fragments described herein that specifically bind to BCMA and / or dexamethasone can be provided as a lyophilized solid composition that can be reconstituted using a pharma- ceutically acceptable buffer or solution (e.g., saline or phosphate buffered saline). In some embodiments, one or more doses of a pharmaceutical composition comprising any of the antibodies or antigen-binding fragments described herein that specifically bind to BCMA and / or dexamethasone can be provided as a liquid composition (e.g., a liquid composition that can be administered to a subject via intravenous administration).

[0324] In some embodiments, one or more doses of a pharmaceutical composition comprising nirogacestat ((S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide) (PF-03084014) can be formulated for oral administration (e.g., any of the pharma- ceutically acceptable salt forms of nirogacestat described herein or known in the art, e.g., nirogacestat hydrobromide or nirogacestat dihydrobromide). In some embodiments, one or more doses of a pharmaceutical composition comprising nirogacestat or a pharma- ceutically acceptable salt thereof is formulated as a tablet, capsule, or aqueous suspension. Non-limiting examples of carriers that may be present in pharmaceutical compositions containing nirogacestat include microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate, and glycine. Non-limiting examples of disintegrants that may be present in pharmaceutical compositions containing nirogacestat include starch (preferably corn, potato, or tapioca starch), methylcellulose, alginic acid, and certain complex silicates. Non-limiting examples of granule binders that may be present in pharmaceutical compositions containing nirogacestat include polyvinylpyrrolidone, sucrose, gelatin, and acacia. Lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often useful for tableting. Similar types of solid compositions may also be used as fillers in gelatin capsules. Preferred materials in this regard include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with diluents such as water, ethanol, glycerin, and various similar combinations thereof, along with various sweetening or flavoring agents, coloring substances or dyes, and, if desired, with emulsifying and / or suspending agents. EXAMPLES

[0325] Example 1. Clinical Trials of SEA-BCMA in the Treatment of Multiple Myeloma SEA-BCMA is a non-fucosylated monoclonal anti-BCMA antibody having a heavy chain amino acid sequence of SEQ ID NO:13 and a light chain amino acid sequence of SEQ ID NO:15.

[0326] SEA-BCMA Heavy Chain (SEQ ID NO:13) TIFF2024534602000014.tif55165

[0327] SEA-BCMA Light Chain (SEQ ID NO:15) TIFF2024534602000015.tif26165

[0328] SEA-BCMA comprises a heavy chain variable region comprising CDR1 comprising DYYIH (SEQ ID NO:1), CDR2 comprising YINPNSGYTNYAQKFQG (SEQ ID NO:2), and CDR3 comprising YMWERVTGFFDF (SEQ ID NO:3), and a light chain variable region comprising CDR1 comprising LASEDISDDLA (SEQ ID NO:5), CDR2 comprising TTSSLQS (SEQ ID NO:6), and CDR3 comprising QQTYKFPPT (SEQ ID NO:7). SEA-BCMA comprises a heavy chain variable region comprising SEQ ID NO:4 and a light chain variable region comprising SEQ ID NO:8.

[0329] Clinical trials are currently underway to evaluate SEA-BCMA in patient populations whose disease has relapsed or is refractory to standard therapy and who have no remaining available treatment options, and initial data indicate that the methods of treating multiple myeloma described herein provide clinical benefit.

[0330] The immune specificity and anti-tumor activity of SEA-BCMA has been demonstrated both in vitro and in vivo in BCMA-expressing MM models.

[0331] This trial evaluated the safety and antitumor activity of SEA-BCMA in patients with RRMM. The specific objectives and corresponding endpoints of this trial are summarized below (Table 1).

[0332] Table 1. Objectives and corresponding endpoints TIFF2024534602000016.tif255164

[0333] Clinical trial design overview Monotherapy dose escalation cohort The monotherapy dose escalation phase of the clinical trial was conducted in approximately 25 patients.

[0334] Enrollment in this trial was by cohort. Multiple cohorts were treated at each dose level, with a maximum of four patients per cohort. Decisions regarding dose escalation and subsequent cohort size were made in consultation with the Safety Management Committee (SMC) after the completion of each cohort. Patients in the current cohort were observed for the entire duration of the DLT period before the next cohort of patients was enrolled. In addition, as a precaution, the first two patients in this trial had a 72-hour observation period before the next patient could be dosed. For dose levels above dose level 1, a 24-hour observation period was required after the first patient received their first dose of SEA-BCMA before any subsequent patients were dosed at that dose level. At least two DLT-evaluable (DE) patients per dose level were treated until the first DLT was observed, and then a minimum of three DE patients per dose level were required before escalating to all higher doses. Patients deemed not evaluable for DLT during cycle 1 were replaced. A minimum of six DE patients were observed at the estimated MTD before determining the MTD or optimal dose, which was estimated based on data from all patients across all doses evaluated.

[0335] Tapering to lower dose levels may occur at any time in consultation with the SMC. If patients tolerate SEA-BCMA and achieve stable disease (SD) or better, intrapatient dose escalation may also be permitted to a dose level shown to be safe.

[0336] Patients continued treatment until disease progression or unacceptable toxicity, whichever occurred first.

[0337] SEA-BCMA was initially administered once every two weeks (q2wk) in a four-week cycle at the planned doses shown in Table 2; a dosing interval of every four weeks (q4wk) was explored.

[0338] Table 2: Dose escalation scheme TIFF2024534602000017.tif32166 a The Safety Assessment Committee may recommend investigating intermediate dose levels based on new clinical data.

[0339] Monotherapy expansion cohort To further characterize the safety and anti-tumor activity of SEA-BCMA, an expansion cohort of up to approximately 40 patients was enrolled. The dose and schedule for the expansion cohort was determined in consultation with the SMC based on the cumulative safety and activity demonstrated during dose escalation (completed without exceeding the MTD at any dose tested).

[0340] Intensive monotherapy dosing The intensified dosing was to evaluate the safety and tolerability of SEA-BCMA dosed once weekly (q1wk) during the induction phase (8 doses during the first 2 cycles of therapy); after completion of the 8-week induction phase, patients who had not yet experienced a confirmed progression then received SEA-BCMA dosed q2wk during the maintenance phase (from cycle 3 onwards dosed at the recommended expanded dose for standard schedule monotherapy).

[0341] Intensive dosing will include a safety run-in with the recommended expanded dose of SEA BCMA monotherapy (1600mg) administered on an intensive dosing schedule (days 1, 8, 15 and 22 of cycles 1 and 2, and days 1 and 15 of subsequent cycles). DLTs will be evaluated in the first 6 patients.

[0342] Patients who are deemed not evaluable for dose-limiting toxicities (DLTs) during dose-finding will be substituted for dose determination of SEA-BCMA in combination with dexamethasone.

[0343] Table 3. Dose levels of monotherapy intensification medications TIFF2024534602000018.tif27166

[0344] Dexamethasone combination therapy cohort Approximately 20 patients per optional combination cohort will be initially enrolled to characterize the safety and tolerability of SEA-BCMA in combination with dexamethasone.

[0345] Enrollment into the combination cohort will begin following identification of a tolerable SEA-BCMA monotherapy dose and schedule.

[0346] In optional cohort 1, SEA-BCMA will be administered on days 1 and 15 of each 28-day cycle (standard dosing; 1600 mg). Dexamethasone will be administered on days 1, 8, 15, and 22 of each 28-day cycle.

[0347] In optional cohort 2, SEA-BCMA will be administered at 800 mg (one dose below the recommended monotherapy expansion dose) on days 1, 8, 15, and 22 of cycles 1 and 2 (intensified dosing) and at 1600 mg on days 1 and 15 of the subsequent cycle (recommended monotherapy expansion dose). Dexamethasone will be administered on days 1, 8, 15, and 22 of each 28-day cycle.

[0348] This expansion cohort included an initial 3-subject safety run-in at 800 mg SEA-BCMA intensive dosing (dose level -1) and, if deemed tolerable, continued with a 6-subject run-in at 1600 mg SEA-BCMA intensive dosing. If 2 or more dose-limiting toxicities (DLTs) occurred among the first 3 patients, cohort 2 would be discontinued. If 1 DLT occurred among the first 3 patients, the cohort would be expanded to 6 patients and escalated only if there were less than 2 DLTs among the 6 patients. If no DLTs (0) occurred among the first 3 patients, the dose would be escalated to 2 cycles of 1600 mg q1wk, then to a subsequent cycle of 1600 mg q2wk, applying the 6-subject safety run-in rules outlined below (see section on "Dose-Limiting Toxicity").

[0349] Dexamethasone will be administered as an intravenous (IV) infusion or PO at a dose of 40 mg on days 1, 8, 15, and 22 of each 28-day cycle. On days when SEA-BCMA is administered, dexamethasone will be administered 1-3 hours prior to the SEA-BCMA infusion.

[0350] Nirogacestat and dexamethasone combination therapy cohort The nirogacestat and dexamethasone combination therapy portion of the trial will be run with approximately 40 patients. This cohort will receive SEA-BCMA with nirogacestat 100 mg orally (PO) twice daily and standard weekly dosing of dexamethasone (IV) 40 mg, with SEA-BCMA administered q1wk for 8 weeks at intensive dosing, followed by q2wk dosing thereafter. This expansion cohort will begin with a 6-subject lead-in phase and the SEA-BCMA dose recommended for expansion from Cohort 2 of the dexamethasone combination therapy cohort.

[0351] Nirogacestat is administered by PO at a dose of 100 mg twice daily on each day of a 28-day cycle. The C of nirogacestat at steady state after a dose of 100 mg BID is minis 232ng / mL or 471nM. Based on in vitro experiments with a panel of BMCA-expressing multiple myeloma and lymphoma cell lines, a dose of 100mg BID would maintain nirogacestat concentrations above the levels required to maximally inhibit BCMA cleavage, leading to a reduction in sBCMA and an increase in mbBCMA. Daily dosing may allow for more consistent BCMA modulation, which has been demonstrated with other GSIs. Daily dosing of nirogacestat would provide sufficient drug exposure for continued inhibition of gamma secretase, resulting in sustained and rapid increases in mbBCMA and reductions in sBCMA levels over time. At the proposed dose level of 100mg BID, nirogacestat is expected to have a tolerable safety profile at least comparable to the 150mg BID dose used in solid tumor studies, some of which had treatment durations and follow-ups of over 5 years.

[0352] Dexamethasone will be administered as an IV infusion at a dose of 40 mg on days 1, 8, 15, and 22 of each 28-day cycle. On days when SEA-BCMA is administered, dexamethasone will be administered 1-3 hours prior to the SEA-BCMA infusion.

[0353] Combination Therapy Cohort Safety Run-in Period The combination cohorts will include a safety run-in phase at the recommended dose and schedule of SEA BCMA monotherapy. DLTs will be evaluated in the first 6 patients enrolled in each combination cohort. If 0 or 1 of the first 6 subjects experience a DLT, the SMC will recommend that the expansion cohorts will proceed to enroll up to 20 patients. If ≥2 DLTs occur in the first 6 subjects, the MTD for the combination will be considered exceeded and the dose of SEA-BCMA will be de-escalated to the next lower dose level. If 0 or 1 of the first 6 subjects experience a DLT at the lower dose level, the SMC will recommend that the expansion cohorts will proceed to enroll up to 20 subjects at this dose level. If ≥2 DLTs occur in the first 6 subjects at the lower dose level, the MTD for the combination will be considered exceeded and the SMC will determine whether to test further de-escalations or to discontinue the combination cohort.

[0354] Patients in whom DLT is deemed not evaluable during dose finding will be substituted for dose determination of SEA-BCMA in combination with dexamethasone.

[0355] Dose-limiting toxicity (DLT) The DLT evaluation period was the first cycle of treatment. DLTs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 and were defined as any of the following events during the DLT evaluation period: Treatment delay > 7 days due to toxicity Any adverse event (AE) ≥ Grade 3 (unless deemed clearly unrelated to SEA-BCMA by the SMC), except for the following AEs, which must meet these specified criteria to be considered DLTs: Grade 4 neutropenia lasting more than 5 days Thrombocytopenia ≥ Grade 4 or Grade 3 with clinically significant bleeding Anemia unrelated to underlying condition ≥ Grade 4 Any grade ≥3 tumor lysis syndrome (including relevant laboratory evaluations) that has not been successfully managed clinically and has not resolved without end-organ dysfunction within 7 days Any ≥ Grade 4 infusion-related reaction (IRR) or Grade 3 IRR that does not resolve to ≤ Grade 2 within 24 hours with infusion interruption, infusion rate reduction, and / or standard support measures. In the event of a Grade 3 IRR in ≥ 20% of patients (i.e., ≥ 2 of the first 10 patients), all subsequent patients will require premedication and / or change in infusion technique as recommended by the SMC. In premedicated patients, any ≥ Grade 3 IRR will be considered a DLT. Asymptomatic laboratory abnormalities of ≤ Grade 1 or any Grade ≥ 3 that do not recover to baseline grade within 72 hours, with or without intervention Any procedure-related death

[0356] Stopping criteria The study was stopped if any of the following occurred: A rate of study-related toxic deaths unrelated to the underlying condition greater than 10% within 30 days of dosing (initially, 2 or more of the first 20 patients) Rate of grade 4 non-hematologic toxicity unrelated to underlying pathology >25% (initially ≥5 of first 20 patients) Rate of ≥15% grade 4 allergic reactions not controlled by standard treatment (initially ≥3 of the first 20 patients)

[0357] The stopping criteria were continuously monitored by the sponsor throughout the study.

[0358] Study design considerations and rationale Early clinical development of SEA-BCMA was targeted for evaluation in RRMM patients who had no other treatment options available that were known to provide clinical benefit and who, as determined by the treating physician, were candidates for SEA-BCMA treatment. Prior therapy should have included at least a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody. Frontline and first relapse standard of care (SOC) treatments were expected to fail in these patients prior to enrollment. As BCMA is a widely expressed tumor antigen in MM patients, initial selection of patients based on BCMA expression was not required, although the relationship between targeted expression and outcome was explored in this phase 1 study.

[0359] The first part of the trial consisted of dose escalation to estimate the MTD and / or optimal dose of SEA-BCMA. Once dose escalation was completed and drug stability was demonstrated, an expansion cohort of approximately 40 patients was enrolled to further evaluate the safety and antitumor activity of SEA-BCMA on a standard q2wk dosing schedule. This expansion cohort allowed for the collection of additional information regarding the safety, tolerability, and activity of SEA-BCMA. This information served as the basis for determining the recommended single-agent dose and schedule of SEA-BCMA. Because maintenance therapy has been shown to prolong remission in patients with MM, patients were allowed to continue treatment until disease progression (PD) or unacceptable toxicity, whichever occurred first. In addition, if patients tolerated SEA-BCMA and achieved a response of SD or better, intrapatient dose escalation was permitted to a dose level shown to be safe.

[0360] Study population All patients met all enrollment criteria prior to study drug administration (within 1 day of dosing) on ​​Day 1 of Cycle 1 to be eligible for this study.

[0361] To be eligible for retreatment, all patients met the inclusion and exclusion criteria outlined in the following section.

[0362] Selection Criteria 1. Diagnosis of multiple myeloma (MM) requiring systemic therapy as defined by the International Myeloma Working Group (IMWG) 2014 criteria (Kumar 2016). 2. Subjects must have relapsed or refractory MM, have no other treatment options available that are known to provide clinical benefit in MM, and be candidates for SEA-BCMA treatment as determined by the treating physician.

[0363] (a) Subjects enrolled in the dose escalation and dose expansion cohorts are required to have no access to other treatment options known to provide clinical benefit in MM. For patients enrolled in the dose escalation study, the subject's prior lines of therapy must have included at least a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody, in any order, during the course of treatment. Subjects who have not tolerated a PI, IMiD, or anti-CD38 antibody are accepted.

[0364] (b) Patients enrolled in monotherapy intensive dosing or dexamethasone combination therapy are required to have no access to other treatment options known to provide clinical benefit in MM. Patients are required to have no access to other treatment options known to provide clinical benefit in MM. Patients must have received at least three prior lines of anti-myeloma therapy and be refractory to at least one agent from each of the following classes: PIs, IMiDs, and anti-CD38 antibodies.

[0365] (c) Patients enrolled in the dexamethasone and nirogacestat combination cohort must have received prior BCMA-directed myeloma therapy (e.g., BCMA-targeted ADC, CAR-T therapy, or bispecific antibody therapy) excluding prior treatment with SEA-BCMA, provided that at least 6 months have elapsed between the last dose of the prior BCMA-targeted therapy and Day 1 of Cycle 1 of this study, and the patient has recovered from any clinically significant toxicity of the prior BCMA-targeted therapy.

[0366] Measurable disease, defined by one or more of the following: a. Serum monoclonal paraprotein (M protein) level ≥ 0.5 g / dL; in subjects with IgA or IgD myeloma, serum IgA or serum IgD ≥ 0.5 g / dL is acceptable. b. Urinary M-protein level ≥ 200 mg / 24 hours c. Serum immunoglobulin free light chains ≥ 10 mg / dL and abnormal serum immunoglobulin kappa lambda free light chain ratio

[0367] Age 18 or older.

[0368] Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 (e.g., conversion of performance status using the Karnofsky-Lansky scale, if available).

[0369] Life expectancy >3 months as determined by the investigator.

[0370] The following baseline laboratory data (hematological criteria must be met in the absence of growth factor or platelet transfusion support): a. Estimated glomerular filtration rate (eGFR) according to the Modified Diet in Renal Disease (MDRD) equation ≥ 30 mL / min / 1.73 m 2 b. Absolute neutrophil count (ANC) ≥ 1000 / μL c. Platelet count ≥75,000 / μL

[0371] Subjects of childbearing potential may be pregnant under the following conditions: A negative serum or urine pregnancy test (beta-human chorionic gonadotropin [β-hCG] with a minimum sensitivity of 25 mIU / mL or equivalent) must be obtained within 10-14 days prior to the first dose of SEA-BCMA and once 24 hours prior to initiating the first dose of SEA-BCMA. Subjects with false positive results and documented non-pregnant status will be eligible to participate. b. You must agree not to become pregnant during the study and for at least 6 months after your final dose of any study drug. c. You must agree not to breast-feed or donate eggs from the time of informed consent until 6 months after the final dose of any investigational drug. d. If sexual activity that may lead to pregnancy is occurring, two highly effective methods of contraception must be consistently used from the time of informed consent and continued throughout the study and for at least 6 months after the final dose of any study drug.

[0372] Patients who can father a child meet the following criteria: a. You must agree not to donate sperm from the time of informed consent through the duration of the study and for at least 6 months after your final dose of the study drug. b. If you are sexually active with a person of childbearing potential that may result in pregnancy, you must consistently use two highly effective methods of contraception from the time of informed consent and continue throughout the study and for at least 6 months after the final dose of any study drug. c. If sexually active with a pregnant or lactating person, they must consistently use one of two contraceptive options from the time of informed consent and continuing throughout the study and for at least 6 months after the last dose of any study drug.

[0373] In addition, subjects must provide written informed consent.

[0374] Exclusion criteria History of another malignancy within 3 years prior to the first dose of SEA-BCMA, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with little risk of metastasis or death (e.g., 5-year overall survival rate ≥ 90%), such as adequately treated cervical intraepithelial neoplasia, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer.

[0375] Active brain / meningeal disease associated with a primary malignancy. Subjects with a history of brain / meningeal disease associated with a primary malignancy are allowed provided the previous central nervous system disease has been treated.

[0376] Any uncontrolled grade 3 or greater (per NCICTCAE version 4.03) viral, bacterial or fungal infection within 2 weeks prior to the first dose of SEA-BCMA. Routine antibiotic prophylaxis is acceptable.

[0377] Hepatitis B positive by surface antigen expression. Active hepatitis C infection (positive by polymerase chain reaction or within the last 6 months on hepatitis C antiviral therapy). Subjects with treated hepatitis C infection will be accepted if they have demonstrated sustained viral response for 12 weeks.

[0378] Known to be positive for Human Immunodeficiency Virus (HIV).

[0379] Subjects who have previously undergone allogeneic stem cell transplantation (SCT).

[0380] History of cerebrovascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association Class III-IV congestive heart failure (see Appendix F) within 6 months prior to that first dose of SEA-BCMA.

[0381] Current therapy with other systemic antineoplastic agents or investigational agents.

[0382] Other antitumor treatment with chemotherapy, radiation therapy, biologics, investigational agents, and / or immunotherapy (not completed 4 weeks prior to the first dose of SEA-BCMA or 2 weeks prior to ongoing and not recovered from treatment-related clinically significant toxicity). CAR T-cell therapy (not completed 8 weeks prior to the first dose of SEA-BCMA). Palliative radiation therapy to a single site of disease is permitted with medical monitor approval.

[0383] Systemic treatment with either corticosteroids (>10 mg prednisolone equivalent / day) or other immunosuppressant therapy within 14 days of enrollment. Inhaled or topical steroids and adrenal replacement steroid doses ≦10 mg prednisolone equivalent / day are permitted.

[0384] Subjects who are lactating, pregnant, or planning to become pregnant from the time of informed consent through 6 months after the last dose of study drug.

[0385] Known hypersensitivity to any of the excipients contained in the formulation of SEA BCMA or nirogacestat.

[0386] Plasma cell leukemia (>2.0 × 10 by standard differential) 9 cells / L of circulating plasma cells), Waldenström's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or subjects with clinically significant amyloidosis.

[0387] Moderate or severe liver impairment, as indicated by any of the following: Serum total bilirubin >1.5 × upper limit of normal (ULN). In subjects with Gilbert's disease, total bilirubin >3 × ULN. b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3×ULN.

[0388] Any significant intercurrent condition or complication that, in the opinion of the Investigator, places the subject at undue risk or prevents proper evaluation of the safety and toxicity of SEA-BCMA.

[0389] For combination therapy only: Known intolerance to corticosteroids.

[0390] For concomitant therapy only: Any uncontrolled psychosis.

[0391] For concomitant therapy only: gastrointestinal diseases that may predispose to drug intolerance or poor drug absorption (e.g., inability to take oral medications, previous surgery affecting absorption (e.g., gastric bypass), malabsorption syndromes, and active peptic ulcers).

[0392] For combination therapy with dexamethasone and nirogacestat only: Known intolerance to pretreatment with nirogacestat or gamma secretase inhibitors.

[0393] For combination therapy with dexamethasone and nirogacestat only: Subjects have an abnormal QT interval at screening (>470 ms by Fridericia formula).

[0394] For combination therapy with dexamethasone and nirogacestat only: Subject has a history of congenital or acquired long QTc syndrome.

[0395] For combination therapy with dexamethasone and nirogacestat only: Concomitant medications known to prolong the QT / QTcF interval at the time of informed consent, including Class Ia and Class III antiarrhythmic drugs. Non-arrhythmic drugs that can prolong the QT / QTcF interval are permitted, provided that participants have no additional risk factors for Torsades de Pointes (TdP).

[0396] For combination therapy with dexamethasone and nirogacestat only: Subjects receiving ongoing treatment with strong inducers or moderate to strong inhibitors of CYP3A4 or strong inhibitors or inducers of P-glycoprotein (P-gp). Strong inducers or moderate to strong inhibitors of CYP3A4 and / or strong inducers or inhibitors of P-gp are not permitted from 14 days prior to enrollment through the end of protocol treatment. However, stable doses of CYP3A4-inducing antiepileptic drugs are permitted.

[0397] Discontinuation of clinical trial treatment A patient may be discontinued from study treatment for any of the following reasons: Progressive disease (PD) AE pregnancy Investigator decision Patient decision, non-AE Termination of clinical trial by sponsor Others, non-AE.

[0398] For monotherapy, patients who discontinued SEA-BCMA were considered to have discontinued study treatment. Patients who discontinue study treatment will remain in the study for follow-up until withdrawal of consent, death, or end of study, whichever occurs first.

[0399] In combination therapy, patients who discontinue SEA BCMA and dexamethasone will be considered to have discontinued study treatment. Patients receiving dexamethasone who discontinue corticosteroid therapy may continue to receive SEA-BCMA as monotherapy with medical monitor approval. Patients who discontinue SEA-BCMA will be considered to have discontinued study treatment.

[0400] In combination therapy with dexamethasone and nirogacestat, patients who discontinue SEA-BCMA, dexamethasone, and nirogacestat will be considered to have discontinued study treatment. Patients receiving dexamethasone who discontinue corticosteroid therapy may continue to receive SEA-BCMA and nirogacestat with approval of the medical monitor. Patients who discontinue nirogacestat may continue to receive SEA-BCMA and dexamethasone with approval of the medical monitor. Patients who discontinue SEA-BCMA will be considered to have discontinued study treatment.

[0401] Patient Dropout from the Trial Any patient may be discontinued from the study for any of the following reasons: a) Withdrawal of consent by the patient; b) retreatment; c) Termination of the trial by the sponsor; d) Unable to trace; e) death; f)Other.

[0402] treatment SEA-BCMA is a non-fucosylated monoclonal antibody directed against BCMA.

[0403] Intra-patient dose escalation guidelines for patients who may achieve greater benefit at higher doses than their assigned dose level during dose escalation are described herein.

[0404] explanation SEA-BCMA is a sterile, preservative-free, colorless to light yellow, clear to slightly opalescent solution free of visible particulate matter. SEA-BCMA is supplied in single-dose glass vials. The drug solution was diluted in sterile 0.9% Sodium Chloride Injection, United States Pharmacopeia (USP), or equivalent, for intravenous (IV) administration.

[0405] The SEA-BCMA drug product was labeled with a nominal strength of 100 mg / vial. Each vial contained 110 mg of SEA-BCMA, and the labeled amount could be withdrawn from the vial at the time of use. The SEA-BCMA drug product consisted of SEA-BCMA (20 mg / mL), histidine, arginine, trehalose, and polysorbate 80. The pH of the product was approximately 6.5.

[0406] Dosage and Administration SEA-BCMA will be administered by IV infusion at the assigned dose. SEA-BCMA will not be administered as an intravenous injection or bolus. SEA-BCMA will not be mixed with other medications.

[0407] On Cycle 1 Day 1, patients will be closely observed in the clinic during dose escalation and for at least 6 hours after completion of study treatment administration. Vital signs will be collected. Safety data will be reviewed to allow for additional monitoring for subsequent cycles. The observation period after completion of study treatment administration on Cycle 1 Day 1 will be shortened to 2 hours during monotherapy dose expansion and in monotherapy intensive dosing and combination therapy cohorts with no reported delayed infusion-related reactions (IRRs) after review of data from the dose escalation cohorts.

[0408] The duration of infusion will vary depending on the method of infusion administration and the SEA-BCMA dose.

[0409] The initial approach to administering SEA-BCMA is a stepwise infusion. In a stepwise infusion, the infusion rate is increased at predetermined time intervals until a defined maximum infusion rate is reached. The initial infusion of SEA-BCMA is initiated at a rate of 50 mg / hour. If well tolerated in the first 30 minutes, the rate is gradually increased every 30 minutes (not to exceed a two-fold increase in rate) until the maximum rate (400 mg / hour) is reached as tolerated. For subsequent infusions, the infusion rate can be increased more rapidly over shorter time intervals; for example, after the first 15 minutes, the rate can be gradually increased every 15 minutes (not to exceed a two-fold increase in rate) until the maximum rate is reached as tolerated.

[0410] As clinical trials with graded infusions progress, the maximum rate may be increased or decreased based on cumulative safety data and / or SMC recommendation. In addition, alternative approaches to SEA-BCMA administration may be evaluated to manage potential safety signals, including IRR, if recommended by the SMC. These may include planned implementation of the following strategies: extending the planned infusion duration, fixed duration infusion (administered at a fixed infusion rate), split dose administration, or modification of premedication.

[0411] Fixed duration injection Several criteria are considered for fixed duration infusions:

[0412] If a fixed duration infusion is implemented, the duration of the SEA-BCMA infusion will be defined by the physician. As the clinical trial progresses with the SEA-BCMA infusion, the duration of the infusion may be increased or decreased based on cumulative safety data and / or SMC recommendations.

[0413] In an individual patient, if the patient does not tolerate the infusion, the infusion duration may be increased; the infusion duration in subsequent infusions may also be increased at the investigator's discretion with approval of the medical monitor. Conversely, if the patient does not experience an IRR greater than Grade 1 with successive infusions, the infusion duration may be decreased (i.e., administered at a faster rate) at the investigator's discretion with approval of the medical monitor, and implementation may be dose-cohort specific.

[0414] When a fixed infusion rate is implemented, a dose is administered at a fixed rate rather than over a fixed period of time.

[0415] For example, at a fixed infusion rate of 50 mg / hour, a dose of 100 mg would be infused over 2 hours. As clinical trials progress with fixed infusion rate administration, the rate may be increased or decreased based on cumulative safety data and / or SMC recommendations.

[0416] For individual patients, if the patient does not tolerate the infusion rate, the infusion rate may be decreased in subsequent infusions at the investigator's discretion with approval of the medical monitor. Conversely, if an individual patient does not experience an IRR greater than Grade 1 with successive infusions, the infusion rate may be increased at the investigator's discretion with approval of the medical monitor.

[0417] Split-dose administration Several criteria for split dose administration are considered:

[0418] If split-dose administration is implemented, the dose is divided and administered separately over a period of time. For example, the dose may be split into two parts, with the first 10% of the dose being infused over approximately 45 minutes, followed by a 30-minute observation period during which the patient remains in the infusion chair. Once the investigator determines that the patient has tolerated the initial SEA-BCMA infusion, the remaining 90% is infused over approximately 45 minutes.

[0419] Dose adjustment On a patient-by-patient basis, dosing interval extension for toxicities, including DLT, is permitted with approval by the Medical Monitor. Patients who experience DLT in cycle 1 will not receive further treatment with SEA-BCMA unless clinical benefit is demonstrated by adequately managing toxicity and with approval from the Medical Monitor. Examples of clinical benefit include objective response (OR) as assessed by imaging, laboratory evaluation, or physical examination; or SD of disease-related symptoms and clinical benefit as determined by the investigator. If clinical benefit is demonstrated, the dosing interval will be extended by 50%-100% after discussion with the Medical Monitor. For this decision, information on the type and severity of AEs observed will be taken into account. For patients treated at the lowest dose level, the dosing interval may be extended or treatment may be discontinued for the patient.

[0420] If a patient has a clinically significant unresolved AE on the scheduled dosing date, the dose will be delayed for up to 7 days. Dose delays for other reasons or lasting >7 days will be discussed with the medical monitor; during the DLT period, patients will not receive further treatment with SEA-BCMA unless clinical benefit is demonstrated by adequately controlled toxicity and approval from the medical monitor. In patients requiring a dose delay >7 days due to an unresolved AE, subsequent doses will be reduced or the dosing interval will be extended by 50-100% after discussion with the medical monitor. Dose delays that extend beyond twice the length of the dosing interval will require discontinuation of study treatment for the patient.

[0421] For once every 2 weeks (q2wk) dosing, if on day 15 the patient has a clinically significant unresolved AE that prevents dosing, the day 15 visit will be delayed ≤7 days. If on day 7 the patient is unable to receive the dose, the second dose of the cycle will be withdrawn, the day 15 visit will be omitted, and a day 22 visit will be performed. If the day 15 dose is delayed ≤7 days, required study evaluations on days 15-28 will be delayed the same number of days according to the dose delay, and administration of study drug for the next cycle will also be delayed by at least the same number of days.

[0422] In intensive dosing weekly induction cycles 1 and 2, if a patient has a clinically significant unresolved AE that prevents dosing on days 8, 15, or 22, the dose may be delayed by ≦3 days. If the patient is unable to receive the dose on day 3, the dose of SEA-BCMA will be withdrawn and the corresponding visit will be omitted; dosing and visit schedule will resume the following week (e.g., day 22 if day 15 is omitted). However, if the day 8, 15, or 22 dose is delayed ≦3 days, subsequent study evaluations within the same cycle will be delayed the same number of days according to the dose delay, and administration of the next dose of study drug will also be delayed by at least the same number of days.

[0423] During the DLT period (Cycle 1), growth factor and transfusion support are discouraged unless medically necessary; patients receiving growth factor (e.g., G-CSF or GM-CSF) or transfusion (other than red blood cell transfusions for MM-associated anemia) support during this period for reasons other than DLT may not be evaluated for DLT. Growth factor support will be considered for prevention or treatment of cytopenias in subsequent cycles (Table 4). During dose escalation, patients with grade 4 neutropenia will have a follow-up complete blood count (CBC) with differential obtained for 5 days from the consideration time of evaluation for DLT. In addition, patients with grade 3 electrolyte abnormalities will have a follow-up chemistry panel obtained for 72 hours from the consideration time of evaluation for DLT. Serum chemistry and CBC will be collected minimally on a weekly schedule during dose delays due to toxicity.

[0424] Table 4 lists recommended dose adjustments for study treatment-related toxicities.

[0425] Table 4. Recommended dose adjustments for SEA-BCMA-related toxicities TIFF2024534602000019.tif120168 a Delays in treatment of >7 days should be discussed with the medical monitor

[0426] If a patient tolerates at least one cycle of SEA-BCMA and achieves SD or better, intrapatient dose escalation is permitted. Additional treatment cycles may be administered at one dose level below the dose level currently ongoing for dose escalation (or at the MTD, if one has been determined).

[0427] Dexamethasone Dosage and Administration Dexamethasone is given on days 1, 8, 15, and 22 of each 28-day cycle. Dexamethasone is administered via IV infusion or orally (PO) at a dose of 40 mg. In combination therapy with nirogacestat and SEA-BCMA, dexamethasone is administered IV only. The dose of dexamethasone is 20 mg in patients ≥75 years, or with a BMI <18.5, or known to be intolerant to 40 mg dexamethasone. On the day SEA-BCMA is administered, dexamethasone is administered 1-3 hours prior to the SEA-BCMA infusion.

[0428] Dose adjustment Dose adjustments due to toxicity and supportive care are listed in Table 5.

[0429] Table 5. Dose Adjustments for Dexamethasone-Related Toxicity TIFF2024534602000020.tif211170 a Patients enrolled in the trial who have high hemoglobin A1c (HbA1c) (≥ 6.5%) or fasting glucose (≥ 126 mg / dL) at screening must be referred to an appropriate provider for glucose management within 1 week prior to or within 1 week of starting study treatment in Cycle 1.

[0430] Nirogacestat Dose Administration Nirogacestat is administered at a dose of 100 mg PO BID on days 1-28 of each 28-day cycle. Patients should take the dose orally BID approximately every 12 hours, regardless of meals. If a patient misses a scheduled dose of nirogacestat and it is within 6 hours of the scheduled dose, the patient should take the missed dose immediately and resume study treatment according to the usual dosing schedule. If more than 6 hours have passed since the scheduled dose, the patient should be instructed not to take the missed dose and to resume study treatment as normal. Patients should not take two doses together to "make up" for the missed dose. If a patient vomits at any time after taking a dose, the patient should be instructed not to take another dose to "make up" for the vomited dose and to resume subsequent doses as normal. If a patient unknowingly takes an extra dose, the patient should not take the next scheduled dose of study treatment. Delivery of nirogacestat via a nasogastric or percutaneous gastrostomy tube is not permitted. Tablets should be swallowed whole with water and not split or chewed. For a once-daily (QD) dose of 100 mg, doses may be taken within 12 hours of a scheduled missed dose.

[0431] Dose adjustment Nirogacestat dosing will be interrupted and / or reduced for AEs listed in Table 6 and below.

[0432] If a patient experiences an AE listed in Table 6 considered to be related to nirogacestat, nirogacestat will be maintained until the event is grade ≦1 or has resolved to baseline, then nirogacestat will be resumed at a reduced dose as listed in Table 6.

[0433] If AEs do not return to grade ≤1 or baseline after 7 days of nirogacestat maintenance, nirogacestat may be restarted only after consultation with the sponsor.

[0434] If the same grade ≥3 AE recurs upon dose reduction and the AE is considered related to nirogacestat, it may be permanently discontinued after consultation with the sponsor.

[0435] Table 6. Recommended dose adjustments for nirogacestat-related toxicities TIFF2024534602000021.tif110166

[0436] A second dose reduction to 50 mg QD may be permitted after consultation with the sponsor's medical monitor. Additional management of nirogacestat-related toxicities is described below:

[0437] Liver Chemistry stopping criteria for Nirogacestat: Discontinuation of Nirogacestat for abnormal liver function should be considered by the investigator when the patient meets one of the conditions outlined in Figure 1 or if the investigator believes it is in the patient's best interest.

[0438] Management of nirogacestat-related adverse events Antidiarrheal, antiemetic therapy Primary prophylaxis of diarrhea, nausea, and vomiting is permitted in the first cycle. Primary prophylaxis in subsequent cycles is at the discretion of the investigator. Diarrhea events have been commonly reported in patients receiving nirogacestat. Patients experiencing diarrhea considered to be related to nirogacestat should be treated with loperamide or other institutional standard of care. The recommended initial dose of loperamide is 4 mg, followed by 2 mg after each loose stool until diarrhea is controlled, after which the dose should be reduced to meet individual requirements. Loperamide should be dosed according to the attending physician's medical discretion. Patients should also receive adequate fluid and electrolyte supplementation, including dietary phosphate supplementation, as needed. If diarrhea is grade ≥ 3 and persists for ≥ 3 days despite maximal medical therapy, nirogacestat should be maintained until diarrhea returns to grade ≤ 1 or baseline, then resumed at a dose of 100 mg QD (Table 6). If diarrhea remains grade ≤1 or has not returned to baseline after 7 days on study treatment, study treatment may be resumed at a reduced dose of 100 mg once daily (QD) but only after consultation with the medical monitor.

[0439] Skin rash Events of skin rash have been reported in patients receiving nirogacestat.

[0440] Non-acne-like rash / skin rash Pruritic skin eruptions / skin rashes and other non-acne-like eruptions should be treated with moisturizers such as Cerave or Eucerin or another equivalent.If symptomatic, low-potency topical steroids such as betamethasone valerate lotion (0.05%), desonide cream (0.05%), fluocinolone acetonide solution (0.01%), dexamethasone sodium phosphate cream (0.1%), hydrocortisone acetate cream (1%), methylprednisolone acetate cream (0.25%) or equivalent may be used.

[0441] Acne-like rash For pustular skin eruptions, topical clindamycin (0.1%) gel or lotion applied BID is most useful, rather than steroids. In severe cases, semisynthetic oral tetracyclines such as doxycycline or minocycline may also be useful, provided appropriate precautions are taken in women of childbearing potential.

[0442] Follicular cyst Follicular cysts may be associated with disruption of the gamma secretase and Notch signaling pathways that help maintain pilosebaceous function. This adverse reaction was observed in a phase 2 trial of nirogacestat in desmoid patients conducted by the NCI (O'Sullivan Coyne, 2018). If this event is suspected, a dermatologist visit is recommended for appropriate management recommendations.

[0443] Management of adverse reactions 1. Management of SEA-BCMA Infusion Reactions IRRs may occur during infusion of monoclonal antibody therapies such as SEA-BCMA. Infusions should be administered in locations appropriately equipped and staffed to manage anaphylaxis if it occurs. Any supportive measures consistent with optimal patient care should be taken throughout the trial according to institutional standards. Supportive measures may include extending the infusion time and / or administering medications for IRR.

[0444] During dose escalation, additional mitigation strategies may be explored to manage IRR. These may be implemented upon recommendation of the SMC and may include, but are not limited to, any or all of the following: Slowing, interrupting, or other decisions regarding administration of SEA-BCMA Possible pre- or post-medications for injection, for example: Antihistamines, such as diphenhydramine 50 mg IV or equivalent and famotidine 40 mg IV or equivalent Antipyretics, e.g., acetaminophen 500-1,000 mg PO Antiemetics, e.g. ondansetron IV fluid support, e.g., saline Anti-rigor medications, such as meperidine Vasopressors Corticosteroids, such as hydrocortisone 100 mg IV or equivalent or methylprednisolone 40 mg IV or equivalent (in patients not receiving concomitant dexamethasone)

[0445] Recommendations for the management of IRR are detailed in Table 7. IRR should be graded according to the NCI-CTCAE version 4.03 guidelines.

[0446] Table 7. Management of infusion-related reactions TIFF2024534602000022.tif221166 by NCI-CTCAE version 4.03

[0447] If anaphylaxis occurs, administration of SEA-BCMA should be immediately and permanently discontinued.

[0448] All grade 3 or 4 IRR events (occurring during or within ≤24 hours post-infusion) or hypersensitivity reactions (occurring >24 hours post-infusion), whether or not related to SEA-BCMA, must be reported immediately to the sponsor or its designee. All grade 4 events are serious adverse events (SAEs) and should be reported within the 24-hour SAE reporting period.

[0449] Patients experiencing a ≥ Grade 3 IRR or delayed hypersensitivity reaction will require an infusion / hypersensitivity reaction (IHR) visit and an IHR return visit for evaluation and collection of blood specimens for mechanism of action analysis of the reaction.

[0450] Pre- and post-medication requirements for SEA-BCMA Routine premedication for infusion reactions should be administered prior to the first dose of SEA-BCMA. However, patients who experience an IRR will receive follow-up treatment with premedication such as an antihistamine (e.g., diphenhydramine 50 mg IV or equivalent and famotidine 40 mg IV or equivalent), corticosteroid (e.g., hydrocortisone 100 mg IV or equivalent), or acetaminophen (e.g., 500-1,000 mg PO) at least 30 minutes prior to infusion. As clinical trials with SEA-BCMA infusions progress, routine premedication prior to the first dose of investigational treatment may be initiated if recommended by the SMC.

[0451] No follow-up medication is required for SEA-BCMA.

[0452] In the intensive dosing cohort, dexamethasone combination cohort, and nirogacestat and dexamethasone combination cohort, routine premedication for infusion reactions should be administered prior to SEA-BCMA infusion with the following regimens, unless contraindicated or otherwise recommended by the SMC or medical monitor: Antipyretics + Antihistamines: Administer approximately 45-90 minutes prior to SEA BCMA infusion (required for all patients at all doses during Cycle 1 and Cycle 2) (1) Acetaminophen, oral, 650-1,000 mg (2) Diphenhydramine, oral or IV, 25 to 50 mg (or equivalent H1 blocker)

[0453] If no IRR (infusion-related reaction) is experienced during Cycle 1 or Cycle 2: Starting with the Day 1 dose of Cycle 3, one or both premedications may be omitted.

[0454] IRR occurs despite acetaminophen + antihistamine

[0455] Treat supportively based on symptoms.

[0456] In monotherapy patients (not receiving dexamethasone), add: Premedicate with methylprednisolone, IV, 100 mg (or equivalent dose of intermediate- to long-acting corticosteroid) if needed 1-3 hours prior to the next SEA-BCMA infusion. If this infusion is tolerated without IRR, the methylprednisolone dose may be reduced to 60 mg (or equivalent dose of intermediate- to long-acting corticosteroid) given either orally or IV prior to the subsequent dose.

[0457] Additional premedication (e.g., H2 blockers or leukotriene inhibitors) may be considered.

[0458] In combination patients (receiving dexamethasone), the following is added: Premedicate with an H2-blocker (famotidine 40 mg IV or equivalent) if needed 45-90 minutes prior to all subsequent SEA-BCMA doses.

[0459] Additional premedication (e.g., leukotriene inhibitors) may be considered.

[0460] Clinical Trial Evaluation Screening / Baseline Assessment Only patients who fulfill all inclusion and exclusion criteria will be enrolled in this study. Evaluation will begin after signed informed consent is obtained from the patient.

[0461] The patient's medical history will include a thorough review of notable medical history, current condition, any prior malignancies and response to prior treatments, and any concomitant medications. The number of prior lines of therapy will be determined using the criteria established by Rajkumar et al. (Rajkumar et al., Blood 126(7): 921-2, 2015). Briefly: A new line of therapy is considered if a treatment regimen is discontinued for any reason and a different treatment regimen is initiated. A new line of therapy is also considered to be initiated when, for any reason, there is an unplanned substitution or addition of one or more drugs to an existing course of therapy. In patients who have received >1 ASCT (except in the case of planned tandem ASCT), each transplant following the first should be considered a new line of treatment. A planned treatment course with multiple phases, such as induction therapy followed by a first ASCT and maintenance therapy, is considered as 1-line therapy.

[0462] Perform baseline plasmacytoma scan during screening only in case of suspected or known plasmacytoma. Perform plasmacytoma evaluations at any time during treatment to confirm a response of PR or better, or to confirm PD if clinically indicated.

[0463] A bone marrow aspirate (including a bone marrow aspirate clot) and biopsy are required as part of the baseline visit.

[0464] The physical examination includes evaluation of the following body parts / systems: abdomen, extremities, head, heart, lungs, neck, and nervous system. Weight and height will also be measured; height measurements obtained within the past 12 months may be used.

[0465] Blood and urine tests include CBC with differential, serum chemistry panel, serology (Hepatitis B and C), PT / PTT / INR, hBA1c (for patients in the combination cohort), and urinalysis. A pregnancy test is performed for patients of childbearing potential. Microscopic urinalysis is required if the urinalysis result is abnormal. A spot urine sample is sufficient for UPC ratio calculation; however, if UPC>2, an additional 24-hour urine collection is required for UPC calculation.

[0466] Blood samples will be collected for pharmacodynamic biomarker assessment.

[0467] Response / Efficacy Assessment Response assessments include SPEP / immunofixation, UPEP / immunofixation (in patients with baseline urinary M-protein ≥ 200 mg / 24 hours or for assessment of VGPR or better), SFLC, quantitative immunoglobulins, and plasmacytoma assessment by imaging (at baseline, every 4 cycles, and at additional time points if clinically indicated). These samples will be collected for evaluation at the site. In addition, for IgG myeloma patients, blood will be analyzed using modified SPEP in a central laboratory.

[0468] Bone marrow aspirate, including BM aspirate clock, and biopsy are required as part of the baseline visit, as well as on day 4 of cycle 1 (expansion cohort only, concomitant with observed or emerging activity during dose escalation), days 22-28 of cycle 2, and to confirm CR in patients with blood and urine M-protein negative. For monotherapy intensive dosing and combination therapy, bone marrow aspirate and biopsy are also required on cycle 6 and every six cycles thereafter. Both bone marrow aspirate and biopsy specimens will be evaluated at the study site for clinical evaluation (except for the cycle 1 day 4 specimen). In addition, biomarker analysis will be performed on these specimens at the central site. Any additional bone marrow aspirates and biopsies collected at any other time during the clinical trial may be submitted for evaluation at the central site.

[0469] Bone marrow specimens will be examined at a central facility for assessment of response / resistance to SEA-BCMA, which may include, but are not limited to, assessment of BCMA expression, immune activation, disease risk profiling, gene expression profiling, and minimal residual disease (MRD) assessment.

[0470] Determination of antitumor activity will be based on response assessments made according to the 2016 IMWG criteria (Kumar et al., Lancet Oncol 17(8): e328-46, 2016) and treatment decisions by the investigator will be based on these assessments. Clinical responses of sCR, CR, VGPR, PR, SD, and PD will be determined at each assessment based on the performing laboratory (and for IgG MM patients, a modified SPEP will be performed by the central laboratory), radiology, and clinical assessments. Disease progression will be based on IMWG 2016 criteria and / or clinical deterioration by the investigator. All IMWG responses are confirmed responses. Determination of immunophenotypic CR, MRD status, and minimal response will be made according to IMWG 2016 criteria, if applicable.

[0471] Pharmacokinetic and immunogenicity evaluation Collect blood and bone marrow samples for PK and ATA assessment. Measure serum and bone marrow concentrations of SEA-BCMA and serum concentrations of ATA using validated assays. Remaining PK samples are stored for potential analysis of SEA-BCMA-related species. Assays include enzyme-linked immunosorbent assay (ELISA) assays as well as other assays if further characterization is required.

[0472] ATA is assessed using a validated electrochemiluminescence assay.

[0473] Biomarker Research Peripheral blood and bone marrow samples for biomarker analysis will be collected at the time points outlined in the following sections. In addition to protocol-defined tumor specimen collections, bone marrow specimens collected at the investigator's discretion may also be submitted for biomarker analysis at the central site. For all bone marrow collections, the site will provide bone marrow aspirates as well as bone marrow biopsy and aspirate clot specimens as formalin-fixed paraffin-embedded (FFPE) blocks. For samples obtained for SOC, unstained slides may be submitted if FFPE blocks for bone marrow biopsy or clot are not available. Samples will be sent to the central laboratory for analysis as described in the test manual.

[0474] Samples are evaluated for expression of BCMA and related biomarkers that may be related to the activity of SEA-BCMA and / or change in response to treatment. Analysis of tumor tissue and peripheral blood can also include markers related to prognosis, response or resistance. Changes in peripheral blood immune cell subsets are measured as potential pharmacodynamic and safety markers.

[0475] Gene profiling of effector cells Determine small nucleotide polymorphisms in FcγRII and FcγRIII that may influence response to SEA-BCMA (including but not limited to testing for the following polymorphisms): FCGRIIIA - 158V / F FCGRIIA-131H / R

[0476] Serum free light chains and improved SPEP Kappa and lambda free light chains are quantified in patient sera as surrogate markers of anti-tumor activity.

[0477] For IgG myeloma patients with low serum M protein SPEP levels, a reflex modified SPEP assay will be used to assess residual serum M protein free from interference from SEA-BCMA.

[0478] Peripheral blood immunophenotyping Peripheral blood samples are collected for evaluation of circulating immune cells by flow cytometry. Changes in circulating immune cell subsets are measured as potential pharmacodynamic markers of SEA-BCMA activity. Flow cytometry measurements include, but are not limited to, characterizing NK cells, monocytes, T cells, and B cells.

[0479] Plasma cytokines / chemokines Circulating cytokine / chemokine levels may be assessed by ELISA and / or multiplex cytokine / chemokine assays.

[0480] Soluble targets and ligands Levels of circulating soluble BCMA (sBCMA), APRIL and BAFF may be assessed by ELISA or other methods (e.g., LC-MS or flow cytometry).

[0481] Plasma biomarkers and PBMCs Plasma and PBMCs will be collected for retrospective analysis of cellular and circulating biomarkers associated with response and / or resistance to SEA-BCMA.

[0482] Tumor tissue characterization Bone marrow aspirates and biopsies are collected at baseline and during treatment to assess disease-associated immune subsets, characterize tumor burden, explore depth of effect, and determine prognostic signatures and response to treatment. Further molecular characterization of tumors for additional proteins, gene expression profiling, and myeloma disease-associated risk markers may also be evaluated to identify biomarkers predictive of response or resistance to SEA-BCMA.

[0483] Bone marrow immunophenotyping Expression of BCMA on tumor plasma cells and the presence and changes of immune components in the bone marrow may be assessed by flow cytometry and / or immunohistochemistry.

[0484] Gene Expression Profiling / NGS / FISH Baseline and treatment-associated changes in gene expression profiles in the tumor and tumor microenvironment may be assessed by RNA sequencing of tumor (CD138 positive) and non-tumor (CD138 negative) cells purified from bone marrow aspirates to determine prognostic disease risk signatures, as well as baseline characteristics and treatment-related changes that may correlate with response or resistance. Cytogenetic analysis or DNA sequencing of enriched CD138 positive plasma cells from bone marrow aspirates collected at baseline may also be performed to further determine genetic changes that may predict or be associated with response to SEA-BCMA.

[0485] MRD To understand SEA-BCMA activity, MRD assessment may be performed on relevant specimens using an adapted NGS for MRD assay (Martinez-Lopez et al., Blood 123(20): 3073-9, 2014).

[0486] Bone marrow plasma Bone marrow plasma may be collected and tested for levels of soluble targets, ligands and / or cytokines / chemokines that may influence or correlate with response to SEA-BCMA.

[0487] Adverse events In accordance with the International Council for Harmonisation (ICH) E2A guideline Definitions and Standards for Expedited Reporting, and 21 CFR 312.32, IND Safety Reporting, an AE is any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product that does not necessarily have a causal relationship to that treatment.

[0488] In general, abnormal laboratory values ​​should not be recorded as AEs unless they are associated with clinical signs or symptoms, do not require intervention, do not result in an SAE, or do not result in study termination or interruption / discontinuation of study treatment (SEA-BCMA and / or dexamethasone). When recording an AE due to a laboratory abnormality, the resulting medical condition should be recorded rather than the abnormality itself (e.g., record "anemia" rather than "low hemoglobin").

[0489] Serious Adverse Events An AE was classified as an SAE if it met one of the following criteria: TIFF2024534602000023.tif126164

[0490] Adverse event severity AE severity will be graded using NCI-CTCAE version 4.03.

[0491] AE severity and seriousness are assessed independently. "Severity" characterizes the intensity of the AE. "Severe" is a regulatory definition and serves as a guide for defining regu...

Claims

1. A pharmaceutical comprising an antibody or antigen-binding fragment thereof that specifically binds to B-cell maturation antigen (BCMA) for use in a method of treating multiple myeloma (MM) in a subject, comprising: The method comprises: one or more doses of the antibody or antigen-binding fragment thereof are independently administered to the subject from about 100 mg of the antibody or antigen-binding fragment thereof to about 2,000 mg of the antibody or antigen-binding fragment thereof; and said one or more doses of nirogacestat are independently administered to said subject at about 80 mg to about 120 mg of nirogacestat; The pharmaceutical composition comprising:

2. The pharmaceutical according to claim 1, wherein the antibody or antigen-binding fragment thereof is a non-fucosylated antibody or antigen-binding fragment thereof.

3. the antibody or antigen-binding fragment thereof a heavy chain variable region comprising CDR1 comprising SEQ ID NO: 1, CDR2 comprising SEQ ID NO: 2, and CDR3 comprising SEQ ID NO: 3; a light chain variable domain comprising CDR1 comprising SEQ ID NO: 5, CDR2 comprising SEQ ID NO: 6, and CDR3 comprising SEQ ID NO: 7; The pharmaceutical composition of claim 1, comprising:

4. The pharmaceutical of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 4, and a light chain variable domain comprising an amino acid sequence that is at least 80% identical to SEQ ID NO:

8.

5. The pharmaceutical composition of claim 4, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 4, and a light chain variable domain comprising an amino acid sequence that is at least 90% identical to SEQ ID NO:

8.

6. The pharmaceutical composition of claim 5, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 4 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:

8.

7. The pharmaceutical of claim 1, wherein the antibody or antigen-binding fragment thereof is humanized.

8. The pharmaceutical according to claim 1, wherein the antibody is an IgG1 antibody.

9. The pharmaceutical described in claim 1, wherein in the method, a single dose of the antibody or its antigen-binding fragment is administered to the subject.

10. A pharmaceutical described in any one of claims 1 to 8, wherein in the method, two or more doses of the antibody or its antigen-binding fragment are administered independently to the subject.

11. The pharmaceutical described in claim 10, wherein in the method, two or more doses of the antibody or its antigen-binding fragment are independently administered to the subject at a frequency of once a week to approximately once every four weeks.

12. The pharmaceutical composition of claim 10, wherein the two or more doses of the antibody or antigen-binding fragment thereof include (1) one or more induction doses administered independently to the subject during an induction phase, and (2) one or more maintenance doses of the antibody or antigen-binding fragment thereof administered independently to the subject during a maintenance phase following the induction phase.

13. The pharmaceutical described in claim 12, wherein in the method, two or more induction doses are administered independently to the subject.

14. 14. The method of claim 13, wherein each induction dose comprises about 100, about 200, about 400, about 800, or about 1600 mg of the antibody or antigen-binding fragment thereof.

15. The pharmaceutical composition described in claim 12, wherein in the method, two or more maintenance doses are administered independently to the subject.

16. The pharmaceutical composition described in claim 15, wherein, in the method, each of the two or more maintenance doses is independently administered to the subject once every 1 to 4 weeks.

17. The pharmaceutical described in claim 12, wherein in the method, a dose of the antibody or its antigen-binding fragment is administered intravenously to the subject.

18. The pharmaceutical composition of claim 12, wherein in the method, a single dose of nirogacestat is administered to the subject.

19. The pharmaceutical composition of claim 12, wherein in the method, two or more doses of nirogacestat are administered independently to the subject.

20. The pharmaceutical composition of claim 12, wherein in said method, each dose of nirogacestat contains about 100 mg of nirogacestat.

21. The pharmaceutical composition of claim 19, wherein in the method, two or more doses of nirogacestat are independently administered to the subject at a frequency of about once per day to about four times per day.

22. The pharmaceutical composition of claim 19, wherein the dose of nirogacestat is administered orally to the subject.

23. The pharmaceutical composition of claim 12, wherein the method further comprises independently administering one or more doses of dexamethasone to the subject.

24. The pharmaceutical described in claim 23, wherein the method includes administering a single dose of dexamethasone to the subject, or administering two or more doses of dexamethasone independently to the subject.

25. (a) one or more doses of a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to B-cell maturation antigen (BCMA), wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR1 comprising SEQ ID NO: 1, a CDR2 comprising SEQ ID NO: 2, and a CDR3 comprising SEQ ID NO: 3, and a light chain variable domain comprising a CDR1 comprising SEQ ID NO: 5, a CDR2 comprising SEQ ID NO: 6, and a CDR3 comprising SEQ ID NO: 7; (b) instructions for carrying out the method in the medicament of claim 12; Includes a kit.

26. 26. The kit of claim 25, further comprising one or more doses of a pharmaceutical composition comprising nirogacestat and / or one or more doses of a pharmaceutical composition comprising dexamethasone.

Images