Methods for treating multiple myeloma

Abstract

Embodiments of the present invention relate to a method for treating subjects requiring treatment for multiple myeloma, and include administering a BCMAxCD3 bispecific antibody to the subjects on a bi-weekly schedule.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims the interests of U.S. Provisional Patent Applications No. 63 / 497,121, No. 63 / 497,122, No. 63 / 497,122, No. 63 / 504,164, No. 63 / 505,587, No. 63 / 505,587, No. 63 / 594,786, No. 63 / 594,786, No. 63 / 568,836, filed on 22 March 2024. The entire contents of the above applications are incorporated herein by reference.

[0002] (Sequence Listing) This application includes a computer-readable sequence listing file submitted with this application in XML file format, the entire contents of which are incorporated herein by reference. The sequence listing XML file submitted with this application is titled "JBI6802WOPCT1_Sequence_Listing.xml", was created on 18 April 2024, and is 26,364 bytes in size.

[0003] (Field of invention) A method for treating multiple myeloma will be disclosed. [Background technology]

[0004] Multiple myeloma (MM) is a type of plasma cell cancer. Mechanistically, multiple myeloma is characterized by the production of monoclonal proteins (M proteins) composed of defunctional pathological immunoglobulins or their fragments. The proliferation of multiple myeloma cells subsequently leads to migration from the normal bone marrow niche, while the overproduction of M proteins causes characteristic osteolytic lesions, increased susceptibility to infection, hypercalcemia, renal dysfunction or failure, and neurological complications.

[0005] Treatment options for multiple myeloma have improved over time and vary depending on the aggressiveness of the disease, underlying prognostic factors, the patient's health status, and existing comorbidities. Therapeutic options include proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), alkylating agents, monoclonal antibodies (mAbs), antibody-drug conjugates, histone deacetylase inhibitors, nucleoprotein transport inhibitors, chimeric antigen receptor (CAR) T-cell therapy, and stem cell transplantation.

[0006] Despite these therapeutic outcomes, the disease relapses and is associated with further risk factors (e.g., comorbidities or aging), thus justifying the need for novel therapeutic approaches, such as new dosages and treatment regimens. Particularly in elderly patients for whom stem cell transplantation is often not a viable option, and in patients with refractory disease who have exhausted numerous therapies, multiple myeloma remains an incurable malignancy with significant morbidity and mortality, representing an unmet medical need. In particular, there is still a need for therapeutic regimens that deliver rapid, deep, and sustained clinical responses while providing a manageable safety profile. [Overview of the Initiative]

[0007] Embodiments of the present invention provide a method for treating subjects in need of treatment for multiple myeloma, the method comprising administering a therapeutically effective dose of a BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W).

[0008] Another embodiment of the present invention provides a method for treating a subject in need of treatment for multiple myeloma, the method comprising administering a therapeutically effective dose of a BCMAxCD3 bispecific antibody in a Q4W dosing schedule.

[0009] In certain embodiments, a method for treating a subject requiring treatment for multiple myeloma comprises administering a therapeutically effective dose of a BCMAxCD3 bispecific antibody (e.g., teclistamaib) to the subject on a bi-weekly (Q2W) and / or monthly (Q4W) schedule, wherein the subject has been diagnosed with multiple myeloma.

[0010] In certain embodiments, a method for treating a subject requiring treatment for multiple myeloma includes administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a bi-weekly (Q2W) schedule.

[0011] In certain embodiments, the BCMA × CD3 bispecific antibody includes a BCMA-binding domain comprising HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, as well as a CD3-binding domain comprising HCDR1 of SEQ ID NO: 14, HCDR2 of SEQ ID NO: 15, HCDR3 of SEQ ID NO: 16, LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO: 19.

[0012] In a particular embodiment, the BCMA-binding domain includes a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and the CD3-binding domain includes a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21.

[0013] In certain embodiments, the BCMA×CD3 bispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0014] In certain embodiments, the BCMA×CD3 bispecific antibody is of the IgG4 isotype.

[0015] In certain embodiments, the BCMAxCD3 bispecific antibody contains one or more substitutions in its Fc region.

[0016] In certain embodiments, the BCMAxCD3 bispecific antibody is of the IgG4 isotype and contains S228P, F234A, and L235A substitutions (by EU numbering) in its Fc region.

[0017] In certain embodiments, the BCMA×CD3 bispecific antibody is of the IgG4 isotype and contains S228P, F234A, L235A, F405L, and R409K substitutions (by EU numbering) in its Fc region.

[0018] In certain embodiments, the Fc region of the BCMA-binding arm contains S228P, F234A, and L235A substitutions (by EU numbering) in its Fc region.

[0019] In certain embodiments, the Fc region of the CD3-binding arm contains S228P, F234A, L235A, F405L, and R409K substitutions (by EU numbering) in its Fc region.

[0020] In certain embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 23.

[0021] In certain embodiments, the BCMA×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 23.

[0022] In certain embodiments, the BCMA×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 23.

[0023] In certain embodiments, the BCMA×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 23.

[0024] In certain embodiments, the BCMAxCD3 bispecific antibody is teclistamab.

[0025] In certain embodiments, the subject has relapsed or refractory multiple myeloma (e.g., the subject has been previously treated in 2 - 14 lines of therapy).

[0026] In certain embodiments, the subject has previously received at least 3 lines of therapy.

[0027] In certain embodiments, the subject has previously received at least 4 lines of therapy.

[0028] In certain embodiments, the subject has previously received at least 5 lines of therapy (pentad exposure).

[0029] In certain embodiments, the subject has previously received at least 3 lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti - CD38 monoclonal antibody.

[0030] In certain embodiments, the subject has previously received at least four lines of treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0031] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W).

[0032] In certain embodiments, the method includes subcutaneous administration of one or more escalating doses of BCMAxCD3 bispecific antibody to the target before administering a first therapeutic dose of BCMAxCD3 bispecific antibody.

[0033] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg to approximately 3000 μg / kg on a bi-weekly (Q2W) schedule.

[0034] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg on a bi-weekly (Q2W) schedule.

[0035] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 3000 μg / kg on a bi-weekly (Q2W) schedule.

[0036] In certain embodiments, the method includes subcutaneously administering at least one therapeutic dose of BCMAxCD3 bispecific antibody to the target on a weekly (QW) schedule, followed by administering a therapeutic dose of BCMAxCD3 bispecific antibody to the target on a bi-weekly (Q2W) schedule.

[0037] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least one 28-day treatment cycle, and then administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W).

[0038] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least two 28-day treatment cycles, followed by administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W).

[0039] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least three 28-day treatment cycles, followed by administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W).

[0040] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least four 28-day treatment cycles, followed by administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W).

[0041] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least five 28-day treatment cycles, followed by administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W).

[0042] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least six 28-day treatment cycles, followed by administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W).

[0043] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly (QW) schedule for at least 6 months, followed by administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly (Q2W) schedule.

[0044] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a weekly dosing schedule (QW) until the subject achieves partial response, very good partial response, complete response, or exact complete response, as determined by the IMWG response criteria, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W).

[0045] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a weekly dosing schedule (QW) until the subject achieves a very good partial response, complete response, or exact complete response, as determined by the IMWG response criteria, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W).

[0046] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a weekly dosing schedule (QW) until the subject achieves complete response or strict complete response as determined by the IMWG response criteria, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W).

[0047] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a weekly dosing schedule (QW) until the subject achieves partial response, very good partial response, complete response, or exact complete response after four or more treatment cycles, as determined by the IMWG response criteria, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W).

[0048] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a weekly dosing schedule (QW) until the subject achieves partial response, very good partial response, complete response, or exact complete response for at least 6 months, as determined by the IMWG response criteria, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W).

[0049] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody to the target on a weekly dosing schedule (QW) until the target achieves a complete response or a strict complete response for at least 6 months, as determined by the IMWG response criteria, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody to the target on a bi-weekly dosing schedule (Q2W).

[0050] In certain embodiments, each therapeutic dose of BCMAxCD3 bispecific antibody administered on a weekly schedule (QW) is the same as the therapeutic dose of BCMAxCD3 bispecific antibody administered on a bi-weekly schedule (Q2W).

[0051] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg to approximately 3000 μg / kg on a weekly (QW) schedule.

[0052] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg on a weekly (QW) schedule.

[0053] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 3000 μg / kg on a weekly (QW) schedule.

[0054] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg on a weekly (QW) schedule, and then subcutaneous administration of the BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg on a bi-weekly (Q2W) schedule.

[0055] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg on a weekly (QW) schedule, followed by subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 3000 μg / kg on a bi-weekly (Q2W) schedule.

[0056] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody on a bi-weekly schedule (Q2W), followed by subcutaneous administration of the BCMAxCD3 bispecific antibody on a monthly schedule (Q4W).

[0057] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody on a weekly (QW) schedule, followed by subcutaneous administration of the BCMAxCD3 bispecific antibody on a bi-weekly (Q2W) schedule, and then subcutaneous administration of the BCMAxCD3 bispecific antibody on a monthly (Q4W) schedule.

[0058] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody on a bi-weekly schedule (Q2W), and, if the subject achieves a partial response, a very good partial response, a complete response, or a complete response, subcutaneous administration of the BCMAxCD3 bispecific antibody on a monthly schedule (Q4W).

[0059] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody on a bi-weekly schedule (Q2W), and, if the subject achieves a complete response or a strict complete response, subcutaneous administration of the BCMAxCD3 bispecific antibody on a monthly schedule (Q4W).

[0060] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody on a bi-weekly schedule (Q2W), and, if the subject achieves a complete response or a severe complete response by or after treatment cycle 12, subcutaneous administration of the BCMAxCD3 bispecific antibody on a monthly schedule (Q4W).

[0061] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody on a bi-weekly schedule (Q2W) for at least 6 months, followed by subcutaneous administration of the BCMAxCD3 bispecific antibody on a monthly schedule (Q4W).

[0062] In certain embodiments, the method includes subcutaneous administration of one, two, or three escalating doses of BCMAxCD3 bispecific antibodies before subcutaneous administration of a first therapeutic dose.

[0063] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody in progressively increasing doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg before subcutaneous administration of a first therapeutic dose.

[0064] In certain embodiments, the method includes subcutaneous administration of one or two escalating doses of BCMAxCD3 bispecific antibodies before subcutaneous administration of a first therapeutic dose.

[0065] In certain embodiments, the method includes subcutaneous administration of two escalating doses of a BCMAxCD3 bispecific antibody before subcutaneous administration of a first therapeutic dose.

[0066] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody in escalating doses of 60 μg / kg and 300 μg / kg before subcutaneous administration of a first therapeutic dose.

[0067] In certain embodiments, the method includes subcutaneous administration of escalating doses of a BCMAxCD3 bispecific antibody, spaced 2 to 4 days apart, before subcutaneous administration of a first therapeutic dose.

[0068] In certain embodiments, the method comprises subcutaneously administering one or more escalating doses of a BCMAxCD3 bispecific antibody before subcutaneously administering a first therapeutic dose, the first therapeutic dose being administered 2 to 4 days after the last escalating dose.

[0069] In a particular embodiment, the method includes subcutaneous administration of a first escalating dose of 60 μg / kg of BCMAxCD3 bispecific antibody, followed by subcutaneous administration of a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, followed by subcutaneous administration of a first therapeutic dose of BCMAxCD3 bispecific antibody 2 to 4 days later.

[0070] In a particular embodiment, the method includes subcutaneous administration of a first escalating dose of 60 μg / kg of BCMAxCD3 bispecific antibody, followed by subcutaneous administration of a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, followed by subcutaneous administration of a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly (QW) schedule over a certain period, followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly (Q2W) schedule.

[0071] In a particular embodiment, the method includes subcutaneous administration of a first escalating dose of 60 μg / kg of BCMAxCD3 bispecific antibody, followed by subcutaneous administration of a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, followed by subcutaneous administration of a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly (QW) schedule for more than 6 months, followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly (Q2W) schedule.

[0072] In a particular embodiment, the method includes subcutaneous administration of a first escalating dose of 60 μg / kg of BCMAxCD3 bispecific antibody, followed by subcutaneous administration of a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2-4 days later, followed by subcutaneous administration of a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody 2-4 days later, followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly (QW) schedule, after the subject has achieved partial response, very good partial response, complete response, or complete response for 6 months or more (according to IMWG criteria), followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly (Q2W) schedule.

[0073] In a particular embodiment, the method includes subcutaneous administration of a first escalating dose of 60 μg / kg of BCMAxCD3 bispecific antibody, followed by subcutaneous administration of a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2-4 days later, followed by subcutaneous administration of a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody 2-4 days later, followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly (QW) schedule, and after the subject has achieved a complete response or a severe complete response for 6 months or more (according to IMWG criteria), followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly (Q2W) schedule.

[0074] In a particular embodiment, the method includes subcutaneous administration of a first escalating dose of 60 μg / kg of BCMAxCD3 bispecific antibody, followed by subcutaneous administration of a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2-4 days later, followed by subcutaneous administration of a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody 2-4 days later, followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly (QW) schedule, after the subject has achieved partial response, very good partial response, complete response, or exact complete response (according to IMWG criteria) after four 28-day treatment cycles or more, followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly (Q2W) schedule.

[0075] In a particular embodiment, the method includes subcutaneous administration of a first escalating dose of 60 μg / kg of BCMAxCD3 bispecific antibody, then, 2 to 4 days later, subcutaneous administration of a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody, then, 2 to 4 days later, subcutaneous administration of a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody, then, over a certain period, subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly schedule (QW), then, over a certain period, subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly schedule (Q2W), and then, subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a monthly schedule (Q4W).

[0076] In a particular embodiment, the method involves subcutaneously administering a first escalating dose of 60 μg / kg of BCMAxCD3 bispecific antibody, then, 2-4 days later, a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody, then, 2-4 days later, a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody, and then, over a certain period of time, administering the therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody. The treatment involves subcutaneous administration on a weekly schedule (QW), followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly schedule (Q2W) for a certain period, and if the subject achieves at least CR (i.e., complete response or exact complete response) by cycle 12 or thereafter, subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a monthly schedule (Q4W).

[0077] In a particular embodiment, the method includes subcutaneous administration of a first escalating dose of 60 μg / kg of BCMAxCD3 bispecific antibody, then, 2 to 4 days later, subcutaneous administration of a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody, then, 2 to 4 days later, subcutaneous administration of a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody, then, for a certain period, subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly schedule (QW), then, for at least 6 months, subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly schedule (Q2W), and then, subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a monthly schedule (Q4W).

[0078] In certain embodiments, the subject achieves a clinical response that is PR, VGPR, CR, or sCR.

[0079] In certain embodiments, the subject achieves a clinical response that is a complete response (CR) or sustained complete response (sCR).

[0080] In certain embodiments, the clinical response is maintained for at least 6 months.

[0081] In certain embodiments, the clinical response is maintained for at least one year.

[0082] In certain embodiments, the clinical response is maintained for at least 18 months.

[0083] In certain embodiments, the clinical response is maintained for at least two years.

[0084] In certain embodiments, the infection rate in subjects is lower (for example, compared to subjects receiving only QW).

[0085] In certain embodiments, the incidence of Grade ≥ 3 infections is lower in subjects (e.g., compared to subjects receiving only QW).

[0086] In certain embodiments, the method achieves a reduction in new infections over time in a population of subjects with RRMM (e.g., compared to subjects remaining on a QW dosing schedule).

[0087] In certain embodiments, the method achieves a reduction in new grade ≥3 infections over time in a population of subjects with RRMM (e.g., compared to subjects remaining on a QW dosing schedule).

[0088] Embodiments of the present invention also provide a method for treating subjects in need of treatment for multiple myeloma, the method comprising prophylactically administering tocilizumab (toci) to the subject before administering a therapeutically effective dose of a BCMAxCD3 bispecific antibody (e.g., tecrista-mab), the method being effective in reducing the risk of cytokine release syndrome (CRS).

[0089] Embodiments of the present invention also provide a method for restarting therapy using a BCMAxCD3 bispecific antibody after a delay in administration.

[0090] All methods described herein, in whatever way they are expressed, may be described as corresponding uses, specifically medical uses. [Brief explanation of the drawing]

[0091] The following figures form part of this specification and are included to further illustrate specific aspects of the invention. The invention can be better understood by referring to one or more of these figures in combination with the description of the specific embodiments presented herein. [Figure 1] This document outlines the design of the MajesTEC-1 clinical trial. [Figure 2] The following is an overview of the MajesTEC-1 administration schedule. [Figure 3] This provides patient characteristics from the MajesTEC-1 Q2W cohort. [Figure 4]This provides infection rates from the MajesTEC-1 Q2W cohort. Detailed description of the invention

[0092] The methods disclosed herein may be more readily understood by referring to the detailed description below. It should be understood that the methods disclosed herein are not limited to any particular methods described and / or shown herein, and furthermore, that the terms used herein are intended solely to illustrate specific embodiments and are not intended to limit the claimed methods. All patents, published patent applications and publications referenced herein are incorporated by reference as if they were described herein in their entirety.

[0093] As used herein, the singular forms "a," "an," and "the" are to be interpreted as including the plural form.

[0094] Various terms relating to aspects of this specification will be used throughout this specification and the claims. Unless otherwise indicated, such terms shall be given their common meanings in the art. Other specifically defined terms shall be construed to be consistent with the definitions provided herein.

[0095] When used in reference to a numerical range, cutoff, or specific value, "approximately" means within the allowable margin of error for that specific value as determined by those skilled in the art, which in part depends on the method by which the value is measured or determined, i.e., the limitations of the measurement system. Unless otherwise specified in the examples or elsewhere in this specification in the context of an assay, result, or embodiment, "approximately" means within one standard deviation or within a maximum of 5%, whichever is greater, in accordance with the practices of the art.

[0096] The term "antibody" has a broad meaning and includes monoclonal antibodies, including mouse, human, humanized, and chimeric monoclonal antibodies; antigen-binding fragments; multispecific antibodies such as bispecific, triplicate, and quadruplicate antibodies; dimers, tetramers, or multimers; single-chain antibodies; domain antibodies; and immunoglobulin molecules, including any other modified forms of immunoglobulin molecules containing antigen-binding sites of the required specificity. A "full-length antibody" consists of two heavy chains (HC) and two light chains (LC), interconnected by disulfide bonds, and a multimer thereof (e.g., IgM). Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (composed of domains CH1, hinge, CH2, and CH3). Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further subdivided into hypervariable regions called complementarity determining regions (CDRs), which are interspersed with framework regions (FRs). Each VH and VL consists of three CDR and four FR segments arranged in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 from the amino terminus to the carboxy terminus. Immunoglobulins can be assigned to five main classes, IgA, IgD, IgE, IgG, and IgM, depending on the amino acid sequence of the heavy chain constant domain. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The antibody light chains of any vertebrate species can be assigned to one of two distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequence of their constant domains.

[0097] An "antigen-binding fragment" or "antigen-binding domain" refers to a portion of an immunoglobulin molecule that binds to an antigen. Antigen-binding fragments can be synthetic polypeptides, enzyme-available polypeptides, or genetically modified polypeptides, and include VH, VL, VH and VL, Fab, F(ab')2, Fd and Fv fragments, domain antibodies (dAb) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelid VH domains, the smallest recognition units consisting of amino acid residues that reproduce the CDR of an antibody, such as the FR3-CDR3-FR4 moiety, HCDR1, HCDR2, and / or HCDR3, and LCDR1, LCDR2, and / or LCDR3. The VH and VL domains can bind to each other via synthetic linkers to form various types of single-chain antibody designs. When the VH and VL domains are expressed by separate single-chain antibody constructs, the VH / VL domains can pair intramolecularly or intermolecularly to form monovalent antigen-binding sites, such as single-chain Fv (scFv) or diabodies. These are described, for example, in International Publications 1998 / 44001, 1988 / 01649, 1994 / 13804, and 1992 / 01047.

[0098] "BCMA" refers to the human B cell maturation antigen, also known as CD269 or TNFRSF17 (UniProt Q02223). The extracellular domain of BCMA encapsulates residues 1-54 of Q02223. Human BCMA contains the amino acid sequence of Sequence ID No. 1.

[0099] Sequence ID 1 MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAILWTCLGLSLIISLAVFVLMFLLRKINSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCKSLPAALSATEIEKSISAR

[0100] "Bispecificity" refers to an antibody that specifically binds to two different antigens, or to two different epitopes within the same antigen. Bispecific antibodies can cross-react to other related antigens, such as the same antigen (homolog) from other species, such as humans or monkeys, for example, cynomolgus monkeys (Macaca cynomolgus, cyno) or chimpanzees (Pan troglodytes), or they can bind to epitopes shared between two or more different antigens.

[0101] A "BCMA x CD3 bispecific antibody" refers to a bispecific antibody that specifically binds to both BCMA and CD3.

[0102] "Cancer" refers to a broad group of diseases characterized by the uncontrolled proliferation of abnormal cells in the body. Uncontrolled cell division and proliferation can lead to the formation of malignant tumors that invade adjacent tissues and can metastasize to distal parts of the body via the lymphatic system or bloodstream. "Cancer" or "cancer tissue" may include tumors.

[0103] "CD3" refers to a human antigen expressed on T cells as part of a multimolecular T cell receptor (TCR) complex, consisting of a homodimer or heterodimer formed from the association of two or four receptor chains: CD3 epsilon, CD3 delta, CD3 zeta, and CD3 gamma. Human CD3 epsilon contains the amino acid sequence shown in SEQ ID NO: 2. SEQ ID NO: 3 shows the extracellular domain of CD3 epsilon.

[0104] Sequence ID 2 MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGS KPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI

[0105] Sequence ID 3 DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMD

[0106] The "CH3 region" or "CH3 domain" refers to the CH3 region of an immunoglobulin. In human IgG1 antibodies, the CH3 region corresponds to amino acid residues 341-446. However, the CH3 region may also be any of the other antibody isotypes described herein.

[0107] "Combination" means administering two or more therapeutic drugs to a subject together in a mixture, simultaneously as single agents, or sequentially as single agents in any order.

[0108] A "complementarity-determining region (CDR)" is the region of an antibody that binds to an antigen. CDRs can be defined using various descriptive methods, such as Kabat (Wu et al. J Exp Med 132:211-50, 1970) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al. J Mol Biol 196:901-17, 1987), IMGT (Lefranc et al. Dev Comp Immunol 27:55-77, 2003), and AbM (Martin and Thornton J Bmol Biol 263:800-15, 1996). Correspondence between various descriptions and variable region numbering is provided (see, for example, Lefranc et al. Dev Comp Immunol 27:55-77, 2003; Honegger and Pluckthun, J Mol Biol 309:657-70, 2001; International ImMunoGeneTics (IMGT) database; web resource, http: / / www_imgt_org). CDRs can be described using available programs such as abYsis by UCL Business PLC. As used herein, the terms “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2”, and “LCDR3”, include CDRs defined by any of the Kabat, Chothia, IMGT, or AbM methods described above, unless otherwise specified herein. Preferably, as used herein, the terms “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2”, and “LCDR3”, include CDRs defined by the Kabat method.

[0109] "Comprising" is intended to include examples that are encompassed by the terms "consisting essentially of" and "consisting of." Similarly, the term "consisting essentially of" is intended to include examples that are encompassed by the term "consisting of." Unless the context clearly indicates otherwise, throughout the specification and claims, words such as "comprise" and "comprising" should be interpreted in a comprehensive sense, as opposed to an exclusive or exhaustive sense, i.e., "including but not limited to."

[0110] The term "Fc gamma receptor" (FcγR) refers to the well-known FcγRI, FcγRIIa, FcγRIIb, or FcγRIII. Activated FcγR includes FcγRI, FcγRIIa, and FcγRIII.

[0111] A “human antibody” refers to an antibody optimized to minimize the immune response when administered to a human subject. The variable region of a human antibody is derived from a human immunoglobulin sequence. If a human antibody contains a constant region or a portion of a constant region, that constant region is also derived from a human immunoglobulin sequence. A human antibody contains heavy-chain and light-chain variable regions that “derive” from a human-derived sequence if the variable region of the human antibody is obtained from a system using human germline immunoglobulin or a rearranged immunoglobulin gene. Examples of such systems include human immunoglobulin gene libraries presented to phages, and transgenic non-human animals possessing human immunoglobulin loci, such as mice or rats. A “human antibody” typically contains amino acid differences compared to immunoglobulin expressed in humans, due to differences in the system used to obtain the human antibody and the human immunoglobulin locus, or intentional introduction of somatic mutations or substitutions into the framework or CDR, or both. Typically, a “human antibody” is at least approximately 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by a human germline immunoglobulin or rearranged immunoglobulin gene. In some cases, a “human antibody” may include a consensus framework sequence derived from human framework sequence analysis, for example, Knappik et al., (2000) J Mol Biol 296:57-86, or synthetic HCDR3 incorporated into a human immunoglobulin gene library presented on phages, for example, Shi et al., (2010) J Mol Biol 397:385-96 and International Publication No. 2009 / 085462. Antibodies in which at least one CDR originates from a non-human species are not included in the definition of "human antibodies."

[0112] A "humanized antibody" refers to an antibody in which at least one CDR is derived from a non-human species and at least one framework is derived from a human immunoglobulin sequence. Because humanized antibodies can contain substitutions in their framework, the framework may not be an exact copy of the expressed human immunoglobulin or human immunoglobulin germline gene sequence.

[0113] "Identity" refers to the relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, determined by aligning and comparing their sequences. The "percentage of sequence identity (%)" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence, after aligning the sequences and introducing gaps as necessary, without considering any conservative substitutions as part of the sequence identity, to achieve the maximum possible sequence identity percentage. Alignment for the purpose of determining the amino acid sequence identity percentage can be achieved using various methods within the scope of skill in the art, such as publicly available computer software like BLAST, BLAST-2, ALIGN, or MEGALIGN (DNAStar, Inc.) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithm necessary to achieve the maximum alignment over the entire length of the sequences being compared.

[0114] "Isolated" refers to a homogeneous population of molecules (e.g., synthetic polynucleotides or proteins such as antibodies) that has been substantially separated and / or purified from other components of a system in which molecules are produced, such as recombinant cells, in addition to proteins subjected to at least one purification or isolation step. "Isolated antibody" refers to an antibody that is substantially free of other cellular material and / or chemical substances, and includes antibodies isolated to higher purities, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0115] A "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibody molecules that is identical except for possible known modifications such as removal of the C-terminal lysine from the antibody heavy chain, isomerization or deamidementation of amino acids, oxidation of methionine, or post-translational modifications such as deamidementation of asparagine or glutamine; in other words, an individual antibody that constitutes a population. Monoclonal antibodies typically bind to one antigenic epitope. Bispecific monoclonal antibodies bind to two different antigenic epitopes. Monoclonal antibodies can have heterogeneous glycosylation within the antibody population. Monoclonal antibodies can be monospecific or bispecific, and can be monovalent, bivalent, or polyvalent.

[0116] A "mutation" refers to a genetically engineered or naturally occurring alteration of a polypeptide or polynucleotide sequence compared to a reference sequence. An alteration can be the substitution, insertion, or deletion of one or more amino acids or polynucleotides.

[0117] "Negative minimal residual disease (MRD) status," "negative MRD status," or "MRD-negative" refers to the permillion count (i.e., the point estimate of malignant myeloma cells per million nucleated cells) of the test bone marrow sample relative to a reference bone marrow sample (i.e., a tecristamab-naïve bone marrow sample) in the patient. Based on this permillion count, each sample is determined to be positive or negative. If the permillion count is above the sensitivity limit, the sample is positive; otherwise, the sample is negative. A negative minimal residual disease status occurs in 0.01% (10 -4 ), 0.001% (10 -5 ), or 0.0001% (10 -6 The diagnosis can be made with the following sensitivity. Negative minimal residual disease status was determined using next-generation sequencing (NGS).

[0118] A "pharmaceutical composition" refers to a composition containing an active ingredient and a pharmaceutically acceptable carrier.

[0119] "Pharmacologically acceptable carriers" or "excipients" refer to components in a pharmaceutical composition other than the active ingredient that are non-toxic to the target.

[0120] "Recombinant" refers to DNA, antibodies, and other proteins prepared, expressed, created, or isolated by recombinant means when segments from different sources join together to produce recombinant DNA, antibodies, or proteins.

[0121] "Refractory" cancer refers to cancer that cannot be repaired even with surgical intervention and does not respond to therapy from the outset.

[0122] "Recurrent" cancer refers to cancer that responds to treatment but subsequently recurs.

[0123] A “dose escalation” refers to the dose of the active drug administered to the subject before the therapeutic dose. The dose escalation is lower than the therapeutic dose. A “priming” dosing strategy to prevent or mitigate certain toxicities, such as cytokine release syndrome (CRS), may involve one or more lower dose escalations followed by a higher therapeutic dose.

[0124] "Subject" includes any human or non-human animal. "Non-human animal" includes, for example, non-human primates, mammals such as sheep, dogs, cats, horses, cattle, chickens, amphibians, and reptiles, and all non-mammalian vertebrates. Unless otherwise noted, the terms "patient" and "subject" are used interchangeably.

[0125] A "T-cell redirecting therapeutic agent" refers to a molecule containing two or more binding domains, one of which specifically binds to a cell surface antigen on a target cell or tissue, and the second binding domain of the molecule specifically binds to a T-cell antigen. Examples of cell surface antigens include tumor-associated antigens such as BCMA. An example of a T-cell antigen is CD3. This dual / multi-target binding ability recruits T cells to target cells or tissues, leading to their eradication.

[0126] The "therapeutic dose" refers to the amount effective in achieving the desired therapeutic outcome at the required dosage and duration. The therapeutic dose may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the drug or combination of drugs to induce the desired response in the individual. An exemplary indicator of an effective drug or combination of drugs is, for example, the patient's improved health status.

[0127] "To treat" or "treatment" refers to both therapeutic treatment and prophylactic or preventative measures, in which an undesirable physiological change or disease is prevented or slowed (reduced). Beneficial or desired clinical outcomes include, whether detectable or undetectable, relief of symptoms, reduction of disease severity, a stable (i.e., non-worsening) disease state, delay or slowing of disease progression, improvement or relief of the disease state, and remission (whether partial or complete). "Treatment" may also mean extending survival compared to the expected survival time if the subject were not treated. Those who require treatment include those who already have a condition or disease, those who are susceptible to a condition or disease, or those seeking to prevent a condition or disease.

[0128] The "therapeutic dose" refers to the amount of active drug administered to a target to treat a disease. Therapeutic doses may be administered repeatedly (e.g., weekly, bi-weekly, monthly) at regular intervals. One or more dose escalations may precede the therapeutic dose.

[0129] A patient described as "triple-class exposed" refers to a patient with multiple myeloma who has been previously treated with (at least) proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0130] "Tumor cells" or "cancer cells" refer to cancerous, precancerous, or transformed cells that exhibit spontaneous or induced phenotypic changes in vivo, ex vivo, or tissue culture. These changes do not necessarily involve the uptake of new genetic material. Transformation may occur through infection with transforming viruses and the incorporation of new genomic nucleic acids, the uptake of exogenous nucleic acids, or spontaneously or after exposure to carcinogens, thereby mutating endogenous genes. Transformation / cancer is exemplified by morphological changes, cell immortalization, abnormal growth control, lesion formation, proliferation, malignant lesions, regulation of tumor-specific marker levels, invasiveness, and tumor growth in suitable animal hosts such as nude mice, in vitro, in vivo, and ex vivo.

[0131] Throughout this specification, unless otherwise specified, the numbering of amino acid residues in the antibody constant region follows the EU index described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD. (1991). The numbering of the antibody constant chain can be found, for example, in the IMGT Web resource of the IMGT Scientific chart on the ImMunoGeneTics website.

[0132] Conventional one-letter and three-letter amino acid codes are used herein as shown in Table 1.

[0133] [Table 1]

[0134] BCMA x CD3 bispecific antibody and its use It is well known in the field of drug development that it is an unpredictable area. This lack of predictability is demonstrated, for example, by the requirements of health organizations (such as the Food and Drug Administration) for establishing safe and effective dosing regimens for each individual drug candidate in clinical trials. Over the past decade (2011–2020), only 7.9% of all drug candidates in development achieved FDA approval from Phase I clinical trials. See Clinical Development Success Rates and Contributing Factors 2011–2020. Success rates are even lower in oncology, with only 5.3% of oncology drug candidates succeeding.

[0135] In the field of oncology, even for drugs with established dosages for specific indications, the Food and Drug Administration (FDA) recommends further clinical trials to identify optimal dosages for new indications. Otherwise, patients may be exposed to unreasonable and significant risks, among other potential drawbacks. See, for example, Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases; Draft Guidance for Industry; January 2023.

[0136] In patients with relapsed or refractory disease who have exhausted numerous therapies, multiple myeloma remains an incurable malignancy, representing an unmet medical need with significant morbidity and mortality rates. We have developed a novel dosing regimen for BCMA x CD3 bispecific antibodies that provides an improved safety profile compared to currently approved regimens while maintaining deep and sustained efficacy.

[0137] Teclistamaib (also known as TECVAYLI®) is the first BCMA-targeted bispecific antibody approved for the treatment of patients with relapsed or refractory multiple myeloma. Teclistamaib is a indicated bispecific B-cell maturation antigen (BCMA)-targeted CD3 T-cell engager for the treatment of adult patients with relapsed or refractory multiple myeloma who have previously received at least three or four lines of treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies. The efficacy of teclistamaib continues to be evaluated in multicenter clinical trials (MajesTEC-1, NCT03145181 [Phase 1] and NCT04557098 [Phase 2]) in patients with relapsed or refractory multiple myeloma. This study included patients who had previously received at least three prior therapies, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies. In the MajesTEC-1 trial, at a median follow-up of 14.1 months, teclistamag demonstrated a rapid, deep, and sustained response with an overall response rate (ORR) of 63% and a median progression-free survival (mPFS) of 11.3 months (see, e.g., Usmani SZ, et al. Lancet 2021;398:665-674 and Moreau P, et al. New Engl J Med 2022;387:495-505, which are incorporated herein by reference).

[0138] Patients with relapsed or refractory multiple myeloma (RRMM) already have an increased risk of infection, and bispecific antibodies targeting B-cell maturation antigen (BCMA) may contribute to this increased risk due to their on-target and off-tumor toxicity. In the MajesTEC-1 clinical trial, patients (N=165) received subcutaneous teclistamag 1.5 mg / kg weekly according to an escalation schedule (0.06 mg / kg and 0.3 mg / kg, each at 2-4 day intervals). At a median follow-up period of 21.6 months (range 0.26–32.69), infections were reported in 129 patients (78.2%). Overall, 86 patients (52.1%) developed grade 3 / 4 infections, most commonly pneumonia (20.6%), COVID-19 (18.8%), sepsis (6.1%), and urinary tract infection (6.1%). Grade 3 / 4 neutropenia occurred in 65.5% of patients. Therefore, an optimized dosing regimen of BCMAxCD3 bispecific antibody with an improved safety profile is still needed. We have developed the optimized dosing regimen described herein, which reduces the infection rate in patients while still achieving a rapid, deep, and sustained clinical response.

[0139] The antibody of the present invention In consideration of this disclosure, any suitable BCMA×CD3 bispecific antibody known to those skilled in the art can be used in the present invention.

[0140] Various bispecific antibody formats include the formats described herein, as well as recombinant IgG-like bitarget molecules in which each of the two sides of the molecule contains Fab fragments or portions of Fab fragments of at least two different antibodies; IgG fusion molecules in which a full-length IgG antibody is fused to an extra Fab fragment or portion of a Fab fragment; Fc fusion molecules in which a single-chain Fv molecule or stabilized diabody is fused to a heavy chain constant domain, Fc region, or portion thereof; Fab fusion molecules in which different Fab fragments are fused together; and ScFv and diabody-based heavy chain antibodies (e.g., domain antibodies, nanobodies) in which different single-chain Fv molecules, different diabodies, or different heavy chain antibodies (e.g., domain antibodies, nanobodies) are fused to each other or to another protein or carrier molecule, or to a bispecific antibody produced by arm exchange.Exemplary bispecific antibody formats include dual-targeting (DT)-Ig (GSK / Domantis) molecules, two-in-one antibodies (Genentech) and mAb2 (F-Star), dual variable domain (DVD)-Ig (Abbott), DuoBody (Genmab), Ts2Ab (MedImmune / AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idec) and TvAb (Roche), ScFv / Fc fusions (Academic Institution), SCORPION (Emergent BioSolutions / Trubion, Zymogenetics / BMS), and dual-affinity retargeting technology. Examples include Technology, Fc-DART) (MacroGenics), F(ab)2 (Medarex / AMGEN), dual-activating or Bis-Fab (Genentech), Dock-and-Lock (DNL) (ImmunoMedics), bivalent bispecificity (Biotecnol) and Fab-Fv (UCB-Celltech), bispecific T cell engager (BITE) (Micromet), tandem diabody (Tandab) (Affimed), dual-affinity retargeting technology (DART) (MacroGenics), single-chain diabody (Academic), TCR-like antibody (AIT, ReceptorLogics), human serum albumin ScFv fusion (Merrimack) and COMBODY (Epigen Biotech), dual-target nanobody (Ablynx), and dual-target heavy chain-only domain antibody. Various formats of bispecific antibodies are described, for example, in Chames and Baty (2009) Curr Opin Drug Disc Dev 12:276 and Nunez-Prado et al., (2015) Drug Discovery Today 20(5):588-594.

[0141] In some embodiments, the BCMA×CD3 bispecific antibody comprises one of the BCMA-binding domains described in International Publication No. 2017 / 031104 (the entire contents of which are incorporated herein by reference). In some embodiments, the BCMA×CD3 bispecific antibody comprises one of the CD3-binding domains described in International Publication No. 2017 / 031104. In some embodiments, the BCMAxCD3 bispecific antibody comprises one of the BCMAxCD3 bispecific antibodies described in International Publication No. 2017 / 031104.

[0142] In some embodiments, the BCMAxCD3 bispecific antibody is chimeric, humanized, or human.

[0143] In some embodiments, the bispecific antibody is an IgG1, IgG2, IgG3, or IgG4 isotype. In preferred embodiments, the bispecific antibody is an IgG4 isotype. An exemplary wild-type IgG4 contains the amino acid sequence of SEQ ID NO: 34.

[0144] Sequence ID 34: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0145] Bispecific antibodies can be of any allotype. Allotype is not expected to affect the properties of bispecific antibodies, such as binding or Fc-mediated effector function. The immunogenicity of therapeutic antibodies is associated with a higher risk of injection reaction and a shorter duration of the therapeutic response (Baert et al., (2003) N Engl J Med 348:602-08). The extent to which a therapeutic antibody induces an immune response in the host may be partially determined by the antibody allotype (Stickler et al., (2011) Genes and Immunity 12:213-21). Antibody allotype is related to variations in the amino acid sequence at specific positions within the antibody's constant region sequence. Table 2 shows the selected IgG1, IgG2, and IgG4 allotypes.

[0146] [Table 2]

[0147] In some embodiments, the bispecific antibody includes one or more Fc substitutions that reduce the binding of the bispecific antibody to the Fcγ receptor (FcγR) and / or reduce Fc effector functions such as C1q binding, complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), or antibody-dependent cell-mediated phagocytosis (ADCP). Specific substitutions can be produced by comparing with wild-type IgG4 of SEQ ID NO: 34.

[0148] Fc positions that can be substituted to reduce the binding of Fc to activated FcγR and subsequently reduce effector function include L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, K214T / E233P / L234V / L235A / G236 deletion / A327G / P331A / on IgG1 These are substitutions of D365E / L358M, H268Q / V309L / A330S / P331S on IgG2, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236 deletion / G237A / P238S on IgG4, where residue numbering follows the EU index.

[0149] The Fc substitution that can be used to reduce CDC is K322A substitution.

[0150] To improve the stability of IgG4, the well-known S228P substitution can be further applied to the IgG4 antibody.

[0151] In some embodiments, the bispecific antibody contains one or more asymmetric substitutions in the first CH3 domain, the second CH3 domain, or both the first and second CH3 domains.

[0152] In some embodiments, one or more asymmetric substitutions are F405L / K409R, wild-type / F405L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S and T366W / T366S_L368A_Y407V, L351Y_F405A_Y407V / T394W, T3 The following are selected from the group consisting of 66I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, and T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0153] In some embodiments, the BCMA×CD3 bispecific antibody is of the IgG4 isotype and contains phenylalanine at position 405 and arginine at position 409 of the first heavy chain (HC1), and leucine at position 405 and lysine at position 409 of the second heavy chain (HC2), with residue numbering following the EU index.

[0154] In some embodiments, the BCMA×CD3 bispecific antibody further comprises proline at position 228, alanine at position 234, and alanine at position 235 in both HC1 and HC2.

[0155] Tables 3 and 4 provide sequences of exemplary embodiments of BCMAxCD3 bispecific antibodies according to the Kabat numbering system.

[0156] [Table 3]

[0157] [Table 4]

[0158] In some embodiments, the BCMA x CD3 bispecific antibody is CC-93269, BI836909, JNJ-64007957 (teclistamag), or PF-06863135. In preferred embodiments, the BCMA x CD3 bispecific antibody is teclistamag (also referred to herein as Tec), having the sequences listed in Tables 3 and 4.

[0159] Teclistamaib and its uses are described, for example, in International Publication Nos. 2017 / 031104, 2019 / 220369, and 2021 / 228783, which are incorporated herein by reference. According to certain embodiments, the BCMAxCD3 bispecific antibody has an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with the amino acid sequence of teclistamaib.

[0160] Further embodiments of the BCMAxCD3 bispecific antibody and GPRC5DxCD3 bispecific antibody that may be used in the combination regimen of the present invention are described below.

[0161] In certain embodiments, the BCMA × CD3 bispecific antibody includes a BCMA-binding domain comprising HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, as well as a CD3-binding domain comprising HCDR1 of SEQ ID NO: 14, HCDR2 of SEQ ID NO: 15, HCDR3 of SEQ ID NO: 16, LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO: 19.

[0162] In a particular embodiment, the BCMA-binding domain includes a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and the CD3-binding domain includes a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21.

[0163] In certain embodiments, the BCMA×CD3 bispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0164] In certain embodiments, the BCMA×CD3 bispecific antibody is of the IgG4 isotype.

[0165] In certain embodiments, the BCMAxCD3 bispecific antibody contains one or more substitutions in its Fc region.

[0166] In certain embodiments, the BCMAxCD3 bispecific antibody is of the IgG4 isotype and contains S228P, F234A, and L235A substitutions in its Fc region (according to EU numbering).

[0167] In certain embodiments, the BCMA×CD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region (according to EU numbering).

[0168] In certain embodiments, the Fc region of the BCMA coupling arm includes S228P, F234A, and L235A substitutions in that Fc region (according to EU numbering).

[0169] In certain embodiments, the Fc region of the CD3CD3 coupling arm includes S228P, F234A, L235A, F405L, and R409K substitutions in that Fc region (according to EU numbering).

[0170] In a particular embodiment, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 23.

[0171] In a particular embodiment, the BCMA×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 23.

[0172] In a particular embodiment, the BCMA×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 23.

[0173] In a particular embodiment, the BCMA×CD3 bispecific antibody includes a first heavy chain (HC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 23.

[0174] In certain embodiments, the BCMAxCD3 bispecific antibody is teclistamaib.

[0175] Patient population with multiple myeloma The BCMAxCD3 bispecific antibodies disclosed herein are intended for use in the treatment of multiple myeloma in subjects, for example, human subjects, who are relapsed or refractory to one or more previous anticancer treatments. Relapsed disease means that the cancer has recurred. Refractory disease means that the cancer has not improved with treatment or has become unresponsive to treatment.

[0176] In some embodiments, the subject is relapsed or refractory to treatment with therapeutic agents used to treat multiple myeloma or other hematological malignancies.

[0177] In certain embodiments, the subject has previously been treated with 2 to 14 treatment lines.

[0178] In certain embodiments, the subject has previously received at least three lines of treatment.

[0179] In certain embodiments, the subject has previously received at least four lines of treatment.

[0180] In certain embodiments, the subject has previously received at least five lines of treatment (pentad exposure).

[0181] In certain embodiments, the subject has previously received at least three lines of treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0182] In certain embodiments, the subject has previously received at least four lines of treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0183] In certain embodiments, patients had relapsed, refractory, or intolerant line of therapy (LOT) conditions, had been exposed to proteasome inhibitors, immunomodulators, and anti-CD38 therapies, and possessed measurable disease.

[0184] In some embodiments, the subjects have received three prior anticancer therapies before administration of the BCMAxCD3 bispecific antibody. In one embodiment, the three prior anticancer therapies are a proteasome inhibitor (PI), an immunomodulator (IMiD), and an anti-CD38 antibody. In certain such embodiments, the proteasome inhibitor is bortezomib, carfilzomib, or ixazomib; the immunomodulator (IMiD) is lenalidomide, pomalidomide, or thalidomide; and the anti-CD38 antibody is daratumumab or isatuximab.

[0185] In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is lenalidomide, and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is lenalidomide, and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is pomalidomide, and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is pomalidomide, and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is thalidomide, and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is thalidomide, and the anti-CD38 antibody is isatuximab.

[0186] In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is lenalidomide, and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is lenalidomide, and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is pomalidomide, and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is pomalidomide, and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is thalidomide, and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is thalidomide, and the anti-CD38 antibody is isatuximab.

[0187] In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is lenalidomide, and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is lenalidomide, and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is pomalidomide, and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is pomalidomide, and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is thalidomide, and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is thalidomide, and the anti-CD38 antibody is isatuximab.

[0188] In some embodiments, the subjects are refractory or relapsed to treatment with one or more therapies, such as THALOMID® (thalidomide), REVLIMID® (lenalidomide), POMALYST® (pomaridomide), VELCADE® (bortezomib), NINLARO (ixazomib), KYPROLIS® (carfilzomib), FARADYK® (panobinostat), AREDIA® (pamidronate), ZOMETA® (zoledronic acid), DARZALEX® (daratumumab), erotozumab or melphalan, Xpovio® (selinexol), Venclexta® (venetoclax), GSK916, CAR-T therapy, or other BCMA-targeted therapies.

[0189] Various qualitative and / or quantitative methods can be used to determine the recurrence or refractory nature of the disease. Possible related symptoms include, for example, a decline or stabilization of the patient's health, recurrence or exacerbation of various symptoms associated with solid tumors, and / or metastasis of cancer cells within the body from one site to other organs, tissues, or cells.

[0190] In some embodiments, multiple myeloma is relapsed or refractory to treatment with anti-CD38 antibodies, selinexol, venetoclax, lenarinomide, bortezomib, pomalidomide, carfilzomib, erotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0191] In one embodiment, the anti-CD38 antibody is daratumumab.

[0192] In another embodiment, the anti-CD38 antibody is isatuximab.

[0193] In some embodiments, multiple myeloma is high-risk multiple myeloma. Subjects with high-risk multiple myeloma are known to experience early relapses and have a poor prognosis and outcome. Subjects that can be classified as having high-risk multiple myeloma have one or more of the following cytogenetic abnormalities: t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p. In some embodiments, subjects with high-risk multiple myeloma have one or more chromosomal abnormalities, including t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof.

[0194] Cytogenetic abnormalities can be detected, for example, by fluorescence in situ hybridization (FISH). In chromosomal translocations, oncogenes are translocated to the IgH region on chromosome 14q32, resulting in dysregulation of these genes. t(4;14)(p16;q32) involves translocations of fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain-containing protein (MMSET) (also known as WHSC1 / NSD2), while t(14;16)(q32;q23) involves a translocation of the MAF transcription factor C-MAF. Deletion of 17p (del17p) involves the loss of the p53 locus.

[0195] Chromosome rearrangements can be identified using well-known methods, such as fluorescence in situ hybridization, karyotype analysis, pulsed-field gel electrophoresis, or sequencing.

[0196] Bi-weekly and monthly administration of BCMAxCD3 bispecific antibody The inventors have developed a novel dosing regimen for BCMA x CD3 bispecific antibodies that provides an improved safety profile compared to currently approved regimens while maintaining a deep and sustained clinical response over time.

[0197] Teclistamag is the first B-cell maturation antigen (BCMA) bispecific antibody approved for the treatment of relapsed / refractory multiple myeloma (RRMM), administered subcutaneously at a dose of 1.5 mg / kg weekly (QW). Less frequent dosing schedules offer greater convenience and flexibility for patients, physicians, and caregivers. According to certain embodiments, subcutaneous administration of 1.5 mg / kg every two weeks (Q2W) is safe and effective in the treatment of RRMM. According to additional embodiments, subcutaneous administration of 1.5 mg / kg every four weeks (Q4W) is safe and effective in the treatment of RRMM.

[0198] As used herein, “body weight-based” refers to a dosage based on the specific body weight of the subject; for example, 3 mg / kg refers to a dose of 3 milligrams of antibody per kilogram of body weight of the subject. Unless otherwise specified herein, body weight-based dosages are used when the dosage is given in units of “mg / kg” or “μg / kg”.

[0199] Unless otherwise specified herein, BCMA x CD3 bispecific antibodies such as teclistamaib are administered in a dosing schedule based on consecutive 28-day cycles, for example, Cycle 1 begins on Day 1 of Cycle 1 and ends on Day 28 of Cycle 1; then Day 1 of Cycle 2 begins the day after Day 28 of Cycle 1 and ends on Day 28 of Cycle 2; then Day 1 of Cycle 3 begins the day after Day 28 of Cycle 2 and ends on Day 28 of Cycle 3, and so on.

[0200] As used herein, “Q4W” means once every four weeks, “Q2W” (also known as “bi-weekly” or “biweekly”) means once every two weeks, and “QW” (also known as “weekly”) means once a week. In this specification, Q4W may refer to “monthly,” but strictly speaking, it refers to once every four weeks or once every 28 days (for example, in a 28-day cycle, the first therapeutic dose is administered on day 1 of cycle 1, and the second therapeutic dose is administered on day 1 of cycle 2). Administering a therapeutic dose once a week (QW) is also referred to herein as a weekly dosing schedule. Administering a therapeutic dose once every two weeks (Q2W) is also referred to herein as a bi-weekly dosing schedule. Administering a therapeutic dose once every four weeks (Q4W) is also referred to herein as a monthly dosing schedule.

[0201] Additional abbreviations used herein include: CR (complete response), PR (partial response); Q2W (once every two weeks); Q4W (once every four weeks); QW (once weekly); RP2D (recommended dose for Phase 2); SUD (escalation dose).

[0202] As used herein, teclistamagb RP2D refers to the FDA-approved weight-based regimen for teclistamagb monotherapy based on the MajesTEC-1 clinical trial, comprising a subcutaneously administered therapeutic dose of 1.5 mg / kg teclistamagb administered weekly until disease progression or unacceptable toxicity, with the therapeutic dose preceded by escalating doses of 0.06 mg / kg and 0.3 mg / kg. According to embodiments of the present invention, subjects in MajesTEC-1 may switch from weekly to Q2W, and then to Q4W, as described herein.

[0203] According to embodiments of the present invention, a method for treating multiple myeloma is effective in inducing a clinical response in a population as determined by the International Myeloma Working Group (IMWG) response criteria. According to certain embodiments, the treatment method is effective in inducing a partial response, very good partial response, complete response, or exact complete response, as determined by the IMWG response criteria. As used herein, overall response rate (ORR) refers to the percentage of patients in a population that achieve a partial response (PR) or better, i.e., a partial response, very good partial response, complete response, or exact complete response. The IMWG criteria for response to multiple myeloma treatment are provided in Table A below.

[0204] [Table 5] CR = Complete Response, FLC = Free Light Chain, IMWG = International Myeloma Working Group, M Protein = Monoclonal Paraprotein, MR = Minimal Response, PC = Plasma Cell, PD = Progressive Disease, PR = Partial Response, sCR = Strict Complete Response, SD = Stable Disease, VGPR = Very Good Partial Response a The presence or absence of clonal cells is based on the kappa / lambda ratio. Abnormal kappa / lambda ratios by immunohistochemistry or immunofluorescence require a minimum of 100 plasma cells for analysis. Abnormal ratios reflecting the presence of abnormal clones are kappa / lambda greater than 4:1 or less than 1:2. *Clarification of IMWG criteria for coding CR and VGPR in subjects where the only measurable disease is due to serum FLC levels: CR in such subjects exhibits a normal FLC ratio of 0.26–1.65, in addition to the CR criteria listed above. VGPR in such subjects requires a reduction of more than 90% in the difference between the involved FLC level and the uninvolved FLC level.

[0205] The IMWG criteria for response to treatment of multiple myeloma are also found in, for example, Durie et al., Kumar et al. and Rajkumar et al.: Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467-1473; Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-346; Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel This is described in 1. Blood. 2011; 117(18): 4691-4695 (these are incorporated herein by reference).

[0206] Study 64007957MMY1001 (MajesTEC-1) is a single-arm, open-label, multicenter study of teclistamagb administered as monotherapy to adult patients with relapsed or refractory multiple myeloma. Following the identification of the proposed RP2D in Phase 1, Phase 2 further evaluated the antimyeloma activity and safety of teclistamagb in a cohort of patients with relapsed or refractory multiple myeloma whose medical needs were not being met. The core population included in the full treatment analysis set of MajesTEC-1 includes 165 patients (40 treated in Phase 1 and 125 treated in Cohort A of Phase 2).

[0207] According to the weekly dosing schedule in MajesTEC-1, teclistamag is administered subcutaneously according to the following body weight-based dosing schedule shown in Table B, where mg / kg refers to the amount of teclistamag in mg per kg of the patient's body weight.

[0208] [Table 6] b The second dose escalation may be administered 2 to 4 days after the first dose escalation, or it may be administered up to 7 days after the first dose escalation to allow for the resolution of adverse reactions. c The first therapeutic dose may be administered 2 to 4 days after the second dose escalation, or up to 7 days after the second dose escalation to allow for the resolution of adverse reactions.

[0209] In a specific embodiment, patients in the MajesTEC-1 trial who transitioned from QW to a lower-frequency Q2W dosing of teclistamagb maintained remission, and the median duration of response was 20.5 months from the date of the switch.

[0210] According to certain embodiments, the subject initiates treatment with teclistamab on a weekly schedule and then switches to an every-other-week dosing schedule after a certain period. According to one embodiment, the treatment method includes administering a BCMAxCD3 bispecific antibody according to the following dosing schedule shown in Table C.

[0211]

Table 7

[0212] According to certain embodiments, the BCMAxCD3 bispecific antibody is administered according to the following schedule shown in Table D.

[0213]

Table 8

[0214] According to certain embodiments, the BCMAxCD3 bispecific antibody is administered according to the following schedule shown in Table E.

[0215]

Table 9

[0216] According to certain embodiments, the BCMAxCD3 bispecific antibody is administered according to the following schedule shown in Table F.

[0217] [Table 10]

[0218] According to one embodiment, the teclistamagb administration regimen includes escalating doses of 0.06 mg / kg and 0.3 mg / kg, followed by 1.5 mg / kg once weekly until disease progression or unacceptable toxicity, and in patients with a response for at least 6 months, the administration frequency may be optionally reduced to 1.5 mg / kg every two weeks until disease progression or unacceptable toxicity.

[0219] According to one embodiment, the teclistamagb administration regimen includes escalating doses of 0.06 mg / kg and 0.3 mg / kg, followed by 1.5 mg / kg once weekly until disease progression or unacceptable toxicity, and in patients with a complete response or better for at least 6 months, the administration frequency may be optionally reduced to 1.5 mg / kg every two weeks until disease progression or unacceptable toxicity.

[0220] Further embodiments of the administration regimen of the present invention are described below.

[0221] In certain embodiments, a method for treating a subject requiring treatment for multiple myeloma includes administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a bi-weekly (Q2W) schedule.

[0222] In certain embodiments, the method includes subcutaneous administration of one or more escalating doses of BCMAxCD3 bispecific antibody to the target before administering a first therapeutic dose of BCMAxCD3 bispecific antibody.

[0223] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg to approximately 3000 μg / kg on a bi-weekly (Q2W) schedule.

[0224] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg on a bi-weekly (Q2W) schedule.

[0225] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 3000 μg / kg on a bi-weekly (Q2W) schedule.

[0226] In certain embodiments, the method includes subcutaneously administering at least one therapeutic dose of BCMAxCD3 bispecific antibody to the target on a weekly (QW) schedule, followed by administering a therapeutic dose of BCMAxCD3 bispecific antibody to the target on a bi-weekly (Q2W) schedule.

[0227] In certain embodiments, the method includes administering a therapeutic dose of BCMAxCD3 bispecific antibody subcutaneously to the subject on a weekly (QW) schedule, and if the subject has achieved a complete response or better (i.e., complete response or strict complete response according to the IMWG 2016 criteria) for at least 6 months, administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a bi-weekly (Q2W) schedule for at least 6 months (i.e., reducing the frequency of therapeutic doses from weekly to bi-weekly after the subject has achieved a complete response or better (complete response or strict response)).

[0228] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least one 28-day treatment cycle, and then administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W).

[0229] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least two 28-day treatment cycles, followed by administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W).

[0230] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least three 28-day treatment cycles, followed by administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W).

[0231] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least four 28-day treatment cycles, followed by administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W).

[0232] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least five 28-day treatment cycles, followed by administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W).

[0233] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least six 28-day treatment cycles, followed by administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W).

[0234] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly (QW) schedule for at least 6 months, followed by administration of a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly (Q2W) schedule.

[0235] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a weekly dosing schedule (QW) until the subject achieves partial response, very good partial response, complete response, or exact complete response, as determined by the IMWG response criteria, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W).

[0236] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a weekly dosing schedule (QW) until the subject achieves a very good partial response, complete response, or exact complete response, as determined by the IMWG response criteria, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W).

[0237] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a weekly dosing schedule (QW) until the subject achieves complete response or strict complete response as determined by the IMWG response criteria, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W).

[0238] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a weekly dosing schedule (QW) until the subject achieves partial response, very good partial response, complete response, or exact complete response after four or more treatment cycles, as determined by the IMWG response criteria, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W).

[0239] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a weekly dosing schedule (QW) until the subject achieves partial response, very good partial response, complete response, or exact complete response for at least 6 months, as determined by the IMWG response criteria, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W).

[0240] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody to the target on a weekly dosing schedule (QW) until the target achieves a complete response or a strict complete response for at least 6 months, as determined by the IMWG response criteria, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody to the target on a bi-weekly dosing schedule (Q2W).

[0241] In certain embodiments, each therapeutic dose of BCMAxCD3 bispecific antibody administered on a weekly schedule (QW) is the same as the therapeutic dose of BCMAxCD3 bispecific antibody administered on a bi-weekly schedule (Q2W).

[0242] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg to approximately 3000 μg / kg on a weekly (QW) schedule.

[0243] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg on a weekly (QW) schedule.

[0244] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 3000 μg / kg on a weekly (QW) schedule.

[0245] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg on a weekly (QW) schedule, and then subcutaneous administration of the BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg on a bi-weekly (Q2W) schedule.

[0246] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg on a weekly (QW) schedule, followed by subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 3000 μg / kg on a bi-weekly (Q2W) schedule.

[0247] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody on a bi-weekly schedule (Q2W), followed by subcutaneous administration of the BCMAxCD3 bispecific antibody on a monthly schedule (Q4W).

[0248] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody on a weekly (QW) schedule, followed by subcutaneous administration of the BCMAxCD3 bispecific antibody on a bi-weekly (Q2W) schedule, and then subcutaneous administration of the BCMAxCD3 bispecific antibody on a monthly (Q4W) schedule.

[0249] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody on a bi-weekly schedule (Q2W), and, if the subject achieves a partial response, a very good partial response, a complete response, or a complete response, subcutaneous administration of the BCMAxCD3 bispecific antibody on a monthly schedule (Q4W).

[0250] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody on a bi-weekly schedule (Q2W), and, if the subject achieves a complete response or a strict complete response, subcutaneous administration of the BCMAxCD3 bispecific antibody on a monthly schedule (Q4W).

[0251] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody on a bi-weekly schedule (Q2W), and, if the subject achieves a complete response or a severe complete response by or after treatment cycle 12, subcutaneous administration of the BCMAxCD3 bispecific antibody on a monthly schedule (Q4W).

[0252] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody on a bi-weekly schedule (Q2W) for at least 6 months, followed by subcutaneous administration of the BCMAxCD3 bispecific antibody on a monthly schedule (Q4W).

[0253] In certain embodiments, the method includes subcutaneous administration of one, two, or three escalating doses of BCMAxCD3 bispecific antibodies before subcutaneous administration of a first therapeutic dose.

[0254] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody in progressively increasing doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg before subcutaneous administration of a first therapeutic dose.

[0255] In certain embodiments, the method includes subcutaneous administration of one or two escalating doses of BCMAxCD3 bispecific antibodies before subcutaneous administration of a first therapeutic dose.

[0256] In certain embodiments, the method includes subcutaneous administration of two escalating doses of a BCMAxCD3 bispecific antibody before subcutaneous administration of a first therapeutic dose.

[0257] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody in escalating doses of 60 μg / kg and 300 μg / kg before subcutaneous administration of a first therapeutic dose.

[0258] In certain embodiments, the method includes subcutaneous administration of escalating doses of a BCMAxCD3 bispecific antibody, spaced 2 to 4 days apart, before subcutaneous administration of a first therapeutic dose.

[0259] In certain embodiments, the method comprises subcutaneously administering one or more escalating doses of a BCMAxCD3 bispecific antibody before subcutaneously administering a first therapeutic dose, the first therapeutic dose being administered 2 to 4 days after the last escalating dose.

[0260] In a particular embodiment, the method includes subcutaneous administration of a first escalating dose of 60 μg / kg of BCMAxCD3 bispecific antibody, followed by subcutaneous administration of a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, followed by subcutaneous administration of a first therapeutic dose of BCMAxCD3 bispecific antibody 2 to 4 days later.

[0261] In a particular embodiment, the method includes subcutaneous administration of a first escalating dose of 60 μg / kg of BCMAxCD3 bispecific antibody, followed by subcutaneous administration of a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, followed by subcutaneous administration of a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly (QW) schedule over a certain period, followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly (Q2W) schedule.

[0262] In a particular embodiment, the method includes subcutaneous administration of a first escalating dose of 60 μg / kg of BCMAxCD3 bispecific antibody, followed by subcutaneous administration of a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, followed by subcutaneous administration of a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly (QW) schedule for more than 6 months, followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly (Q2W) schedule.

[0263] In a particular embodiment, the method includes subcutaneous administration of a first escalating dose of 60 μg / kg of BCMAxCD3 bispecific antibody, followed by subcutaneous administration of a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2-4 days later, followed by subcutaneous administration of a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody 2-4 days later, followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly (QW) schedule, and after the subject has achieved partial response, very good partial response, complete response, or complete response for 6 months or more (according to IMWG criteria), subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly (Q2W) schedule.

[0264] In a particular embodiment, the method includes subcutaneous administration of a first escalating dose of 60 μg / kg of BCMAxCD3 bispecific antibody, followed by subcutaneous administration of a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2-4 days later, followed by subcutaneous administration of a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody 2-4 days later, followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly (QW) schedule, and after the subject has achieved a complete response or a severe complete response for 6 months or more (according to IMWG criteria), followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly (Q2W) schedule.

[0265] In a particular embodiment, the method includes subcutaneous administration of a first escalating dose of 60 μg / kg of BCMAxCD3 bispecific antibody, followed by subcutaneous administration of a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2-4 days later, followed by subcutaneous administration of a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody 2-4 days later, followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly (QW) schedule, after the subject has achieved partial response, very good partial response, complete response, or exact complete response (according to IMWG criteria) after four 28-day treatment cycles or more, followed by subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly (Q2W) schedule.

[0266] In a particular embodiment, the method includes subcutaneous administration of a first escalating dose of 60 μg / kg of BCMAxCD3 bispecific antibody, then, 2 to 4 days later, subcutaneous administration of a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody, then, 2 to 4 days later, subcutaneous administration of a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody, then, over a certain period, subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly schedule (QW), then, over a certain period, subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly schedule (Q2W), and then, subcutaneous administration of a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a monthly schedule (Q4W).

[0267] In certain embodiments, the method involves subcutaneously administering a first escalating dose of a BCMAxCD3 bispecific antibody at 60 μg / kg, then, 2 to 4 days later, subcutaneously administering a second escalating dose of the BCMAxCD3 bispecific antibody at 300 μg / kg, then, 2 to 4 days later, subcutaneously administering a first therapeutic dose of the BCMAxCD3 bispecific antibody at 1500 μg / kg, then, over a period of time, subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg on a weekly dosing schedule (QW), then, over a period of time, subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg on a bi-weekly dosing schedule (Q2W), and if the subject achieves at least a CR (i.e., complete response or stringent complete response) by cycle 12 or later, subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg on a monthly dosing schedule (Q4W).

[0268] In certain embodiments, the method involves subcutaneously administering a first escalating dose of a BCMAxCD3 bispecific antibody at 60 μg / kg, then, 2 to 4 days later, subcutaneously administering a second escalating dose of the BCMAxCD3 bispecific antibody at 300 μg / kg, then, 2 to 4 days later, subcutaneously administering a first therapeutic dose of the BCMAxCD3 bispecific antibody at 1500 μg / kg, then, over a period of time, subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg on a weekly dosing schedule (QW), then, over at least 6 months, subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg on a bi-weekly dosing schedule (Q2W), and then subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg on a monthly dosing schedule (Q4W).

[0269] In certain embodiments, the subject achieves a clinical response that is a PR, or VGPR, or CR, or sCR.

[0270] In certain embodiments, the subject achieves a clinical response that is a CR or sCR.

[0271] In certain embodiments, the clinical response is maintained for at least 6 months.

[0272] In certain embodiments, the clinical response is maintained for at least one year.

[0273] In certain embodiments, the clinical response is maintained for at least 18 months.

[0274] In certain embodiments, the clinical response is maintained for at least two years.

[0275] In certain embodiments, the infection rate in subjects is lower (for example, compared to subjects receiving only QW).

[0276] In certain embodiments, the incidence of Grade ≥ 3 infections is lower in subjects (e.g., compared to subjects receiving only QW).

[0277] In certain embodiments, the method achieves a reduction in new infections over time in a population of subjects with RRMM (e.g., compared to subjects remaining on a QW dosing schedule).

[0278] In certain embodiments, the method achieves a reduction in new grade ≥3 infections over time in a population of subjects with RRMM (e.g., compared to subjects remaining on a QW dosing schedule).

[0279] Combination regimens including daratumumab In certain embodiments, the BCMAxCD3 bispecific antibody described herein (e.g., teclistamaib) is administered as part of a combination regimen with daratumumab, and the BCMAxCD3 bispecific antibody is administered according to a dosing schedule including a QW dose, followed by a Q2W dose, and then a Q4W dose. Note that daratumumab SC is available as DARZALEX FASPRO® and teclistamaib is available as TECVAYLI®. In certain embodiments, the subject has previously received 1 to 3 lines of antimyeloma treatment including a proteasome inhibitor (PI) and lenalidomide. In certain embodiments, the subject has previously received only one line of antimyeloma treatment and is lenalidomide-refractory.

[0280] According to certain embodiments, daratumumab is administered subcutaneously. According to certain embodiments, each dose of daratumumab is: Day 1 of Cycle 1 and every week thereafter (QW) (for example, Day 1, Day 8, Day 15 and Day 22), Cycle 2: Weekly (QW) (for example, day 1, day 8, day 15 and day 22), Cycles 3-6: Every other week (Q2W) (for example, day 1 and day 15), Cycle 7 and subsequent cycles: Administer subcutaneously at a dose of 1800 mg in 28-day treatment cycles, such as monthly (Q4W) (e.g., on day 1).

[0281] According to certain embodiments, there is an interval of 5 days or more between doses of daratumumab.

[0282] According to a particular embodiment, a BCMAxCD3 bispecific antibody (e.g., tecrista-mab) is, Cycle 1: A dose escalates to 0.06 mg / kg on day 2, then to 0.3 mg / kg (e.g., day 4), then to 1.5 mg / kg (e.g., day 8), and thereafter to a weekly (QW) therapeutic dose of 1.5 mg / kg (e.g., on days 15 and 22). Cycle 2: 1.5 mg / kg weekly (QW) (for example, on days 1, 8, 15, and 22), Cycles 3-6: 3 mg / kg is administered subcutaneously every other week (Q2W) (for example, on day 1 and day 15), in a 28-day treatment cycle. Cycle 7 and subsequent cycles: 3 mg / kg monthly (Q4W) (e.g., day 1).

[0283] According to certain embodiments, daratumumab is administered subcutaneously on day 1 of cycle 1, and the first escalating dose of BCMAxCD3 bispecific antibody is administered at least 20 hours after daratumumab. According to certain embodiments, there is an interval of at least 2 days between escalating doses of BCMAxCD3 bispecific antibody. According to certain embodiments, the first 1.5 mg / kg dose of teclistamag is administered at least 2 days after the second escalating dose. According to certain embodiments, there is an interval of at least 5 days between 1.5 mg / kg therapeutic doses (or between 1.5 mg / kg and the first 3 mg / kg dose), and at least 12 days between 3 mg / kg therapeutic doses. According to certain embodiments, on the first day when daratumumab and BCMAxCD3 bispecific antibody are administered on the same day (e.g., day 8 of cycle 1), the BCMAxCD3 bispecific antibody is administered at least 3 hours after daratumumab.

[0284] According to a particular embodiment, a method for improving progression-free survival in a target population with multiple myeloma who have previously received one to three lines of antimyeloma therapy including proteasome inhibitors (PIs) and lenalidomide is: The regimen includes administering a combination regimen containing teclistamaib and daratumumab to the target population, wherein teclistamaib is Cycle 1: A dose escalates to 0.06 mg / kg on day 2, then to 0.3 mg / kg (e.g., day 4), then to 1.5 mg / kg (e.g., day 8), and thereafter to a weekly (QW) therapeutic dose of 1.5 mg / kg (e.g., on days 15 and 22). Cycle 2: 1.5 mg / kg weekly (QW) (for example, on days 1, 8, 15, and 22), Cycles 3 - 6: 3 mg / kg administered subcutaneously every other week (Q2W) (e.g., on days 1 and 15), Cycles 7 and subsequent cycles: 3 mg / kg administered subcutaneously monthly (Q4W) (e.g., on day 1) in 28-day treatment cycles, and daratumumab is On day 1 of cycle 1 and then weekly (QW) (e.g., on days 1, 8, 15, and 22), Cycle 2: Weekly (QW) (e.g., on days 1, 8, 15, and 22), Cycles 3 - 6: Every other week (Q2W) (e.g., on days 1 and 15), Cycles 7 and subsequent cycles: Administered subcutaneously in a 28-day treatment cycle in an amount of 1800 mg monthly (Q4W) (e.g., on day 1), The improvement in the median progression-free survival is compared to the median progression-free survival in the reference population, and the reference population has been administered a treatment regimen (DPd) (i.e., not including teclistamab) effective in treating, including daratumumab SC, pomalidomide, and dexamethasone, or (ii) a treatment regimen (DVd) (i.e., not including teclistamab) effective in treating, including daratumumab SC, bortezomib, and dexamethasone. According to certain embodiments, the improvement in the median progression-free survival is at least about 2 months, or at least about 4 months, or at least about 6 months, or at least about 8 months, or at least about 10 months, or at least about 12 months, or at least about 14 months, or at least about 16 months, or at least about 18 months, or at least about 20 months, or at least about 22 months, or at least about 24 months compared to the reference population.

[0285] Prophylactic administration of toci In MajesTEC-1, cytokine release syndrome (CRS) occurred in 72.1% of patients treated with the recommended Phase 2 dose (RP2D) of teclistamagb 1.5 mg / kg (50.3% grade [gr]1, 21.2% gr2, 0.6% gr3) once weekly, and was successfully managed with tocilizumab ("toci") in 36.4% of patients (± other interventions) without affecting the response to teclistamagb. We found that prophylactic administration of toci prior to the first dose of BCMAxCD3 bispecific antibody may reduce the incidence and severity of CRS and facilitate the initiation of treatment in outpatients.

[0286] Embodiments of the present invention provide a method for treating multiple myeloma in a subject by administering a therapeutically effective dose of tocilizumab to the subject in need before administering a first dose of a BCMAxCD3 bispecific antibody (e.g., tecristamag).

[0287] In certain embodiments, patients had relapsed, refractory, or end-of-line (LOT) disease, were exposed to proteasome inhibitors, immunomodulators, and anti-CD38 therapies, and had measurable disease.

[0288] In some embodiments, the subjects have received three prior anticancer therapies before administration of the BCMAxCD3 bispecific antibody. In one embodiment, the three prior anticancer therapies are a proteasome inhibitor (PI), an immunomodulator (IMiD), and an anti-CD38 antibody. In certain such embodiments, the proteasome inhibitor is bortezomib, carfilzomib, or ixazomib; the immunomodulator (IMiD) is lenalidomide, pomalidomide, or thalidomide; and the anti-CD38 antibody is daratumumab or isatuximab.

[0289] In certain embodiments, a single dose of toci prior to teclistamagb treatment reduces the incidence of CRS compared to the overall MajesTEC-1 study population, without evidence of new safety signals or impact on response to teclistamagb. In certain embodiments, prophylactic administration of toci reduces the risk of CRS in patients with a disease profile suitable for outpatient administration and reduces the burden of hospitalization during teclistamagb escalation.

[0290] In certain embodiments, toci is administered as a single dose of 8 mg / kg IV prior to teclistamaib. In certain embodiments, teclistamaib is administered subcutaneously according to a body weight-based dosing schedule as shown in Table B, Table C, Table D, or Table E.

[0291] How to restart treatment after a delay in administration Methods are also provided herein for restarting a BCMAxCD3 bispecific antibody administration regimen in a subject after a delay has occurred between administrations of the BCMAxCD3 bispecific antibody during the planned administration regimen, following initiation of a planned administration regimen for the treatment of multiple myeloma (e.g., the administration regimens shown in Table F). According to a particular embodiment, the planned administration regimen includes an escalation schedule comprising a first escalating dose of 0.06 mg / kg, a second escalating dose of 0.3 mg / kg 2 to 4 days (or 2 to 7 days) after the first escalating dose, a first therapeutic dose of 1.5 mg / kg 2 to 4 days (or 2 to 7 days) after the second escalating dose, and subsequent therapeutic doses of 1.5 mg / kg one week after the first therapeutic dose and thereafter weekly. According to a particular embodiment, the planned dosing regimen includes an escalating dosing schedule comprising a first escalating dose of 0.06 mg / kg, a second escalating dose of 0.3 mg / kg 2 to 4 days (or 2 to 7 days) after the first escalating dose, a first therapeutic dose of 1.5 mg / kg 2 to 4 days (or 2 to 7 days) after the second escalating dose, and a subsequent therapeutic dose of 1.5 mg / kg one week after the first therapeutic dose and thereafter weekly, provided that the subject achieves and maintains a complete response or better for at least 6 months, after which the subsequent therapeutic dose of 1.5 mg / kg is administered every other week (i.e., the frequency of administration may be reduced from 1.5 mg / kg weekly to 1.5 mg / kg every two weeks). According to a particular embodiment, the planned dosing regimen includes an escalating dosing schedule comprising a first escalating dose of 0.06 mg / kg, a second escalating dose of 0.3 mg / kg 2 to 4 days (or 2 to 7 days) after the first escalating dose, a first therapeutic dose of 1.5 mg / kg 2 to 4 days (or 2 to 7 days) after the second escalating dose, and a subsequent therapeutic dose of 1.5 mg / kg one week after the first therapeutic dose and thereafter weekly, provided that the subject achieves any clinical response and maintains it for at least 6 months, the subsequent therapeutic dose of 1.5 mg / kg is administered every other week (i.e., the dosing frequency may be reduced to 1.5 mg / kg every two weeks).

[0292] Drug administration regimens are developed based on extensive preclinical and clinical data. Once a safe and effective administration regimen (also referred to herein as a planned administration regimen) is established for a given therapy, subjects must adhere to the regimen or face significant risks, such as increased side effects and / or decreased efficacy. However, subjects often experience administration delays, particularly those with multiple myeloma who face routine health and lifestyle challenges. When subjects experience delays between doses of BCMAxCD3 bispecific antibody that are longer than the intervals between doses in an established (planned) administration regimen, there is a need for a safe and effective way to restart therapy. We have developed a novel method for restarting therapy with BCMAxCD3 bispecific antibody, which is adjusted to the length and timing of specific administration delays. Specifically, the method is selected from several options based on the last dose administered to the subject and the number of days since the last dose was administered. This method enables subjects to receive a safe and effective administration regimen to treat their multiple myeloma despite experiencing administration delays.

[0293] According to the previous procedures for restarting teclistamag, for example, if a patient experiences a delay in administration after initiating a therapeutic dose of 1.5 mg / kg, (1) if the delay is 28 days or less, the patient may continue teclistamag at the latest therapeutic dose and schedule (1.5 mg / kg, weekly or bi-weekly), or (2) if the delay exceeds 28 days, the patient must restart the escalation schedule with the first escalation dose (0.06 mg / kg).

[0294] Based at least in part on clinical data from patients with MajesTEC-1 who had received two or more therapeutic doses prior to a long-term dosing delay, the inventors developed an optimized method for restarting teclistamag. The incidence of cytokine release syndrome (CRS) and the frequency of step-up dosing (SUD) were evaluated in patients with Tec dosing intervals exceeding 28 days. Of 61 subjects with 128 intervals exceeding 28 days, only two experienced a recurrence of CRS. Both subjects had intervals >28–62 days and both received step-up doses of 60 ug / kg and 300 ug / kg. One subject had grade 2 CRS at the start of cycle 2 after a 44-day delay, and the other had grade 1 CRS at the start of cycle 6. Both subjects had delays due to infection. 100 intervals were between >28–62 days, and in the majority of these, step-up dosing was not administered (78%). The 78 subjects had intervals of >28–62 days without repeated dose escalations and without recurrent CRS upon restart. Based on the new safety data, the inventors have developed a restart schedule that allows patients to restart the regimen with a more effective dose, e.g., a therapeutic dose of 1.5 mg / kg or a second dose escalation of 0.3 mg / kg, despite administration delays longer than 28 days. According to a particular embodiment, a patient who started with a therapeutic dose of 1.5 mg / kg does not need to restart the regimen from a first dose escalation of 0.06 mg / kg, as long as the administration delay does not exceed 111 days (instead of more than 28 days). Compared to previous methods, the new “restart” method allows patients to safely restart their treatment regimen at a more effective dose, even if they have experienced a delay of more than 28 days. For example, if a patient has experienced a delay of 62 days or less, they can restart treatment at 1.5 mg / kg, or if a patient has experienced a delay of 63 to 111 days, they can restart escalating treatment at 0.3 mg / kg.

[0295] According to a particular embodiment, if a patient experiences a delay in administration after initiating a therapeutic dose of 1.5 mg / kg, (1) if the delay is 62 days or less (instead of 28 days or less), the patient may continue teclistamag at the patient's most recent therapeutic dose and schedule (1.5 mg / kg, weekly or bi-weekly); or (2) if the delay is between 63 and 111 days, the patient may resume the escalation schedule with a second escalation dose (0.3 mg / kg); or (3) if the delay exceeds 111 days, the patient may resume the escalation schedule with a first escalation dose (0.06 mg / kg).

[0296] According to a particular embodiment of the present invention, a method for restarting teclistamag after a delayed administration includes continuing teclistamag at the same dose and schedule if the delay is up to 62 days, restarting teclistamag at a second escalating dose (0.3 mg / kg) if the delay is between 63 and 111 days, and restarting teclistamag at a first escalating dose (0.06 mg / kg) if the delay exceeds 111 days.

[0297] According to a particular embodiment, the subject initiates a planned dosing regimen for the treatment of multiple myeloma, and after a delay occurs between administrations of the BCMAxCD3 bispecific antibody (e.g., tecristamab) during the planned dosing regimen, the subject restarts the BCMAxCD3 bispecific antibody dosing regimen, wherein the planned dosing regimen is (1) An escalation schedule including (a) a first escalation dose of 0.06 mg / kg, (b) a second escalation dose of 0.3 mg / kg 2 to 7 days after the first escalation dose (e.g., 2 to 4 days after the first escalation dose), and (c) a first therapeutic dose of 1.5 mg / kg 2 to 7 days after the second escalation dose (e.g., 2 to 4 days after the second escalation dose). (2) A weekly administration schedule including a subsequent therapeutic dose of 1.5 mg / kg once a week thereafter, and (3) If the subject achieves a clinical response and maintains it for at least 6 months (for example, if the subject achieves a complete response and maintains it for at least 6 months), a bi-weekly administration schedule including a subsequent therapeutic dose of 1.5 mg / kg every two weeks, Next, the method for restarting the target administration regimen is: (i) If the last dose administered to the subject was a therapeutic dose of 1.5 mg / kg and the time elapsed since the last dose was 62 days or less, the planned dosing regimen should be continued with the last therapeutic dose and schedule (1.5 mg / kg weekly or 1.5 mg / kg every other week), or (ii) If the last dose administered to the subject was a therapeutic dose of 1.5 mg / kg and the time elapsed since the last dose was 63 to 111 days, restart the escalation schedule with a second escalation dose of 0.3 mg / kg and resume the planned dosing regimen, or (iii) A method comprising restarting the escalation schedule with a first escalation dose of 0.06 mg / kg and resuming the planned dosing regimen if the last dose administered to the subject was a therapeutic dose of 1.5 mg / kg and more than 111 days have passed since the last dose administered.

[0298] According to a particular embodiment, if the administration of a BCMAxCD3 bispecific antibody (e.g., teclistamag) is delayed, the patient resumes treatment based on Table 7 and, accordingly, resumes the weekly or bi-weekly (every two weeks) administration schedule.

[0299] [Table 11] a Consider the benefits and risks of restarting teclistamag in patients who require a delay of more than 28 days due to adverse reactions. b Consider the benefits and risks of restarting teclistamag in patients requiring a dosing delay of more than 111 days due to adverse reactions.

[0300] Exemplary Embodiments The embodiments of the present invention listed above are provided below. These embodiments are for illustrative purposes only and do not limit the scope of the claims attached to this disclosure or this specification. 1A. A method for treating a subject in need of treatment for multiple myeloma, comprising administering a therapeutically effective dose of a BCMAxCD3 bispecific antibody (e.g., teclistamag) to the subject on a bi-weekly schedule (Q2W), wherein the subject has relapsed or refractory multiple myeloma and has previously received at least three lines of treatment including proteasome inhibitors, immunomodulators and anti-CD38 monoclonal antibodies. 2A. The method according to Embodiment 1A, wherein the BCMA × CD3 bispecific antibody comprises a BCMA-binding domain including HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, and a CD3-binding domain including HCDR1 of SEQ ID NO: 14, HCDR2 of SEQ ID NO: 15, HCDR3 of SEQ ID NO: 16, LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO: 19. 3A. The method according to Embodiment 2A, wherein the BCMA binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and the CD3 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21. 4A. The method according to any one of Embodiments 1A to 3A, wherein the BCMA×CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 23. 5A. The method according to any one of Embodiments 1A to 4A, wherein the BCMAxCD3 bispecific antibody is tecristamag. 6A. The method according to any one of Embodiments 1A to 5A, comprising administering a therapeutic dose of a BCMAxCD3 bispecific antibody once every two weeks. 7A. The method according to Embodiment 6A, comprising administering one or more escalating doses of BCMAxCD3 bispecific antibody before administering a therapeutic dose of BCMAxCD3 bispecific antibody. 8A. The method according to any one of Embodiments 1A to 7A, comprising administering a therapeutic dose of BCMAxCD3 bispecific antibody once a week, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody once every two weeks. 9A. The method according to any one of Embodiments 1A to 7A, comprising administering a BCMAxCD3 bispecific antibody according to the following administration schedule.

[0301] [Table 12] 10A. The method according to any one of Embodiments 1A to 7A, comprising administering a BCMAxCD3 bispecific antibody according to the following administration schedule.

[0302] [Table 13] 11A. The method according to any one of Embodiments 1A to 10A, wherein a BCMAxCD3 bispecific antibody is administered subcutaneously. 12A. The method according to any one of Embodiments 1A to 5A, comprising subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg every other week (Q2W) (for example, on day 1 and day 15 of each 28-day cycle). 13A. The method according to any one of Embodiments 1A to 5A, comprising subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg every month (Q4W) (e.g., on day 1 of each 28-day cycle). 14A. The method according to any one of Embodiments 1A to 5A, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg weekly (QW) (e.g., on days 1, 8, 15, and 22 of each 28-day cycle) for a certain period, and then subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg every other week (Q2W) (e.g., on days 1 and 15 of each 28-day cycle). The method according to any one of Embodiments 1A to 5A, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg weekly (QW) (e.g., on days 1, 8, 15, and 22 of each 28-day cycle) for at least 6 months, and then subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg every other week (Q2W) (e.g., on days 1 and 15 of each 28-day cycle). The method according to any one of Embodiments 1A to 5A, comprising administering a BCMAxCD3 bispecific antibody subcutaneously at a therapeutic dose of 1500 μg / kg for at least 6 months on weekly (QW) (e.g., on days 1, 8, 15, and 22 of each 28-day cycle), and then, after the subject achieves PR, VGPR, CR, or sCR, administering the BCMAxCD3 bispecific antibody subcutaneously at a therapeutic dose of 1500 μg / kg every other week (Q2W) (e.g., on days 1 and 15 of each 28-day cycle). The method according to any one of Embodiments 1A to 5A, comprising administering a BCMAxCD3 bispecific antibody subcutaneously at a therapeutic dose of 1500 μg / kg weekly (QW) (e.g., on days 1, 8, 15, and 22 of each 28-day cycle) for at least 4 cycles, and then, after the subject achieves PR, VGPR, CR, or sCR, administering the BCMAxCD3 bispecific antibody subcutaneously at a therapeutic dose of 1500 μg / kg every other week (Q2W) (e.g., on days 1 and 15 of each 28-day cycle). The method according to any one of Embodiments 1A to 5A, comprising administering a BCMAxCD3 bispecific antibody subcutaneously at a therapeutic dose of 1500 μg / kg weekly (QW) (e.g., on days 1, 8, 15, and 22 of each 28-day cycle) for at least 6 months, and then, after the subject achieves CR or sCR, administering the BCMAxCD3 bispecific antibody subcutaneously at a therapeutic dose of 1500 μg / kg every other week (Q2W) (e.g., on days 1 and 15 of each 28-day cycle). 19A. The method according to any one of Embodiments 1A to 5A, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg weekly (QW) (e.g., on days 1, 8, 15, and 22 of each 28-day cycle) for at least 4 cycles, and then, after the subject achieves CR or sCR, subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg every other week (Q2W) (e.g., on days 1 and 15 of each 28-day cycle). 20A. The method according to any one of Embodiments 1A to 19A, wherein the subject achieves a clinical response of PR, VGPR, CR, or sCR after initiation of Q2W administration of a therapeutic dose. 21A. The method according to any one of Embodiments 1A to 19A, wherein the subject achieves a clinical response of PR, VGPR, CR, or sCR after initiation of Q4W administration of a therapeutic dose. 22A. Any one of the embodiments 20A to 21A, wherein the clinical response is maintained for at least 6 months. 23A. The method according to any one of embodiments 20A to 21A, wherein the clinical response is maintained for at least one year. 24A. The method according to any one of embodiments 20A to 21A, wherein the clinical response is maintained for at least 18 months. 25A. The method according to any one of embodiments 20A to 21A, wherein the clinical response is maintained for at least two years. 26A. The method according to any one of Embodiments 1A to 25A, wherein the infection occurring in the subjects is less (for example, compared to subjects who remain on QW administration). 27A. The method according to any one of Embodiments 1A to 25A, wherein fewer Grade ≥ 3 infections occur in the subjects (for example, compared to subjects who remain on QW administration).

[0303] Further embodiments of the invention listed above are provided below. These embodiments are for illustrative purposes only and do not limit the scope of the claims appended to this disclosure or this specification. 1B. A method for treating a subject in need of treatment for multiple myeloma, comprising administering a therapeutically effective dose of a BCMAxCD3 bispecific antibody (e.g., teclistamag) to the subject on a bi-weekly (Q2W) and / or monthly (Q4W) schedule, wherein the subject has been diagnosed with multiple myeloma. 2B. The method according to Embodiment 1B, wherein the subject has relapsed or refractory multiple myeloma and has previously received at least three lines of treatment comprising a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody. 3B. The method according to Embodiment 1B or 2B, wherein the BCMA × CD3 bispecific antibody comprises a BCMA-binding domain including HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, and a CD3-binding domain including HCDR1 of SEQ ID NO: 14, HCDR2 of SEQ ID NO: 15, HCDR3 of SEQ ID NO: 16, LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO: 19. The method according to Embodiment 1B or 2B, wherein the BCMA binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and the CD3 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21. The method according to any one of Embodiments 1B to 4B, wherein the BCMA×CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 23. The method according to any one of Embodiments 1B to 4B, wherein the 6B.BCMA×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 23. 7B. The method according to any one of Embodiments 1B to 5B, wherein the BCMAxCD3 bispecific antibody is tecristamag. 8B. The method according to any one of Embodiments 1B to 6B, comprising administering a therapeutic dose of a BCMAxCD3 bispecific antibody once every two weeks. 9B. The method according to Embodiment 8B, comprising administering one or more escalating doses of BCMAxCD3 bispecific antibody before administering a therapeutic dose of BCMAxCD3 bispecific antibody. 10B. The method according to any one of Embodiments 1B to 9B, comprising administering a therapeutic dose of BCMAxCD3 bispecific antibody once a week, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody once every two weeks. 11B. The method according to any one of Embodiments 1B to 9B, comprising administering a BCMAxCD3 bispecific antibody according to the following administration schedule.

[0304] [Table 14] 12B. The method according to any one of Embodiments 1B to 9B, comprising administering a BCMAxCD3 bispecific antibody according to the following administration schedule.

[0305] [Table 15] 13B. The method according to any one of Embodiments 1B to 12B, wherein a BCMAxCD3 bispecific antibody is administered subcutaneously. The method according to any one of Embodiments 1B to 7B, comprising subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg every other week (Q2W) (for example, on day 1 and day 15 of each 28-day cycle). The method according to any one of Embodiments 1B to 7B, comprising subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg monthly (Q4W) (e.g., on day 1 of each 28-day cycle). The method according to any one of Embodiments 1B to 7B, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg weekly (QW) (e.g., on days 1, 8, 15, and 22 of each 28-day cycle) for a certain period, and then subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg every other week (Q2W) (e.g., on days 1 and 15 of each 28-day cycle). The method according to any one of Embodiments 1B to 7B, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg weekly (QW) (e.g., on days 1, 8, 15, and 22 of each 28-day cycle) for at least 6 months, and then subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg every other week (Q2W) (e.g., on days 1 and 15 of each 28-day cycle). The method according to any one of Embodiments 1B to 7B, comprising: subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg for at least 6 months weekly (QW) (e.g., on days 1, 8, 15, and 22 of each 28-day cycle); and then, after the subject achieves PR, VGPR, CR, or sCR, subcutaneous administration of the BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg every other week (Q2W) (e.g., on days 1 and 15 of each 28-day cycle). The method according to any one of Embodiments 1B to 7B, comprising: subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg for at least 4 cycles weekly (QW) (e.g., on days 1, 8, 15, and 22 of each 28-day cycle); and then, after the subject achieves PR, VGPR, CR, or sCR, subcutaneous administration of the BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg every other week (Q2W) (e.g., on days 1 and 15 of each 28-day cycle). The method according to any one of Embodiments 1B to 7B, comprising administering a BCMAxCD3 bispecific antibody subcutaneously at a therapeutic dose of 1500 μg / kg for at least 6 months on weekly (QW) (e.g., on days 1, 8, 15, and 22 of each 28-day cycle), and then, after the subject achieves CR or sCR, administering the BCMAxCD3 bispecific antibody subcutaneously at a therapeutic dose of 1500 μg / kg every other week (Q2W) (e.g., on days 1 and 15 of each 28-day cycle). The method according to any one of Embodiments 1B to 7B, comprising administering a BCMAxCD3 bispecific antibody subcutaneously at a therapeutic dose of 1500 μg / kg weekly (QW) (e.g., on days 1, 8, 15, and 22 of each 28-day cycle) for at least 4 cycles, and then, after the subject achieves CR or sCR, administering the BCMAxCD3 bispecific antibody subcutaneously at a therapeutic dose of 1500 μg / kg every other week (Q2W) (e.g., on days 1 and 15 of each 28-day cycle). 22B. The method according to any one of Embodiments 1B to 21B, wherein the subject achieves a clinical response which is PR, VGPR, CR, or sCR after initiation of Q2W administration of a therapeutic dose. 23B. The method according to any one of Embodiments 1B to 21B, wherein the subject achieves a clinical response which is PR, VGPR, CR, or sCR after initiation of Q4W administration of a therapeutic dose. 24B. The method according to any one of Embodiments 22B to 23B, wherein the clinical response is maintained for at least 6 months. 25B. The method according to any one of Embodiments 22B to 23B, wherein the clinical response is maintained for at least one year. 26B. The method according to any one of Embodiments 22B to 23B, wherein the clinical response is maintained for at least 18 months. 27B. The method according to any one of Embodiments 22B to 23B, wherein the clinical response is maintained for at least two years. 28B. The method according to any one of Embodiments 1B to 27B, which results in fewer infections occurring in the subjects (for example, compared to subjects who remain on QW administration). 29B. The method according to any one of Embodiments 1B to 27B, wherein fewer Grade ≥ 3 infections occur in the subjects (for example, compared to subjects who remain on QW administration).

[0306] Further embodiments of the invention listed above are provided below. These embodiments are for illustrative purposes only and do not limit the scope of the claims appended to this disclosure or this specification. 1C. A method for treating a subject in need of treatment for multiple myeloma, comprising administering a therapeutically effective dose of teclistamag, followed by a therapeutically effective dose of a BCMAxCD3 bispecific antibody (e.g., teclistamag) to the subject, wherein the subject has relapsed or refractory multiple myeloma and has previously received at least three lines of treatment including proteasome inhibitors, immunomodulators and anti-CD38 monoclonal antibodies. The method according to Embodiment 1C, wherein the 2C.BCMA×CD3 bispecific antibody comprises a BCMA-binding domain including HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, and a CD3-binding domain including HCDR1 of SEQ ID NO: 14, HCDR2 of SEQ ID NO: 15, HCDR3 of SEQ ID NO: 16, LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO: 19. The method according to Embodiment 2C, wherein the 3C.BCMA binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and the CD3 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21. The method according to any one of Embodiments 1C to 3C, wherein the 4C.BCMA×CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 23. The method according to any one of Embodiments 1C to 4C, wherein the 5C.BCMAxCD3 bispecific antibody is tecristamag. 6C. The method according to any one of Embodiments 1C to 5C, wherein the method reduces the risk of CRS in a subject compared to a subject that has not been administered toci prior to receiving a BCMAxCD3 bispecific antibody. 7C. The method according to any one of Embodiments 1C to 6C, wherein tocilizumab is administered within approximately 4 hours before the first escalating dose of teclistamadab (for example, approximately 2 to 4 hours before the first escalating dose of teclistamadab). 8C. The method according to any one of Embodiments 1C to 7C, wherein tocilizumab is administered as a single dose of 8 mg / kg IV. 9C. The method according to any one of Embodiments 1C to 8C, wherein the method achieves a CRS rate in the target population that is lower than the reference CRS rate in the reference population, and the reference population has not received tocilizumab prior to receiving the BCMAxCD3 bispecific antibody.

[0307] Further embodiments of the invention listed above are provided below. These embodiments are for illustrative purposes only and do not limit the scope of the claims appended to this disclosure or this specification. 1D. A method for restarting a BCMAxCD3 bispecific antibody administration regimen for a subject who has initiated a planned dosing regimen for the treatment of multiple myeloma, after a delay in administration of the BCMAxCD3 bispecific antibody (e.g., tecristamab) during the planned dosing regimen, wherein the planned dosing regimen is: (1) An escalation schedule including (a) a first escalation dose of 0.06 mg / kg, (b) a second escalation dose of 0.3 mg / kg 2 to 7 days after the first escalation dose (e.g., 2 to 4 days after the first escalation dose), and (c) a first therapeutic dose of 1.5 mg / kg 2 to 7 days after the second escalation dose (e.g., 2 to 4 days after the second escalation dose). (2) A weekly administration schedule including a subsequent therapeutic dose of 1.5 mg / kg once a week thereafter, and (3) If the subject achieves a clinical response and maintains it for at least 6 months (for example, if the subject achieves a complete response and maintains it for at least 6 months), a bi-weekly administration schedule including a subsequent therapeutic dose of 1.5 mg / kg every two weeks, The method for restarting the treatment regimen in question is: (i) If the last dose administered to the subject was a therapeutic dose of 1.5 mg / kg and the time elapsed since the last dose was 62 days or less, the planned dosing regimen should be continued with the last therapeutic dose and schedule (1.5 mg / kg weekly or 1.5 mg / kg every other week), or (ii) If the last dose administered to the subject was a therapeutic dose of 1.5 mg / kg and the time elapsed since the last dose was 63 to 111 days, restart the escalation schedule with a second escalation dose of 0.3 mg / kg and resume the planned dosing regimen, or (iii) A method comprising restarting the escalation schedule with a first escalation dose of 0.06 mg / kg and resuming the planned dosing regimen if the last dose administered to the subject was a therapeutic dose of 1.5 mg / kg and more than 111 days have passed since the last dose administered. 2D. How to restart the target dosing regimen: (i) If the last dose administered to the subject was a therapeutic dose of 1.5 mg / kg and the time elapsed since the last dose was 62 days or less, the planned dosing regimen should be continued with the last therapeutic dose and schedule (1.5 mg / kg weekly or 1.5 mg / kg every other week), or (ii) If the last dose administered to the subject was a therapeutic dose of 1.5 mg / kg and the time elapsed since the last dose was 63 to 111 days, restart the escalation schedule with a second escalation dose of 0.3 mg / kg and resume the planned dosing regimen, or (iii) If the last dose administered to the subject was a therapeutic dose of 1.5 mg / kg and more than 111 days have passed since the last dose administered, restart the escalation schedule with a first escalation dose of 0.06 mg / kg and resume the planned dosing regimen, or (iv) If the last dose administered to the subject was the first escalation dose of 0.06 mg / kg and more than 7 days have passed since the last dose administered, restart the escalation schedule with the first escalation dose of 0.06 mg / kg and resume the planned dosing regimen, or (v) If the last dose administered to the subject was the second escalating dose of 0.3 mg / kg and the time elapsed since the last dose was 8 to 28 days, the second escalating dose of 0.3 mg / kg should be repeated and the escalating schedule continued (thus restarting the planned dosing regimen), or (vi) The method of Embodiment 1D, which includes restarting the escalation schedule with a first escalation dose of 0.06 mg / kg if the last dose administered to the subject was a second escalation dose of 0.3 mg / kg and more than 28 days have passed since the last dose administered. 3D. If the subject achieves a complete response and maintains it for at least 6 months, the planned dosing regimen is the method according to Embodiment 1D or 2D, comprising a bi-weekly dosing schedule including a therapeutic dose of 1.5 mg / kg once every two weeks. 4D. The method according to any one of Embodiments 1D to 3D, wherein the dose escalation schedule includes (a) a first dose escalation of 0.06 mg / kg on day 1, (b) a second dose escalation of 0.3 mg / kg on day 4, and (c) a first therapeutic dose of 1.5 mg / kg on day 7. 5D. The method according to any one of Embodiments 1D to 3D, wherein each of the second escalating dose and the first therapeutic dose is administered 2 to 4 days after the previous dose, or optionally up to 7 days after the previous dose, in order to allow for the resolution of adverse reactions. 6D. The method according to any one of Embodiments 1D to 5D, further comprising administering a prior agent to the subject before restarting the planned dosing regimen, wherein the prior agent comprises 16 mg or equivalent of oral or intravenous dexamethasone, 50 mg or equivalent of oral or intravenous diphenhydramine, and 650 mg to 1000 mg or equivalent of oral or intravenous acetaminophen. The method according to any one of Embodiments 1D to 6D, wherein the 7D.BCMA×CD3 bispecific antibody comprises a BCMA-binding domain including HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, and a CD3-binding domain including HCDR1 of SEQ ID NO: 14, HCDR2 of SEQ ID NO: 15, HCDR3 of SEQ ID NO: 16, LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO: 19. The method according to any one of Embodiments 1D to 7D, wherein the 8D.BCMA×CD3 bispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype. The method according to any one of Embodiments 1D to 8D, wherein the 9D.BCMA×CD3 bispecific antibody is of the IgG4 isotype. The method according to any one of Embodiments 1D to 9D, wherein the 10D.BCMA×CD3 bispecific antibody contains one or more substitutions in its Fc region. The method according to any one of Embodiments 1D to 10D, wherein the 11D.BCMAxCD3 bispecific antibody is of the IgG4 isotype and contains proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235 (according to EU index numbering) of its Fc region, respectively. The method according to any one of Embodiments 1D to 11D, wherein the 12D.BCMA×CD3 bispecific antibody is of the IgG4 isotype and contains F405L and R409K substitutions (according to EU index numbering) in its Fc region. The method according to any one of Embodiments 1D to 12D, wherein the Fc region of the BCMA binding arm contains proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235 (according to EU index numbering), respectively. The method according to any one of Embodiments 1D to 13D, wherein the Fc region of the 14D CD3 binding arm includes proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235, in addition to F405L and R409K substitutions (as assigned by EU index numbering). The method according to any one of Embodiments 1D to 14D, wherein the BCMA × CD3 bispecific antibody comprises a BCMA-binding domain and a CD3-binding domain, the BCMA-binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and the CD3-binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21. The method according to any one of Embodiments 1D to 15D, wherein the 16D.BCMA×CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 23. The method according to any one of Embodiments 1D to 15D, wherein the 17D.BCMA×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 23. The method according to any one of Embodiments 1D to 15D, wherein the 18D.BCMA×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 23. The method according to any one of Embodiments 1D to 15D, wherein the 19D.BCMA×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 99% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 99% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 99% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 99% identity with the amino acid sequence of SEQ ID NO: 23. The method according to any one of Embodiments 1D to 15D, wherein the 20D.BCMAxCD3 bispecific antibody is tecristamag. 21D. The method according to any one of Embodiments 1D to 20D, wherein the subject has relapsed or refractory multiple myeloma. 22D. The method according to any one of Embodiments 1D to 21D, wherein the subject has relapsed and refractory multiple myeloma, has received at least three prior therapies including immunomodulators, proteasome inhibitors, and anti-CD38 antibodies, and has shown disease progression to the last therapy. 23D. The method according to any one of Embodiments 1D to 21D, wherein the subject has relapsed or refractory multiple myeloma and has previously received at least four lines of treatment comprising a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody.

[0308] Further embodiments of the invention listed above are provided below. These embodiments are for illustrative purposes only and do not limit the scope of the claims appended to this disclosure or this specification. 1. A method for treating a patient requiring treatment for multiple myeloma, comprising administering a therapeutic dose of BCMAxCD3 bispecific antibody to the patient on a bi-weekly administration schedule (Q2W). 2. The method according to Embodiment 1, wherein the BCMA × CD3 bispecific antibody comprises a BCMA-binding domain including HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, and a CD3-binding domain including HCDR1 of SEQ ID NO: 14, HCDR2 of SEQ ID NO: 15, HCDR3 of SEQ ID NO: 16, LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO: 19. 3. The method according to Embodiment 1 or 2, wherein the BCMA binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and the CD3 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21. 4. The method according to any one of Embodiments 1 to 3, wherein the BCMA×CD3 bispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype. 5. The method according to any one of Embodiments 1 to 4, wherein the BCMA×CD3 bispecific antibody is of the IgG4 isotype. 6. The method according to any one of Embodiments 1 to 5, wherein the BCMA×CD3 bispecific antibody contains one or more substitutions in its Fc region. 7. The method according to any one of Embodiments 1 to 6, wherein the BCMA×CD3 bispecific antibody is of the IgG4 isotype and contains S228P, F234A, and L235A substitutions in its Fc region (according to EU numbering). 8. The method according to any one of Embodiments 1 to 7, wherein the BCMA×CD3 bispecific antibody is of the IgG4 isotype and contains S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region (according to EU numbering). 9. The method according to any one of Embodiments 1 to 8, wherein the Fc region of the BCMA coupling arm includes S228P, F234A, and L235A substitutions in the Fc region (according to EU numbering). 10. The method according to any one of Embodiments 1 to 9, wherein the Fc region of the CD3 coupling arm includes substitutions of S228P, F234A, L235A, F405L, and R409K in the Fc region (according to EU numbering). 11. The method according to any one of Embodiments 1 to 10, wherein the BCMA×CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 23. 12. The method according to any one of Embodiments 1 to 10, wherein the BCMA×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 23. 13. The method according to any one of Embodiments 1 to 10, wherein the BCMA×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 23. 14. The method according to any one of Embodiments 1 to 10, wherein the BCMA×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 23. 15. The method according to any one of Embodiments 1 to 10, wherein the BCMAxCD3 bispecific antibody is teclistamagb. 16. The method according to any one of Embodiments 1 to 15, wherein the subject has relapsed or refractory multiple myeloma (for example, the subject has been previously treated with 2 to 14 lines of treatment). 17. The method according to any one of Embodiments 1 to 16, wherein the subject has previously received at least three lines of treatment. 18. The method according to any one of Embodiments 1 to 16, wherein the subject has previously received at least four lines of treatment. 19. The method according to any one of Embodiments 1 to 16, wherein the subject has previously received at least five lines of treatment (pentad exposure). 20. Any method of Embodiments 1 to 16, wherein the subject has previously received at least three lines of treatment comprising a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody. 21. Any method of Embodiments 1 to 16, wherein the subject has previously received at least four lines of treatment comprising a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody. 22. The method according to any one of Embodiments 1 to 21, comprising subcutaneously administering a therapeutic dose of a BCMAxCD3 bispecific antibody to a subject on a bi-weekly administration schedule (Q2W). 23. The method according to any one of Embodiments 1 to 22, comprising subcutaneously administering one or more escalating doses of BCMAxCD3 bispecific antibody to the target before administering a first therapeutic dose of BCMAxCD3 bispecific antibody. 24. The method according to any one of Embodiments 1 to 23, comprising subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg to approximately 3000 μg / kg on a bi-weekly administration schedule (Q2W). 25. The method according to any one of Embodiments 1 to 23, comprising subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg on a bi-weekly administration schedule (Q2W). 26. The method according to any one of Embodiments 1 to 23, comprising subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 3000 μg / kg on a bi-weekly administration schedule (Q2W). 27. The method according to any one of Embodiments 1 to 26, comprising subcutaneously administering at least one therapeutic dose of BCMAxCD3 bispecific antibody to the target on a weekly administration schedule (QW), and then administering a therapeutic dose of BCMAxCD3 bispecific antibody to the target on a bi-weekly administration schedule (Q2W). 28. The method according to any one of Embodiments 1 to 27, comprising subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least one 28-day treatment cycle, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W). 29. The method according to any one of Embodiments 1 to 27, comprising subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least two 28-day treatment cycles, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W). 30. The method according to any one of Embodiments 1 to 27, comprising subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least three 28-day treatment cycles, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W). 31. The method according to any one of Embodiments 1 to 27, comprising subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least four 28-day treatment cycles, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W). 32. The method according to any one of Embodiments 1 to 27, comprising subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least five 28-day treatment cycles, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W). 33. The method according to any one of Embodiments 1 to 27, comprising subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least six 28-day treatment cycles, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W). 34. The method according to any one of Embodiments 1 to 27, comprising subcutaneously administering a therapeutic dose of BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least 6 months, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W). 35. The method according to any one of Embodiments 1 to 34, comprising administering a therapeutic dose of BCMAxCD3 bispecific antibody subcutaneously to the target patient on a weekly dosing schedule (QW) until the target patient achieves partial response, very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody to the target patient on a bi-weekly dosing schedule (Q2W). 36. The method according to any one of Embodiments 1 to 34, comprising administering a therapeutic dose of BCMAxCD3 bispecific antibody subcutaneously to the target patient on a weekly dosing schedule (QW) until the target patient achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody to the target patient on a bi-weekly dosing schedule (Q2W). 37. The method according to any one of Embodiments 1 to 34, comprising administering a therapeutic dose of BCMAxCD3 bispecific antibody subcutaneously to the target patient on a weekly dosing schedule (QW) until the target patient achieves complete response or strict complete response as determined by the IMWG response criteria, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody to the target patient on a bi-weekly dosing schedule (Q2W). 38. The method according to any one of Embodiments 1 to 27, comprising administering a therapeutic dose of BCMAxCD3 bispecific antibody subcutaneously to the target patient on a weekly dosing schedule (QW) until the target patient achieves partial response, very good partial response, complete response, or exact complete response after four or more treatment cycles, as determined by the IMWG response criteria, and then administering a therapeutic dose of BCMAxCD3 bispecific antibody to the target patient on a bi-weekly dosing schedule (Q2W). 39. (i) until the subject achieves a partial response, very good partial response, complete response, or exact complete response for at least 6 months as determined by the IMWG response criteria, or (ii) until the subject achieves a complete response or exact complete response for at least 6 months as determined by the IMWG response criteria, the therapeutic dose of BCMAxCD3 bispecific antibody is administered subcutaneously on a weekly dosing schedule (QW). The method according to any one of Embodiments 1 to 27, further comprising administering a therapeutic dose of a BCMAxCD3 bispecific antibody to the target population on a bi-weekly administration schedule (Q2W). 40. The method according to any one of Embodiments 27 to 39, wherein each therapeutic dose of BCMAxCD3 bispecific antibody administered on a weekly dosing schedule (QW) is the same as the therapeutic dose of BCMAxCD3 bispecific antibody administered on a bi-weekly dosing schedule (Q2W). 41. The method according to any one of Embodiments 27 to 40, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg to approximately 3000 μg / kg on a weekly dosing schedule (QW). 42. The method according to any one of Embodiments 27 to 40, comprising subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg on a weekly dosing schedule (QW). 43. The method according to any one of Embodiments 27 to 40, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 3000 μg / kg on a weekly dosing schedule (QW). 44. The method according to any one of Embodiments 27 to 40, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg on a weekly administration schedule (QW), and then subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg on a bi-weekly administration schedule (Q2W). 45. The method according to any one of Embodiments 27 to 40, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg on a weekly administration schedule (QW), and then subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 3000 μg / kg on a bi-weekly administration schedule (Q2W). 46. ​​The method according to any one of Embodiments 1 to 45, comprising subcutaneously administering a BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W), and then subcutaneously administering the BCMAxCD3 bispecific antibody on a monthly administration schedule (Q4W). 47. The method according to any one of Embodiments 1 to 46, comprising: subcutaneous administration of a BCMAxCD3 bispecific antibody on a weekly administration schedule (QW); subcutaneous administration of a BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W); and subcutaneous administration of a BCMAxCD3 bispecific antibody on a monthly administration schedule (Q4W). 48. The method according to any one of Embodiments 1 to 47, comprising: subcutaneously administering a BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W); and, if the subject achieves a partial response, a very good partial response, a complete response, or a complete response, then subcutaneously administering the BCMAxCD3 bispecific antibody on a monthly administration schedule (Q4W). 49. The method according to any one of Embodiments 1 to 47, comprising subcutaneously administering a BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W), and, if the subject achieves a complete response or a strict complete response, subcutaneously administering the BCMAxCD3 bispecific antibody on a monthly administration schedule (Q4W). 50. The method according to any one of Embodiments 1 to 47, comprising subcutaneously administering a BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W), and if the subject achieves a complete response or a severe complete response by or after treatment cycle 12, subcutaneously administering the BCMAxCD3 bispecific antibody on a monthly administration schedule (Q4W). 51. The method according to any one of Embodiments 1 to 47, comprising subcutaneously administering a BCMAxCD3 bispecific antibody on a bi-weekly schedule (Q2W) for at least 6 months, and then subcutaneously administering a BCMAxCD3 bispecific antibody on a monthly schedule (Q4W). 52. The method according to any one of Embodiments 1 to 51, comprising subcutaneously administering one, two, or three escalating doses of BCMAxCD3 bispecific antibodies before subcutaneously administering a first therapeutic dose. 53. The method according to any one of Embodiments 1 to 52, comprising subcutaneously administering a BCMAxCD3 bispecific antibody in escalating doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg before subcutaneously administering a first therapeutic dose. 54. The method according to any one of Embodiments 1 to 52, comprising subcutaneously administering one or two escalating doses of BCMAxCD3 bispecific antibodies before subcutaneously administering a first therapeutic dose. 55. The method according to any one of Embodiments 1 to 52, comprising subcutaneously administering two escalating doses of a BCMAxCD3 bispecific antibody before subcutaneously administering a first therapeutic dose. 56. The method according to any one of Embodiments 1 to 52, comprising subcutaneously administering a BCMAxCD3 bispecific antibody in escalating doses of 60 μg / kg and 300 μg / kg before subcutaneously administering a first therapeutic dose. 57. The method according to any one of Embodiments 1 to 56, comprising subcutaneously administering escalating doses of a BCMAxCD3 bispecific antibody at intervals of 2 to 4 days from each other, prior to subcutaneous administration of a first therapeutic dose. 58. The method according to any one of Embodiments 1 to 57, comprising subcutaneously administering one or more escalating doses of a BCMAxCD3 bispecific antibody before subcutaneously administering a first therapeutic dose, wherein the first therapeutic dose is administered 2 to 4 days after the last escalating dose. The method according to any one of Embodiments 1 to 58, comprising subcutaneously administering a first escalating dose of 59.60 μg / kg of BCMAxCD3 bispecific antibody, then subcutaneously administering a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, and then subcutaneously administering a first therapeutic dose of BCMAxCD3 bispecific antibody 2 to 4 days later. The method according to any one of Embodiments 1 to 59, comprising subcutaneously administering a first escalating dose of 60.60 μg / kg of BCMAxCD3 bispecific antibody, then subcutaneously administering a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly administration schedule (QW) for a certain period, and then subcutaneously administering a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W). The method according to any one of Embodiments 1 to 59, comprising subcutaneously administering a first escalating dose of 61.60 μg / kg of BCMAxCD3 bispecific antibody, then subcutaneously administering a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly (QW) schedule for more than 6 months, and then subcutaneously administering a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly (Q2W) schedule. The method according to any one of Embodiments 1 to 59, comprising subcutaneously administering a first escalating dose of 62.60 μg / kg of BCMAxCD3 bispecific antibody, then subcutaneously administering a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly (QW) schedule, and after the subject has achieved partial response, very good partial response, complete response, or exact complete response for 6 months or more (according to IMWG criteria), then subcutaneously administering a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly (Q2W) schedule. The method according to any one of Embodiments 1 to 59, comprising subcutaneously administering a first escalating dose of 63.60 μg / kg of BCMAxCD3 bispecific antibody, then subcutaneously administering a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly (QW) schedule, and after the subject has achieved a complete response or a severe complete response for 6 months or more (according to IMWG criteria), then subcutaneously administering a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly (Q2W) schedule. The method according to any one of Embodiments 1 to 59, comprising subcutaneously administering a first escalating dose of 64.60 μg / kg of BCMAxCD3 bispecific antibody, then subcutaneously administering a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly administration schedule (QW), and after the subject has achieved partial response, very good partial response, complete response, or exact complete response (according to IMWG criteria) after four 28-day treatment cycles or more, then subcutaneously administering a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W). The method according to any one of Embodiments 1 to 64, comprising subcutaneously administering a first escalating dose of 65.60 μg / kg of BCMAxCD3 bispecific antibody, then subcutaneously administering a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly administration schedule (QW) for a certain period, then subcutaneously administering a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W) for a certain period, and then subcutaneously administering a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a monthly administration schedule (Q4W). The first escalating dose of BCMAxCD3 bispecific antibody at 66.60 μg / kg is administered subcutaneously, followed by a second escalating dose of BCMAxCD3 bispecific antibody at 300 μg / kg 2-4 days later, followed by a first therapeutic dose of BCMAxCD3 bispecific antibody at 1500 μg / kg 2-4 days later, and then a therapeutic dose of BCMAxCD3 bispecific antibody at 1500 μg / kg is administered subcutaneously on a weekly (QW) schedule for a certain period. The method according to any one of Embodiments 1 to 64, further comprising: subcutaneously administering a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly schedule (Q2W) for a certain period, and if the subject achieves at least CR (i.e., complete response or exact complete response) by cycle 12 or thereafter, then subcutaneously administering a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a monthly schedule (Q4W). The method according to any one of Embodiments 1 to 64, comprising subcutaneously administering a first escalating dose of 67.60 μg / kg of BCMAxCD3 bispecific antibody, then subcutaneously administering a second escalating dose of 300 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a first therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a weekly schedule (QW) for a certain period, then subcutaneously administering a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a bi-weekly schedule (Q2W) for at least 6 months, and then subcutaneously administering a therapeutic dose of 1500 μg / kg of BCMAxCD3 bispecific antibody on a monthly schedule (Q4W). 68. The method according to any one of Embodiments 1 to 67, for achieving a clinical response in which the subject is PR, VGPR, CR, or sCR. 69. A method according to any one of Embodiments 1 to 67, wherein the subject achieves a clinical response that is CR or sCR. 70. The method according to embodiment 68 or 69, wherein the clinical response is maintained for at least 6 months. 71. The method according to Embodiment 68 or 69, wherein the clinical response is maintained for at least one year. 72. The method according to Embodiment 68 or 69, wherein the clinical response is maintained for at least 18 months. 73. The method according to Embodiment 68 or 69, wherein the clinical response is maintained for at least two years. 74. The method according to any one of Embodiments 1 to 73, which results in fewer infections occurring in the subjects (for example, compared to subjects who remain on QW administration). 75. The method according to any one of Embodiments 1 to 74, wherein fewer Grade ≥ 3 infections occur in the subjects (for example, compared to subjects who remain on QW administration). 76. The method according to any one of Embodiments 1 to 73, which achieves a reduction in new infections over time in a population of subjects having RRMM (e.g., compared to subjects remaining on a QW dosing schedule). 77. The method according to any one of Embodiments 1 to 73, which achieves a reduction in new Grade ≥ 3 infections over time in a population of subjects having RRMM (e.g., compared to subjects remaining on a QW dosing schedule). 78. The method according to any one of Embodiments 1 to 77, further comprising administering a therapeutically effective dose of tocilizumab to the target before administering a first dose of a BCMAxCD3 bispecific antibody (e.g., tecristamag). 79. The method according to Embodiment 78, wherein the method reduces the risk of CRS in subjects compared to subjects who have not received tocilizumab prior to receiving the BCMAxCD3 bispecific antibody. 80. The method according to Embodiment 78 or 79, wherein tocilizumab is administered within approximately 4 hours before the first escalating dose of teclistamai (for example, approximately 2 to 4 hours before the first escalating dose of teclistamai). 81. The method according to any one of embodiments 78 to 80, wherein tocilizumab is administered as a single dose of 8 mg / kg IV. 82. The method according to any one of Embodiments 78 to 81, wherein the method achieves a CRS rate in the control population that is lower than the reference CRS rate in the reference population, and the reference population has not received tocilizumab prior to receiving the BCMAxCD3 bispecific antibody. 83. The method according to any one of Embodiments 1 to 82, comprising administering a combination regimen comprising a BCMAxCD3 bispecific antibody and daratumumab. 84. The method according to Embodiment 83, wherein the subject has previously received one to three lines of antimyeloma treatment including a proteasome inhibitor (PI) and lenalidomide. 85. The method according to Embodiment 84, wherein the subject has previously received only one line of antimyeloma treatment and is refractory to lenalidomide. 86. The method according to any one of embodiments 83 to 85, wherein daratumumab is administered subcutaneously. 87. Daratumumab, Day 1 of Cycle 1 and every week thereafter (QW) (for example, Day 1, Day 8, Day 15 and Day 22), Cycle 2: Weekly (QW) (for example, day 1, day 8, day 15 and day 22), Cycles 3-6: Every other week (Q2W) (for example, day 1 and day 15), Cycle 7 and subsequent cycles: The method according to any one of embodiments 82 to 86, administered subcutaneously in a dose of 1800 mg in a 28-day treatment cycle, such as monthly (Q4W) (e.g., day 1). 88. The method according to embodiment 87, wherein there is an interval of 5 days or more between doses of daratumumab. 89. The subjects had previously received 1 to 3 lines of antimyeloma treatment including proteasome inhibitors (PIs) and lenalidomide, and the method was: The treatment involves administering a combination regimen including a BCMAxCD3 bispecific antibody (e.g., tecristamab) and daratumumab, wherein the BCMAxCD3 bispecific antibody is Cycle 1: A dose escalates to 0.06 mg / kg on day 2, then to 0.3 mg / kg (e.g., day 4), then to 1.5 mg / kg (e.g., day 8), and thereafter to a weekly (QW) therapeutic dose of 1.5 mg / kg (e.g., on days 15 and 22). Cycle 2: 1.5 mg / kg weekly (QW) (for example, on days 1, 8, 15, and 22), Cycles 3-6: 3 mg / kg every other week (Q2W) (for example, on day 1 and day 15), The method according to any one of Embodiments 1 to 15, wherein Cycle 7 and subsequent cycles are administered subcutaneously in a 28-day treatment cycle, such as monthly (Q4W) (e.g., Day 1). 90. The method according to Embodiment 89, wherein daratumumab is administered subcutaneously on day 1 of cycle 1, and a first escalating dose of BCMAxCD3 bispecific antibody is administered at least 20 hours after daratumumab. 91. The method according to Embodiment 89 or 90, wherein there is an interval of 2 days or more between dose escalations of the BCMAxCD3 bispecific antibody. 92. The method according to any one of embodiments 89 to 91, wherein a first dose of 1.5 mg / kg of teclistamag is administered at least two days after the second dose escalation. The method according to any one of embodiments 89 to 92, wherein there is an interval of 5 days or more between therapeutic doses of 93.1.5 mg / kg (or between 1.5 mg / kg and the first dose of 3 mg / kg), and an interval of 12 days or more between therapeutic doses of 3 mg / kg. 94. Daratumumab, Day 1 of Cycle 1 and every week thereafter (QW) (for example, Day 1, Day 8, Day 15 and Day 22), Cycle 2: Weekly (QW) (for example, day 1, day 8, day 15 and day 22), Cycles 3-6: Every other week (Q2W) (for example, day 1 and day 15), Cycle 7 and subsequent cycles: Administer subcutaneously at a dose of 1800 mg in 28-day treatment cycles, such as monthly (Q4W) (e.g., on day 1). 95. The method according to any one of Embodiments 89 to 94, wherein on the first day when daratumumab and BCMAxCD3 bispecific antibody are administered on the same day (e.g., day 8 of cycle 1), the BCMAxCD3 bispecific antibody is administered at least 3 hours after daratumumab. 96. The method according to any one of Embodiments 89 to 95, wherein the BCMAxCD3 bispecific antibody is tecristamag. 97. A method for improving progression-free survival in a target population with multiple myeloma who have previously received 1 to 3 lines of antimyeloma therapy including proteasome inhibitors (PIs) and lenalidomide, wherein the method is: The regimen includes administering a combination regimen containing teclistamaib and daratumumab to the target population, wherein teclistamaib is Cycle 1: A dose escalates to 0.06 mg / kg on day 2, then to 0.3 mg / kg (e.g., day 4), then to 1.5 mg / kg (e.g., day 8), and thereafter to a weekly (QW) therapeutic dose of 1.5 mg / kg (e.g., on days 15 and 22). Cycle 2: 1.5 mg / kg weekly (QW) (for example, on days 1, 8, 15, and 22), Cycles 3-6: 3 mg / kg every other week (Q2W) (for example, on day 1 and day 15), Cycle 7 and subsequent cycles: 3 mg / kg is administered subcutaneously every month (Q4W) (e.g., on day 1), in a 28-day treatment cycle, and daratumumab is administered. Day 1 of Cycle 1 and every week thereafter (QW) (for example, Day 1, Day 8, Day 15 and Day 22), Cycle 2: Weekly (QW) (for example, day 1, day 8, day 15 and day 22), Cycles 3-6: Every other week (Q2W) (for example, day 1 and day 15), Cycle 7 and subsequent cycles: Administered subcutaneously at a dose of 1800 mg every month (e.g., Q4W) (day 1), in a 28-day treatment cycle. Improvement in median progression-free survival is compared to the median progression-free survival in the reference population, which is defined as patients receiving (i) an effective regimen (DPd) containing daratumumab SC, pomalidomide, and dexamethasone, or (ii) an effective regimen (DVd) containing daratumumab SC, bortezomib, and dexamethasone. 98. The method of Embodiment 97, wherein the improvement in median progression-free survival is at least about 2 months, or at least about 4 months, or at least about 6 months, or at least about 8 months, or at least about 10 months, or at least about 12 months, or at least about 14 months, or at least about 16 months, or at least about 18 months, or at least about 20 months, or at least about 22 months, or at least about 24 months. 99. The method according to Embodiment 97 or 98, wherein the first escalating dose of teclistamagb is administered at least 20 hours after daratumumab. 100. The method according to any one of embodiments 97 to 99, wherein on the first day when daratumumab and teclistamaib are administered on the same day (e.g., day 8 of cycle 1), teclistamaib is administered at least 3 hours after daratumumab.

[0309] Those skilled in the art will understand that numerous changes and modifications can be made to preferred embodiments of the present invention, and that such changes and modifications can be made without departing from the spirit of the invention. Accordingly, the appended claims are intended to cover all such equivalent variations that fall within the true spirit and scope of the invention.

[0310] Any patent, patent application, and publication disclosure cited or referenced herein is incorporated herein by reference in its entirety. [Examples]

[0311] To further illustrate some of the embodiments disclosed herein, the following examples are provided. These examples are illustrative and not intended to limit the embodiments of the present disclosure.

[0312] Example 1: Sustained response to bi-weekly administration of teclistamag in patients with relapsed / refractory multiple myeloma (RRMM) achieving a clinical response in the MajesTEC-1 trial. antibody The anti-BCMA / anti-CD3 antibody teclistamaib (also known as Tec) (for example, described in International Publication No. 2017031104(A1), the entirety of which is incorporated herein by reference) was manufactured by Janssen Pharmaceuticals. Teclistamaib contains a BCMA-binding arm BCMB69 and a CD3-binding arm CD3B219, the amino acid sequences of which are shown in Tables 5 and 6, respectively.

[0313] [Table 16]

[0314] [Table 17]

[0315] the purpose: In the core Phase 1 / Phase 2 MajesTEC-1 trial (NCT03145181 / NCT04557098), the objective is to evaluate whether patients can maintain their response after transitioning from a weekly (QW) to a bi-weekly (Q2W) dosing schedule.

[0316] method: Eligible patients had RRMM and had previously received three or more lines of treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 antibodies. Prior BCMA-targeted therapies were not permitted in this cohort. All patients submitted informed consent. Patients with MajesTEC-1 who achieved and maintained a response could switch to a less frequent dosing schedule, providing further convenience and flexibility for patients, physicians, and caregivers. The persistence of response in patients with MajesTEC-1 who switched from a QW to a Q2W or Q4W dosing schedule was evaluated. Specifically, patients who received the recommended Phase 2 dose (RP2D) of 1.5 mg / kg teclistamagb QW had the option to switch to Q2W dosing if they achieved a confirmed partial response or better after four or more treatment cycles (Phase 1) or a confirmed complete response (CR) or better over six months or longer (Phase 2). Responses were evaluated according to IMWG2016 criteria. A diagram of the study design is shown in Figure 1.

[0317] Dosage regimen: Eligible patients received teclistamag at RP2D (1.5 mg / kg teclistamag QW), and respondents had the option to switch to Q2W or Q4W administration. The dose escalation diagram is shown in Figure 2.

[0318] Dosage schedule: RP2D based on body weight: Teclistamag SC (subcutaneous) at 60 μg / kg and 300 μg / kg (priming dose), followed by a weekly therapeutic dose of 1500 μg / kg.

[0319] Priming dose schedule: The priming schedule includes two priming doses of 60 μg / kg and 300 μg / kg. Each priming dose should be administered 2 to 4 days apart, and completed 2 to 4 days before the first therapeutic dose. If there is no delay in treatment, the first therapeutic dose should be administered 4 to 8 days after the first priming dose and 2 to 4 days after the second priming dose.

[0320] Therapeutic dose schedule: Total dose on each administration day (1500 μg / kg): - Weekly (QW) administration: Days 1, 8, 15, and 22 of a 28-day cycle. - Administered every other week (Q2W): on day 1 and day 15 of a 28-day cycle. - Monthly administration (Q4W): Day 1 of a 28-day cycle.

[0321] Any patient receiving weekly dosing was permitted to switch from a weekly dosing schedule to a bi-weekly dosing schedule. Patients had the option to switch from QW dosing to Q2W dosing in the following cases: - Achieved at least PR (i.e., partial response, very good partial response, complete response, or exact complete response) after at least 4 cycles (Phase 1), or - Achieved at least CR (i.e., complete response or strict complete response) for at least 6 months (Phase 2).

[0322] Patients had the option to switch to Q4W administration in the following cases: - Approved by the clinical trial sponsor (Phase 1), or - Achieved at least CR (i.e., complete response or exact complete response) by cycle 12 or thereafter (phase 2), - If Q2W administration has been ongoing for at least 6 months (Phase 2).

[0323] Primary endpoint: Overall response rate (ORR) [Time frame: up to 2.9 years]. ORR is defined as the percentage of participants who achieve a partial response (PR) or better, according to the International Myeloma Working Group (IMWG) criteria.

[0324] Eligibility criteria: Selection Criteria ●A diagnosis of multiple myeloma according to the IMWG diagnostic criteria has been recorded. ● The Eastern Cooperative Oncology Group (ECOG) performance status score is 0 or 1. ● Measurable diseases: Cohorts A, C, and D: Multiple myeloma must be measurable by central laboratory assessment. ● Female participants who may be pregnant must have a negative pregnancy test result at the time of screening. ● You must be willing and able to abide by the prohibitions and restrictions specified in this protocol. ● Cohorts A and D: Previously received at least three lines of MM treatment. Previous treatment must include IMiD, PI, and anti-CD38 monoclonal antibody. Cohort C: Previously received ≥3 lines of treatment including PI, IMiD, anti-CD38 monoclonal antibody, and anti-B cell maturation antigen (BCMA) treatment (using CART-T cells or antibody drug conjugate (ADC)).

[0325] Exclusion criteria ● Plasma cell leukemia, Waldenström macroglobulinemia, POEMS syndrome, or primary amyloid light chain amyloidosis ● The following medical conditions: lung damage requiring the use of supplemental oxygen to maintain adequate oxygen supply, human immunodeficiency virus (HIV) infection, hepatitis B or C infection, stroke or seizure of 6 months or less (<=), autoimmune disease, uncontrolled systemic infection, cardiac conditions (myocardial infarction <= 6 months, stage III-IV congestive heart failure, etc.) ● Except for Cohort C in Part 3, all participants received any therapy targeting BCMA. ● Prior antitumor therapy within 21 days prior to the first administration of the investigational drug (PI or radiotherapy within 14 days, IMiD within 7 days, genetically modified adoptive cell therapy within 3 months) ● Toxicity from previous anticancer therapy (excluding alopecia or peripheral neuropathy) did not subside to baseline levels or grade 1 or lower. ● The patient received cumulative doses of a corticosteroid equivalent to 140 mg or more of prednisone within 14 days prior to the first dose of the study drug (excluding prior treatments). ● The involvement of the central nervous system (CNS) in multiple myeloma (MM) is known, or the patient shows clinical signs of meningeal involvement. ● Active malignant tumors other than myelodysplastic syndrome or relapsed / refractory multiple myeloma, with exceptions, are: 1) non-muscle-invasive bladder cancer treated within the past 24 months and considered to be completely cured; 2) skin cancer (non-melanoma or melanoma) treated within the past 24 months and considered to be completely cured; 3) non-invasive cervical cancer treated within the past 24 months and considered to be completely cured; 4) localized prostate cancer (N0M0); 5) breast cancer: a history of appropriately treated lobular carcinoma or ductal carcinoma in situ, or localized breast cancer, and treatment with anti-hormone agents, with a very low risk of recurrence; 6) malignant tumors considered to be cured with minimal risk of recurrence. ●Previous allogeneic stem cell transplant ≤ 6 months ●Previous autologous stem cell transplants ≤ 12 weeks ● Attenuated live vaccine within 4 weeks prior to the first dose of teclistamag.

[0326] Results as of the data cutoff date of December 9, 2022: As of December 9, 2022, 165 patients in the core cohort were receiving teclistamagb on RP2D. Of 104 responders, 60 patients switched to Q2W dosing. 50 patients met the protocol-defined switching criteria, and 10 switched without meeting the criteria (4 due to adverse events [AEs]; 6 for other reasons). The switched patients had a median age of 64 years, 58% were male, 25% had high-risk cytogenetic features, 7% had extramedullary plasmacytoma, and 3% had disease at stage III of the International Staging System at baseline. Patients had previously received a median of 4 lines of treatment, and 75% were triple-class refractory. At the time of switching, 49 patients (82%) achieved ≥CR, and 11 patients (18%) had a very good partial response. The median time to switch from QW dosing to Q2W dosing was 11.1 months (range, 3–20). During a median follow-up period of 11.1 months (range, 2–24) from the switch, the median duration of response from the switch date was 20.5 months (range, 1–23), with 40 / 60 patients still responding and continuing treatment. Of the remaining patients, 13 / 60 progressed (median time from switch to progression could not be estimated), 2 discontinued due to adverse events, 1 discontinued for other reasons, and 4 died. Further results are shown below.

[0327] Summary / Conclusion: Overall, patients in the MajesTEC-1 trial who transitioned from QW to the lower frequency of teclistamagb Q2W maintained remission, and the median duration of response was 20.5 months from the switch date.

[0328] Results as of the data cutoff date of January 4, 2023: Figure 3 summarizes the characteristics of MajesTEC-1 patients who switched to a less frequent dosing regimen. As of January 4, 2023 (median follow-up period: 22.8 months), 165 patients were receiving teclistamag in the core cohort. Of the 104 responders, 63 switched to Q2W dosing (22 from Phase 1, 41 from Phase 2), and 9 responded to Q4W. 54 patients met the protocol-defined switching criteria. The 9 patients who switched did not meet the criteria due to adverse events (AEs) (n=3) or other reasons (n=6). The median time to switch from the first dose in the QW schedule to the first dose in the Q2W schedule was 11.3 months (range, 3-30, median: 6.8 months in Phase 1, 12.7 months in Phase 2). The median follow-up period from the switch was 12.6 months (range, 1-25). The efficacy results from the MajesTEC-1 Q2W cohort included the following: - At the time of switching, 54 patients (85.7%) achieved ≥CR (complete response or exact complete response), 8 patients (12.7%) had VGPR (very good partial response), and 1 patient (1.6%) had PR (partial response). - 68.7% (95% CI, 53.6–79.7) of patients who switched to this treatment remained responsive for more than two years from the time of the initial response (they had not yet reached mDOR). - As of the data cutoff date of January 4, 2023, patients who switched (N=63): - 42 people maintained a response, and 41 were still undergoing treatment. -14 people proceeded after responding. - Five people died (four of them from COVID-19). -One person received follow-up therapy after the response. -One person withdrew their consent.

[0329] As shown in Figure 4, there was a decrease in new infections of grade ≥3 over time. Patients who switched to Q2W therapy by 1 year had fewer grade 3 or higher infections developed under treatment between 1 and 1.5 years compared to patients who were on QW therapy by 1 year (15.6% vs. 33.3%).

[0330] In summary, as of the data cutoff on January 4, 2023, most patients in the MajesTEC-1 Q2W cohort who switched to Q2W or Q4W teclistamagab maintained a deep response. Of 104 responders, 63 switched from QW to Q2W or Q4W, and 65% (41 / 63) continued treatment. 68.7% of patients maintained their response for more than two years. Compared to patients receiving QW teclistamagab, patients who switched to Q2W or Q4W experienced fewer new Grade 3 infections.

[0331] As of January 4, 2023, MajesTEC-1 is noteworthy for having the longest follow-up period (23 months) for a bispecific antibody in multiple myeloma.

[0332] Example 2: Evaluation of prophylactic tocilizumab for reducing cytokine release syndrome antibody The anti-BCMA / anti-CD3 antibody teclistamag (also known as Tec) (for example, described in International Publication No. 2017031104(A1), the entirety of which is incorporated herein by reference) was manufactured by Janssen Pharmaceuticals. Teclistamag contains a BCMA-binding arm BCMB69 and a CD3-binding arm CD3B219, the amino acid sequences of which are shown in Tables 5 and 6 above.

[0333] Methods: Eligible patients had RRMM, were aged ≥18 years, and had previously received PI, IMiD, and anti-CD38 antibody. All patients provided informed consent. Patients received subcutaneous teclistamag (after two escalating doses) in a prospective exploratory cohort or fixed-dose cohort in RP2D. Toci (a single IV dose of 8 mg / kg) was administered within 4 hours prior to the first teclistamag escalating dose. CRS was graded according to Lee et al (2014) and managed according to institutional guidelines.

[0334] Initial results: Fourteen patients were included: median age 64 years (range 50–82). All patients had an ECOG score ≤1 and ISS I / II. 91% had standard cytogenetic risk. 21% had extramedullary plasmacytoma. 31% had BMPC ≥30%. Median 4 previous lines of treatment (range 2–7). 64% were triple-class refractory. The median follow-up period was 1.2 months (range 0.2–4.6). CRS occurred in 4 patients (29%, no CRS with gr ≥3). One patient had a subsequent CRS event (Table). The median time to onset was 2 days (range 1–3). The median duration was 2 days (range 2–4). All events were managed with toci and resolved without discontinuation of tecristamab. Of the 14 patients, 7 had gr3 / 4 neutropenia (consistent with the overall MajesTEC-1 population). 2 / 14 had gr3 / 4 infection. 2 / 14 had neurotoxic AEs. Of the patients whose response could be evaluated, 4 / 7 responded. Cytokine and PK data from additional patients with longer follow-up periods will be presented to further inform patient management. The results are shown in the table below.

[0335] [Table 18] BMPC, myeloid plasma cells; CRS, cytokine release syndrome; pts, patient; toci, tocilizumab.

[0336] Follow-up results: As of April 28, 2023, 23 patients had received prophylactic toci prior to teclistamagb (median follow-up period of 2.6 months). The median number of previous treatment lines received by patients was 4. Prophylactic toci reduced the incidence of CRS to 26.1% (6 / 23 patients). Two patients had grade 1 CRS, and four patients had grade 2 CRS. No cases of grade 3 or higher CRS were reported. Of the 16 evaluable patients, 2 (12.5%) had CR, 6 (37%) had VGPR, and 3 (18.8%) had PR. Prophylactic toci did not appear to affect the PK profile of teclistamagb. Prophylactic toci reduced the overall incidence of CRS to 26% without affecting the response to teclistamagb, representing a 46% reduction in CRS observed in MajesTEC-1.

[0337] Summary / Conclusion: A single dose of toci prior to teclistamagb treatment appeared to reduce the incidence of CRS compared to the overall MajesTEC-1 study population, without any new safety signals and without evidence of the impact on the response to teclistamagb, considering the short follow-up period. Prophylactic toci may reduce the risk of CRS in patients with a disease profile suitable for outpatient administration and reduce the burden of hospitalization during teclistamagb escalation.

[0338] Example 3: Model-based exploration of the effect of prophylactic tocilizumab on IL-6 dynamics in multiple myeloma patients receiving teclistamaib therapy. Using a mechanism-based PK / PD model, we evaluated the effect of tocilizumab prophylactic treatment on the duration of soluble IL-6R (sIL-6R), IL-6, and IL-6 signaling pathway blockade in patients treated with teclistamag in the MajesTEC-1 cohort described in Example 2 above.

[0339] Methods: Mechanism-based PK / PD models were constructed using reported tocilizumab PK parameters and sIL-6R target association. The time course of IL-6R RO in patients who received prophylactic tocilizumab after tecrista-mab treatment was estimated from the tocilizumab PK profile and competitive binding kinetics. Among patients with evaluable serum IL-6 levels, the highest peak serum IL-6 concentration in patients without CRS from the MajesTEC-1 prophylactic tocilizumab cohort (N=9) was selected as the worst-case scenario. IL-6R RO in patients who received prophylactic tocilizumab in the worst-case scenario was characterized by model simulation, and the results were compared with IL-6R RO calculated in the tecrista-mab treatment cohort without prophylactic tocilizumab (N=40).

[0340] Results: The time course of serum IL-6 levels after teclistamagb treatment was higher and induced earlier in the cohort that received tocilizumab prophylaxis compared to the cohort that did not receive tocilizumab prophylaxis. In patients who received tocilizumab prophylaxis and did not have CRS, the median peak serum IL-6 level was 208.6 pg / mL, and the highest peak serum IL-6 level was 1701.8 pg / mL. Model simulation results showed that a single dose of 8 mg / kg of tocilizumab administered intravenously prophylactically could reduce the IL-6R RO mediated by IL-6. In patients with serum IL-6 of 1700 pg / mL treated with tocilizumab, the IL-6R RO was maintained for approximately 10 days below the RO level achieved with serum IL-6 of 10 pg / mL in the absence of tocilizumab. An IL-6 level of 10 pg / mL was considered representative in patients who did not experience CRS after teclistamai in an approved dosing regimen without prophylactic tocilizumab, as more than half (58%) of these patients showed peak serum IL-6 levels below 10 pg / mL. The duration of IL-6R RO reduction covers two escalating doses (SUDs) and the first complete therapeutic dose, according to the approved teclistamai dosing schedule.

[0341] Conclusion: Modeling and simulation results showed that a single prophylactic dose of tocilizumab at 8 mg / kg could block IL-6R RO for approximately 10 days after the first dose escalation of teclistamai. The results further support this approach for reducing the overall risk of CRS during the SUD schedule in multiple myeloma patients treated with teclistamai.

[0342] Example 4: A phase 3 randomized trial comparing tecristamagb in combination with daratumumab SC (Tec-Dara) with daratumumab SC, pomalidomide, and dexamethasone (DPd) or daratumumab SC, bortezomib, and dexamethasone (DVd) in participants with relapsed or refractory multiple myeloma (MajesTEC-3). (Clinical trial government ID: NCT05083169) antibody Daratumumab and teclistamaib (also known as Tec) (for example, described in International Publication No. 2017031104(A1), the entirety of which is incorporated herein by reference) were manufactured by Janssen Pharmaceuticals. Teclistamaib contains a BCMA-binding arm BCMB69 and a CD3-binding arm CD3B219, the amino acid sequences of which are shown in Tables 5 and 6 above, respectively.

[0343] Exam Overview The purpose of this study is to compare the efficacy of tecristamagb and daratumumab (Tec-Dara) with daratumumab subcutaneous (SC) (DPd) in combination with pomalidomide and dexamethasone, or daratumumab SC (DVd) in combination with bortezomib and dexamethasone.

[0344] The primary hypothesis of this study is that Tec-Dara significantly improves progression-free survival (PFS) in participants with relapsed / refractory multiple myeloma compared to the investigator's choice of DPd / DVd. Approximately 560 participants will be randomly assigned in a 1:1 ratio to receive either Tec-Dara (Arch A) or the investigator's choice of DPd / DVd (Arch B). The study will consist of three phases: a screening phase, a treatment phase, and a follow-up phase. Participants will be treated until disease progression, unacceptable toxicity, or other reasons for discontinuing the study. Disease assessments will be performed cycle by cycle. Safety will be assessed throughout the study. Efficacy will be evaluated using the International Myeloma Working Group (IMWG) criteria. The total duration of the study is approximately 5 years.

[0345] Eligibility Criteria The selection criteria for this exam include the following: ● Multiple myeloma is recorded as defined by the following criteria: a. Diagnosis of multiple myeloma in accordance with the diagnostic criteria of the International Myeloma Working Group (IMWG). b. A measurable disease at the time of screening as defined by any of the following: 1) Serum M protein level of 0.5 grams / deciliter (g / dL) or higher (>=), or 2) Urinary M protein level ≥ 200 milligrams (mg) / 24 hours, or 3) Serum immunoglobulin free light chain of 10 mg / dL or higher and an abnormal serum immunoglobulin kappa-lambda free light chain ratio ● Previously received 1 to 3 lines of antimyeloma treatment including proteasome inhibitors (PIs) and lenalidomide. a. Participants who have previously received only one line of antimyeloma treatment must be lenalidomide-refractory. Stable disease or progression within 60 days of the last dose of lenalidomide given as maintenance meets this criterion. ● Evidence of progressive disease is documented at the time of the last regimen or based on the IMWG criteria determination by the principal investigator thereafter. ● Having a performance status score of 0, 1, or 2 in the East Coast Cancer Group (ECOG) at the time of screening and before the start of administration of the investigational treatment. ● The values ​​from the clinical laboratory are within the specified range.

[0346] The exclusion criteria for this examination include the following: ● Contraindications to the test drug or its excipients, or life-threatening allergies, hypersensitivity, or intolerance. Further exclusion criteria for specific test drugs include: 1. Participants are ineligible to receive daratumumab subcutaneous (SC)(DPd) in combination with pomalidomide and dexamethasone as a control therapy if any of the following are present: 1) Contraindications to or life-threatening allergies, hypersensitivity, or intolerance to pomalidomide; 2) Diseases considered refractory to pomalidomide according to the IMWG. 2. Participants are ineligible to receive daratumumab SC (DVd) in combination with bortezomib and dexamethasone as a control therapy if any of the following are present: 1) contraindications to bortezomib or life-threatening allergies, hypersensitivity, or intolerance to bortezomib; 2) painful grade 1 or grade ≥ 2 peripheral neuropathy as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0; 3) a disease considered refractory to bortezomib according to the IMWG; 4) receipt of a potent cytochrome P450 (CYP3A4) inducer within 5 half-lives prior to randomization. ●Received any previous B-cell maturation antigen (BCMA) targeted therapy. ● Patients with diseases considered refractory to antidifferentiation antigen group 38 (CD38) monoclonal antibodies by IMWG ●Received a cumulative dose of corticosteroids equivalent to ≥140 mg of prednisone within 14 days prior to randomization. ● Received a live attenuated vaccine within 4 weeks prior to randomization. ● Plasma cell leukemia, Waldenström macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrine disorders, M protein, and skin changes) or primary amyloid light chain amyloidosis at the time of screening.

[0347] Arms and interventions Experimental Arm A: Teclistamaib-Daratumumab (Tec-Dara). Participants receive teclistamaib and daratumumab by subcutaneous (SC) injection. Escalating doses of teclistamaib are administered before the first total dose.

[0348] Experimental Arm B: DPd or DVd. Participants will be randomized to receive either daratumumab, pomalidomide, or dexamethasone (DPd) treatment, consisting of daratumumab SC injection, oral pomalidomide, and oral or intravenous dexamethasone, or daratumumab, bortezomib, or dexamethasone (DVd) treatment, consisting of daratumumab SC injection, bortezomib SC injection, and oral or intravenous dexamethasone.

[0349] Therapeutic dose and route of administration for teclistamag. Tecristamag SC is Cycle 1: A gradually increasing dose of 0.06 mg / kg on day 2, 0.3 mg / kg on day 4, 1.5 mg / kg on day 8 (also called the therapeutic dose), and thereafter 1.5 mg / kg weekly (QW) (for example, on days 15 and 22). Cycle 2: 1.5 mg / kg weekly (QW) (for example, on days 1, 8, 15, and 22), Cycles 3-6: 3 mg / kg every other week (Q2W) (for example, on day 1 and day 15), Cycle 7 and subsequent cycles: 3 mg / kg is administered monthly (e.g., on day 1 of Q4W), in a 28-day treatment cycle.

[0350] The first dose escalation must be administered ≥20 hours after the daratumumab SC dose given on C1D1. Thereafter, there must be an interval of at least 2 days between dose escalations of Tec. Teclistamag at a therapeutic dose of 1.5 mg / kg must be administered ≥2 days after the second dose escalation. Thereafter, there must be an interval of ≥5 days between 1.5 mg / kg therapeutic doses (or between 1.5 mg / kg and the switch to the 3 mg / kg dose), and an interval of ≥12 days between 3 mg / kg therapeutic doses. On C1D8 (or, in cases of delayed administration, the first time daratumumab and teclistamag are administered on the same day), teclistamag should be administered ≥3 hours after daratumumab SC. If a participant experiences a treatment delay of daratumumab SC longer than 3 months, the interval between daratumumab SC and teclistamag should be at least 3 hours after the first restarted daratumumab administration.

[0351] Reasons why the dosage is correct: As described above, the teclistamagb SC administration schedule was initiated with an RP2D dose including two escalating doses (0.06 mg / kg and 0.3 mg / kg), followed by a weekly therapeutic dose of 1.5 mg / kg. In trial 64007957MMY1001, the escalation of teclistamagb to 1.5 mg / kg therapeutic dose for arm A was selected after a review of safety, efficacy, PK, and pharmacodynamic data from participants with relapsed or refractory multiple myeloma treated with this regimen as monotherapy. No dose-limiting trials (DLTs) were observed during the dose-escalation phase for this dose level. CRS was generally low-grade, with a median duration of CRS of 2 days. Neurotoxic events were rare and all were low-grade. Cytopenia was common and manageable. Among the 150 participants treated with 1.5 mg / kg weekly, the ORR was stable, with responses occurring rapidly and deepening over time.

[0352] Trough levels after 1.5 mg / kg SC injection are equivalent to the maximum EC90 of the ex vivo cytotoxicity assay. This assay evaluated the tecristamag's killing ability using mononuclear cells derived from bone marrow samples of multiple myeloma patients, co-cultured with T cells from healthy donors. Pharmacodynamic data also support this regimen, demonstrating the induction of cytokine and T cell activation after dose escalation, illustrating its mechanism of action.

[0353] In this study, participants will receive teclistamag SC Q2W at a therapeutic dose of 3 mg / kg, starting on day 1 of cycle 3 (to be performed in conjunction with protocol repair). This change in the dosing schedule from 1.5 mg / kg weekly to 3 mg / kg Q2W increases convenience and flexibility for patients, caregivers, and healthcare providers. Considering the PK profile of teclistamag described below, 3 mg / kg The Q2W dosing schedule is estimated to provide exposure equivalent to a 1.5 mg / kg weekly exposure, with appropriate exposure over the intended dosing interval.

[0354] In MajesTEC-1, teclistamagb exposure increased dose-proportionally across the range of weekly SC dosing from 0.08 to 6 mg / kg. Considering the robust PK data and acceptable safety data from all cohorts evaluated to date, this SC dosing schedule is... A weekly dose of 1.5 mg / kg of teclistamag over two cycles, followed by a 3 mg / kg dose of teclistamag in Q2W of cycles 3-6, is estimated to result in equivalent exposure to a weekly dosing schedule of 1.5 mg / kg of teclistamag. Therefore, this dosing schedule is calculated to achieve equivalent efficacy and acceptable safety.

[0355] Population PK analysis was performed using serum teclistamagb concentration data from MajesTEC-1 with a PK data cutoff of June 14, 2021. The final dataset contained a total of 4143 measurable serum teclistamagb concentrations from 308 PK-evaluable adult participants with relapsed or refractory multiple myeloma (n=83 received IV therapy and n=225 received SC therapy). The weight distribution in this study population ranged from 41 to 139 kg, with a median weight of 74 kg. Teclistamagb concentration-time profiles were simulated using the final population PK model. Participants in the simulation were randomly sampled from the analysis dataset (n=1000).

[0356] The model showed that teclistamagb SC Q2W administration at 3 mg / kg resulted in a maximum EC90 (target exposure) exceeding the target exposure level in the majority of participants. トラフ It was estimated that this would result in a result equivalent to a 1.5 mg / kg teclistamaib SC weekly dose. After the 20th week of 3 mg / kg teclistamaib SC Q2W administration, the model showed C トラフ , C 最大 , and AUC 0~14日 However, it is estimated to be equivalent to that of weekly administration of 1.5 mg / kg teclistamaib SC. The accumulation rate after teclistamaib SC Q2W administration is estimated to be less than half that of weekly administration of 1.5 mg / kg teclistamaib SC.

[0357] After administration of 3 mg / kg teclistamag SC Q4W, the model estimated C トラフ、ss , C 最大、ss , and AUC ss、0~28日The median steady-state level was lower than that of the 1.5 mg / kg teclistamagb SC weekly dose group. However, the median trough level after 3 mg / kg Q4W was estimated to be equivalent to the maximum EC90. Furthermore, all 37 participants in MajesTEC-1 switched to lower dose frequencies, and all responded before the switch. As of March 16, 2022, these participants had a median duration of maintaining a response after dose frequency change of 12.9 months (range 1–18 months), with 28 participants (76%) maintaining a response. It should be noted that in Majes-TEC-1, the vast majority of responders (approximately 90%) achieved VGPR or higher by cycle 7 (median time to VGPR: 2.1 months, range 0.2–10.3 months). Therefore, this predicted exposure should be sufficient to maintain efficacy.

[0358] In particular, the safety profile of teclistamab in combination with daratumumab SC in trial 64407564MMY1002 (including the teclistamab 3 mg / kg Q2W dosing schedule) appears to be consistent with that of the individual study agents, without adverse effects on the incidence or severity of CRS, sARR, neurotoxicity, or other potentially clinically significant overlapping toxicities (i.e., injection site reactions, cytopenia, or infection). Although the response data in this trial are preliminary, they suggest a promising efficacy of teclistamab in combination with daratumumab SC. Overall, the teclistamab SC dosing schedule of 1.5 mg / kg weekly for two cycles, followed by 3 mg / kg Q2W in cycle 7, and then 3 mg / kg teclistamab Q4W, is estimated to have comparable safety and efficacy to the 1.5 mg / kg teclistamab weekly dosing schedule, while further increasing convenience and flexibility for patients, caregivers, and healthcare providers.

[0359] Therapeutic doses and routes of administration of other investigational drugs The administration schedule for daratumumab SC is outlined below. Pomalidomide or bortezomib and dexamethasone are administered at standard doses used in clinical practice for the treatment of multiple myeloma, as detailed in the prescribing information for your region.

[0360] Daratumumab SC (1800 mg) is Day 1 of Cycle 1 and every week thereafter (QW) (for example, Day 1, Day 8, Day 15 and Day 22), Cycle 2: Weekly (QW) (for example, day 1, day 8, day 15 and day 22), Cycles 3-6: Every other week (Q2W) (for example, day 1 and day 15), Cycle 7 and subsequent cycles: Administer subcutaneously at a dose of 1800 mg in 28-day treatment cycles, such as monthly (Q4W) (e.g., on day 1).

[0361] The interval between doses of daratumumab SC must be ≥ 5 days.

[0362] Evaluation items The primary endpoint is progression-free survival (PFS), defined as the time from the date of randomization to the first recorded date of disease progression as defined by the IMWG criteria, or death from any cause, whichever occurs first. Response to treatment is assessed by the Investigator Research Council (IRC), the principal investigator, and validated computerized algorithms. Assessment by the IRC is used as the primary method.

[0363] Secondary endpoints can be summarized as follows: A complete response (PR or better) is defined as a participant who has achieved a PR or better according to the IMWG criteria.

[0364] VGPR or higher (sCR+CR+VGPR) is defined as a participant who achieves VGPR or higher according to the IMWG standards.

[0365] A CR or higher (sCR+CR) is defined as a participant who achieves a CR or higher according to the IMWG criteria.

[0366] MRD negativity is 10 at any point after the day of randomization and before disease progression or initiation of subsequent antimyeloma therapy. -5 Participants are defined as those who achieve MRD negativity at the specified threshold.

[0367] Progression-free survival (PFS2) in the next treatment line is defined as the time interval between the day of randomization and the day of the event defined as the earlier of antimyeloma therapy or death from any cause. Patients who are alive and have not experienced a second disease progression are censored on the last day of the follow-up period.

[0368] Overall survival (OS) is measured from randomized data regarding the date of death of participants. If a participant is alive or their life status is unknown, the participant's data is censored on the date the participant's survival was last confirmed.

[0369] The Time to Next Treatment (TTNT) is defined as the time from randomization to the initiation of subsequent anti-myeloma treatment. Death due to disease progression without subsequent treatment initiation is considered an event. Participants who withdraw their consent to the trial, are lost to follow-up, or die from causes other than disease progression are terminated on the date of death or the last confirmed date of survival.

[0370] The duration of response was calculated from the date of the first recorded response (PR or better) to the date of the first recorded evidence of disease progression, or the date of death from any cause, whichever came first, according to the IMWG response criteria, among respondents (those with a PR or better). Participants who were not experiencing disease progression and were still alive were terminated at the time of their last disease assessment before initiation of subsequent antimyeloma therapy.

Claims

1. A method for treating a patient requiring treatment for multiple myeloma, comprising administering a therapeutic dose of BCMAxCD3 bispecific antibody to the patient on a bi-weekly administration schedule (Q2W).

2. The method according to claim 1, wherein the BCMA × CD3 bispecific antibody comprises a BCMA-binding domain including HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, and a CD3-binding domain including HCDR1 of SEQ ID NO: 14, HCDR2 of SEQ ID NO: 15, HCDR3 of SEQ ID NO: 16, LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO:

19.

3. The method according to claim 1 or claim 2, wherein the BCMA-binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and the CD3-binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO:

21.

4. The method according to any one of claims 1 to 3, wherein the BCMA x CD3 bispecific antibody is an IgG1, IgG2, IgG3, or IgG4 isotype.

5. The method according to any one of claims 1 to 4, wherein the BCMA x CD3 bispecific antibody is of the IgG4 isotype.

6. The method according to any one of claims 1 to 5, wherein the BCMA×CD3 bispecific antibody comprises one or more substitutions in its Fc region.

7. The method according to any one of claims 1 to 6, wherein the BCMA×CD3 bispecific antibody is of the IgG4 isotype and comprises S228P, F234A, and L235A substitutions in its Fc region.

8. The method according to any one of claims 1 to 7, wherein the BCMA×CD3 bispecific antibody is of the IgG4 isotype and comprises S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region.

9. The method according to any one of claims 1 to 8, wherein the Fc region of the BCMA coupling arm includes substitution of S228P, F234A, and L235A in the Fc region.

10. The method according to any one of claims 1 to 9, wherein the Fc region of the CD3 coupling arm includes substitution of S228P, F234A, L235A, F405L, and R409K in the Fc region.

11. The method according to any one of claims 1 to 10, wherein the BCMA × CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO:

23.

12. The method according to any one of claims 1 to 10, wherein the BCMA × CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 90% identity with the amino acid sequence of SEQ ID NO:

23.

13. The method according to any one of claims 1 to 10, wherein the BCMA × CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 95% identity with the amino acid sequence of SEQ ID NO:

23.

14. The method according to any one of claims 1 to 10, wherein the BCMA × CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 98% identity with the amino acid sequence of SEQ ID NO:

23.

15. The method according to any one of claims 1 to 10, wherein the BCMAxCD3 bispecific antibody is tecristamag.

16. The method according to any one of claims 1 to 15, wherein the subject has relapsed or refractory multiple myeloma (for example, the subject has been previously treated with 2 to 14 lines of treatment).

17. The method according to any one of claims 1 to 16, wherein the subject has previously received at least three treatment lines.

18. The method according to any one of claims 1 to 16, wherein the subject has previously received at least four treatment lines.

19. The method according to any one of claims 1 to 16, wherein the subject has previously received at least five treatment lines (five-drug exposure).

20. The method according to any one of claims 1 to 16, wherein the subject has previously received at least three lines of treatment comprising a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody.

21. The method according to any one of claims 1 to 16, wherein the subject has previously received at least four lines of treatment comprising a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody.

22. The method according to any one of claims 1 to 21, comprising subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody according to the bi-weekly administration schedule (Q2W).

23. The method according to any one of claims 1 to 22, comprising subcutaneously administering one or more incremental doses of the BCMAxCD3 bispecific antibody to the subject before administering a first therapeutic dose of the BCMAxCD3 bispecific antibody.

24. The method according to any one of claims 1 to 23, comprising subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg to approximately 3000 μg / kg in accordance with the bi-weekly administration schedule (Q2W).

25. The method according to any one of claims 1 to 23, comprising subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg according to the bi-weekly administration schedule (Q2W).

26. The method according to any one of claims 1 to 23, comprising subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 3000 μg / kg according to the bi-weekly administration schedule (Q2W).

27. The method according to any one of claims 1 to 26, comprising subcutaneously administering at least one therapeutic dose of the BCMAxCD3 bispecific antibody to the subject on a weekly administration schedule (QW), and then administering a therapeutic dose of the BCMAxCD3 bispecific antibody to the subject on a bi-weekly administration schedule (Q2W).

28. The method according to any one of claims 1 to 27, comprising subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody on a weekly administration schedule (QW) for at least one 28-day treatment cycle, and then administering a therapeutic dose of the BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W).

29. The method according to any one of claims 1 to 27, comprising subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody on a weekly administration schedule (QW) for at least two 28-day treatment cycles, and then administering a therapeutic dose of the BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W).

30. The method according to any one of claims 1 to 27, comprising subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody on a weekly administration schedule (QW) for at least three 28-day treatment cycles, and then administering a therapeutic dose of the BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W).

31. The method according to any one of claims 1 to 27, comprising subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody on a weekly administration schedule (QW) for at least four 28-day treatment cycles, and then administering a therapeutic dose of the BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W).

32. The method according to any one of claims 1 to 27, comprising subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody on a weekly administration schedule (QW) for at least five 28-day treatment cycles, and then administering a therapeutic dose of the BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W).

33. The method according to any one of claims 1 to 27, comprising subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody on a weekly administration schedule (QW) for at least six 28-day treatment cycles, and then administering a therapeutic dose of the BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W).

34. The method according to any one of claims 1 to 27, comprising subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody on a weekly administration schedule (QW) for at least six months, and then administering a therapeutic dose of the BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W).

35. The method according to any one of claims 1 to 34, comprising: subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody to the subject on a weekly dosing schedule (QW) until the subject achieves partial response, very good partial response, complete response, or exact complete response as determined by the IMWG response criteria; and thereafter administering a therapeutic dose of the BCMAxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W).

36. The method according to any one of claims 1 to 34, comprising: subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody to the subject on a weekly administration schedule (QW) until the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria; and thereafter administering a therapeutic dose of the BCMAxCD3 bispecific antibody to the subject on a bi-weekly administration schedule (Q2W).

37. The method according to any one of claims 1 to 34, comprising: subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody to the subject on a weekly administration schedule (QW) until the subject achieves complete response or strict complete response as determined by the IMWG response criteria; and thereafter administering a therapeutic dose of the BCMAxCD3 bispecific antibody to the subject on a bi-weekly administration schedule (Q2W).

38. The method according to any one of claims 1 to 27, comprising: subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody to the subject on a weekly dosing schedule (QW) until the subject achieves partial response, very good partial response, complete response, or exact complete response after four or more treatment cycles, as determined by the IMWG response criteria; and then administering a therapeutic dose of the BCMAxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W).

39. (i) until the subject achieves partial response, very good partial response, complete response or complete response for six months or more as determined by the IMWG response criteria, or (ii) until the subject achieves complete response or complete response for six months or more as determined by the IMWG response criteria, the therapeutic dose of the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject on a weekly dosing schedule (QW), The method according to any one of claims 1 to 27, further comprising administering a therapeutic dose of the BCMAxCD3 bispecific antibody to the subject according to the bi-weekly administration schedule (Q2W).

40. The method according to any one of claims 27 to 39, wherein each therapeutic dose of the BCMAxCD3 bispecific antibody administered in the weekly administration schedule (QW) is the same as the therapeutic dose of the BCMAxCD3 bispecific antibody administered in the bi-weekly administration schedule (Q2W).

41. The method according to any one of claims 27 to 40, comprising subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg to approximately 3000 μg / kg according to the weekly administration schedule (QW).

42. The method according to any one of claims 27 to 40, comprising subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg according to the weekly administration schedule (QW).

43. The method according to any one of claims 27 to 40, comprising subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 3000 μg / kg according to the weekly administration schedule (QW).

44. The method according to any one of claims 27 to 40, comprising: subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg according to the weekly administration schedule (QW); and then subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg according to the bi-weekly administration schedule (Q2W).

45. The method according to any one of claims 27 to 40, comprising: subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg according to the weekly administration schedule (QW); and then subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 3000 μg / kg according to the bi-weekly administration schedule (Q2W).

46. The method according to any one of claims 1 to 45, comprising subcutaneously administering the BCMAxCD3 bispecific antibody according to the bi-weekly administration schedule (Q2W), and then subcutaneously administering the BCMAxCD3 bispecific antibody according to the monthly administration schedule (Q4W).

47. The method according to any one of claims 1 to 46, comprising: subcutaneously administering the BCMAxCD3 bispecific antibody on a weekly administration schedule (QW); subcutaneously administering the BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W); and subcutaneously administering the BCMAxCD3 bispecific antibody on a monthly administration schedule (Q4W).

48. The method according to any one of claims 1 to 47, comprising: subcutaneously administering the BCMAxCD3 bispecific antibody according to the bi-weekly administration schedule (Q2W); and, if the subject achieves a partial response, a very good partial response, a complete response, or a complete response, subcutaneously administering the BCMAxCD3 bispecific antibody according to a monthly administration schedule (Q4W).

49. The method according to any one of claims 1 to 47, comprising: subcutaneously administering the BCMAxCD3 bispecific antibody according to the bi-weekly administration schedule (Q2W); and, if the subject achieves a complete response or a strict complete response, subcutaneously administering the BCMAxCD3 bispecific antibody according to the monthly administration schedule (Q4W).

50. The method according to any one of claims 1 to 47, comprising: subcutaneously administering the BCMAxCD3 bispecific antibody according to the bi-weekly administration schedule (Q2W); and, if the subject achieves a complete response or a strict complete response by or after treatment cycle 12, subcutaneously administering the BCMAxCD3 bispecific antibody according to the monthly administration schedule (Q4W).

51. The method according to any one of claims 1 to 47, comprising subcutaneously administering the BCMAxCD3 bispecific antibody according to the bi-weekly administration schedule (Q2W) for at least six months, and then subcutaneously administering the BCMAxCD3 bispecific antibody according to the monthly administration schedule (Q4W).

52. The method according to any one of claims 1 to 51, comprising subcutaneously administering one, two, or three escalating doses of the BCMAxCD3 bispecific antibody before subcutaneously administering the first therapeutic dose.

53. The method according to any one of claims 1 to 52, comprising subcutaneously administering the BCMAxCD3 bispecific antibody in gradually increasing doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg before subcutaneously administering the first therapeutic dose.

54. The method according to any one of claims 1 to 52, comprising subcutaneously administering one or two escalating doses of the BCMAxCD3 bispecific antibody before subcutaneously administering the first therapeutic dose.

55. The method according to any one of claims 1 to 52, comprising subcutaneously administering two escalating doses of the BCMAxCD3 bispecific antibody before subcutaneously administering the first therapeutic dose.

56. The method according to any one of claims 1 to 52, comprising subcutaneously administering the BCMAxCD3 bispecific antibody in gradually increasing doses of 60 μg / kg and 300 μg / kg before subcutaneously administering the first therapeutic dose.

57. The method according to any one of claims 1 to 56, comprising administering gradually increasing doses of the BCMAxCD3 bispecific antibody subcutaneously at intervals of 2 to 4 days from each other, before subcutaneously administering the first therapeutic dose.

58. The method according to any one of claims 1 to 57, comprising subcutaneously administering one or more escalating doses of the BCMAxCD3 bispecific antibody before subcutaneously administering the first therapeutic dose, wherein the first therapeutic dose is administered 2 to 4 days after the last escalating dose.

59. The method according to any one of claims 1 to 58, comprising subcutaneously administering a first escalating dose of 60 μg / kg of the BCMAxCD3 bispecific antibody, then subcutaneously administering a second escalating dose of 300 μg / kg of the BCMAxCD3 bispecific antibody 2 to 4 days later, and then subcutaneously administering a first therapeutic dose of the BCMAxCD3 bispecific antibody 2 to 4 days later.

60. The method according to any one of claims 1 to 59, comprising subcutaneously administering a first escalating dose of 60 μg / kg of the BCMAxCD3 bispecific antibody, then subcutaneously administering a second escalating dose of 300 μg / kg of the BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a first therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody on a weekly administration schedule (QW) for a certain period of time, and then subcutaneously administering a therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W).

61. The method according to any one of claims 1 to 59, comprising subcutaneously administering a first escalating dose of 60 μg / kg of the BCMAxCD3 bispecific antibody, then subcutaneously administering a second escalating dose of 300 μg / kg of the BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a first therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody on a weekly administration schedule (QW) for six months or more, and then subcutaneously administering a therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody on the bi-weekly administration schedule (Q2W).

62. The method according to any one of claims 1 to 59, comprising subcutaneously administering a first escalating dose of 60 μg / kg of the BCMAxCD3 bispecific antibody, then subcutaneously administering a second escalating dose of 300 μg / kg of the BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a first therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody on a weekly administration schedule (QW), and after the subject has achieved partial response, very good partial response, complete response, or complete response for 6 months or more (according to IMWG criteria), then subcutaneously administering a therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W).

63. The method according to any one of claims 1 to 59, comprising subcutaneously administering a first escalating dose of 60 μg / kg of the BCMAxCD3 bispecific antibody, then subcutaneously administering a second escalating dose of 300 μg / kg of the BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a first therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody on a weekly administration schedule (QW), and after the subject has achieved a complete response or a severe complete response for 6 months or more (according to IMWG criteria), then subcutaneously administering a therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W).

64. The method according to any one of claims 1 to 59, comprising subcutaneously administering a first escalating dose of 60 μg / kg of the BCMAxCD3 bispecific antibody, then subcutaneously administering a second escalating dose of 300 μg / kg of the BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a first therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody on a weekly administration schedule (QW), and after the subject has achieved partial response, very good partial response, complete response, or exact complete response (according to IMWG criteria) after four 28-day treatment cycles or thereafter, then subcutaneously administering a therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W).

65. The method according to any one of claims 1 to 64, comprising subcutaneously administering a first escalating dose of 60 μg / kg of the BCMAxCD3 bispecific antibody, then subcutaneously administering a second escalating dose of 300 μg / kg of the BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a first therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody on a weekly administration schedule (QW) for a certain period, then subcutaneously administering a therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W) for a certain period, and then subcutaneously administering a therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody on a monthly administration schedule (Q4W).

66. The first escalating dose of the BCMAxCD3 bispecific antibody at 60 μg / kg is administered subcutaneously, followed by a second escalating dose of the BCMAxCD3 bispecific antibody at 300 μg / kg two to four days later, followed by a first therapeutic dose of the BCMAxCD3 bispecific antibody at 1500 μg / kg two to four days later, followed by a weekly (QW) administration of the BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg over a certain period. The method according to any one of claims 1 to 64, further comprising: subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg over a certain period of time according to the bi-weekly administration schedule (Q2W); and if the subject achieves at least a CR (i.e., complete response or exact complete response) by cycle 12 or thereafter, subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg according to the monthly administration schedule (Q4W).

67. The method according to any one of claims 1 to 64, comprising subcutaneously administering a first escalating dose of 60 μg / kg of the BCMAxCD3 bispecific antibody, then subcutaneously administering a second escalating dose of 300 μg / kg of the BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a first therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody 2 to 4 days later, then subcutaneously administering a therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody on a weekly administration schedule (QW) for a certain period of time, then subcutaneously administering a therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody on a bi-weekly administration schedule (Q2W) for at least 6 months, and then subcutaneously administering a therapeutic dose of 1500 μg / kg of the BCMAxCD3 bispecific antibody on a monthly administration schedule (Q4W).

68. The method according to any one of claims 1 to 67, wherein the subject achieves a clinical response in which PR, VGPR, CR, or sCR.

69. The method according to any one of claims 1 to 67, wherein the subject achieves a clinical response in which CR or sCR.

70. The method according to claim 68 or 69, wherein the clinical response is maintained for at least six months.

71. The method according to claim 68 or 69, wherein the clinical response is maintained for at least one year.

72. The method according to claim 68 or 69, wherein the clinical response is maintained for at least 18 months.

73. The method according to claim 68 or 69, wherein the clinical response is maintained for at least two years.

74. The method according to any one of claims 1 to 73, wherein fewer infections occur in the subject.

75. The method according to any one of claims 1 to 74, wherein fewer Grade 3 or higher infections occur in the subject.

76. The method according to any one of claims 1 to 73, wherein the method achieves a reduction in new infections over time in a target population having RRMM.

77. The method according to any one of claims 1 to 73, wherein the method achieves a reduction in new Grade 3 or higher infections over time in a target population having RRMM.

78. The method according to any one of claims 1 to 77, further comprising administering a therapeutically effective dose of tocilizumab to the subject before administering a first dose of the BCMAxCD3 bispecific antibody (e.g., teclistamaib).

79. The method according to claim 78, wherein the method reduces the risk of CRS in the subject compared to a subject who has not received tocilizumab before receiving the BCMAxCD3 bispecific antibody.

80. The method according to claim 78 or 79, wherein the tocilizumab is administered within approximately 4 hours before the first escalating dose of teclistamagab (for example, approximately 2 to 4 hours before the first escalating dose of teclistamagab).

81. The method according to any one of claims 78 to 80, wherein the tocilizumab is administered as a single dose of 8 mg / kg IV.

82. The method according to any one of claims 78 to 81, wherein the method achieves a CRS rate in the target population that is lower than the reference CRS rate in the reference population, and the reference population has not received tocilizumab prior to receiving the BCMAxCD3 bispecific antibody.

83. The method according to any one of claims 1 to 82, comprising administering a combination regimen comprising the BCMAxCD3 bispecific antibody and daratumumab.

84. The method according to claim 83, wherein the subject has previously received one to three lines of antimyeloma treatment comprising a proteasome inhibitor (PI) and lenalidomide.

85. The method according to claim 84, wherein the subject has previously received only one line of antimyeloma treatment and is refractory to lenalidomide.

86. The method according to any one of claims 83 to 85, wherein the daratumumab is administered subcutaneously.

87. The aforementioned daratumumab, Day 1 of Cycle 1 and every week thereafter (QW) (for example, Day 1, Day 8, Day 15 and Day 22), Cycle 2: Weekly (QW) (for example, day 1, day 8, day 15 and day 22), Cycles 3-6: Every other week (Q2W) (for example, on day 1 and day 15), The method according to any one of claims 82 to 86, wherein the drug is administered subcutaneously in an amount of 1800 mg in a 28-day treatment cycle, such as cycle 7 and subsequent cycles: monthly (Q4W) (e.g., day 1).

88. The method according to claim 87, wherein there is an interval of five days or more between administrations of daratumumab.

89. The subject has previously received one to three lines of antimyeloma treatment including a proteasome inhibitor (PI) and lenalidomide, and the method is The treatment includes administering a combination regimen comprising the BCMAxCD3 bispecific antibody (e.g., teclistamab) and daratumumab, wherein the BCMAxCD3 bispecific antibody is Cycle 1: A dose escalates to 0.06 mg / kg on day 2, then to 0.3 mg / kg (e.g., day 4), then to 1.5 mg / kg (e.g., day 8), and thereafter to a weekly (QW) therapeutic dose of 1.5 mg / kg (e.g., on days 15 and 22). Cycle 2: 1.5 mg / kg weekly (QW) (e.g., on day 1, day 8, day 15 and day 22), Cycles 3-6: 3 mg / kg every other week (Q2W) (for example, on day 1 and day 15). The method according to any one of claims 1 to 15, wherein 3 mg / kg is administered subcutaneously in a 28-day treatment cycle, such as monthly (Q4W) (e.g., day 1).

90. The method according to claim 89, wherein the daratumumab is administered subcutaneously on day 1 of cycle 1, and the first escalating dose of the BCMAxCD3 bispecific antibody is administered at least 20 hours after the daratumumab.

91. The method according to claim 89 or 90, wherein there is an interval of two days or more between dose escalations of the BCMAxCD3 bispecific antibody.

92. The method according to any one of claims 89 to 91, wherein a first dose of 1.5 mg / kg of teclistamag is administered at least two days after the second dose escalation.

93. The method according to any one of claims 89 to 92, wherein there is an interval of 5 days or more between therapeutic doses of 1.5 mg / kg (or between 1.5 mg / kg and a first dose of 3 mg / kg), and an interval of 12 days or more between therapeutic doses of 3 mg / kg.

94. The aforementioned daratumumab, Day 1 of Cycle 1 and every week thereafter (QW) (for example, Day 1, Day 8, Day 15 and Day 22), Cycle 2: Weekly (QW) (for example, day 1, day 8, day 15 and day 22), Cycles 3-6: Every other week (Q2W) (for example, on day 1 and day 15), The method according to any one of claims 89 to 93, wherein the drug is administered subcutaneously in an amount of 1800 mg in a 28-day treatment cycle, such as cycle 7 and subsequent cycles: monthly (Q4W) (e.g., day 1).

95. The method according to any one of claims 89 to 94, wherein, on the first day in which the daratumumab and the BCMAxCD3 bispecific antibody are administered on the same day (for example, day 8 of cycle 1), the BCMAxCD3 bispecific antibody is administered at least 3 hours after the daratumumab.

96. The method according to any one of claims 89 to 95, wherein the BCMAxCD3 bispecific antibody is tecristamag.

97. A method for improving progression-free survival in a target population with multiple myeloma who have previously received one to three lines of antimyeloma therapy including proteasome inhibitors (PIs) and lenalidomide, wherein the method is: The regimen comprises administering the combination regimen containing the teclistamaib and the daratumumab to the target population, wherein the teclistamaib is Cycle 1: A dose escalates to 0.06 mg / kg on day 2, then to 0.3 mg / kg (e.g., day 4), then to 1.5 mg / kg (e.g., day 8), and thereafter to a weekly (QW) therapeutic dose of 1.5 mg / kg (e.g., on days 15 and 22). Cycle 2: 1.5 mg / kg weekly (QW) (e.g., on day 1, day 8, day 15 and day 22), Cycles 3-6: 3 mg / kg every other week (Q2W) (for example, on day 1 and day 15). Cycle 7 and subsequent cycles: 3 mg / kg is administered subcutaneously every month (Q4W) (e.g., on day 1) in a 28-day treatment cycle, and the daratumumab is, Day 1 of Cycle 1 and every week thereafter (QW) (for example, Day 1, Day 8, Day 15 and Day 22), Cycle 2: Weekly (QW) (for example, day 1, day 8, day 15 and day 22), Cycles 3-6: Every other week (Q2W) (for example, on day 1 and day 15), Cycle 7 and subsequent cycles: Administered subcutaneously at a dose of 1800 mg in a 28-day treatment cycle, such as monthly (Q4W) (e.g., on day 1). The improvement in median progression-free survival is compared to the median progression-free survival in a reference population, the reference population being administered (i) an effective regimen (DPd) comprising daratumumab SC, pomalidomide, and dexamethasone, or (ii) an effective regimen (DVd) comprising daratumumab SC, bortezomib, and dexamethasone.

98. The method according to claim 97, wherein the improvement in median progression-free survival is at least about two months, or at least about four months, or at least about six months, or at least about eight months, or at least about ten months, or at least about twelve months, or at least about fourteen months, or at least about sixteen months, or at least about eighteen months, or at least about twenty months, or at least about twenty-two months, or at least about twenty-four months.

Images