Methods for treating multiple myeloma

Abstract

Embodiments of the present invention relate to a method for treating multiple myeloma in subjects requiring treatment for multiple myeloma, and include administering therapeutically effective doses of BCMAxCD3 bispecific antibody and GPRC5DxCD3 bispecific antibody to the subjects.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims the interests of U.S. Provisional Patent Application No. 63 / 497,119, filed on 19 April 2023; No. 63 / 504,150, filed on 24 May 2023; No. 63 / 505,594, filed on 1 June 2023; No. 63 / 588,480, filed on 6 October 2023; and No. 63 / 621,871, filed on 17 January 2024. The entire contents of the above applications are incorporated herein by reference.

[0002] (Sequence Listing) This application includes a computer-readable sequence listing filed with this application in XML file format, the entire contents of which are incorporated herein by reference. The sequence listing XML file filed with this application is titled "JBI6800WOPCT1_Sequence_Listing.xml", was created on 18 April 2024, and is 33,886 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] Extramedullary disease (EMD) is an aggressive form of multiple myeloma characterized by the ability of malignant plasma cells to grow and proliferate independently of the bone marrow microenvironment, resulting in organ infiltration and soft tissue plasmacytoma that are not contiguous with bone. The reported incidence of EMD in newly diagnosed patients ranges from 0.5% to 4.8%, while the reported incidence in relapsed / refractory multiple myeloma ranges from 3.4% to 14%.

[0006] 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.

[0007] 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] [Means for solving the problem]

[0008] Embodiments of the present invention provide combination regimens for the treatment of multiple myelomas, comprising a BCMAxCD3 bispecific antibody and a GPRC5DxCD3 bispecific antibody.

[0009] One embodiment of the present invention provides a method for treating multiple myeloma in a subject requiring treatment for multiple myeloma, the method comprising administering a combination regimen to the subject comprising a therapeutically effective dose of BCMAxCD3 bispecific antibody and a therapeutically effective dose of GPRC5DxCD3 bispecific antibody. In a particular embodiment, the subject has relapsed or refractory multiple myeloma and has previously received at least three lines of treatment comprising proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0010] 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.

[0011] 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.

[0012] In certain embodiments, the BCMA×CD3 bispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.

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

[0014] In certain embodiments, the BCMAxCD3 bispecific antibody contains one or more substitutions in its Fc region.

[0015] In certain embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and includes S228P, F234A, and L235A substitutions in its Fc region.

[0016] 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.

[0017] In certain embodiments, the Fc region of the BCMA-specific IgG4 antibody from which the BCMA-binding arm is derived includes S228P, L234A, and L235A substitutions in the Fc region.

[0018] In certain embodiments, the Fc region of the CD3-specific IgG4 antibody from which the CD3 binding arm is derived includes S228P, L234A, L235A, F405L, and R409K substitutions in the Fc region. In certain embodiments, the BCMAxCD3 bispecific antibody includes 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.

[0019] 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.

[0020] 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.

[0021] 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.

[0022] In certain embodiments, the BCMAxCD3 bispecific antibody is teclistamab.

[0023] In certain embodiments, the GPRC5D×CD3 bispecific antibody comprises a GPRC5D binding domain comprising HCDR1 of SEQ ID NO: 24, HCDR2 of SEQ ID NO: 25, HCDR3 of SEQ ID NO: 26, LCDR1 of SEQ ID NO: 27, LCDR2 of SEQ ID NO: 28, and LCDR3 of SEQ ID NO: 29, and 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.

[0024] In certain embodiments, the GPRC5D binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 30 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 31, 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.

[0025] In certain embodiments, the GPRC5DxCD3 bispecific antibody is an IgG1, IgG2, IgG3, or IgG4 isotype.

[0026] In certain embodiments, the GPRC5DxCD3 bispecific antibody is of the IgG4 isotype.

[0027] In certain embodiments, the GPRC5DxCD3 bispecific antibody contains one or more substitutions in its Fc region.

[0028] In certain embodiments, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A, and L235A substitutions in its Fc region.

[0029] In certain embodiments, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and includes S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region.

[0030] In certain embodiments, the Fc region of the GPRC5D-specific IgG4 antibody from which the GPRC5D-binding arm is derived includes S228P, L234A, and L235A substitutions in the Fc region.

[0031] In certain embodiments, the Fc region of the CD3-specific IgG4 antibody from which the CD3 binding arm is derived includes S228P, L234A, L235A, F405L, and R409K substitutions in the Fc region.

[0032] In a particular embodiment, the GPRC5DxCD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 32, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 33, 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.

[0033] In a particular embodiment, the GPRC5DxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 32, a first light chain (LC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 33, 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.

[0034] In a particular embodiment, the GPRC5DxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 32, a first light chain (LC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 33, 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.

[0035] In a particular embodiment, the GPRC5DxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 32, a first light chain (LC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 33, 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.

[0036] In certain embodiments, the GPRC5DxCD3 bispecific antibody is talketamab.

[0037] In certain embodiments, the subject has relapsed or refractory multiple myeloma.

[0038] In certain embodiments, the subject has been treated with 1 to 11 previous treatment lines, or with 1 to 10 previous treatment lines.

[0039] In certain embodiments, the subjects have previously undergone autologous stem cell transplantation (ASCT).

[0040] In certain embodiments, the subject has previously received at least three lines of treatment.

[0041] In certain embodiments, the subject has previously received at least four lines of treatment.

[0042] In certain embodiments, the subject has previously received at least five lines of treatment (pentad exposure).

[0043] In certain embodiments, the subject has previously received at least three lines of treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0044] In certain embodiments, the subject has previously received at least four lines of treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0045] In certain embodiments, the subject has an extramedullary disease (EMD).

[0046] In certain embodiments, the method includes subcutaneous administration of one or more escalating doses of BCMAxCD3 bispecific antibody to the target before administering a therapeutic dose of BCMAxCD3 bispecific antibody.

[0047] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody to a subject weekly (QW).

[0048] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody to the subject every two weeks (Q2W).

[0049] In certain embodiments, the method involves subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 750 μg / kg to approximately 3000 μg / kg on a weekly (QW) basis.

[0050] In certain embodiments, the method involves subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 750 μg / kg on a weekly (QW) basis.

[0051] In certain embodiments, the method involves subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg on a weekly (QW) basis.

[0052] In certain embodiments, the method involves subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 3000 μg / kg on a weekly (QW) basis.

[0053] In certain embodiments, the method involves subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 750 μg / kg to approximately 3000 μg / kg every two weeks (Q2W).

[0054] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 750 μg / kg every two weeks (Q2W).

[0055] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg every two weeks (Q2W).

[0056] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 3000 μg / kg every two weeks (Q2W).

[0057] In certain embodiments, the method includes subcutaneous administration of two or three escalating doses of a BCMAxCD3 bispecific antibody before subcutaneous administration of a therapeutic dose.

[0058] 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 therapeutic dose.

[0059] 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 therapeutic dose.

[0060] In certain embodiments, the method includes subcutaneous administration of escalating doses of a BCMAxCD3 bispecific antibody, spaced 2 to 4 days apart from each other.

[0061] In certain embodiments, before subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody, 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, and then, 2 to 4 days later, subcutaneous administration of a third escalating dose of 1500 μg / kg of BCMAxCD3 bispecific antibody.

[0062] In certain embodiments, the method includes subcutaneous administration of one or more escalating doses of GPRC5DxCD3 bispecific antibody to the target before administering a therapeutic dose of GPRC5DxCD3 bispecific antibody.

[0063] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of GPRC5DxCD3 bispecific antibody to a subject weekly (QW).

[0064] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of GPRC5DxCD3 bispecific antibody to the subject every two weeks (Q2W).

[0065] In certain embodiments, the method involves subcutaneously administering a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 200 μg / kg to approximately 800 μg / kg on a weekly (QW) basis.

[0066] In certain embodiments, the method includes subcutaneous administration of a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 200 μg / kg weekly (QW).

[0067] In certain embodiments, the method includes subcutaneous administration of a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 400 μg / kg weekly (QW).

[0068] In certain embodiments, the method includes subcutaneous administration of a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 800 μg / kg weekly (QW).

[0069] In certain embodiments, the method involves subcutaneously administering a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 200 μg / kg to approximately 800 μg / kg every two weeks (Q2W).

[0070] In certain embodiments, the method includes subcutaneous administration of a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 200 μg / kg every two weeks (Q2W).

[0071] In certain embodiments, the method includes subcutaneous administration of a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 400 μg / kg every two weeks (Q2W).

[0072] In certain embodiments, the method includes subcutaneous administration of a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 800 μg / kg every two weeks (Q2W).

[0073] In certain embodiments, the method includes subcutaneous administration of two or three escalating doses of a GPRC5DxCD3 bispecific antibody before subcutaneous administration of a therapeutic dose.

[0074] In certain embodiments, the method includes subcutaneous administration of GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg and 60 μg / kg before subcutaneous administration of a therapeutic dose. In certain embodiments, the method includes subcutaneous administration of GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg and 400 μg / kg before subcutaneous administration of a therapeutic dose.

[0075] In certain embodiments, the method includes subcutaneous administration of escalating doses of a GPRC5DxCD3 bispecific antibody, spaced 2 to 4 days apart from each other.

[0076] In certain embodiments, before subcutaneously administering a therapeutic dose of GPRC5DxCD3 bispecific antibody, the method includes subcutaneously administering a first escalating dose of 10 μg / kg of GPRC5DxCD3 bispecific antibody, then, 2 to 4 days later, a second escalating dose of 60 μg / kg of GPRC5DxCD3 bispecific antibody, and then, 2 to 4 days later, a third escalating dose of 400 μg / kg of GPRC5DxCD3 bispecific antibody.

[0077] In certain embodiments, the method includes subcutaneous administration of a GPRC5DxCD3 bispecific antibody in progressively increasing doses of 10 μg / kg, 60 μg / kg, and 300 μg / kg before subcutaneous administration of a therapeutic dose.

[0078] In certain embodiments, the method includes subcutaneous administration of escalating doses of a GPRC5DxCD3 bispecific antibody, spaced 2 to 4 days apart from each other.

[0079] In certain embodiments, before subcutaneous administration of a therapeutic dose of GPRC5DxCD3 bispecific antibody, the method includes subcutaneous administration of a first escalating dose of 10 μg / kg of GPRC5DxCD3 bispecific antibody, then, 2 to 4 days later, subcutaneous administration of a second escalating dose of 60 μg / kg of GPRC5DxCD3 bispecific antibody, and then, 2 to 4 days later, subcutaneous administration of a third escalating dose of 300 μg / kg of GPRC5DxCD3 bispecific antibody.

[0080] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 3000 μg / kg every two weeks (Q2W) and a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 800 μg / kg every two weeks (Q2W).

[0081] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg every two weeks (Q2W) and a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 800 μg / kg every two weeks (Q2W).

[0082] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg weekly (QW) and a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 800 μg / kg weekly (QW).

[0083] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg weekly (QW) and a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 400 μg / kg weekly (QW).

[0084] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg weekly (QW) and a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 200 μg / kg weekly (QW).

[0085] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 750 μg / kg weekly (QW) and a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 200 μg / kg weekly (QW).

[0086] In certain embodiments, the method includes subcutaneously administering one or more escalating doses of a BCMAxCD3 bispecific antibody before subcutaneously administering a therapeutic dose, and subcutaneously administering one or more escalating doses of a GPRC5DxCD3 bispecific antibody before subcutaneously administering a therapeutic dose.

[0087] In certain embodiments, the method includes subcutaneously administering two or three escalating doses of a BCMAxCD3 bispecific antibody before subcutaneously administering a therapeutic dose, and subcutaneously administering two or three escalating doses of a GPRC5DxCD3 bispecific antibody before subcutaneously administering a therapeutic dose.

[0088] In certain embodiments, the method includes subcutaneously administering a BCMAxCD3 bispecific antibody in progressively increasing doses of 60 μg / kg and 300 μg / kg before subcutaneously administering a therapeutic dose, and subcutaneously administering a GPRC5DxCD3 bispecific antibody in progressively increasing doses of 10 μg / kg and 60 μg / kg before subcutaneously administering a therapeutic dose.

[0089] In certain embodiments, the method includes subcutaneously administering a BCMAxCD3 bispecific antibody in gradually increasing doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg before subcutaneously administering a therapeutic dose, and subcutaneously administering a GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg, and 300 μg / kg before subcutaneously administering a therapeutic dose.

[0090] In certain embodiments, the method includes subcutaneously administering a BCMAxCD3 bispecific antibody in gradually increasing doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg before subcutaneously administering a therapeutic dose, and subcutaneously administering a GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneously administering a therapeutic dose.

[0091] In certain embodiments, the escalating doses of the BCMAxCD3 bispecific antibody are administered with a 2-4 day interval between doses, and the escalating doses of the GPRC5DxCD3 bispecific antibody are administered with a 2-4 day interval between doses.

[0092] In a particular embodiment, the method is The first escalating dose of BCMAxCD3 bispecific antibody at 60 μg / kg is administered subcutaneously, followed 2-4 days later by a second escalating dose of BCMAxCD3 bispecific antibody at 300 μg / kg, followed 2-4 days later by a third escalating dose of BCMAxCD3 bispecific antibody at 1500 μg / kg, followed 2-4 days later by a first therapeutic dose of BCMAxCD3 bispecific antibody at 3000 μg / kg. The first escalating dose of GPRC5DxCD3 bispecific antibody at 10 μg / kg is administered subcutaneously, followed 2-4 days later by a second escalating dose of GPRC5DxCD3 bispecific antibody at 60 μg / kg, followed 2-4 days later by a third escalating dose of GPRC5DxCD3 bispecific antibody at 400 μg / kg, followed 2-4 days later by a first therapeutic dose of GPRC5DxCD3 bispecific antibody at 800 μg / kg. The treatment then includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 3000 μg / kg every two weeks (Q2W), and a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 800 μg / kg every two weeks (Q2W).

[0093] In certain embodiments, each therapeutic dose of the BCMAxCD3 bispecific antibody is administered on the same day as each therapeutic dose of the GPRC5DxCD3 bispecific antibody.

[0094] In certain embodiments, each escalating dose of the BCMAxCD3 bispecific antibody is administered on the same day as each escalating dose of the GPRC5DxCD3 bispecific antibody.

[0095] In a particular embodiment, a first therapeutic dose of BCMAxCD3 bispecific antibody and a first therapeutic dose of GPRC5DxCD3 bispecific antibody are administered subcutaneously on day 1 of cycle 1 of a 28-day cycle, and in Q2W, for example on day 1 and day 15 (±3 days) of each 28-day cycle, a subsequent therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously at a dose of 800 μg / kg, and in Q2W, for example on day 1 and day 15 (±3 days) of a 28-day cycle, a subsequent therapeutic dose of BCMAxCD3 bispecific antibody is administered subcutaneously at a dose of 3000 μg / kg.

[0096] In certain embodiments, the method includes subcutaneous administration of BCMAxCD3 bispecific antibody in escalating doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg before subcutaneous administration of a first therapeutic dose, and subcutaneous administration of GPRC5DxCD3 bispecific antibody in escalating doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneous administration of a first therapeutic dose, wherein the first therapeutic dose is administered 2 to 4 days after the administration of the final escalating dose of each bispecific antibody.

[0097] In a particular embodiment, the method is Before subcutaneously administering the first therapeutic dose of BCMAxCD3 bispecific antibody, BCMAxCD3 bispecific antibody should be subcutaneously administered in gradually increasing doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg. The procedure includes subcutaneous administration of GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneous administration of the first therapeutic dose of GPRC5DxCD3 bispecific antibody, The first therapeutic dose of BCMAxCD3 bispecific antibody and the first therapeutic dose of GPRC5DxCD3 bispecific antibody are administered subcutaneously on day 1 of cycle 1 of a 28-day cycle. During Q2W, for example, on day 1 and day 15 (±3 days) of each 28-day cycle, a subsequent therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously at a dose of 800 μg / kg. During Q2W, for example, on day 1 and day 15 (±3 days) of a 28-day cycle, a subsequent therapeutic dose of BCMAxCD3 bispecific antibody is administered subcutaneously at a dose of 3000 μg / kg.

[0098] In a particular embodiment, the method is The first escalating dose of BCMAxCD3 bispecific antibody at 60 μg / kg is administered subcutaneously, followed 2-4 days later by a second escalating dose of BCMAxCD3 bispecific antibody at 300 μg / kg, followed 2-4 days later by a third escalating dose of BCMAxCD3 bispecific antibody at 1500 μg / kg, followed 2-4 days later by the first therapeutic dose of BCMAxCD3 bispecific antibody. The treatment involves subcutaneously administering a first escalating dose of 10 μg / kg of GPRC5DxCD3 bispecific antibody, followed 2-4 days later by subcutaneously administering a second escalating dose of 60 μg / kg of GPRC5DxCD3 bispecific antibody, followed 2-4 days later by subcutaneously administering a third escalating dose of 400 μg / kg of GPRC5DxCD3 bispecific antibody, followed 2-4 days later by subcutaneously administering the first therapeutic dose of GPRC5DxCD3 bispecific antibody. The first therapeutic dose of BCMAxCD3 bispecific antibody and the first therapeutic dose of GPRC5DxCD3 bispecific antibody are administered subcutaneously on day 1 of cycle 1 of a 28-day cycle. During Q2W, for example, on day 1 and day 15 (±3 days) of each 28-day cycle, a subsequent therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously at a dose of 800 μg / kg. During Q2W, for example, on day 1 and day 15 (±3 days) of a 28-day cycle, a subsequent therapeutic dose of BCMAxCD3 bispecific antibody is administered subcutaneously at a dose of 3000 μg / kg.

[0099] In a particular embodiment, the method is Before subcutaneously administering the first therapeutic dose of BCMAxCD3 bispecific antibody, BCMAxCD3 bispecific antibody should be subcutaneously administered in gradually increasing doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg. The procedure includes subcutaneous administration of GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg, and 300 μg / kg before subcutaneous administration of the first therapeutic dose of GPRC5DxCD3 bispecific antibody, The first therapeutic dose of BCMAxCD3 bispecific antibody and the first therapeutic dose of GPRC5DxCD3 bispecific antibody are administered subcutaneously on day 1 of cycle 1 of a 28-day cycle. During Q2W, for example, on day 1 and day 15 (±3 days) of each 28-day cycle, a subsequent therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously at a dose of 800 μg / kg. During Q2W, for example, on day 1 and day 15 (±3 days) of a 28-day cycle, a subsequent therapeutic dose of BCMAxCD3 bispecific antibody is administered subcutaneously at a dose of 3000 μg / kg.

[0100] In a particular embodiment, the method is The first escalating dose of BCMAxCD3 bispecific antibody at 60 μg / kg is administered subcutaneously, followed 2-4 days later by a second escalating dose of BCMAxCD3 bispecific antibody at 300 μg / kg, followed 2-4 days later by a third escalating dose of BCMAxCD3 bispecific antibody at 1500 μg / kg, followed 2-4 days later by the first therapeutic dose of BCMAxCD3 bispecific antibody. The treatment involves subcutaneously administering a first escalating dose of 10 μg / kg of GPRC5DxCD3 bispecific antibody, followed 2-4 days later by subcutaneous administration of a second escalating dose of 60 μg / kg of GPRC5DxCD3 bispecific antibody, followed 2-4 days later by subcutaneous administration of a third escalating dose of 300 μg / kg of GPRC5DxCD3 bispecific antibody, followed 2-4 days later by subcutaneous administration of the first therapeutic dose of GPRC5DxCD3 bispecific antibody. The first therapeutic dose of BCMAxCD3 bispecific antibody and the first therapeutic dose of GPRC5DxCD3 bispecific antibody are administered subcutaneously on day 1 of cycle 1 of a 28-day cycle. During Q2W, for example, on day 1 and day 15 (±3 days) of each 28-day cycle, a subsequent therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously at a dose of 800 μg / kg. During Q2W, for example, on day 1 and day 15 (±3 days) of a 28-day cycle, a subsequent therapeutic dose of BCMAxCD3 bispecific antibody is administered subcutaneously at a dose of 3000 μg / kg.

[0101] In certain embodiments, the method achieves partial response, very good partial response, complete response, or exact complete response in the subject, as determined by the IMWG response criteria.

[0102] In certain embodiments, the method achieves an overall response rate of at least 50% in a population of subjects with relapsed or refractory multiple myeloma (RRMM), for example, in subjects with EMD.

[0103] In certain embodiments, the method achieves an overall response rate of at least 55% in a population of subjects with relapsed or refractory multiple myeloma (RRMM), for example, in subjects with EMD.

[0104] In certain embodiments, the method achieves an overall response rate of at least 60% in a population of subjects with relapsed or refractory multiple myeloma (RRMM), for example, in subjects with EMD.

[0105] In certain embodiments, the method achieves an overall response rate of at least 65% in a population of subjects with relapsed or refractory multiple myeloma (RRMM), for example, in subjects with EMD.

[0106] In certain embodiments, the method achieves an overall response rate of at least 70% in a population of subjects with relapsed or refractory multiple myeloma (RRMM), for example, in subjects with EMD.

[0107] In a particular embodiment, the method achieves an overall response rate of at least 80% in a population of subjects having RRMM, for example, subjects having EMD.

[0108] In a particular embodiment, the method achieves an overall response rate of at least 85% in a population of subjects having RRMM, for example, subjects having EMD.

[0109] In certain embodiments, the method achieves an overall response rate of at least 90% in a population of subjects having RRMM.

[0110] In certain embodiments, the method achieves an overall response rate of at least 95% in a population of subjects having RRMM.

[0111] In certain embodiments, the method achieves at least a 20% complete response or a strict complete response rate in a population of subjects having RRMM, for example, subjects having EMD.

[0112] In certain embodiments, the method achieves at least a 25% complete response or a strict complete response rate in a population of subjects having RRMM, for example, subjects having EMD.

[0113] In certain embodiments, the method achieves at least 30% complete response or a strict complete response rate in a population of subjects having RRMM, for example, subjects having EMD.

[0114] In certain embodiments, the method achieves at least a 35% complete response or a strict complete response rate in a population of subjects having RRMM, for example, subjects having EMD.

[0115] In certain embodiments, the method achieves at least 40% complete response or a strict complete response rate in a population of subjects having RRMM, for example, subjects having EMD.

[0116] All methods described herein, in whatever way they are expressed, may be described as corresponding uses, specifically medical uses. [Brief explanation of the drawing]

[0117] 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 provides a Phase 1b clinical trial design for the Phase 1b RedirecTT-1 trial (NCT04586426) using tecristamab (Tec) and talketamab (Tal), which simultaneously targets BCMA and GPRC5D in patients with relapsed / refractory multiple myeloma (RRMM). [Figure 2] This provides patient characteristics from the Phase 1b RedirecTT-1 trial (NCT04586426) as of March 16, 2023. [Figure 3] This document provides safety profile information for the Phase 1b RedirecTT-1 trial (NCT04586426) as of March 16, 2023. [Figure 4] This document provides safety profile information for the Phase 1b RedirecTT-1 trial (NCT04586426) as of March 16, 2023. [Figure 5] This document provides safety profile information for the Phase 1b RedirecTT-1 trial (NCT04586426) as of March 16, 2023. [Figure 6] This document provides safety profile information for the Phase 1b RedirecTT-1 trial (NCT04586426) as of March 16, 2023. [Figure 7] This document provides safety profile information for the Phase 1b RedirecTT-1 trial (NCT04586426) as of March 16, 2023. [Figure 8] This document provides efficacy results from the Phase 1b RedirecTT-1 trial (NCT04586426) as of March 16, 2023. [Figure 9] This report provides efficacy results for patients in the EMD subgroup from the Phase 1b RedirecTT-1 trial (NCT04586426) as of March 16, 2023. [Figure 10] This document provides the clinical trial design for Part 3 of the RedirecTT-1 trial (Phase 2). [Figure 11] This diagram shows the dosing regimen for Arm B (Tal+Tec) of the MonumenTAL-6 clinical trial (Phase 3). [Modes for carrying out the invention]

[0118] 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.

[0119] As used herein, the singular forms "a," "an," and "the" are to be interpreted as including the plural form.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] "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.

[0125] Sequence ID 1 MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAILWTCLGLSLIISLAVFVLMFLLRKINSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCKSLPAALSATEIEKSISAR

[0126] "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.

[0127] A "BCMA x CD3 bispecific antibody" refers to a bispecific antibody that specifically binds to both BCMA and CD3.

[0128] "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.

[0129] "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.

[0130] Sequence ID 2 MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGS KPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI Sequence ID 3 DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMD

[0131] 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.

[0132] "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.

[0133] A “combination dosing regimen” (also referred to herein as a “combination regimen”) means that two or more therapeutic agents are administered to a subject over a period of time according to the respective dosing schedules of each therapeutic agent (for example, the period may include one or more treatment cycles, such as one or more 28-day treatment cycles). For example, a combination dosing regimen may include administering to a subject (i) Therapeutic Agent #1 on its weekly, bi-weekly, or monthly dosing schedule, beginning on day 1 of the treatment cycle, and (ii) Therapeutic Agent #2 on its weekly, bi-weekly, or monthly dosing schedule, beginning on day 1 of the same treatment cycle. In certain embodiments, Therapeutic Agent #1 and Therapeutic Agent #2 have the same or similar dosing schedules (for example, both have bi-weekly dosing schedules and treatment begins on the same day), and are therefore intended to be administered on the same day throughout the combination dosing regimen.

[0134] 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.

[0135] "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 exclusionary sense, i.e., "including but not limited to."

[0136] The term "Fc gamma receptor" (FcγR) refers to the well-known FcγRI, FcγRIIa, FcγRIIb, or FcγRIII. Activated FcγR includes FcγRI, FcγRIIa, and FcγRIII.

[0137] A "GPRC5DxCD3 bispecific antibody" refers to a bispecific antibody that specifically binds to GPRC5D and CD3.

[0138] 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."

[0139] 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.

[0140] "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.

[0141] "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%.

[0142] 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.

[0143] 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.

[0144] "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).

[0145] A "pharmaceutical composition" refers to a composition containing an active ingredient and a pharmaceutically acceptable carrier.

[0146] "Pharmacologically acceptable carriers" or "excipients" refer to components in a pharmaceutical composition other than the active ingredient that are non-toxic to the target.

[0147] "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.

[0148] "Refractory" refers to cancer that cannot be repaired even with surgical intervention and does not respond to therapy from the outset.

[0149] "Recurrent" cancer refers to cancer that responds to treatment but subsequently recurs.

[0150] "Dose escalation" refers to the dose of the active drug administered to the subject before the therapeutic dose. 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 include one or more lower dose escalations followed by a higher therapeutic dose. "Elevation phase" refers to the initial phase of a therapeutically effective regime in which at least one dose escalation of the therapeutic agent is administered to the subject. Elevation phase may also include one or more therapeutic doses; that is, escalation phase can include one or more dose escalations followed by one or more therapeutic doses, for example, escalation phase may include two dose escalations followed by two therapeutic doses, or three dose escalations followed by one therapeutic dose. In certain embodiments, escalation phase is 28 days, i.e., escalation phase is a therapeutically effective regimen with a 28-day cycle. According to certain embodiments, escalation phase occurs in treatment cycle 1 of a therapeutic regimen, which includes a series of treatment cycles.

[0151] "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.

[0152] 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.

[0153] 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.

[0154] "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.

[0155] 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.

[0156] A patient described as "triple-class exposed" refers to a patient diagnosed with multiple myeloma (MM) who has been previously treated with (at least) proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0157] "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.

[0158] 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.

[0159] Conventional one-letter and three-letter amino acid codes are used herein as shown in Table 1.

[0160] [Table 1]

[0161] BCMAxCD3 and GPRC5DxCD3 bispecific antibodies and their use In patients with relapsed or refractory disease who have exhausted numerous therapies, multiple myeloma remains an incurable malignancy with significant morbidity and mortality rates, representing an unmet medical need. New dosing regimens offering improved safety profiles and enhanced efficacy are still in demand.

[0162] The inventors have developed a novel combination regimen that overcomes the challenges associated with targeting two different antigens and combining two therapeutic agents. This specification describes a combination regimen comprising BCMA and GPRC5D-targeted bispecific antibodies. This specification also describes the clinical results from the initial BCMA and GPRC5D-targeted combination trial, in which patients were treated with a combination regimen of teclistamagb (BCMA x CD3 bispecific antibody) and talketamab (GPRC5D x CD3 bispecific antibody).

[0163] Novel combination regimens involving two therapeutic agents are known to carry a risk of overlapping toxicity profiles. For example, cytokine release syndrome (CRS) commonly occurs after immunotherapy. Patients with 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 on-target and off-tumor toxicity. In the Phase 1 / 2 MajesTEC-1 clinical trial of teclistamagb (NCT03145181 and NCT04557098), patients (N=165) received subcutaneous teclistamagb 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.

[0164] Considering that BCMAxCD3 and GPRC5DxCD3 bispecific antibodies act through stimulation of the endogenous immune system, they may exhibit toxicity to other tissues or organs by activating immune cells through potential inflammatory mechanisms. Despite these challenges, we have developed a highly effective combination regimen that does not exhibit additional toxicity. While not bound by theory, targeting two different antigens found on multiple myeloma cells may overcome common resistance mechanisms to monotherapy by reducing the risk of loss of activity due to loss of a single target antigen and enhancing antigen-antibody interactions. Therefore, dual targeting may also reduce target molecule-associated avoidance and lower the risk of relapse.

[0165] For patients whose myeloma relapses after exposure to daratumumab and lenalidomide in the first or subsequent line of treatment, treatment options are limited. Retrospective reviews of patients refractory to anti-CD38 therapy and who received subsequent therapy after progression with PI, IMiD, and anti-CD38 therapy showed that efficacy observed after subsequent treatment was dismal, regardless of the chosen salvage therapy. Therefore, there remains a significant and critical unmet need for new treatment options targeting alternative mechanisms of action that could lead to better disease control and deeper, more sustained responses, including better long-term outcomes such as maintenance of health-related quality of life (HRQoL).

[0166] According to a particular embodiment, a combination regimen of the present invention comprising BCMAxCD3 and GPRC5DxCD3 bispecific antibodies (e.g., a regimen comprising tecristamab and talketamab) improves the median progression-free survival (PFS) in a population of subjects with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, the improvement in median PFS compared to the median PFS of a reference population of subjects with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, the reference population which has been administered either (i) elotuzumab, pomalidomide, and dexamethasone (EPd), or (ii) pomalidomide, bortezomib, and dexamethasone (PVd). PFS refers to the period from the start of treatment to the earlier of progressive disease or death.

[0167] According to a particular embodiment, a combination regimen of the present invention comprising BCMAxCD3 and GPRC5DxCD3 bispecific antibodies (e.g., a regimen comprising tecristamab and talketamab) improves the overall response rate (ORR) in a population of subjects with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, the improvement in ORR being compared to the ORR of a reference population of subjects with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, the reference population being administered either (i) elotuzumab, pomalidomide, and dexamethasone (EPd), or (ii) pomalidomide, bortezomib, and dexamethasone (PVd). ORR refers to the percentage of patients who have the best overall response, such as a partial response (PR), according to the response criteria of the International Myeloma Working Group (IMWG).

[0168] According to a particular embodiment, a combination regimen of the present invention comprising BCMAxCD3 and GPRC5DxCD3 bispecific antibodies (e.g., a regimen comprising tecristamab and talketamab) improves the complete response (CR) or better rate in a population of subjects with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, compared to the CR or better rate in a reference population of subjects with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, the reference population which has been administered either (i) elotuzumab, pomalidomide, and dexamethasone (EPd), or (ii) pomalidomide, bortezomib, and dexamethasone (PVd). The response rate of CR or higher refers to the percentage of subjects with the best overall response of CR or higher according to the IMWG response criteria.

[0169] According to certain embodiments, a combination regimen of the present invention comprising BCMAxCD3 and GPRC5DxCD3 bispecific antibodies (e.g., a regimen comprising tecristamab and talketamab) results in a very good partial response in a population of subjects with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide. The response rate (VGPR) or higher was improved, and the improvement in the VGPR or higher response rate was compared to the improvement in the VGPR or higher response rate of a reference population of subjects with relapsed or refractory multiple myeloma who had previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, and the reference population was administered either (i) elotuzumab, pomalidomide, and dexamethasone (EPd) or (ii) pomalidomide, bortezomib, and dexamethasone (PVd). The VGPR or higher response rate refers to the percentage of subjects with the best overall response of VGPR or higher according to the IMWG response criteria.

[0170] According to a particular embodiment, a combination regimen of the present invention comprising BCMAxCD3 and GPRC5DxCD3 bispecific antibodies (e.g., a regimen comprising tecristamab and talketamab) improves the minimal residual disease (MRD) negative complete response rate in a population of subjects with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, the improvement in the MRD-negative CR rate compared to the MRD-negative CR rate of a reference population of subjects with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, the reference population which has been administered either (i) elotuzumab, pomalidomide, and dexamethasone (EPd), or (ii) pomalidomide, bortezomib, and dexamethasone (PVd). MRD-negative complete response (CR) refers to the percentage of subjects who achieve both CR or better and MRD negativity at a threshold of 10^-5 at any point after the day of randomization and before disease progression or initiation of subsequent antimyeloma therapy (SST).

[0171] According to certain embodiments, a combination regimen of the present invention comprising BCMAxCD3 and GPRC5DxCD3 bispecific antibodies (e.g., a regimen comprising tecristamab and talketamab) improves overall survival (OS) in a population of subjects with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, the improvement in OS compared to the OS of a reference population of subjects with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, the reference population which has received either (i) elotuzumab, pomalidomide, and dexamethasone (EPd), or (ii) pomalidomide, bortezomib, and dexamethasone (PVd). OS refers to the time from the start of treatment to the date of death of the subject.

[0172] 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. In consideration of this disclosure, any suitable GPRC5D×CD3 bispecific antibody known to those skilled in the art can be used in the present invention.

[0173] 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.

[0174] 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.

[0175] In some embodiments, the GPRC5DxCD3 bispecific antibody comprises one of the GPRC5D binding domains described in U.S. Patent No. 10,562,968 (the entire contents of which are incorporated herein by reference). In some embodiments, the GPRC5DxCD3 bispecific antibody comprises one of the CD3 binding domains described in U.S. Patent No. 10,562,968. In some embodiments, the GPRC5DxCD3 bispecific antibody comprises one of the GPRC5DxCD3 bispecific antibodies described in U.S. Patent No. 10,562,968.

[0176] In some embodiments, the BCMAxCD3 bispecific antibody is chimeric, humanized, or human.

[0177] In some embodiments, the GPRC5DxCD3 bispecific antibody is chimeric, humanized, or human.

[0178] 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.

[0179] Sequence ID 34: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0180] 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.

[0181] [Table 2]

[0182] 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.

[0183] 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.

[0184] The Fc substitution that can be used to reduce CDC is K322A substitution.

[0185] To improve the stability of IgG4, the well-known S228P substitution can be further applied to the IgG4 antibody.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] In some embodiments, the GPRC5DxCD3 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.

[0190] 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.

[0191] In some embodiments, the GPRC5DxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234, and alanine at position 235 in both HC1 and HC2.

[0192] Tables 3 and 4 provide sequences of exemplary embodiments of BCMAxCD3 bispecific antibodies according to the Kabat numbering system.

[0193] [Table 3]

[0194] [Table 4]

[0195] 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.

[0196] Teclistamaib (also known as TECVAYLI®) is the first BCMA-targeted bispecific antibody approved for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). Teclistamaib is a bispecific B-cell maturation antigen (BCMA)-targeted CD3 T-cell engager indicated as monotherapy for 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. See, for example, Usmani SZ, et al. Lancet 2021;398:665-674 and Moreau P, et al. New Engl J Med 2022;387:495-505 (which is incorporated herein by reference).

[0197] 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.

[0198] Tables 5 and 6 provide sequences of exemplary embodiments of GPRC5DxCD3 bispecific antibodies according to the Kabat numbering system.

[0199] [Table 5]

[0200] [Table 6]

[0201] In some embodiments, the GPRC5DxCD3 bispecific antibody is JNJ-64407564 or talketamab (also referred to herein as Tal) and has the sequences described in Tables 5 and 6.

[0202] Talketamab is a GPRC5D-targeted bispecific antibody developed for the treatment of patients with relapsed or refractory multiple myeloma. See, for example, Chari A, et al. Blood 2022;140(suppl 1):384-387 (which is incorporated herein by reference). Talketamab is a bispecific GPRC5D-targeted CD3 T-cell engager developed as monotherapy for adult patients with relapsed or refractory multiple myeloma who have previously received at least three or four prior treatments, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0203] Talketamab and its uses are described, for example, in International Publication No. 2018 / 017786 and International Publication No. 2022 / 058445, which are incorporated herein by reference. According to certain embodiments, the GPRC5DxCD3 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 talketamab.

[0204] Further embodiments of the BCMAxCD3 bispecific antibody and GPRC5DxCD3 bispecific antibody that can be used in the combination regimen of the present invention are described below.

[0205] 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.

[0206] 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.

[0207] In certain embodiments, the BCMA×CD3 bispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0208] In certain embodiments, the BCMA×CD3 bispecific antibody is of the IgG4 isotype.

[0209] In certain embodiments, the BCMAxCD3 bispecific antibody contains one or more substitutions in its Fc region.

[0210] In certain embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and includes S228P, F234A, and L235A substitutions in its Fc region.

[0211] 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.

[0212] In certain embodiments, the Fc region of the BCMA-specific IgG4 antibody from which the BCMA-binding arm is derived includes S228P, L234A, and L235A substitutions in the Fc region.

[0213] In certain embodiments, the Fc region of the CD3-specific IgG4 antibody from which the CD3 binding arm is derived includes S228P, L234A, L235A, F405L, and R409K substitutions in the Fc region. In certain embodiments, the BCMAxCD3 bispecific antibody includes 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] In certain embodiments, the BCMAxCD3 bispecific antibody is teclistamaib.

[0218] In certain embodiments, the GPRC5D × CD3 bispecific antibody comprises a GPRC5D binding domain including HCDR1 of SEQ ID NO: 24, HCDR2 of SEQ ID NO: 25, HCDR3 of SEQ ID NO: 26, LCDR1 of SEQ ID NO: 27, LCDR2 of SEQ ID NO: 28, and LCDR3 of SEQ ID NO: 29, 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.

[0219] In a particular embodiment, the GPRC5D binding domain includes a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 30 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 31, 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.

[0220] In certain embodiments, the GPRC5DxCD3 bispecific antibody is an IgG1, IgG2, IgG3, or IgG4 isotype.

[0221] In certain embodiments, the GPRC5DxCD3 bispecific antibody is of the IgG4 isotype.

[0222] In certain embodiments, the GPRC5DxCD3 bispecific antibody contains one or more substitutions in its Fc region.

[0223] In certain embodiments, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A, and L235A substitutions in its Fc region.

[0224] In certain embodiments, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and includes S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region.

[0225] In certain embodiments, the Fc region of the GPRC5D-specific IgG4 antibody from which the GPRC5D-binding arm is derived includes S228P, L234A, and L235A substitutions in the Fc region.

[0226] In certain embodiments, the Fc region of the CD3-specific IgG4 antibody from which the CD3 binding arm is derived includes S228P, L234A, L235A, F405L, and R409K substitutions in the Fc region.

[0227] In a particular embodiment, the GPRC5DxCD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 32, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 33, 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.

[0228] In a particular embodiment, the GPRC5DxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 32, a first light chain (LC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 33, 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.

[0229] In a particular embodiment, the GPRC5DxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 32, a first light chain (LC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 33, 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.

[0230] In a particular embodiment, the GPRC5DxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 32, a first light chain (LC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 33, 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.

[0231] In certain embodiments, the GPRC5DxCD3 bispecific antibody is talketamab.

[0232] Patient population with multiple myeloma The BCMAxCD3 bispecific antibodies and GPRC5DxCD3 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.

[0233] In certain embodiments, the subjects have relapsed or refractory multiple myeloma and have previously received one to four lines of treatment including anti-CD38 antibodies and lenalidomide.

[0234] The inventors have further discovered that the combination regimens described herein demonstrate high efficacy in patients with extramedullary disease (EMD). In certain embodiments, the patient has one or more lesions of EMD that are not contiguous with bone lesions and meet the criteria of any previously irradiated extramedullary plasmacytoma with a diameter ≥ 2 cm (at its maximum dimension) as seen on PET-CT.

[0235] In some embodiments, the subject is relapsed or refractory to treatment with therapeutic agents used to treat multiple myeloma or other hematological malignancies.

[0236] In certain embodiments, the subject has been treated with 1 to 11 previous treatment lines, or with 1 to 10 previous treatment lines.

[0237] In certain embodiments, the subjects have previously undergone autologous stem cell transplantation (ASCT).

[0238] In certain embodiments, the subject has previously received at least three lines of treatment.

[0239] In certain embodiments, the subject has previously received at least four lines of treatment.

[0240] In certain embodiments, the subject has previously received at least five lines of treatment (pentad exposure).

[0241] In certain embodiments, the subject has previously received at least three lines of treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0242] In certain embodiments, the subject has previously received at least four lines of treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0243] 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.

[0244] In some embodiments, subjects had received three anticancer therapies prior to administration of BCMAxCD3 bispecific antibody and GPRC5DxCD3 bispecific antibody.

[0245] In one embodiment, the three prior anticancer therapies consist of a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 antibody. In certain such embodiments, the proteasome inhibitor is bortezomib, carfilzomib, or ixazomib; the immunomodulatory agent (IMiD) is lenalidomide, pomalidomide, or thalidomide; and the anti-CD38 antibody is daratumumab or isatuximab.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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-oriented therapies.

[0250] 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.

[0251] 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.

[0252] In one embodiment, the anti-CD38 antibody is daratumumab.

[0253] In another embodiment, the anti-CD38 antibody is isatuximab.

[0254] 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.

[0255] 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.

[0256] Chromosome rearrangements can be identified using well-known methods, such as fluorescence in situ hybridization, karyotype analysis, pulsed-field gel electrophoresis, or sequencing.

[0257] Combination dosing regimens The inventors have found that patients requiring treatment for relapsed or refractory multiple myeloma that has relapsed or become refractory to previous anticancer treatments may be particularly well-suited to treatment with a combination regimen containing both a BCMAxCD3 bispecific antibody (e.g., teclista mab or "Tec") and a GPRC5DxCD3 bispecific antibody (e.g., talketamab or "Tal").

[0258] 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”.

[0259] Unless otherwise specified herein, BCMA x CD3 bispecific antibodies or GPRC5DxCD3 bispecific antibodies, such as teclista mab or talketamab, 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. In certain embodiments, one or more escalating doses are administered before the first treatment cycle, i.e., before Day 1 of Cycle 1. In other embodiments, one or more escalating doses are administered during Cycle 1 (for example, the first escalating dose may be administered on Day 1 of Cycle 1).

[0260] As used herein, a treatment cycle refers to a 28-day treatment cycle. When used herein in relation to treatment cycles, "C1" refers to cycle 1, "C2" refers to cycle 2, "C3" refers to cycle 3, and so on. Multiple cycles may be described; for example, "C3-6" refers to cycles 3-6 (cycles 3, 4, 5, and 6). A cycle number with a "+" sign refers to that cycle and all subsequent cycles; for example, "C5+" refers to cycle 5 and all subsequent cycles (i.e., C5, C6, C7, C8, C9, etc.).

[0261] 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). Administration of a once-weekly (QW) therapeutic dose is also referred to herein as a weekly dosing schedule, and for example, a 28-day treatment cycle may have a weekly dosing schedule including four doses spaced one week apart from each other (e.g., days 1, 8, 15, and 22), or three doses spaced one week apart from each other (e.g., days 8, 15, and 22), or two doses spaced one week apart from each other (e.g., days 8 and 15). A therapeutic dose administered every two weeks (Q2W) is also referred to herein as a bi-weekly dosing schedule. A therapeutic dose administered every four weeks (Q4W) is also referred to herein as a monthly dosing schedule. Dosing regimens may be described herein in terms of dosage and frequency. For example, "C1: 0.4 mg / kg QW" refers to an administration of 0.4 mg / kg once a week in cycle 1 of a therapeutically effective regimen, "C3~6: 0.8 mg / kg Q2W" refers to an administration of 0.8 mg / kg every two weeks from cycle 3 to cycle 6, and "C7+: 0.8 mg / kg Q4W" refers to an administration of 0.8 mg / kg every four weeks starting from cycle 7.

[0262] As used herein, "BCMAxCD3 treatment cycle" refers to each treatment cycle in a therapeutically effective regimen in which at least one therapeutic dose of a BCMAxCD3 bispecific antibody is administered to a subject.

[0263] As used herein, "GPRC5DxCD3 treatment cycle" refers to each treatment cycle in a therapeutically effective regimen in which at least one therapeutic dose of a GPRC5DxCD3 bispecific antibody is administered to a subject.

[0264] According to certain embodiments, a subject is administered (i) 3.0 mg / kg of teclistamab every two weeks (Q2W), and (ii) 0.8 mg / kg of talquetamab every two weeks (Q2W), subcutaneously.

[0265] [[ID=13000901>According to certain embodiments, the method comprises administering talquetamab in combination with teclistamab for the treatment of adult patients with relapsed or refractory multiple myeloma having extramedullary disease who have been administered a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

[0266] According to embodiments of the present invention, the method of treating multiple myeloma is effective in inducing a clinical response in a subject 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, a very good partial response, a complete response, or a stringent complete response as determined by the IMWG response criteria. As used herein, the overall response rate (ORR) refers to the percentage of patients in a population achieving a partial response (PR) or greater, i.e., a partial response, a very good partial response, a complete response, or a stringent complete response. The IMWG criteria for response to multiple myeloma treatment are provided in Table 7 below.

[0267] [Table 7] 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.

[0268] 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).

[0269] In certain embodiments, combination therapy regimens comprising a BCMAxCD3 bispecific antibody (e.g., teclistamaib) and a GPRC5DxCD3 bispecific antibody (e.g., talketamab) are safe and well-tolerated in patients. In certain embodiments, treatment of a target with a combination therapy regimen does not result in additional toxicity. For example, administration of a combination therapy regimen to a patient population may result in adverse event incidence and severity consistent with those observed in patient populations treated with either monotherapy regimen (teclistamaib or talketamab).

[0270] In certain embodiments, the overall response rate in subjects treated with a combination regimen including a BCMAxCD3 bispecific antibody (e.g., teclistamab) and a GPRC5DxCD3 bispecific antibody (e.g., talketamab) is at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% of the treated subjects. In one embodiment, treatment with a combination regimen including teclistamab and talketamab achieves an overall response rate of about 92% ORR in patients with advanced relapsed / refractory multiple myeloma and an overall response rate of about 83% in patients with extramedullary disease (EMD) and high-risk populations whose needs are not met. In certain embodiments, the patient population has previously received a median of 4 lines of treatment (e.g., 1–10 or 1–11 previous lines of treatment). In certain embodiments, the patients have previously undergone autologous stem cell transplantation (ASCT). In certain embodiments, the proportion of patients with EMD who achieve a clinical response (PR or better) is higher in patients receiving a combination regimen including teclistamag and talketamab compared to patients with EMD who receive talketamab monotherapy or teclistamag monotherapy. For example, as described in Example 1 of this specification, the response to talquetamab monotherapy in patients with EMD was 45.5% (0.4 mg / kg QW) and 40.0% (0.8 mg / kg Q2W), compared to 37.5% with teclistamag monotherapy in other clinical trials (see, for example, Moreau P, Garfall AL, van de Donk N, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med 2022;387:495-505; and Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med 2022;387:2232-44).In contrast, with RedirecTT-1 (teclistamag + talketamab), 66.7% of patients with EMD responded at dose level 5 (33.3% achieved complete response or better), and the probability of maintaining response at 18 months was 81.8%.

[0271] In another embodiment, treatment with a combination regimen including teclistamag and talketamab achieved an overall response rate of approximately 96% ORR in patients with advanced relapsed / refractory multiple myeloma and approximately 86% ORR in patients with extramedullary disease (EMD) and high-risk populations whose needs are not met. In certain embodiments, the patient population had previously received a median of four lines of treatment (e.g., 1–10 or 1–11 previous lines of treatment). In certain embodiments, the patients had previously undergone autologous stem cell transplantation (ASCT).

[0272] In certain embodiments, teclistamaib may be administered subcutaneously according to the following body weight-based dosing schedule shown in Table 8A, where mg / kg refers to mg of teclistamaib per kg of the patient's body weight.

[0273] [Table 8] 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.

[0274] In certain embodiments, teclistamag may be administered subcutaneously according to the following body weight-based dosing schedule shown in Table 8B (mg / kg refers to mg of teclistamag per kg of the patient's body weight).

[0275]

Table 9

[0276] In certain embodiments, talquetamab can be administered subcutaneously according to either of the following weight-based dosing schedules shown in Table 9 and Table 10, where mg / kg refers to the mg of talquetamab per 1 kg of the patient's body weight.

[0277]

Table 10

[0278]

Table 11

[0279] Further embodiments of the combination regimens of the present invention are described below.

[0280] In certain embodiments, the method includes administering one or more escalating doses of a BCMAxCD3 bispecific antibody subcutaneously to a subject prior to administering a therapeutic dose of the BCMAxCD3 bispecific antibody.

[0281] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody to a subject weekly (QW).

[0282] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody to the subject every two weeks (Q2W).

[0283] In certain embodiments, the method involves subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 750 μg / kg to approximately 3000 μg / kg on a weekly (QW) basis.

[0284] In certain embodiments, the method involves subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 750 μg / kg on a weekly (QW) basis.

[0285] In certain embodiments, the method involves subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg on a weekly (QW) basis.

[0286] In certain embodiments, the method involves subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 3000 μg / kg on a weekly (QW) basis.

[0287] In certain embodiments, the method involves subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 750 μg / kg to approximately 3000 μg / kg every two weeks (Q2W).

[0288] In certain embodiments, the method involves subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg to approximately 3000 μg / kg every two weeks (Q2W).

[0289] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 750 μg / kg every two weeks (Q2W).

[0290] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg every two weeks (Q2W).

[0291] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 3000 μg / kg every two weeks (Q2W).

[0292] In certain embodiments, the method includes subcutaneous administration of two or three escalating doses of a BCMAxCD3 bispecific antibody before subcutaneous administration of a therapeutic dose.

[0293] 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 therapeutic dose.

[0294] 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 therapeutic dose.

[0295] In certain embodiments, the method includes subcutaneous administration of escalating doses of a BCMAxCD3 bispecific antibody, spaced 2 to 4 days apart from each other.

[0296] In certain embodiments, before subcutaneous administration of a therapeutic dose of BCMAxCD3 bispecific antibody, 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, and then, 2 to 4 days later, subcutaneous administration of a third escalating dose of 1500 μg / kg of BCMAxCD3 bispecific antibody.

[0297] In certain embodiments, the method includes subcutaneous administration of one or more escalating doses of GPRC5DxCD3 bispecific antibody to the target before administering a therapeutic dose of GPRC5DxCD3 bispecific antibody.

[0298] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of GPRC5DxCD3 bispecific antibody to a subject weekly (QW).

[0299] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of GPRC5DxCD3 bispecific antibody to the subject every two weeks (Q2W).

[0300] In certain embodiments, the method involves subcutaneously administering a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 200 μg / kg to approximately 800 μg / kg on a weekly (QW) basis.

[0301] In certain embodiments, the method includes subcutaneous administration of a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 200 μg / kg weekly (QW).

[0302] In certain embodiments, the method includes subcutaneous administration of a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 400 μg / kg weekly (QW).

[0303] In certain embodiments, the method includes subcutaneous administration of a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 800 μg / kg weekly (QW).

[0304] In certain embodiments, the method involves subcutaneously administering a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 200 μg / kg to approximately 800 μg / kg every two weeks (Q2W).

[0305] In certain embodiments, the method includes subcutaneous administration of a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 200 μg / kg every two weeks (Q2W).

[0306] In certain embodiments, the method includes subcutaneous administration of a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 400 μg / kg every two weeks (Q2W).

[0307] In certain embodiments, the method includes subcutaneous administration of a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 800 μg / kg every two weeks (Q2W).

[0308] In certain embodiments, the method includes subcutaneous administration of two or three escalating doses of a GPRC5DxCD3 bispecific antibody before subcutaneous administration of a therapeutic dose.

[0309] In certain embodiments, the method includes subcutaneous administration of a GPRC5DxCD3 bispecific antibody in escalating doses of 10 μg / kg and 60 μg / kg before subcutaneous administration of a therapeutic dose.

[0310] In certain embodiments, the method includes subcutaneous administration of a GPRC5DxCD3 bispecific antibody in progressively increasing doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneous administration of a therapeutic dose.

[0311] In certain embodiments, the method includes subcutaneous administration of escalating doses of a GPRC5DxCD3 bispecific antibody, spaced 2 to 4 days apart from each other.

[0312] In certain embodiments, before subcutaneously administering a therapeutic dose of GPRC5DxCD3 bispecific antibody, the method includes subcutaneously administering a first escalating dose of 10 μg / kg of GPRC5DxCD3 bispecific antibody, then, 2 to 4 days later, a second escalating dose of 60 μg / kg of GPRC5DxCD3 bispecific antibody, and then, 2 to 4 days later, a third escalating dose of 400 μg / kg of GPRC5DxCD3 bispecific antibody.

[0313] In certain embodiments, the method includes subcutaneous administration of a GPRC5DxCD3 bispecific antibody in progressively increasing doses of 10 μg / kg, 60 μg / kg, and 300 μg / kg before subcutaneous administration of a therapeutic dose.

[0314] In certain embodiments, the method includes subcutaneous administration of escalating doses of a GPRC5DxCD3 bispecific antibody, spaced 2 to 4 days apart from each other.

[0315] In certain embodiments, before subcutaneous administration of a therapeutic dose of GPRC5DxCD3 bispecific antibody, the method includes subcutaneous administration of a first escalating dose of 10 μg / kg of GPRC5DxCD3 bispecific antibody, then, 2 to 4 days later, subcutaneous administration of a second escalating dose of 60 μg / kg of GPRC5DxCD3 bispecific antibody, and then, 2 to 4 days later, subcutaneous administration of a third escalating dose of 300 μg / kg of GPRC5DxCD3 bispecific antibody.

[0316] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 3000 μg / kg every two weeks (Q2W) and a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 800 μg / kg every two weeks (Q2W).

[0317] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg every two weeks (Q2W) and a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 800 μg / kg every two weeks (Q2W).

[0318] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg weekly (QW) and a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 800 μg / kg weekly (QW).

[0319] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg weekly (QW) and a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 400 μg / kg weekly (QW).

[0320] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg weekly (QW) and a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 200 μg / kg weekly (QW).

[0321] In certain embodiments, the method includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 750 μg / kg weekly (QW) and a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 200 μg / kg weekly (QW).

[0322] In certain embodiments, the method includes subcutaneously administering one or more escalating doses of a BCMAxCD3 bispecific antibody before subcutaneously administering a therapeutic dose, and subcutaneously administering one or more escalating doses of a GPRC5DxCD3 bispecific antibody before subcutaneously administering a therapeutic dose.

[0323] In certain embodiments, the method includes subcutaneously administering two or three escalating doses of a BCMAxCD3 bispecific antibody before subcutaneously administering a therapeutic dose, and subcutaneously administering two or three escalating doses of a GPRC5DxCD3 bispecific antibody before subcutaneously administering a therapeutic dose.

[0324] In certain embodiments, the method includes subcutaneously administering a BCMAxCD3 bispecific antibody in progressively increasing doses of 60 μg / kg and 300 μg / kg before subcutaneously administering a therapeutic dose, and subcutaneously administering a GPRC5DxCD3 bispecific antibody in progressively increasing doses of 10 μg / kg and 60 μg / kg before subcutaneously administering a therapeutic dose.

[0325] In certain embodiments, the method includes subcutaneously administering a BCMAxCD3 bispecific antibody in gradually increasing doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg before subcutaneously administering a therapeutic dose, and subcutaneously administering a GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg, and 300 μg / kg before subcutaneously administering a therapeutic dose.

[0326] In certain embodiments, the method includes subcutaneously administering a BCMAxCD3 bispecific antibody in gradually increasing doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg before subcutaneously administering a therapeutic dose, and subcutaneously administering a GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneously administering a therapeutic dose.

[0327] In certain embodiments, the escalating doses of the BCMAxCD3 bispecific antibody are administered with a 2-4 day interval between doses, and the escalating doses of the GPRC5DxCD3 bispecific antibody are administered with a 2-4 day interval between doses.

[0328] In a particular embodiment, the method is The first escalating dose of BCMAxCD3 bispecific antibody at 60 μg / kg is administered subcutaneously, followed 2-4 days later by a second escalating dose of BCMAxCD3 bispecific antibody at 300 μg / kg, followed 2-4 days later by a third escalating dose of BCMAxCD3 bispecific antibody at 1500 μg / kg, followed 2-4 days later by a first therapeutic dose of BCMAxCD3 bispecific antibody at 3000 μg / kg. The first escalating dose of GPRC5DxCD3 bispecific antibody at 10 μg / kg is administered subcutaneously, followed 2-4 days later by a second escalating dose of GPRC5DxCD3 bispecific antibody at 60 μg / kg, followed 2-4 days later by a third escalating dose of GPRC5DxCD3 bispecific antibody at 400 μg / kg, followed 2-4 days later by a first therapeutic dose of GPRC5DxCD3 bispecific antibody at 800 μg / kg. The treatment then includes subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of 3000 μg / kg every two weeks (Q2W), and a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 800 μg / kg every two weeks (Q2W).

[0329] In certain embodiments, each therapeutic dose of BCMAxCD3 bispecific antibody is administered on the same day as each therapeutic dose of GPRC5DxCD3 bispecific antibody. In certain embodiments, each therapeutic dose of BCMAxCD3 bispecific antibody is administered on the same day as each therapeutic dose of GPRC5DxCD3 bispecific antibody, separated by at least 15 minutes from each other, for example, by about 30 (±10) minutes.

[0330] In certain embodiments, each escalating dose of BCMAxCD3 bispecific antibody is administered on the same day as each escalating dose of GPRC5DxCD3 bispecific antibody. In certain embodiments, each escalating dose of BCMAxCD3 bispecific antibody is administered on the same day as each escalating dose of GPRC5DxCD3 bispecific antibody, separated by at least 15 minutes from each other, for example, by about 30 (±10) minutes from each other.

[0331] In a particular embodiment, a first therapeutic dose of BCMAxCD3 bispecific antibody and a first therapeutic dose of GPRC5DxCD3 bispecific antibody are administered subcutaneously on day 1 of cycle 1 of a 28-day cycle, and in Q2W, for example on day 1 and day 15 (±3 days) of each 28-day cycle, a subsequent therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously at a dose of 800 μg / kg, and in Q2W, for example on day 1 and day 15 (±3 days) of a 28-day cycle, a subsequent therapeutic dose of BCMAxCD3 bispecific antibody is administered subcutaneously at a dose of 3000 μg / kg.

[0332] In certain embodiments, the method includes subcutaneous administration of BCMAxCD3 bispecific antibody in escalating doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg before subcutaneous administration of a first therapeutic dose, and subcutaneous administration of GPRC5DxCD3 bispecific antibody in escalating doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneous administration of a first therapeutic dose, wherein the first therapeutic dose is administered 2 to 4 days after the administration of the final escalating dose of each bispecific antibody.

[0333] In a particular embodiment, the method is Before subcutaneously administering the first therapeutic dose of BCMAxCD3 bispecific antibody, BCMAxCD3 bispecific antibody should be subcutaneously administered in gradually increasing doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg. The procedure includes subcutaneous administration of GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneous administration of the first therapeutic dose of GPRC5DxCD3 bispecific antibody, The first therapeutic dose of BCMAxCD3 bispecific antibody and the first therapeutic dose of GPRC5DxCD3 bispecific antibody are administered subcutaneously on day 1 of cycle 1 of a 28-day cycle. During Q2W, for example, on day 1 and day 15 (±3 days) of each 28-day cycle, a subsequent therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously at a dose of 800 μg / kg. During Q2W, for example, on day 1 and day 15 (±3 days) of a 28-day cycle, a subsequent therapeutic dose of BCMAxCD3 bispecific antibody is administered subcutaneously at a dose of 3000 μg / kg.

[0334] In a particular embodiment, the method is The first escalating dose of BCMAxCD3 bispecific antibody at 60 μg / kg is administered subcutaneously, followed 2-4 days later by a second escalating dose of BCMAxCD3 bispecific antibody at 300 μg / kg, followed 2-4 days later by a third escalating dose of BCMAxCD3 bispecific antibody at 1500 μg / kg, followed 2-4 days later by the first therapeutic dose of BCMAxCD3 bispecific antibody. The treatment involves subcutaneously administering a first escalating dose of 10 μg / kg of GPRC5DxCD3 bispecific antibody, followed 2-4 days later by subcutaneously administering a second escalating dose of 60 μg / kg of GPRC5DxCD3 bispecific antibody, followed 2-4 days later by subcutaneously administering a third escalating dose of 400 μg / kg of GPRC5DxCD3 bispecific antibody, followed 2-4 days later by subcutaneously administering the first therapeutic dose of GPRC5DxCD3 bispecific antibody. The first therapeutic dose of BCMAxCD3 bispecific antibody and the first therapeutic dose of GPRC5DxCD3 bispecific antibody are administered subcutaneously on day 1 of cycle 1 of a 28-day cycle. During Q2W, for example, on day 1 and day 15 (±3 days) of each 28-day cycle, a subsequent therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously at a dose of 800 μg / kg. During Q2W, for example, on day 1 and day 15 (±3 days) of a 28-day cycle, a subsequent therapeutic dose of BCMAxCD3 bispecific antibody is administered subcutaneously at a dose of 3000 μg / kg.

[0335] In a particular embodiment, the method is Before subcutaneously administering the first therapeutic dose of BCMAxCD3 bispecific antibody, BCMAxCD3 bispecific antibody should be subcutaneously administered in gradually increasing doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg. The procedure includes subcutaneous administration of GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg, and 300 μg / kg before subcutaneous administration of the first therapeutic dose of GPRC5DxCD3 bispecific antibody, The first therapeutic dose of BCMAxCD3 bispecific antibody and the first therapeutic dose of GPRC5DxCD3 bispecific antibody are administered subcutaneously on day 1 of cycle 1 of a 28-day cycle. During Q2W, for example, on day 1 and day 15 (±3 days) of each 28-day cycle, a subsequent therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously at a dose of 800 μg / kg. During Q2W, for example, on day 1 and day 15 (±3 days) of a 28-day cycle, a subsequent therapeutic dose of BCMAxCD3 bispecific antibody is administered subcutaneously at a dose of 3000 μg / kg.

[0336] In a particular embodiment, the method is The first escalating dose of BCMAxCD3 bispecific antibody at 60 μg / kg is administered subcutaneously, followed 2-4 days later by a second escalating dose of BCMAxCD3 bispecific antibody at 300 μg / kg, followed 2-4 days later by a third escalating dose of BCMAxCD3 bispecific antibody at 1500 μg / kg, followed 2-4 days later by the first therapeutic dose of BCMAxCD3 bispecific antibody. The treatment involves subcutaneously administering a first escalating dose of 10 μg / kg of GPRC5DxCD3 bispecific antibody, followed 2-4 days later by subcutaneous administration of a second escalating dose of 60 μg / kg of GPRC5DxCD3 bispecific antibody, followed 2-4 days later by subcutaneous administration of a third escalating dose of 300 μg / kg of GPRC5DxCD3 bispecific antibody, followed 2-4 days later by subcutaneous administration of the first therapeutic dose of GPRC5DxCD3 bispecific antibody. The first therapeutic dose of BCMAxCD3 bispecific antibody and the first therapeutic dose of GPRC5DxCD3 bispecific antibody are administered subcutaneously on day 1 of cycle 1 of a 28-day cycle. During Q2W, for example, on day 1 and day 15 (±3 days) of each 28-day cycle, a subsequent therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously at a dose of 800 μg / kg. During Q2W, for example, on day 1 and day 15 (±3 days) of a 28-day cycle, a subsequent therapeutic dose of BCMAxCD3 bispecific antibody is administered subcutaneously at a dose of 3000 μg / kg.

[0337] In certain embodiments, the combination therapy includes a series of 28-day treatment cycles. Administration of the GPRC5DxCD3 bispecific antibody is initiated in cycle 1, and administration of the BCMAxCD3 bispecific antibody is initiated in cycle 1. According to certain embodiments, the subject is administered the GPRC5DxCD3 bispecific antibody and the BCMAxCD3 bispecific antibody over a finite number of treatment cycles. For example, if the subject does not have a progressive disease or signs of toxicity, the bispecific antibodies may be administered for up to 26 cycles.

[0338] The inventors developed a combined dosing regimen for the administration of Tal and Tec based on several considerations, including, for example: 1) the ease and convenience of SC administration compared to IV administration; 2) PK data showing a selected therapeutic dose that achieved the desired target exposure; 3) pharmacodynamic data showing T cell activation and redistribution; 4) a favorable clinical safety profile that appears to be comparable to that observed in lower SC dosing cohorts; 5) a favorable efficacy profile of the selected SC dose; and 6) the clinical outcomes of tecristamag in the RedirecTT-1 trial.

[0339] Partially supporting data for the talketamab-teclistamai combination in participants with relapsed and refractory multiple myeloma comes from the Phase 1 dose-escalation trial 64007957MMY1003 (RedirecTT-1). The RedirecTT-1 trial evaluated different dose combinations of talketamab and teclistamai. Preliminary data from RedirecTT-1 show that 0.8 mg / kg Q2W of talketamab and 3 mg / kg Q4W of teclistamai provides stable clinical efficacy with a manageable safety profile. Other dosing regimens, e.g., weekly administration of both bispecific antibodies, did not receive very good tolerance. An exploratory ER analysis of the RedirecTT-1 trial showed that The study showed a trend toward improved depth of response associated with Q2W talketamab administration in the initial treatment cycle. Reducing the frequency of talketamab administration after response may improve GPRC5D-specific adverse events without compromising efficacy. Monthly administration of 3 mg / kg teclistamag in cycle 2 is estimated to achieve equivalent exposure to 1.5 mg / kg Q2W, based on data from the 64007957MMY1001 (MajesTEC-1) and RedirecTT-1 trials. Furthermore, tolerance may improve with lower dose frequencies while maintaining response.

[0340] Data from trial 64407564MMY1001 showed the median time to first response at 1.2 months and the median time to best response at 2.2 months for participants treated with 0.8 mg / kg SC Q2W talketamab. The median concentration-time profile exposure after Q4W administration was estimated to be ≥EC90 as identified in the ex vivo cytotoxicity assay, which is estimated to be sufficient to maintain efficacy in the low tumor load setting. Therefore, in certain embodiments, talketamab administration is continued at Q4W intervals from cycle 7 onward (as early as cycle 5 for participants confirmed to have VGPR or higher) to reduce exposure while maintaining efficacy and improving participant convenience.

[0341] In certain embodiments, the method includes initial administration of therapeutic doses of BCMAxCD3 bispecific and GPRC5DxCD3 bispecific antibodies on a bi-weekly (Q2W) dosing schedule, followed by a switch from bi-weekly to monthly (Q4W) dosing. In certain embodiments, the switch from bi-weekly to monthly dosing is performed after the subject has achieved a response of VGPR or better and has received at least four cycles of therapy. In certain embodiments, the switch from bi-weekly to monthly dosing is performed after the subject has achieved a response of PR or better and has received at least four cycles of therapy. In certain embodiments, the switch from bi-weekly to monthly dosing is performed after the subject has completed six cycles of therapy, regardless of clinical response.

[0342] In certain embodiments, the therapeutic dose of 0.8 mg / kg of talketamab is administered after the escalation period as follows: every other week (Q2W) from cycles 2-4. After cycle 5 (C5), if a VGPR or better is confirmed, the schedule may be changed to Q4W, and the change to Q4W is made on day 1 (±3 days) of cycle 5 or cycle 6. If a PR or better is confirmed on day 1 (±3 days) of cycle 7, the schedule must be changed to Q4W administration. If a PR or better is not confirmed on day 1 (±3 days) of cycle 7, Q2W administration is continued until a PR or better is confirmed. In certain embodiments, the therapeutic dose of 3 mg / kg of teclistamagab is administered Q4W from cycle 2 after the escalation period. In certain embodiments, subjects receive a combination regimen including teclistamag and talketamab for 26 treatment cycles (approximately 24 months).

[0343] In certain embodiments, talketamab and tecristamag are administered in a 28-day treatment cycle as follows: -In Cycle 1, the following doses of talketamab will be administered subcutaneously. ○First dose escalation of tarketamab (SU1): 0.01 mg / kg, administered on day 1. ○Second dose escalation of talketamab (SU2): 0.06 mg / kg, administered ≥2 days after SU1, on days 3-6. ○Talketamab therapeutic dose (sometimes called the third dose escalation): 0.4 mg / kg, administered ≥2 days after SU2, on days 5-10. ○Talketamab therapeutic dose: Administered ≥2 days after the first therapeutic dose (third dose escalation) of 0.8 mg / kg or 0.4 mg / kg, on days 7-15. -In subsequent treatment cycles following Cycle 1, administer a therapeutic dose of 0.8 mg / kg of talketamab subcutaneously as follows: ○In cycles 2 to 4 (C2 to C4), talketamab SC is administered every other week (Q2W), i.e., 14 days (±3 days) after the previous therapeutic dose. ○If a VGPR or better result is confirmed from cycle 5 (C5), the schedule can be changed to Q4W administration (only on day 1 of each 28-day cycle). Regardless of clinical response, cycle 7 (C7) to Q4W. -In Cycle 1, the following doses of teclistamag are administered subcutaneously. ○First dose escalation of Tec (SU1): 0.06 mg / kg, administered on day 1. ○Second dose escalation of Tec (SU2): 0.3 mg / kg, administered ≥2 days after SU1, on days 3-6. ○Tec therapeutic dose (sometimes called the third dose escalation): 1.5 mg / kg, administered ≥2 days after SU2, on days 5-10. ○Tec therapeutic dose: Administer ≥2 days after the first therapeutic dose (third dose escalation) of 3.0 mg / kg or 1.5 mg / kg, on days 7-15. -In subsequent treatment cycles following Cycle 1, administer a therapeutic dose of 3.0 mg / kg of Tec subcutaneously as follows: ○In cycle 2, Tec is administered 14 days (±3 days) after the previous therapeutic dose. ○If a partial response (PR) or better is confirmed from cycle 3 (C3), the schedule can be changed to Q4W administration (only on day 1 of each 28-day cycle). Regardless of clinical response, cycle 7 (C7) to Q4W.

[0344] In certain embodiments, subjects are administered talketamab SC in escalating doses as follows:

[0345] Starting in Cycle 2, the treatment regimen is administered in combination with teclistamag, which is given in escalating doses of 0.01 and 0.06 mg / kg, then 0.4 mg / kg, followed by 0.8 mg / kg SC Q2W, followed by two doses of 1.5 mg / kg, then 3 mg / kg Q4W. From Cycle 5, subjects who demonstrate a response of VGPR or better may switch to talketamab Q4W from Cycle 7, and participants who demonstrate a response of PR or better must switch to talketamab 0.8 mg / kg Q4W.

[0346] In certain embodiments, talketamab and tecristamag are administered in a 28-day treatment cycle as follows: -In Cycle 1, the following doses of talketamab will be administered subcutaneously. ○First dose escalation of tarketamab (SU1): 0.01 mg / kg, administered on day 1. ○Second dose escalation of talketamab (SU2): 0.06 mg / kg, administered ≥2 days after SU1. ○Talketamab therapeutic dose (sometimes called the third dose escalation): 0.4 mg / kg, administered ≥2 days after SU2. ○Talketamab therapeutic dose: Administered ≥2 days after the first therapeutic dose (third dose escalation) of 0.8 mg / kg or 0.4 mg / kg, on days 7-15. -In subsequent treatment cycles following Cycle 1, administer a therapeutic dose of 0.8 mg / kg of talketamab subcutaneously as follows: ○In cycles 2 to 4 (C2 to C4), talketamab SC is administered every other week (Q2W), i.e., 14 days (±3 days) after the previous therapeutic dose. ○If VGPR or better is confirmed from Cycle 5 (C5), the schedule can be changed to Q4W administration (only on the first day of each 28-day cycle), and the change to Q4W will occur on the first day (±3 days) of Cycle 5 or Cycle 6. ○If a partial response (PR) or better is confirmed on day 1 (±3 days) of cycle 7, the schedule must be changed to Q4W administration. ○If a partial response (PR) or better is not confirmed on day 1 (±3 days) of cycle 7, Q2W administration will be continued until a PR or better is confirmed. -In Cycle 1, the following doses of teclistamag are administered subcutaneously. ○First dose escalation of Tec (SU1): 0.06 mg / kg, administered on day 1. ○Second dose escalation of Tec (SU2): 0.3 mg / kg, administered ≥ 2 days after SU1. ○Tec therapeutic dose (sometimes called the third dose escalation): 1.5 mg / kg, administered ≥ 2 days after SU2. ○Tec therapeutic dose: 1.5 mg / kg, administered ≥ 2 days after the first therapeutic dose (third dose escalation) of 1.5 mg / kg, on days 7-15. -In subsequent treatment cycles following Cycle 1, administer a therapeutic dose of 3.0 mg / kg of Tec subcutaneously as follows: ○ Starting from cycle 2 (C2), administer Q4W (on day 1 only), regardless of clinical response.

[0347] In certain embodiments, the subjects have previously received 1 to 4 treatment lines including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, and the method is as follows: This includes treating the subject according to a therapeutically effective regimen that includes a continuous 28-day treatment cycle. cycle During the dose escalation phase of step 1, the patient was subcutaneously administered doses of GPRC5DxCD3 bispecific antibody (e.g., talketamab) and BCMAxCD3 bispecific antibody (e.g., teclistamaib), and then, Therapeutic doses of BCMAxCD3 bispecific antibodies are administered subcutaneously to subjects at a dose of 3.0 mg / kg each, starting from treatment cycle 2 on a monthly dosing schedule (Q4W), regardless of the clinical response in the subjects. The therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 0.8 mg / kg on a bi-weekly dosing schedule (Q2W) starting from treatment cycle 2 (e.g., on day 1 and day 15), and then the therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 5 if (i) the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) the subject achieves a partial response, very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (iii) the subject achieves a partial response, very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, at any time after treatment cycle 7.

[0348] In certain embodiments, a method for improving the median progression-free survival (PFS) in a target population with relapsed or refractory multiple myeloma who has previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide comprises administering a combination therapy to the target population comprising a therapeutically effective dose of a GPRC5DxCD3 bispecific antibody (e.g., talketamab) and a therapeutically effective dose of a BCMAxCD3 bispecific antibody (e.g., tecristamag), wherein the method This includes treating the subject according to a therapeutically effective regimen that includes a continuous 28-day treatment cycle. During the escalation phase of Cycle 1, the patient was subcutaneously administered escalating doses of a GPRC5DxCD3 bispecific antibody (e.g., talketamab) and a BCMAxCD3 bispecific antibody (e.g., teclistamaib), and then, Therapeutic doses of BCMAxCD3 bispecific antibodies are administered subcutaneously to subjects at a dose of 3.0 mg / kg each, starting from treatment cycle 2 on a monthly dosing schedule (Q4W), regardless of the clinical response in the subjects. The therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 0.8 mg / kg on a bi-weekly dosing schedule (Q2W) starting from treatment cycle 2 (e.g., on day 1 and day 15). Subsequently, the therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 5 if (i) the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or starting in treatment cycle 7 if the subject achieves a partial response, very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (iii) if a partial response, very good partial response, complete response, or exact complete response is achieved as determined by the IMWG response criteria, anytime after treatment cycle 7.

[0349] Improvement in median PFS is compared to the median PFS of a reference population of patients with relapsed or refractory multiple myeloma who had previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, and who received either (i) elotuzumab, pomalidomide, and dexamethasone (EPd) or (ii) pomalidomide, bortezomib, and dexamethasone (PVd).

[0350] In certain embodiments, a method for improving the overall response rate (ORR) in a target population with relapsed or refractory multiple myeloma who has previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide comprises administering a combination therapy to the target population comprising a therapeutically effective dose of a GPRC5DxCD3 bispecific antibody (e.g., talketamab) and a therapeutically effective dose of a BCMAxCD3 bispecific antibody (e.g., tecristamag), the method being: This includes treating the subject according to a therapeutically effective regimen that includes a continuous 28-day treatment cycle. During the escalation phase of Cycle 1, the patient was subcutaneously administered escalating doses of a GPRC5DxCD3 bispecific antibody (e.g., talketamab) and a BCMAxCD3 bispecific antibody (e.g., teclistamaib), and then, Therapeutic doses of BCMAxCD3 bispecific antibodies are administered subcutaneously to subjects at a dose of 3.0 mg / kg each, starting from treatment cycle 2 on a monthly dosing schedule (Q4W), regardless of the clinical response in the subjects. The therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 0.8 mg / kg on a bi-weekly dosing schedule (Q2W) starting from treatment cycle 2 (e.g., on day 1 and day 15). Subsequently, the therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 5 if (i) the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or starting in treatment cycle 7 if the subject achieves a partial response, very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (iii) if a partial response, very good partial response, complete response, or exact complete response is achieved as determined by the IMWG response criteria, anytime after treatment cycle 7.

[0351] Improvement in ORR is compared to the ORR of a reference population of subjects with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, and who have received either (i) elotuzumab, pomalidomide, and dexamethasone (EPd) or (ii) pomalidomide, bortezomib, and dexamethasone (PVd).

[0352] In certain embodiments, the dose escalation phase includes subcutaneous administration of 0.01 mg / kg and 0.06 mg / kg doses of GPRC5DxCD3 bispecific antibody, spaced 2 to 4 days apart from each other (for example, on day 1 and day 4, respectively). In certain embodiments, the dose escalation phase includes subcutaneous administration of 0.01 mg / kg, 0.06 mg / kg and 0.4 mg / kg doses of GPRC5DxCD3 bispecific antibody, spaced 2 to 4 days apart from each other (for example, on day 1, day 4 and day 8, respectively). In certain embodiments, the dose escalation phase includes subcutaneous administration of escalating doses of 0.01 mg / kg, 0.06 mg / kg, and 0.4 mg / kg of GPRC5DxCD3 bispecific antibody, spaced 2 to 4 days apart (for example, on days 1, 4, and 8, respectively), followed by subcutaneous administration of a therapeutic dose of 0.8 mg / kg of GPRC5DxCD3 bispecific antibody at least 2 days after the 0.4 mg / kg dose (for example, on days 7 to 15, e.g., on day 15).

[0353] In certain embodiments, the dose escalation phase includes subcutaneous administration of 0.06 mg / kg and 0.3 mg / kg doses of BCMAxCD3 bispecific antibody, spaced 2 to 4 days apart from each other (for example, on day 1 and day 4, respectively). In certain embodiments, the dose escalation phase includes subcutaneous administration of 0.06 mg / kg, 0.3 mg / kg and 1.5 mg / kg doses of BCMAxCD3 bispecific antibody, spaced 2 to 4 days apart from each other (for example, on day 1, day 4 and day 8, respectively). In certain embodiments, the dose escalation period includes subcutaneous administration of 0.06 mg / kg, 0.3 mg / kg, and 1.5 mg / kg doses of BCMAxCD3 bispecific antibody at intervals of 2 to 4 days from each other (for example, on days 1, 4, and 8, respectively), followed by subcutaneous administration of a 1.5 mg / kg dose of BCMAxCD3 bispecific antibody at least 2 days after the 1.5 mg / kg dose escalation (for example, on days 7 to 15, e.g., on day 15).

[0354] In certain embodiments, the GPRC5DxCD3 bispecific antibody (e.g., talketamab) and the BCMAxCD3 bispecific antibody (e.g., teclistamaib) are administered at least 15 minutes apart from each other on each day the doses are administered (e.g., the GPRC5DxCD3 bispecific antibody is administered first).

[0355] In certain embodiments, the combination regimen has a finite period of 26 treatment cycles.

[0356] In an alternative embodiment, the method includes the following:

[0357] Subcutaneous administration of escalating doses of BCMAxCD3 bispecific antibody (e.g., teclista mab) and GPRC5DxCD3 bispecific antibody (e.g., talketamab) is performed, followed by, Therapeutic doses of 3000 μg / kg of BCMAxCD3 bispecific antibody and 800 μg / kg of GPRC5DxCD3 bispecific antibody are administered subcutaneously at least four 28-day cycles every other week (Q2W) (e.g., on day 1 and day 15 (±3 days) of each cycle). (i) If the subject achieves a response of VGPR or better and has received at least four 28-day cycles of treatment (e.g., starting at cycle 5), administer a therapeutic dose of 3000 μg / kg of BCMAxCD3 bispecific antibody and 800 μg / kg of GPRC5DxCD3 bispecific antibody subcutaneously every month (Q4W) (e.g., on day 1 of each 28-day cycle), or (ii) After the subject has completed six 28-day treatment cycles (e.g., starting at cycle 7), regardless of the clinical response in the subject, administer a therapeutic dose of 3000 μg / kg of BCMAxCD3 bispecific antibody and 800 μg / kg of GPRC5DxCD3 bispecific antibody subcutaneously every month (Q4W) (e.g., on day 1 of each 28-day cycle).

[0358] In certain embodiments, doses of teclistamaib and talketamab are administered on the same day, separated by at least 15 minutes. In certain embodiments, doses of teclistamaib and talketamab are administered approximately 20 to 40 minutes apart, for example, within approximately 30 minutes of each other. In certain embodiments, teclistamaib is administered before talketamab, for example, at least 15 minutes before talketamab, or approximately 30 minutes before talketamab. In other embodiments, talketamab is administered before teclistamai, for example, at least 15 minutes before teclistamai, or approximately 30 minutes before teclistamai.

[0359] In certain embodiments, the method achieves partial response, very good partial response, complete response, or exact complete response in the subject, as determined by the IMWG response criteria.

[0360] In certain embodiments, the method achieves an overall response rate of at least 50% in a population of subjects with relapsed or refractory multiple myeloma (RRMM), for example, in subjects with EMD.

[0361] In certain embodiments, the method achieves an overall response rate of at least 55% in a population of subjects with relapsed or refractory multiple myeloma (RRMM), for example, in subjects with EMD.

[0362] In certain embodiments, the method achieves an overall response rate of at least 60% in a population of subjects with relapsed or refractory multiple myeloma (RRMM), for example, in subjects with EMD.

[0363] In certain embodiments, the method achieves an overall response rate of at least 65% in a population of subjects with relapsed or refractory multiple myeloma (RRMM), for example, in subjects with EMD.

[0364] In certain embodiments, the method achieves an overall response rate of at least 70% in a population of subjects with relapsed or refractory multiple myeloma (RRMM), for example, in subjects with EMD.

[0365] In a particular embodiment, the method achieves an overall response rate of at least 80% in a population of subjects having RRMM, for example, subjects having EMD.

[0366] In a particular embodiment, the method achieves an overall response rate of at least 85% in a population of subjects having RRMM, for example, subjects having EMD.

[0367] In certain embodiments, the method achieves an overall response rate of at least 90% in a population of subjects having RRMM.

[0368] In certain embodiments, the method achieves an overall response rate of at least 95% in a population of subjects having RRMM.

[0369] In certain embodiments, the method achieves at least a 20% complete response or a strict complete response rate in a population of subjects having RRMM, for example, subjects having EMD.

[0370] In certain embodiments, the method achieves at least a 25% complete response or a strict complete response rate in a population of subjects having RRMM, for example, subjects having EMD.

[0371] In certain embodiments, the method achieves at least 30% complete response or a strict complete response rate in a population of subjects having RRMM, for example, subjects having EMD.

[0372] In certain embodiments, the method achieves at least a 35% complete response or a strict complete response rate in a population of subjects having RRMM, for example, subjects having EMD.

[0373] In certain embodiments, the method achieves at least 40% complete response or a strict complete response rate in a population of subjects having RRMM, for example, subjects having EMD.

[0374] In a particular embodiment, the subject has previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, and the method comprises treating the subject according to a therapeutically effective regimen comprising consecutive 28-day treatment cycles, wherein one or more escalating doses of a GPRC5DxCD3 bispecific antibody (e.g., talketamab) are subcutaneously administered to the subject during the escalation phase of cycle 1, and then each therapeutic dose of the GPRC5DxCD3 bispecific antibody is subcutaneously administered to the subject at an amount of 0.8 mg / kg. The therapeutic dose of the bispecific antibody is administered to the subject on a bi-weekly schedule (Q2W) starting in treatment cycle 2 (e.g., days 1 and 15), and then the therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a monthly schedule (Q4W), either (i) starting in treatment cycle 5 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in treatment cycle 7 regardless of the clinical response in the subject.

[0375] In certain embodiments, one or more escalating doses of a BCMAxCD3 bispecific antibody (e.g., teclistamaib) are administered subcutaneously to the subject during the escalation phase of cycle 1, with each therapeutic dose of BCMAxCD3 bispecific antibody being administered subcutaneously to the subject at a dose of 3.0 mg / kg, and the therapeutic dose of BCMAxCD3 bispecific antibody being administered to the subject on a bi-weekly schedule (Q2W) starting from treatment cycle 2 (e.g., on days 1 and 15), and then the therapeutic dose of BCMAxCD3 bispecific antibody being administered subcutaneously to the subject on a monthly schedule (Q4W), either (i) starting in treatment cycle 3 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in treatment cycle 7 regardless of the clinical response in the subject.

[0376] In certain embodiments, a method to improve the median progression-free survival (PFS) in a target population with relapsed or refractory multiple myeloma who has previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide is to administer a combination therapy to the target population comprising a therapeutically effective dose of a GPRC5DxCD3 bispecific antibody (e.g., talketamab) and a therapeutically effective dose of a BCMAxCD3 bispecific antibody (e.g., tecristamag). Including the above, the improvement in median PFS is compared to the median PFS of a reference population of subjects with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, and who have received either (i) elotuzumab, pomalidomide, and dexamethasone (EPd) or (ii) pomalidomide, bortezomib, and dexamethasone (PVd). According to a particular embodiment, the method comprises treating a subject according to a therapeutically effective regimen comprising a 28-day consecutive treatment cycle, wherein one or more escalating doses of GPRC5DxCD3 bispecific antibody are subcutaneously administered to the subject during the escalation phase of cycle 1, and each therapeutic dose of GPRC5DxCD3 bispecific antibody is then subcutaneously administered to the subject at a dose of 0.8 mg / kg, and the therapeutic dose of GPRC5DxCD3 bispecific antibody is administered to the subject on a bi-weekly dosing schedule (Q2W) starting from treatment cycle 2 (e.g., on days 1 and 15), and then the therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a monthly dosing schedule (Q4W), either (i) starting in treatment cycle 5 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in treatment cycle 7 regardless of the clinical response in the subject.One or more escalating doses of a BCMAxCD3 bispecific antibody (e.g., teclistamaib) are administered subcutaneously to the subject during the escalation phase of Cycle 1, with each therapeutic dose of BCMAxCD3 bispecific antibody being administered subcutaneously at a dose of 3.0 mg / kg, and the therapeutic dose of BCMAxCD3 bispecific antibody being administered to the subject on a bi-weekly schedule (Q2W) starting from Cycle 2 (e.g., on days 1 and 15), and then the therapeutic dose of BCMAxCD3 bispecific antibody being administered subcutaneously on a monthly schedule (Q4W), either (i) starting in Cycle 3 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in Cycle 7 regardless of the clinical response in the subject.

[0377] In certain embodiments, a method for improving the ORR in a population of subjects with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide comprises administering to the population a combination therapy comprising a therapeutically effective dose of a GPRC5DxCD3 bispecific antibody (e.g., talketamab) and a therapeutically effective dose of a BCMAxCD3 bispecific antibody (e.g., tecrista-mab), wherein the improvement in ORR is compared to the ORR of a reference population of subjects with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, and the reference population is administered either (i) elotuzumab, pomalidomide, and dexamethasone (EPd), or (ii) pomalidomide, bortezomib, and dexamethasone (PVd). According to a particular embodiment, the method comprises treating a subject according to a therapeutically effective regimen comprising a 28-day consecutive treatment cycle, wherein one or more escalating doses of GPRC5DxCD3 bispecific antibody are subcutaneously administered to the subject during the escalation phase of cycle 1, and each therapeutic dose of GPRC5DxCD3 bispecific antibody is then subcutaneously administered to the subject at a dose of 0.8 mg / kg, and the therapeutic dose of GPRC5DxCD3 bispecific antibody is administered to the subject on a bi-weekly dosing schedule (Q2W) starting from treatment cycle 2 (e.g., on days 1 and 15), and then the therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a monthly dosing schedule (Q4W), either (i) starting in treatment cycle 5 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in treatment cycle 7 regardless of the clinical response in the subject.One or more escalating doses of a BCMAxCD3 bispecific antibody (e.g., teclistamaib) are administered subcutaneously to the subject during the escalation phase of Cycle 1, with each therapeutic dose of BCMAxCD3 bispecific antibody being administered subcutaneously at a dose of 3.0 mg / kg, and the therapeutic dose of BCMAxCD3 bispecific antibody being administered to the subject on a bi-weekly schedule (Q2W) starting from Cycle 2 (e.g., on days 1 and 15), and then the therapeutic dose of BCMAxCD3 bispecific antibody being administered subcutaneously on a monthly schedule (Q4W), either (i) starting in Cycle 3 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in Cycle 7 regardless of the clinical response in the subject.

[0378] 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 appended to this disclosure or this specification.

[0379] 1A. A method for treating multiple myeloma in a patient requiring treatment for multiple myeloma, comprising administering a combination regimen to the patient comprising a therapeutically effective dose of a BCMAxCD3 bispecific antibody (e.g., tecristamag) and a therapeutically effective dose of a GPRC5DxCD3 bispecific antibody (e.g., talketamab), wherein the patient has relapsed or refractory multiple myeloma and has previously received at least three lines of treatment comprising proteasome inhibitors, immunomodulators and anti-CD38 monoclonal antibodies.

[0380] 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.

[0381] 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.

[0382] 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.

[0383] 5A. The method according to any one of Embodiments 1A to 4A, wherein the BCMAxCD3 bispecific antibody is tecristamag.

[0384] 6A. The method according to any one of Embodiments 1A to 5A, wherein the GPRC5D × CD3 bispecific antibody comprises a GPRC5D binding domain including HCDR1 of SEQ ID NO: 24, HCDR2 of SEQ ID NO: 25, HCDR3 of SEQ ID NO: 26, LCDR1 of SEQ ID NO: 27, LCDR2 of SEQ ID NO: 28, and LCDR3 of SEQ ID NO: 29, 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.

[0385] The method according to Embodiment 6A, wherein the GPRC5D binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 30 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 31, 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.

[0386] The method according to any one of Embodiments 1A to 7A, wherein the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 32, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 33, 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.

[0387] 9A. The method according to any one of Embodiments 1A to 8A, wherein the GPRC5D×CD3 bispecific antibody is talketamab.

[0388] 10A. The method according to any one of Embodiments 1A to 9A, wherein the subject has an extramedullary disease (EMD).

[0389] 11A. The method according to any one of Embodiments 1A to 9A, wherein the method achieves an overall response rate of at least about 80% in subjects having EMD.

[0390] 12A. The method according to any one of Embodiments 1A to 9A, wherein the method achieves an overall response rate of at least about 90%.

[0391] 13A. The method according to any one of Embodiments 1A to 12A, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 3000 μg / kg every two weeks (Q2W) and subcutaneously administering a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 800 μg / kg every two weeks (Q2W).

[0392] 14A. The method according to any one of Embodiments 1A to 12A, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg every two weeks (Q2W) and subcutaneously administering a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 800 μg / kg every two weeks (Q2W).

[0393] 15A. The method according to any one of Embodiments 1A to 12A, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg weekly (QW) and a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 800 μg / kg every two weeks (Q2W).

[0394] 16A. The method according to any one of Embodiments 1A to 12A, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg weekly (QW) and a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 400 μg / kg weekly (QW).

[0395] 17A. The method according to any one of Embodiments 13A to 16A, comprising subcutaneously administering one or more escalating doses of a BCMAxCD3 bispecific antibody before subcutaneously administering a therapeutic dose, and subcutaneously administering one or more escalating doses of a GPRC5DxCD3 bispecific antibody before subcutaneously administering a therapeutic dose.

[0396] 18A. The method according to any one of Embodiments 13A to 16A, comprising subcutaneously administering two to three escalating doses of a BCMAxCD3 bispecific antibody before subcutaneously administering a therapeutic dose, and subcutaneously administering two to three escalating doses of a GPRC5DxCD3 bispecific antibody before subcutaneously administering a therapeutic dose.

[0397] 19A. The method according to any one of Embodiments 13A to 16A, comprising subcutaneously administering a BCMAxCD3 bispecific antibody in gradually increasing doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg before subcutaneously administering a therapeutic dose, and subcutaneously administering a GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg, and 300 μg / kg before subcutaneously administering a therapeutic dose.

[0398] 20A. The method according to any one of Embodiments 13A to 16A, comprising subcutaneously administering a BCMAxCD3 bispecific antibody in gradually increasing doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg before subcutaneously administering a therapeutic dose, and subcutaneously administering a GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneously administering a therapeutic dose.

[0399] 21A. The method according to any one of Embodiments 17A to 20A, wherein the gradually increasing dose is administered at intervals of 2 to 4 days.

[0400] 22A. The method according to any one of Embodiments 13A to 21A, wherein each therapeutic dose of the BCMAxCD3 bispecific antibody is administered on the same day as each therapeutic dose of the GPRC5DxCD3 bispecific antibody.

[0401] 23A. A combination regimen for the treatment of patients with relapsed or refractory multiple myeloma, comprising the administration of a BCMAxCD3 bispecific antibody (e.g., teclista mab) and a GPRC5DxCD3 bispecific antibody (e.g., talketamab) in amounts effective to achieve an overall response rate of at least about 80%.

[0402] 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.

[0403] 1. A method for treating multiple myeloma in a patient requiring treatment for multiple myeloma, comprising administering a combination regimen containing a therapeutically effective amount of BCMAxCD3 bispecific antibody and a therapeutically effective amount of GPRC5DxCD3 bispecific antibody to the patient.

[0404] 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.

[0405] 3. The method according to Embodiment 1 or 2, wherein the BCMA × CD3 bispecific antibody comprises a BCMA-binding domain having 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 a CD3-binding domain having 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.

[0406] 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.

[0407] 5. The method according to any one of Embodiments 1 to 4, wherein the BCMA×CD3 bispecific antibody is of the IgG4 isotype.

[0408] 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.

[0409] 7. The method according to any one of Embodiments 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.

[0410] 8. The method according to any one of Embodiments 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.

[0411] 9. The method according to any one of Embodiments 1 to 8, wherein the Fc region of the BCMA-specific IgG4 antibody from which the BCMA-binding arm is derived includes S228P, L234A, and L235A substitutions in the Fc region.

[0412] 10. The method according to any one of Embodiments 1 to 9, wherein the Fc region of the CD3-specific IgG4 antibody from which the CD3 binding arm is derived includes S228P, L234A, L235A, F405L, and R409K substitutions in the Fc region.

[0413] 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.

[0414] 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.

[0415] 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.

[0416] 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.

[0417] 15. The method according to any one of Embodiments 1 to 10, wherein the BCMAxCD3 bispecific antibody is teclistamagb.

[0418] 16. The method according to any one of Embodiments 1 to 15, wherein the GPRC5D × CD3 bispecific antibody comprises a GPRC5D binding domain including HCDR1 of SEQ ID NO: 24, HCDR2 of SEQ ID NO: 25, HCDR3 of SEQ ID NO: 26, LCDR1 of SEQ ID NO: 27, LCDR2 of SEQ ID NO: 28, and LCDR3 of SEQ ID NO: 29, 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.

[0419] 17. The method according to any one of Embodiments 1 to 16, wherein the GPRC5D × CD3 bispecific antibody comprises a GPRC5D binding domain having a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 30 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 31, and a CD3 binding domain having 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.

[0420] 18. The method according to any one of Embodiments 1 to 17, wherein the GPRC5DxCD3 bispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0421] 19. The method according to any one of Embodiments 1 to 18, wherein the GPRC5DxCD3 bispecific antibody is of the IgG4 isotype.

[0422] 20. The method according to any one of Embodiments 1 to 19, wherein the GPRC5DxCD3 bispecific antibody comprises one or more substitutions in its Fc region.

[0423] 21. The method according to any one of Embodiments 1 to 20, wherein the GPRC5DxCD3 bispecific antibody is of the IgG4 isotype and comprises S228P, F234A and L235A substitutions in its Fc region.

[0424] 22. The method according to any one of Embodiments 1 to 21, wherein the GPRC5DxCD3 bispecific antibody is of the IgG4 isotype and comprises S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region.

[0425] 23. The method according to any one of Embodiments 1 to 22, wherein the Fc region of the GPRC5D-specific IgG4 antibody from which the GPRC5D-binding arm is derived includes S228P, L234A, and L235A substitutions in the Fc region.

[0426] 24. The method according to any one of Embodiments 1 to 23, wherein the Fc region of the CD3-specific IgG4 antibody from which the CD3 binding arm is derived includes S228P, L234A, L235A, F405L, and R409K substitutions in the Fc region.

[0427] 25. The method according to any one of Embodiments 1 to 24, wherein the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 32, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 33, 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.

[0428] 26. The method according to any one of Embodiments 1 to 24, wherein the GPRC5DxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 32, a first light chain (LC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 33, 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.

[0429] 27. The method according to any one of Embodiments 1 to 24, wherein the GPRC5DxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 32, a first light chain (LC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 33, 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.

[0430] 28. The method according to any one of Embodiments 1 to 24, wherein the GPRC5DxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 32, a first light chain (LC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 33, 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.

[0431] 29. The method according to any one of Embodiments 1 to 25, wherein the GPRC5D×CD3 bispecific antibody is talketamab.

[0432] 30. The method according to any one of Embodiments 1 to 29, wherein the subject has relapsed or refractory multiple myeloma (for example, the subject has been previously treated with 1 to 11 or 1 to 10 lines of treatment, and / or the subject has previously undergone autologous stem cell transplantation).

[0433] 31. The method according to any one of Embodiments 1 to 30, wherein the subject has previously received at least three lines of treatment.

[0434] 32. The method according to any one of Embodiments 1 to 30, wherein the subject has previously received at least four lines of treatment.

[0435] 33. The method according to any one of Embodiments 1 to 30, wherein the subject has previously received at least five lines of treatment (pentad exposure).

[0436] 34. Any method of Embodiments 1 to 30, wherein the subject has previously received at least three lines of treatment comprising a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody.

[0437] 35. Any method of Embodiments 1 to 30, wherein the subject has previously received at least four lines of treatment comprising a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody.

[0438] 36. The method according to any one of Embodiments 1 to 35, wherein the subject has an extramedullary disease (EMD).

[0439] 37. The method according to any one of Embodiments 1 to 36, comprising subcutaneously administering one or more escalating doses of BCMAxCD3 bispecific antibody to the target before administering a therapeutic dose of BCMAxCD3 bispecific antibody.

[0440] 38. The method according to any one of Embodiments 1 to 37, comprising subcutaneously administering a therapeutic dose of a BCMAxCD3 bispecific antibody to a subject weekly (QW).

[0441] 39. The method according to any one of Embodiments 1 to 37, comprising subcutaneously administering a therapeutic dose of a BCMAxCD3 bispecific antibody to a subject every two weeks (Q2W).

[0442] 40. The method according to any one of Embodiments 1 to 37, comprising subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 750 μg / kg to approximately 1500 μg / kg on a weekly (QW) basis.

[0443] 41. The method according to any one of Embodiments 1 to 37, comprising subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 750 μg / kg weekly (QW).

[0444] 42. The method according to any one of Embodiments 1 to 37, comprising subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg weekly (QW).

[0445] 43. The method according to any one of Embodiments 1 to 37 or 39, comprising subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg to approximately 3000 μg / kg every two weeks (Q2W).

[0446] 44. The method according to any one of Embodiments 1 to 37, 39, or 43, comprising subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg every two weeks (Q2W).

[0447] 45. The method according to any one of Embodiments 1 to 37, 39, or 43, comprising subcutaneous administration of a BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 3000 μg / kg every two weeks (Q2W).

[0448] 46. ​​The method according to any one of Embodiments 1 to 45, comprising subcutaneously administering two or three escalating doses of a BCMAxCD3 bispecific antibody before subcutaneously administering a therapeutic dose.

[0449] 47. The method according to any one of Embodiments 1 to 46, comprising subcutaneously administering a BCMAxCD3 bispecific antibody in escalating doses of 60 μg / kg and 300 μg / kg before subcutaneously administering a therapeutic dose.

[0450] 48. The method according to any one of Embodiments 1 to 47, comprising subcutaneously administering a BCMAxCD3 bispecific antibody in gradually increasing doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg before subcutaneously administering a therapeutic dose.

[0451] 49. The method according to any one of Embodiments 1 to 48, comprising subcutaneously administering escalating doses of a BCMAxCD3 bispecific antibody with intervals of 2 to 4 days between doses.

[0452] 50. The method according to any one of Embodiments 1 to 49, comprising subcutaneously administering one or more escalating doses of GPRC5DxCD3 bispecific antibody to the target before administering a therapeutic dose of GPRC5DxCD3 bispecific antibody.

[0453] 51. The method according to any one of Embodiments 1 to 50, comprising subcutaneously administering a therapeutic dose of a GPRC5DxCD3 bispecific antibody to a subject weekly (QW).

[0454] 52. The method according to any one of Embodiments 1 to 50, comprising subcutaneously administering a therapeutic dose of a GPRC5DxCD3 bispecific antibody to a subject every two weeks (Q2W).

[0455] 53. The method according to any one of Embodiments 1 to 50, comprising subcutaneous administration of a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 200 μg / kg to approximately 400 μg / kg on a weekly (QW) basis.

[0456] 54. The method according to any one of Embodiments 1 to 50, comprising subcutaneous administration of a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 200 μg / kg weekly (QW).

[0457] 55. The method according to any one of Embodiments 1 to 50, comprising subcutaneous administration of a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 400 μg / kg weekly (QW).

[0458] 56. The method according to any one of Embodiments 1 to 50, comprising subcutaneous administration of a GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 800 μg / kg every two weeks (Q2W).

[0459] 57. The method according to any one of Embodiments 1 to 56, comprising subcutaneously administering two or three escalating doses of a GPRC5DxCD3 bispecific antibody before subcutaneously administering a therapeutic dose.

[0460] 58. The method according to any one of Embodiments 1 to 57, comprising subcutaneously administering a GPRC5DxCD3 bispecific antibody in escalating doses of 10 μg / kg and 60 μg / kg before subcutaneously administering a therapeutic dose.

[0461] 59. The method according to any one of Embodiments 1 to 58, comprising subcutaneously administering a GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneously administering a therapeutic dose.

[0462] 60. The method according to any one of Embodiments 1 to 59, comprising subcutaneously administering escalating doses of a GPRC5DxCD3 bispecific antibody with intervals of 2 to 4 days between doses.

[0463] 61. The method according to any one of Embodiments 1 to 36, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 3000 μg / kg every two weeks (Q2W) and subcutaneously administering a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 800 μg / kg every two weeks (Q2W).

[0464] 62. The method according to any one of Embodiments 1 to 36, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg every two weeks (Q2W) and subcutaneously administering a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 800 μg / kg every two weeks (Q2W).

[0465] 63. The method according to any one of Embodiments 1 to 36, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg weekly (QW) and subcutaneously administering a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 800 μg / kg weekly (QW).

[0466] 64. The method according to any one of Embodiments 1 to 36, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg weekly (QW) and subcutaneously administering a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 400 μg / kg weekly (QW).

[0467] 65. The method according to any one of Embodiments 1 to 36, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg weekly (QW) and subcutaneously administering a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 200 μg / kg weekly (QW).

[0468] 66. The method according to any one of Embodiments 1 to 36, comprising subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 750 μg / kg weekly (QW) and subcutaneously administering a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 200 μg / kg weekly (QW).

[0469] 67. The method according to any one of Embodiments 61 to 66, comprising subcutaneously administering one or more escalating doses of a BCMAxCD3 bispecific antibody before subcutaneously administering a therapeutic dose, and subcutaneously administering one or more escalating doses of a GPRC5DxCD3 bispecific antibody before subcutaneously administering a therapeutic dose.

[0470] 68. The method according to any one of Embodiments 61 to 67, comprising subcutaneously administering two or three escalating doses of BCMAxCD3 bispecific antibody before subcutaneously administering a therapeutic dose, and subcutaneously administering two or three escalating doses of GPRC5DxCD3 bispecific antibody before subcutaneously administering a therapeutic dose.

[0471] 69. The method according to any one of Embodiments 61 to 68, comprising subcutaneously administering a BCMAxCD3 bispecific antibody in gradually increasing doses of 60 μg / kg and 300 μg / kg before subcutaneously administering a therapeutic dose, and subcutaneously administering a GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg and 60 μg / kg before subcutaneously administering a therapeutic dose.

[0472] 70. The method according to any one of Embodiments 61 to 69, comprising subcutaneously administering a BCMAxCD3 bispecific antibody in gradually increasing doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg before subcutaneously administering a therapeutic dose, and subcutaneously administering a GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg, and 300 μg / kg before subcutaneously administering a therapeutic dose.

[0473] 71. The method according to any one of Embodiments 61 to 69, comprising subcutaneously administering a BCMAxCD3 bispecific antibody in gradually increasing doses of 60 μg / kg, 300 μg / kg, and 1500 μg / kg before subcutaneously administering a therapeutic dose, and subcutaneously administering a GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneously administering a therapeutic dose.

[0474] 72. The method according to any one of embodiments 67 to 71, wherein the escalating doses of the BCMAxCD3 bispecific antibody are administered 2 to 4 days apart from each other, and the escalating doses of the GPRC5DxCD3 bispecific antibody are administered 2 to 4 days apart from each other.

[0475] 73. The method according to any one of Embodiments 1 to 72, wherein each therapeutic dose of the BCMAxCD3 bispecific antibody is administered on the same day as each therapeutic dose of the GPRC5DxCD3 bispecific antibody.

[0476] 74. The method according to any one of Embodiments 1 to 73, wherein each escalating dose of the BCMAxCD3 bispecific antibody is administered on the same day as each escalating dose of the GPRC5DxCD3 bispecific antibody.

[0477] 75. The first therapeutic dose of BCMAxCD3 bispecific antibody and the first therapeutic dose of GPRC5DxCD3 bispecific antibody are administered subcutaneously on day 1 of cycle 1 of a 28-day cycle. During Q2W, for example, on day 1 and day 15 (±3 days) of each 28-day cycle, a subsequent therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously at a dose of 800 μg / kg. The method according to any one of Embodiments 1 to 36, wherein, for example, on day 1 and day 15 (±3 days) of a 28-day cycle during Q2W, a subsequent therapeutic dose of BCMAxCD3 bispecific antibody is subcutaneously administered at a dose of 3000 μg / kg.

[0478] 76. The method according to Embodiment 75, comprising: subcutaneously administering 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; and subcutaneously administering GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg and 400 μg / kg before subcutaneously administering the first therapeutic dose, wherein the first therapeutic dose is administered 2 to 4 days after the administration of the final gradually increasing dose of each bispecific antibody.

[0479] The first escalating dose of BCMAxCD3 bispecific antibody at 76.5.60 μg / kg is administered subcutaneously, followed 2-4 days later by a second escalating dose of BCMAxCD3 bispecific antibody at 300 μg / kg, followed 2-4 days later by a third escalating dose of BCMAxCD3 bispecific antibody at 1500 μg / kg, followed 2-4 days later by a first therapeutic dose of BCMAxCD3 bispecific antibody at 3000 μg / kg. The first escalating dose of GPRC5DxCD3 bispecific antibody at 10 μg / kg is administered subcutaneously, followed 2-4 days later by a second escalating dose of GPRC5DxCD3 bispecific antibody at 60 μg / kg, followed 2-4 days later by a third escalating dose of GPRC5DxCD3 bispecific antibody at 300 μg / kg or 400 μg / kg, followed 2-4 days later by a first therapeutic dose of GPRC5DxCD3 bispecific antibody at 800 μg / kg. The method according to any one of Embodiments 1 to 76, further comprising: subcutaneously administering a BCMAxCD3 bispecific antibody at a therapeutic dose of 3000 μg / kg every two weeks (Q2W); and subcutaneously administering a GPRC5DxCD3 bispecific antibody at a therapeutic dose of 800 μg / kg every two weeks (Q2W).

[0480] 77. A method according to any one of Embodiments 1 to 76.5, wherein the method achieves partial response, very good partial response, complete response, or exact complete response in a subject, as determined by the IMWG response criteria.

[0481] 78. The method according to Embodiment 77, relating to a patient with extramedullary disease (EMD).

[0482] 79. A method according to any one of Embodiments 1 to 77, wherein the method achieves an overall response rate of at least 70% in a target population having relapsed or refractory multiple myeloma (RRMM).

[0483] 80. The method according to Embodiment 79, wherein the subject has an extramedullary disease (EMD).

[0484] 81. A method according to any one of Embodiments 1 to 77, wherein the method achieves an overall response rate of at least 80% in a target population having RRMM.

[0485] 82. The method according to Embodiment 81, wherein the subject has an extramedullary disease (EMD).

[0486] 83. A method according to any one of Embodiments 1 to 77, wherein the method achieves an overall response rate of at least 85% in a population of subjects having RRMM.

[0487] 84. The method according to Embodiment 83, wherein the subject has an extramedullary disease (EMD).

[0488] 85. A method according to any one of Embodiments 1 to 77, wherein the method achieves an overall response rate of at least 90% in a population of subjects having RRMM.

[0489] 86. A method according to any one of Embodiments 1 to 77, wherein the method achieves an overall response rate of at least 95% in a population of subjects having RRMM.

[0490] 87. The method according to any one of Embodiments 1 to 77, wherein the method achieves at least a 20% complete response or a tight complete response rate in a target population having RRMM.

[0491] 88. The method according to Embodiment 87, wherein the subject has an extramedullary disease (EMD).

[0492] 89. The method according to any one of Embodiments 1 to 77, which achieves at least a 25% complete response or a strict complete response rate in a target population having RRMM.

[0493] 90. The method according to Embodiment 89, wherein the subject has an extramedullary disease (EMD).

[0494] 91. The method according to any one of Embodiments 1 to 77, wherein the method achieves at least 30% complete response or a tight complete response rate in a target population having RRMM.

[0495] 92. The method according to Embodiment 91, wherein the subject has an extramedullary disease (EMD).

[0496] 93. The method according to any one of Embodiments 1 to 77, which achieves at least a 35% complete response or a strict complete response rate in a target population having RRMM.

[0497] 94. The method according to Embodiment 93, wherein the subject has an extramedullary disease (EMD).

[0498] 95. The method according to any one of Embodiments 1 to 77, which achieves at least 40% complete response or a strict complete response rate in a target population having RRMM.

[0499] 96. The method according to Embodiment 95, wherein the subject has an extramedullary disease (EMD).

[0500] 97. A combination dosing regimen for the treatment of multiple myeloma comprising a BCMAxCD3 bispecific antibody and a GPRC5DxCD3 bispecific antibody, wherein the bispecific antibodies may be selected from any one of embodiments 2 to 29.

[0501] 98. The subjects were those who had previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, and the method was as follows: This includes treating the subject according to a therapeutically effective regimen that includes a continuous 28-day treatment cycle. One or more escalating doses of a GPRC5DxCD3 bispecific antibody (e.g., talketamab) are administered subcutaneously to the subject during the escalation phase of Cycle 1, and then each therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 0.8 mg / kg. The method according to any one of the implementations 1 to 77, wherein a therapeutic dose of GPRC5DxCD3 bispecific antibody is administered to the subject on a bi-weekly dosing schedule (Q2W) starting from treatment cycle 2 (e.g., on days 1 and 15), and then the therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a monthly dosing schedule (Q4W), either (i) starting in treatment cycle 5 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in treatment cycle 7 regardless of the clinical response in the subject.

[0502] 99. One or more escalating doses of a BCMAxCD3 bispecific antibody (e.g., teclistamag) are administered subcutaneously to the subject during the escalation phase of Cycle 1, with each therapeutic dose of BCMAxCD3 bispecific antibody being administered subcutaneously to the subject at a dose of 3.0 mg / kg. The method according to Implementation 98, wherein a therapeutic dose of BCMAxCD3 bispecific antibody is administered to the subject on a bi-weekly dosing schedule (Q2W) starting from treatment cycle 2 (e.g., on days 1 and 15), and then the therapeutic dose of BCMAxCD3 bispecific antibody is administered subcutaneously to the subject on a monthly dosing schedule (Q4W), either (i) starting in treatment cycle 3 if the subject achieves a partial response, very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in treatment cycle 7 regardless of the clinical response in the subject.

[0503] 100. A method for improving the median progression-free survival (PFS) in a target population with relapsed or refractory multiple myeloma who has previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, the method comprising administering to the target population a combination therapy comprising a therapeutically effective dose of a GPRC5DxCD3 bispecific antibody (e.g., talketamab) and a therapeutically effective dose of a BCMAxCD3 bispecific antibody (e.g., teclistamaib), the method is This includes treating the subject according to a therapeutically effective regimen that includes a continuous 28-day treatment cycle. One or more escalating doses of GPRC5DxCD3 bispecific antibody are administered subcutaneously to the subjects during the escalation phase of Cycle 1, and then each therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subjects at a dose of 0.8 mg / kg. The therapeutic dose of GPRC5DxCD3 bispecific antibody is administered to the subject on a bi-weekly schedule (Q2W) starting from treatment cycle 2 (e.g., on days 1 and 15), and then the therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a monthly schedule (Q4W), either (i) starting in treatment cycle 5 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in treatment cycle 7 regardless of the clinical response in the subject. One or more escalating doses of a BCMAxCD3 bispecific antibody (e.g., teclistamag) are administered subcutaneously to the subject during the escalation phase of Cycle 1, with each therapeutic dose of the BCMAxCD3 bispecific antibody being administered subcutaneously at a dose of 3.0 mg / kg. The therapeutic dose of BCMAxCD3 bispecific antibody is administered to the subject on a bi-weekly schedule (Q2W) starting from treatment cycle 2 (e.g., on days 1 and 15), and then the therapeutic dose of BCMAxCD3 bispecific antibody is administered subcutaneously to the subject on a monthly schedule (Q4W), either (i) starting in treatment cycle 3 if the subject achieves a partial response, very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in treatment cycle 7 regardless of the clinical response in the subject. Improvement in median PFS is compared to the median PFS of a reference population of patients with relapsed or refractory multiple myeloma who had previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, and who received either (i) elotuzumab, pomalidomide, and dexamethasone (EPd) or (ii) pomalidomide, bortezomib, and dexamethasone (PVd).

[0504] 101. A method for improving the median overall response rate (ORR) in a target population with relapsed or refractory multiple myeloma who has previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, the method comprising administering to the target population a combination therapy comprising a therapeutically effective dose of a GPRC5DxCD3 bispecific antibody (e.g., talketamab) and a therapeutically effective dose of a BCMAxCD3 bispecific antibody (e.g., teclistamaib), the method is: This includes treating the subject according to a therapeutically effective regimen that includes a continuous 28-day treatment cycle. One or more escalating doses of GPRC5DxCD3 bispecific antibody are administered subcutaneously to the subjects during the escalation phase of Cycle 1, and then each therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subjects at a dose of 0.8 mg / kg. The therapeutic dose of GPRC5DxCD3 bispecific antibody is administered to the subject on a bi-weekly schedule (Q2W) starting from treatment cycle 2 (e.g., on days 1 and 15), and then the therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a monthly schedule (Q4W), either (i) starting in treatment cycle 5 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in treatment cycle 7 regardless of the clinical response in the subject. One or more escalating doses of a BCMAxCD3 bispecific antibody (e.g., teclistamag) are administered subcutaneously to the subject during the escalation phase of Cycle 1, with each therapeutic dose of the BCMAxCD3 bispecific antibody being administered subcutaneously at a dose of 3.0 mg / kg. The therapeutic dose of BCMAxCD3 bispecific antibody is administered to the subject on a bi-weekly schedule (Q2W) starting from treatment cycle 2 (e.g., on days 1 and 15), and then the therapeutic dose of BCMAxCD3 bispecific antibody is administered subcutaneously to the subject on a monthly schedule (Q4W), either (i) starting in treatment cycle 3 if the subject achieves a partial response, very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in treatment cycle 7 regardless of the clinical response in the subject. Improvement in ORR is compared to the ORR of a reference population of subjects with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, wherein the reference population is administered either (i) elotuzumab, pomalidomide, and dexamethasone (EPd), or (ii) pomalidomide, bortezomib, and dexamethasone (PVd).

[0505] 102. The method according to any one of Embodiments 98 to 101, wherein the dose escalation phase comprises subcutaneous administration of escalating doses of 0.01 mg / kg and 0.06 mg / kg of GPRC5DxCD3 bispecific antibody, spaced 2 to 4 days apart from each other (for example, on day 1 and day 4, respectively).

[0506] 103. The method according to any one of Embodiments 98 to 101, wherein the dose escalation phase comprises subcutaneous administration of escalating doses of 0.01 mg / kg, 0.06 mg / kg, and 0.4 mg / kg of GPRC5DxCD3 bispecific antibody, spaced 2 to 4 days apart from each other (for example, on day 1, day 4, and day 8, respectively).

[0507] 104. The method according to any one of Embodiments 98 to 101, comprising administering subcutaneously escalating doses of 0.01 mg / kg, 0.06 mg / kg, and 0.4 mg / kg of GPRC5DxCD3 bispecific antibody at intervals of 2 to 4 days from each other (for example, on days 1, 4, and 8, respectively), followed by subcutaneous administration of a therapeutic dose of 0.8 mg / kg of GPRC5DxCD3 bispecific antibody at least 2 days after the administration of 0.4 mg / kg (for example, on days 7 to 15, for example, on day 15).

[0508] 105. The method according to any one of Embodiments 98 to 104, wherein the dose escalation phase comprises subcutaneous administration of escalating doses of 0.06 mg / kg and 0.3 mg / kg of BCMAxCD3 bispecific antibody, spaced 2 to 4 days apart from each other (for example, on day 1 and day 4, respectively).

[0509] 106. The method according to any one of Embodiments 98 to 104, wherein the dose escalation phase comprises subcutaneous administration of escalating doses of BCMAxCD3 bispecific antibody at doses of 0.06 mg / kg, 0.3 mg / kg, and 1.5 mg / kg, spaced 2 to 4 days apart from each other (for example, on day 1, day 4, and day 8, respectively).

[0510] 107. The method according to any one of Embodiments 98 to 104, comprising administering subcutaneous doses of BCMAxCD3 bispecific antibody at doses of 0.06 mg / kg, 0.3 mg / kg, and 1.5 mg / kg, spaced 2 to 4 days apart from each other (for example, on days 1, 4, and 8, respectively), followed by a therapeutic dose of 3.0 mg / kg of BCMAxCD3 bispecific antibody subcutaneously at least 2 days after the 1.5 mg / kg dose (for example, on days 7 to 15, e.g., on day 15).

[0511] 108. The subjects were those who had previously received 1 to 4 treatment lines including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, and the method was as follows: This includes treating the subject according to a therapeutically effective regimen that includes a continuous 28-day treatment cycle. During the escalation phase of Cycle 1, the patient was subcutaneously administered escalating doses of a GPRC5DxCD3 bispecific antibody (e.g., talketamab) and a BCMAxCD3 bispecific antibody (e.g., teclistamaib), and then, Therapeutic doses of BCMAxCD3 bispecific antibodies are administered subcutaneously to subjects at a dose of 3.0 mg / kg each, starting from treatment cycle 2 on a monthly dosing schedule (Q4W), regardless of the clinical response in the subjects. The method according to any one of Embodiments 1 to 36, wherein a therapeutic dose of GPRC5DxCD3 bispecific antibody is subcutaneously administered to the subject at a dose of 0.8 mg / kg on a bi-weekly administration schedule (Q2W) starting from treatment cycle 2 (e.g., on day 1 and day 15), and then the therapeutic dose of GPRC5DxCD3 bispecific antibody is subcutaneously administered to the subject on a monthly administration schedule (Q4W), starting in treatment cycle 5 if (i) the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or starting in treatment cycle 7 if the subject achieves a partial response, very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (iii) a partial response, very good partial response, complete response, or exact complete response is achieved as determined by the IMWG response criteria, at any time after treatment cycle 7.

[0512] 109. The method according to claim 108, wherein a GPRC5DxCD3 bispecific antibody (e.g., talketamab) and a BCMAxCD3 bispecific antibody (e.g., teclistamaib) are administered at intervals of at least 15 minutes from each other on each day the dose is administered.

[0513] 110. A method for improving the median progression-free survival (PFS) in a target population with relapsed or refractory multiple myeloma who has previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, the method comprising administering to the target population a combination therapy comprising a therapeutically effective dose of a GPRC5DxCD3 bispecific antibody (e.g., talketamab) and a therapeutically effective dose of a BCMAxCD3 bispecific antibody (e.g., teclistamaib), the method is This includes treating the subject according to a therapeutically effective regimen that includes a continuous 28-day treatment cycle. During the escalation phase of Cycle 1, the patient was subcutaneously administered escalating doses of a GPRC5DxCD3 bispecific antibody (e.g., talketamab) and a BCMAxCD3 bispecific antibody (e.g., teclistamaib), and then, Therapeutic doses of BCMAxCD3 bispecific antibodies are administered subcutaneously to subjects at a dose of 3.0 mg / kg each, starting from treatment cycle 2 on a monthly dosing schedule (Q4W), regardless of the clinical response in the subjects. The therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 0.8 mg / kg on a bi-weekly dosing schedule (Q2W) starting from treatment cycle 2 (e.g., on day 1 and day 15). Subsequently, the therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 5 if (i) the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or starting in treatment cycle 7 if the subject achieves a partial response, very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (iii) if a partial response, very good partial response, complete response, or exact complete response is achieved as determined by the IMWG response criteria, anytime after treatment cycle 7.

[0514] Improvement in median PFS is compared to the median PFS of a reference population of patients with relapsed or refractory multiple myeloma who had previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, and who received either (i) elotuzumab, pomalidomide, and dexamethasone (EPd) or (ii) pomalidomide, bortezomib, and dexamethasone (PVd).

[0515] 111. A method for improving the median overall response rate (ORR) in a target population with relapsed or refractory multiple myeloma who has previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, the method comprising administering to the target population a combination therapy comprising a therapeutically effective dose of a GPRC5DxCD3 bispecific antibody (e.g., talketamab) and a therapeutically effective dose of a BCMAxCD3 bispecific antibody (e.g., teclistamaib), the method is This includes treating the subject according to a therapeutically effective regimen that includes a continuous 28-day treatment cycle. During the escalation phase of Cycle 1, the patient was subcutaneously administered escalating doses of a GPRC5DxCD3 bispecific antibody (e.g., talketamab) and a BCMAxCD3 bispecific antibody (e.g., teclistamaib), and then, Therapeutic doses of BCMAxCD3 bispecific antibodies are administered subcutaneously to subjects at a dose of 3.0 mg / kg each, starting from treatment cycle 2 on a monthly dosing schedule (Q4W), regardless of the clinical response in the subjects. The therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 0.8 mg / kg on a bi-weekly dosing schedule (Q2W) starting from treatment cycle 2 (e.g., on day 1 and day 15). Subsequently, the therapeutic dose of GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 5 if (i) the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or starting in treatment cycle 7 if the subject achieves a partial response, very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (iii) if a partial response, very good partial response, complete response, or exact complete response is achieved as determined by the IMWG response criteria, anytime after treatment cycle 7.

[0516] Improvement in ORR is compared to the ORR of a reference population of subjects with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, wherein the reference population is administered either (i) elotuzumab, pomalidomide, and dexamethasone (EPd), or (ii) pomalidomide, bortezomib, and dexamethasone (PVd).

[0517] 112. The method according to any one of Embodiments 108 to 111, wherein the dose escalation phase comprises subcutaneous administration of escalating doses of 0.01 mg / kg and 0.06 mg / kg of GPRC5DxCD3 bispecific antibody, spaced 2 to 4 days apart from each other (for example, on day 1 and day 4, respectively).

[0518] 113. The method according to any one of Embodiments 108 to 111, wherein the dose escalation phase comprises subcutaneous administration of escalating doses of 0.01 mg / kg, 0.06 mg / kg, and 0.4 mg / kg of GPRC5DxCD3 bispecific antibody, spaced 2 to 4 days apart from each other (for example, on day 1, day 4, and day 8, respectively).

[0519] 114. The method according to any one of Embodiments 108 to 111, comprising administering subcutaneously escalating doses of 0.01 mg / kg, 0.06 mg / kg, and 0.4 mg / kg of GPRC5DxCD3 bispecific antibody at intervals of 2 to 4 days from each other (for example, on days 1, 4, and 8, respectively), followed by subcutaneous administration of a therapeutic dose of 0.8 mg / kg of GPRC5DxCD3 bispecific antibody at least 2 days after the administration of 0.4 mg / kg (for example, on days 7 to 15, for example, on day 15).

[0520] 115. The method according to any one of Embodiments 108 to 114, wherein the dose escalation phase comprises subcutaneous administration of escalating doses of 0.06 mg / kg and 0.3 mg / kg of BCMAxCD3 bispecific antibody, spaced 2 to 4 days apart from each other (for example, on day 1 and day 4, respectively).

[0521] 116. The method according to any one of Embodiments 108 to 114, wherein the dose escalation phase comprises subcutaneous administration of escalating doses of 0.06 mg / kg, 0.3 mg / kg, and 1.5 mg / kg of BCMAxCD3 bispecific antibody, spaced 2 to 4 days apart from each other (for example, on day 1, day 4, and day 8, respectively).

[0522] 117. The method according to any one of Embodiments 108 to 114, comprising administering subcutaneous doses of BCMAxCD3 bispecific antibody at doses of 0.06 mg / kg, 0.3 mg / kg, and 1.5 mg / kg, spaced 2 to 4 days apart from each other (for example, on days 1, 4, and 8, respectively), and then administering a dose of BCMAxCD3 bispecific antibody at least 2 days after the 1.5 mg / kg dose (for example, on days 7 to 15, e.g., on day 15).

[0523] 118. Subcutaneous administration of escalating doses of BCMAxCD3 bispecific antibody (e.g., teclista mab) and GPRC5DxCD3 bispecific antibody (e.g., talketamab) is performed, followed by, Therapeutic doses of 3000 μg / kg of BCMAxCD3 bispecific antibody and 800 μg / kg of GPRC5DxCD3 bispecific antibody are administered subcutaneously at least four 28-day cycles every other week (Q2W) (e.g., on day 1 and day 15 (±3 days) of each cycle). (i) If the subject achieves a response of VGPR or better and has received at least four 28-day cycles of treatment (e.g., starting at cycle 5), administer a therapeutic dose of 3000 μg / kg of BCMAxCD3 bispecific antibody and 800 μg / kg of GPRC5DxCD3 bispecific antibody subcutaneously every month (Q4W) (e.g., on day 1 of each 28-day cycle), or (ii) The method according to any one of Embodiments 1 to 36, wherein, after the subject has completed six 28-day treatment cycles (e.g., starting at cycle 7), regardless of the clinical response in the subject, a therapeutic dose of 3000 μg / kg of BCMAxCD3 bispecific antibody and 800 μg / kg of GPRC5DxCD3 bispecific antibody is administered subcutaneously monthly (Q4W) (e.g., on day 1 of each 28-day cycle).

[0524] 119. The method according to Embodiment 118, comprising administering two or three escalating doses of BCMAxCD3 bispecific antibody and two or three escalating doses of GPRC5DxCD3 bispecific antibody, wherein the escalating doses are administered 2 to 4 days apart from each other.

[0525] The method according to Embodiment 118, comprising administering three escalating doses of BCMAxCD3 bispecific antibody (e.g., 60 μg / kg, 300 μg / kg, and 1500 μg / kg) and three escalating doses of GPRC5DxCD3 bispecific antibody (e.g., 10 μg / kg, 60 μg / kg, and 400 μg / kg), wherein the escalating doses are administered 2 to 4 days apart from each other.

[0526] 121. The method according to any one of Embodiments 118 to 120, comprising administering a first therapeutic dose of BCMAxCD3 bispecific antibody and GPRC5DxCD3 bispecific antibody 2 to 4 days after the final escalating dose (e.g., initiated on day 1 of cycle 1).

[0527] 122. The method according to any one of Embodiments 118 to 121, wherein the subject has relapsed or refractory multiple myeloma with extramedullary disease and has previously been administered proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0528] 123. The method according to any one of Embodiments 1 to 122, wherein the method achieves an overall response rate of at least 60% in a target population having relapsed or refractory multiple myeloma (RRMM).

[0529] 124. The method according to Embodiment 123, wherein the subject has an extramedullary disease (EMD).

[0530] 125. The method according to any one of Embodiments 1 to 122, wherein the method achieves an overall response rate of at least 65% in a target population having relapsed or refractory multiple myeloma (RRMM).

[0531] 126. The method according to Embodiment 125, wherein the subject has an extramedullary disease (EMD).

[0532] 127. The method according to any one of embodiments 1 to 126, wherein each subject having EMD has one or more lesions of EMD that are not contiguous with bone lesions with a diameter ≥ 2 cm (at their maximum dimension) on PET-CT and that meet the criteria for any previously irradiated extramedullary plasmacytoma.

[0533] 128. The method according to any one of Embodiments 1 to 127, wherein a GPRC5DxCD3 bispecific antibody (e.g., talketamab) and a BCMAxCD3 bispecific antibody (e.g., teclistamaib) are administered at intervals of at least 15 minutes from each other on each day the dose is administered.

[0534] 129. The method according to Embodiment 128, wherein a GPRC5DxCD3 bispecific antibody (e.g., talketamab) and a BCMAxCD3 bispecific antibody (e.g., teclistamaib) are administered to each other within approximately 30 (±10) minutes.

[0535] 130. The method according to Embodiment 128 or 129, wherein each dose of the BCMAxCD3 bispecific antibody is administered before each dose of the GPRC5DxCD3 bispecific antibody.

[0536] 131. The method according to Embodiment 128 or 129, wherein each dose of the GPRC5DxCD3 bispecific antibody is administered before each dose of the BCMAxCD3 bispecific antibody.

[0537] 132. The method according to any one of Embodiments 1 to 131, wherein a combination regimen comprising a BCMAxCD3 bispecific antibody and a GPRC5DxCD3 bispecific antibody is administered to the subject over 26 therapeutic cycles.

[0538] 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.

[0539] Any patent, patent application, and publication disclosure cited or referenced herein is incorporated herein by reference in its entirety. [Examples]

[0540] 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.

[0541] Example 1: Results of the Phase 1b RedirecTT-1 trial (NCT04586426) using tecristamag (Tec) and talketamab (Tal), which simultaneously target BCMA and GPRC5D, in patients with relapsed / refractory multiple myeloma (RRMM). Trial name: RedirecTT-1; NCT number: NCT04586426 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 11 and 12, respectively.

[0542] The anti-GPRC5D / anti-CD3 antibody talketamab (also known as Tal) (for example, described in U.S. Patent No. 10,562,968, the entirety of which is incorporated herein by reference) was manufactured by Janssen Pharmaceuticals. It was produced by culturing recombinant Chinese hamster ovary cells, followed by isolation, chromatographic purification, and formulation. Talketamab contains a GPRC5D binding arm GC5B596 and a CD3 binding arm CD3B219, the amino acid sequences of which are shown in Tables 13 and 12, respectively.

[0543] [Table 12]

[0544] [Table 13]

[0545] [Table 14]

[0546] Method: Part 1 and Part 2 The objectives of this study are to identify the recommended Phase 2 regimen (RP2R) and the schedule of the study treatment (Part 1), and to characterize the safety of the study treatment RP2R (Part 2). The RP2R describes the combined dose and schedule (tal + tec + dara) of the treatment combination pursued in Phase 2. The study design diagram is shown in Figure 1.

[0547] Parts 1 and 2: The increasing and expanding cohorts will investigate combinations of talketamab and tecristamab with or without SC daratumumab in participants with relapsed or refractory multiple myeloma.

[0548] Part 3: In the Phase 2 component, we examine the tal+tec combinations of participants with EMD in RP2R selected from Parts 1 and 2.

[0549] Talketamab is a humanized IgG4 PAA bispecific antibody designed to target the G protein-coupled receptor family C group 5-member D (GPRC5D) and the CD3 molecule found on T lymphocytes (T cells). Teclistamaib is a humanized IgG4 PAA bispecific antibody designed to target the B cell maturation antigen (BCMA) and the CD3 molecule found on T cells. Daratumumab (also known as Dara) is a human IgG1κ monoclonal antibody that binds with high affinity to a unique epitope on differentiation antigen group 38 (CD38) in various hematological malignancies, including multiple myeloma.

[0550] This trial consists of three phases: a screening phase (up to 28 days), a treatment phase (start of investigational drug administration and continuing until completion of the end of treatment (EOT) visit), and a post-treatment follow-up phase (for each participant, after the end of treatment and up to 16 weeks after the last dose of the investigational drug). Trial completion is defined as the final trial evaluation for the last trial participant. The total duration of the trial is up to 1 year and 6 months. Efficacy, safety, pharmacokinetics (PK), immunogenicity, and biomarkers will be evaluated at specific points in time during this trial. Participant safety and trial behavior will be monitored throughout the trial.

[0551] Dosing regimens for Part 1 and Part 2: During dose escalation, the tal+tec combination regimen was initiated on day 1 of cycle 1 and administered over a 28-day cycle. For dose level 1 of the tal+tec combination regimen, the weekly therapeutic dose was 200 μg / kg talketamab and 750 μg / kg teclistamag. Subsequent dose escalation was carried out in stages as follows: dose level 2 (weekly, 200 μg / kg talketamab and 1500 μg / kg teclistamag), dose level 3 (weekly, 400 μg / kg talketamab and 1500 μg / kg teclistamag), dose level 4 (every other week, 800 μg / kg talketamab and 1500 μg / kg teclistamag), and dose level 5 (every other week, 800 μg / kg talketamab and 3000 μg / kg teclistamag). A diagram of the dose escalation is shown in Figure 1.

[0552] The identified RP2R (recommended phase 2 regimen) for teclistamagb was 3000 μg / kg administered subcutaneously every two weeks (Q2W), while the RP2R for talketamab was 800 μg / kg administered subcutaneously every two weeks (Q2W).

[0553] Talketamab and teclistambab are administered in body weight-based doses. Teclistambab should be administered approximately 30 minutes before talketamab.

[0554] Participants will receive three escalating doses of talketamab and teclistamag before day 1 of cycle 1, as described in Table 14. The escalating doses will be administered 2 to 4 days apart (intervals of less than 2 days or more than 4 days may be permitted with the sponsor's approval).

[0555] [Table 15] Note: While the escalating dose 3 of talketamab was 300 μg / kg in Parts 1 and 2, the 400 μg / kg dose was identified as RP2D based on PK, pharmacodynamic, safety, and efficacy findings, and is therefore used as the escalating dose 3 in Part 3.

[0556] The first therapeutic dose of talketamab and teclistamaib combination therapy is administered 2-4 days after the final dose escalation, which represents day 1 of cycle 1. - Administer talketamab 800 μg / kg SC on days 1 and 15 (±3 days) of a 28-day cycle in Q2W. - Teclistamag 3000 μg / kg SC is administered on days 1 and 15 (±3 days) of a 28-day cycle in Q2W.

[0557] Part 3 Dosage Regimen: The tec+tal combination therapy is initiated with three escalating doses prior to day 1 of cycle 1. Teclistamag should be administered approximately 30 minutes before talketamab. The first therapeutic dose is administered 2-4 days after the final escalating dose, which represents day 1 of cycle 1. Teclistamag 3000 μg / kg SC is administered every other week on days 1 and 15 (±3 days) of a 28-day cycle, and talketamab 800 μg / kg SC is administered every other week on days 1 and 15 (±3 days) of a 28-day cycle. A change to Q4W may occur for both bispecific antibodies if the participant achieves a confirmed response of VGPR or better and has received at least 4 cycles of treatment (i.e., initiated in cycle 5) at the discretion of the investigator. After completing 6 cycles of treatment (i.e., initiated in cycle 7), the frequency of administration may be reduced to Q4W for both bispecific antibodies at the discretion of the investigator. Please refer to Figure 10.

[0558] Arms and interventions: Experiment: Part 1: Dose escalation. Participants received tec+tal with or without daratumumab in 28-day cycles after an initial dose escalation.

[0559] Experiment: Part 2: Dose Expansion. Participants will receive the therapeutic dose (a combination of the tal+tec regimen and the dara+tal+tec regimen) determined by the RP2R of the investigational treatment identified in Part 1.

[0560] Experiment: Part 3: In Part 3, participants with RRMM and at least one EMD lesion will receive tal+tec combination therapy, starting with three escalating doses of both talketamab and teclistamag (Figure 10). To be eligible, participants with EMD must have RRMM documented on whole-body PET-CT (or whole-body MRI approved by the sponsor) with at least one non-contiguous EMD lesion with a bone lesion of at least ≥2 cm in diameter (at its maximum dimension) and must not have been previously irradiated.

[0561] Primary evaluation criteria: 1. Part 1: Number of participants with dose-limiting toxicity (DLT) [Time frame: up to 1 year 6 months]. Dose-limiting toxicity is defined as either a hematological or non-hematological toxic event of grade 3 or higher, based on drug-related adverse events. 2. Part 1: Severity of DLT as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) [Time frame: up to 1 year 6 months]. Severity is graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. The severity scale ranges from Grade 1 (mild) to Grade 5 (death). Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life-threatening, and Grade 5: death related to adverse events. 3. Part 2: Number of participants experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) as measures of safety and tolerance [Time frame: up to 1 year 6 months]. An AE is any undesirable medical event in a clinical trial participant who has been administered a drug (investigational or non-investigational drug). An AE is not necessarily causally related to the treatment. A SAE is any AE resulting in death, persistent or significant disability / incapacity, hospitalization or extension of existing hospitalization, a life-threatening experience, a birth defect / birth disorder, and suspected transmission of any infectious agent via the drug. 4. Part 2: Number of participants with adverse events and SAEs by severity [Time frame: up to 1 year 6 months]. Severity is graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0). The severity scale ranges from Grade 1 (mild) to Grade 5 (death). Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life-threatening, and Grade 5: death related to the adverse event.

[0562] Purpose and endpoint: Parts 1 and 2: The primary objective of Part 1 is to identify the RP2R for each treatment combination by evaluating the incidence and severity of DLTs. The primary objective of Part 2 is to characterize the safety of each RP2R for the selected treatment combinations by evaluating the incidence and severity of AEs and SAEs. The RP2R describes the combination dose and treatment combination schedule pursued in Phase 2. An important secondary objective of both parts is to characterize the pharmacokinetics of the investigational treatments. For Part 2, a more important secondary objective is to evaluate the preliminary anticancer activity of the RP2R.

[0563] Part 3: The primary objective of Part 3 is to evaluate the anticancer activity of tal+tec combination therapy in terms of RP2R in participants with relapsed or refractory multiple myeloma and EMD by assessing ORR. The primary secondary objectives are to evaluate attributes of response, PFS, and OS, and to further characterize the safety of the combination therapy.

[0564] Eligibility criteria: The selection criteria include: ● Based on the recorded medical history, an initial diagnosis of multiple myeloma has been recorded in accordance with the International Myeloma Working Group diagnostic criteria. ● Parts 1 and 2: Participants must not be resistant to established treatments, including the final line of treatment, or have relapsed or refractory disease (except as described in points "a" and "b"). (a) For cohorts not containing daratumumab, the prior line of treatment must include proteasome inhibitors (PIs) (e.g., bortezomib, carfilzomib, ixazomib), immunomodulatory drugs (IMiDs) (e.g., thalidomide, lenalidomide, pomalidomide), and anti-CD38 therapies (e.g., daratumumab, isatuximab) in any order. (b) For cohorts containing daratumumab, the prior line of treatment must include PIs (e.g., bortezomib, carfilzomib, ixazomib) and IMiDs (e.g., thalidomide, lenalidomide, pomalidomide). Treatment with anti-CD38 therapy (e.g., daratumumab) is permitted at least 90 days prior to the study treatment if the participant has not discontinued previous treatment due to an adverse event associated with anti-CD38 therapy. ●Part 3: a. The patient has a relapsing or refractory disease and has been exposed to PIs, IMiDs, and anti-CD38 mAbs. Exposure is defined as follows: Unless the progressive disease is the best response to the regimen, or if the regimen is discontinued due to significant toxicity, the participant must have received at least one complete cycle of treatment for each regimen. b. Evidence of progressive disease is documented at the time of the final regimen or based on the investigator's response decision according to IMWG criteria. Relapsed or refractory diseases as defined below: -Relapsed disease follows an initial response to previous treatment. According to the IMWG criteria, progressive diseases are This is defined as being confirmed >60 days after discontinuation of treatment. -Intractable diseases are characterized by a <25% decrease in M ​​protein, or This is defined as a progressive disease according to IMWG criteria that is identified during or within 60 days after the discontinuation of previous treatment. ● Parts 1 and 2: A disease measurable at the time of screening, defined by at least one of the following: a. Serum M protein level ≥ 1.0 g / dL, or b. Urinary M protein level ≥ 200 mg / 24 hours, or c. In participants without measurable diseases in serum or urine, light chain multiple myeloma, serum immunoglobulin FLC ≥ 10 mg / dL and abnormal serum Ig kappa-lambda FLC ratio, or d. Presence of plasmacytoma (≥2cm) in participants who do not have measurable disease in serum or urine, or who have FLC. Regarding Part 1 and Part 2 cohorts, including EMD participants: Relapsed or refractory multiple myeloma with one or more EMD lesions meeting the following criteria has been recorded: the extramedullary plasmacytoma is not contiguous with a bone lesion with a diameter of ≥2 cm (at its maximum dimension) on PET-CT and has not been previously irradiated. ●Part 3: A relapsed or refractory multiple myeloma with one or more EMD lesions meeting the following criteria has been recorded: an extramedullary plasmacytoma is not contiguous with a bone lesion in at least one lesion with a diameter ≥ 2 cm (at its maximum dimension) as seen on whole-body PET-CT (or whole-body MRI approved by the sponsor), and has not been previously irradiated. Note: In exceptional circumstances, whole-body PET-CT (or whole-body MRI) with local facility imaging confirming at least one EMD lesion ≥ 3 cm may be considered eligible with the sponsor's approval. ● Part 1 and Part 2: ECOG performance status grade 0 or 1 at the time of screening and immediately before the start of investigational drug administration. ● Part 3: ECOG performance status grade 0, 1, or 2 at the time of screening and immediately before the start of investigational drug administration. ●All parts: Participants who may be pregnant must have negative serum pregnancy tests at the time of screening and within 24 hours of the start of the study treatment, and must consent to further serum or urine pregnancy tests during the study.

[0565] Exclusion criteria include: ●All parts: Prior or simultaneous exposure to any of the following during a specific time frame prior to registration: a. Targeted therapy, epigenetic therapy, or treatment from a clinical trial, or invasive medical device, within 21 days or at least 5 half-lives, whichever is shorter. b. Other investigational vaccines besides SARS-CoV-2 vaccines approved / in use under emergency authorization within the last 4 weeks c. Monoclonal antibody therapy within 21 days d. Cytotoxic therapy within 21 days e. PI therapy within 14 days f. IMiD therapy within 7 days g. Radiotherapy within 21 days. However, if the radioactive portal is less than 5% of the bone marrow reserve, the participant will be eligible regardless of the completion date of radiotherapy. h. Genetically modified adoptive cell therapy within 3 months (e.g., chimeric antigen receptor modified T cells, NK cells). Part 3: i. Inability to previously receive BCMA-targeted bispecific antibody therapy j. GPRC5D-targeted therapy was not previously available. ●All parts: Cumulative administration of a corticosteroid equivalent to 140 mg or more of prednisone (excluding prior treatments) within 14 days prior to the first administration of the study drug. ●All parts: Live attenuated live vaccine within 4 weeks prior to the first dose of the investigational drug, unless otherwise approved by the clinical trial sponsor. Non-live or non-replicated vaccines authorized for emergency use (e.g., COVID-19) are permitted. ● Active hepatitis C infection was determined by a positive hepatitis C virus (HCV)-RNA test. Participants with a history of HCV antibody positivity were required to undergo an HCV RNA test. ● You have a known allergy, hypersensitivity, or intolerance to daratumumab, talketamab, teclistamag, or their excipients.

[0566] Enrolled patients had myeloma (MM) according to the International Myeloma Working Group 2016 criteria, were intolerant to reactive response (RR) or last-line therapy (LOT), had been exposed to proteasome inhibitors, immunomodulatory agents, and anti-CD38 therapy, and had measurable disease. All patients provided informed consent. The primary objectives were to evaluate safety and identify recommended phase 2 regimens (RP2R) for combination therapy. Response rates were assessed by the principal investigator. AEs were graded according to CTCAE v5.0. Cytokine release syndrome (CRS) and cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT criteria.

[0567] Results as of the data cutoff date of December 12, 2022: Sixty-three patients received tec+tal. The median age (range) was 67 years (39–81 years). The median number of previous treatment lines (LOT) was 5 (1–11). 33% (15 / 45) had high-risk cytogenetic features. 78% (49 / 63) had triple-class refractory disease. 63% (40 / 63) were exposed to five drugs. 43% (27 / 63) had extramedullary disease (EMD, all bone-independent). The median follow-up period (range) was 14.4 mos (0.5–21.9). The most common adverse events (AEs) under treatment were CRS (81%, grade [gr] 3, 3%, no gr4), neutropenia (76%, gr3 / 4, 75%), and anemia (60%, gr3 / 4, 43%). Dose-limiting toxicities (DLTs) were reported at dose level 1 (herpes stomatitis at gr3) and dose level 3 (elevated AST / ALT at gr3). One ICANS event was reported at dose level 3. No DLTs were reported in the RP2R. Across all dose levels, the overall response rate (ORR) was 84% ​​(52 / 62) of all evaluable patients and 73% (19 / 26) of evaluable patients with EMD. The proportion of CR or better (≧CR) was 34% (21 / 62) and 31% (8 / 26), respectively. In the RP2R, the ORR was 92% (12 / 13) of all evaluable patients and 83% (5 / 6) of evaluable patients with EMD. The proportion of CR or better was 31% (4 / 13) and 33% (2 / 6), respectively.

[0568] Summary / Conclusion: In this first combined trial of BCMA-targeted bispecific antibodies and GPRC5D-targeted bispecific antibodies, tec+tal in RP2R exhibits a manageable safety profile consistent with each monotherapy. An ORR of 92% was observed in patients with advanced RRMM in RP2R, and an ORR of 83% was achieved in patients with EMD (a high-risk population with unmet needs).

[0569] Results as of the data cutoff date of March 16, 2023: The characteristics of patients enrolled in the RedirecTT-1 trial are summarized in Figure 2, showing, for example, that enrolled patients had a median of four previous treatment lines (1 to 11 previous lines for patients treated at all dose levels, and 2 to 10 previous lines for patients treated with RP2R). Many patients enrolled in the trial had previously undergone autologous stem cell transplantation (ASCT) (78.5% of patients treated at all dose levels and 70.6% of patients treated with RP2R). Safety results are summarized in Tables 3 to 7.

[0570] As shown in Figure 3, the combination regimen had a clinically manageable safety profile with low discontinuation and mortality rates. A TEAE (Therapeutic Adverse Event) is defined as a new or worsening event occurring in the safety population from the time of or after the first drug treatment until 30 days after the last dose of the study drug, or until the day before the start of subsequent treatment (whichever comes first). Adverse events (AEs) that begin after 30 days after the last dose of the study drug and are determined to be related to the study drug are also considered TEAEs. All deaths due to drug-related TEAEs were due to infection.

[0571] As shown in Figure 4, the hematological safety profile was consistent with Tec and Tal monotherapy. There were no discontinuations due to hematological TEAEs. Febrile neutropenia occurred in 12.9% of patients across all dose levels, including 8.8% at RP2R.

[0572] As shown in Figure 5, non-hematological TEAEs were generally of low severity. The proportion of non-hematological TEAEs of grade 3 / 4 was low overall, including RP2R 5 ICANS events in three patients, with the maximum severity being grade 3. In RP2R, one patient experienced two events, with the maximum severity being grade 1. The AE profiles were consistent with each drug as monotherapy.

[0573] As shown in Figure 6, the incidence and severity of cytokine release syndrome (CRS) were consistent with Tec and Tal monotherapy. The majority of CRS events occurred during dose escalation or cycle 1. All CRS events resolved or had resolved by the data cutoff.

[0574] As shown in Figure 7, infections were common and mostly low-grade. Most infections were grade 1 or grade 2. 81.7% had baseline IgG levels <400 mg / dL or hypogammaglobulinemia TEAE with ≥1, and all were grade 1 or grade 2 (85.3% in RP2R).

[0575] As shown in Figure 8, the overall response rate (ORR) was high at 86.6% across the tested dose levels and 96.3% at RP2R. At the data cutoff, 61% (57 / 93) of patients continued treatment.

[0576] As shown in Figure 9, a high ORR was observed in the EMD subgroup. All were soft tissue plasmacytomas. With a median RP2R (n=11) of 7.2 months (range 0.7-14.2), an ORR of 85.7% (6 / 7) was observed, and a complete or exact complete response rate of 28.6% (2 / 7) was observed.

[0577] In summary, at the data cutoff on March 16, 2023, a 96% ORR was observed with Q2W Tec+Tal in triple-class exposed MM with RP2R, competing with current CAR T-cell therapies. In patients with extramedullary soft tissue plasmacytoma, a noteworthy ORR of 85.7% was observed, and the median DOR was not reached at 7.2 months. The safety profile of the combination was consistent with monotherapy. No novel or additional toxicities were observed with either teclistamag or talketamab.

[0578] Latest RedirecTT-1 trial methods, results, and discussion as of March 2024: treatment Patients received subcutaneous escalating talketamab + tecristamag in 28-day cycles. Escalating doses, adapted from the schedules used for each monotherapy to alleviate severe CRS, were administered 2–4 days apart, prior to the total therapeutic dose. The escalating doses and total therapeutic dose were administered on the same day, separated by 30 (±10) days. Hospitalization and prior treatment with dexamethasone, diphenhydramine, and acetaminophen were required before all escalations and the initial therapeutic dose. After achieving a partial response or better from cycle 5, patients could switch from QW to Q2W, and from Q2W to monthly (Q4W) talketamab and tecristamag administration. Infection prevention measures were recommended and administered according to institutional guidelines. Immunoglobulin replacement was a recommended protocol to maintain serum immunoglobulin G levels above 400 mg / dL, regardless of infection activity or history. Intravenous immunoglobulin at a dose of 0.4 g / kg every 3–6 weeks was recommended. Immunoglobulin G levels were recommended to be measured at least every 3 months after a steady state was reached. For severe or recurrent / chronic infections, immunoglobulin replacement was administered according to institutional guidelines. Patients received the study treatment until unacceptable toxicity, withdrawal of consent, confirmation of disease progression, death, decision to discontinue treatment by the principal investigator or sponsor, or termination of the study.

[0579] Endpoints and evaluation The primary objective of the Phase 1 dose escalation was to identify the talketamab + tecristamagab dose for Phase 2 expansion by evaluating adverse events and dose-limiting toxicities. Secondary endpoints included overall response rate, duration of response, time to response, pharmacokinetics, pharmacodynamics, and immunogenicity. Progression-free survival was also assessed. Responses were assessed by the principal investigator according to the IMWG 2016 criteria. The best response was reported (both confirmed and unconfirmed responses). Endometrial mass disease (EMD) was assessed by physical examination every 4 weeks and by radiological assessment every 12 weeks. Adverse events were graded according to the Common Terminology Criteria for Adverse Events v5.0 and recorded for up to 30 days after the patient last received the study treatment. CRS and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) were graded according to the American Society for Transplantation and Cellular Therapy guidelines. Blood and serum samples were obtained for pharmacokinetic, pharmacodynamic, and immunogenicity analysis.

[0580] statistical analysis Safety, pharmacokinetics, pharmacodynamics, and immunogenicity were evaluated in patients who received one or more therapeutic doses. In addition to patients who died, progressed, or discontinued the study treatment (regardless of whether the patient had one or more post-baseline disease assessments), all treated patients with one or more post-baseline disease assessments were included in the estimation of the overall response rate. Response rates were calculated using the corresponding exact 95% confidence intervals. Time to response and progression-free survival were evaluated for all treated patients. The Kaplan-Meier method was used to estimate time to response, duration of response, and progression-free survival. All data were analyzed using SAS v9.4. No formal statistical hypothesis testing was conducted.

[0581] result Between December 9, 2020, and April 26, 2023, 116 patients were screened. As of March 15, 2024, 94 patients were receiving talketamab + teclistamai, of which 44 received talketamab 0.8 mg / kg + teclistamai 3.0 mg / kg Q2W (dose level 5), which was selected for phase 2 expansion. The median follow-up period for dose level 5 was 20.3 months (range, 0.5–37.1) and 18.2 months (range, 0.7–27.0) overall. 49 patients (50.1%) continued talketamab + teclistamai, and one patient continued teclistamai monotherapy. Across all doses, patients received a median of 10 (range, 1–39) talketamab cycles and 12 (range, 1–39) teclistamai cycles.

[0582] The patients had a median age (range, 39–81) of 64.5 years and had previously received a median of four lines of treatment (range, 1–11) over a median period (range, 0.3–14.6) since diagnosis. All patients were triple-class exposed, and most were quintactic (n=61 [64.9%]). Seven patients had previously received bispecific antibodies, and four had previously received CAR-T therapy. 87 patients (92.6%) were refractory to their last line of treatment, and 81 patients (86.2%) were triple-class refractory. 34 patients (36.2%) had EMD.

[0583] safety Three patients had dose-limiting toxicity, and one patient was treated with talketamab 0.2 mg / kg + teclistamagb 0.75 mg / kg QW (grade 3 oral herpes), talketamab 0.4 mg / kg + teclistamagb 1.5 mg / kg QW (grade 3 elevated alanine aminotransferase / aspartate aminotransferase), and dose level 5 (grade 4 thrombocytopenia). Across all dose levels, all patients experienced an adverse event of ≥1. 90 patients (95.7%) experienced a grade 3 / 4 event of ≥1. The most common adverse events were CRS, neutropenia, dysgeusia, and non-rash skin adverse events. Hematological adverse events (neutropenia, anemia, and thrombocytopenia) were the most common grade 3 / 4 events. 87 patients (92.6%) experienced cycle delays or dose adjustments due to adverse events (64 [68.1%] due to infection). Adverse events led to discontinuation of one or both medications in 15 patients (16.0%) (12 patients [12.8%] discontinued due to fatal events). 7 patients (7.4%) discontinued one or both medications due to drug-related adverse events (5 patients [5.3%] due to infection). 14 patients (14.9%) died due to adverse events (11 patients [11.7%] died due to infection). There were six drug-related grade 5 adverse events. 4 patients (4.3%) died due to progressive disease.

[0584] Taste alterations, including dysgeusia, dysgeusia, hypogeusia, and anastomosis, occurred in 61 patients (64.9%), resulting in cycle delay or dose modification in 5 patients (5.3%) and discontinuation in 1 patient (1.1%). Rash and non-rash skin adverse events occurred in 37 patients (39.4%) and 57 patients (60.6%), respectively. All were grade 1 / 2, with the exception of one grade 3 rash adverse event at dose level 5. Rash resulted in cycle delay or dose modification in 2 patients (2.1%). No patients discontinued treatment due to rash or non-rash skin adverse events. Nail-related adverse events occurred in 49 patients (52.1%). All were grade 1 / 2, and none resulted in cycle delay, dose modification, or discontinuation.

[0585] Infection occurred in 84 patients (89.4%), with grade 3 / 4 in 60 patients (63.8%). 47 patients (50.0%) received antiviral prophylaxis for herpes, and 11 patients (11.7%) received antiviral prophylaxis for Pneumocystis ziloveticii pneumonia. 59 patients (62.8%) received COVID-19 vaccination. 38 patients (40.4%) had COVID-19 infection, and 17 patients (18.1%) had grade 3 / 4 events. Two patients (2.1%) had fatal COVID-19 adverse events. The onset of most grade 3 or higher infections occurred within the first 12 months of treatment (65 patients [69.1%]). Opportunistic infections occurred in 10 patients (10.6%). At baseline, 37 patients (39.4%) had hypogammaglobulinemia defined as immunoglobulin G levels <400 mg / dL, compared to 30 patients (31.9%) with post-treatment hypogammaglobulinemia. Evaluation was discontinued for patients with immunoglobulin G myeloma and those who received intravenous immunoglobulin replacement. Intravenous immunoglobulin was administered to 38 patients (40.4%).

[0586] CRS occurred in 74 patients (78.7%), most of which were of low grade. Grade 3 events occurred in 2 patients (2.1%). CRS resulted in cycle delay or dose adjustment in 14 patients (14.9%). The median time to onset and duration of CRS were 2.0 days, respectively. 61 patients (64.9%) received symptomatic treatment for CRS, including tocilizumab in 24 patients (25.5%, 9 for grade 1, 2, and 3 events, respectively). ICANS occurred in 3 patients (3.2%), with one grade 3 event reported. The event occurred during dose escalation, had a median duration of 3.0 days, and all events resolved.

[0587] Effectiveness Across all doses, a response was observed in 77 / 94 (81.9%) patients, including 23 / 34 (67.6%) with EMD. The median time to first response was 1.8 months (range, 0.3–7.7) overall and 2.8 months (range, 1.4–5.1) in patients with EMD. 72 patients (76.6%) achieved a very good partial response or better, and 46 patients (48.9%) achieved a complete response or better. In patients with EMD, 20 patients (58.8%) achieved a very good partial response or better, and 10 patients (29.4%) achieved a complete response or better. Responses were consistent across clinically relevant subgroups.

[0588] At dose level 5, responses occurred in 36 / 44 (81.8%) of patients and 12 / 18 (66.7%) of patients with EMD. The median time to first response was 1.5 months overall (range, 0.3–5.1) and 3.0 months in patients with EMD (range, 1.4–5.1). Deep responses were observed in both patients with and without EMD treated at dose level 5. Responses were consistent across clinically relevant subgroups at this dose level.

[0589] The probability of maintaining a response at 12 and 18 months was 85.6% (95% CI, 74.9–92.0) and 76.6% (95% CI, 64.0–85.3) for all doses, and 91.0% (95% CI, 74.6–97.0) and 85.9% (95% CI, 65.6–94.7) for dose level 5. In patients with EMD, the probability of maintaining a response at 12 and 18 months was 70.0% (95% CI, 45.1–85.3) and 52.5% (95% CI, 25.1–74.1) for all doses, and 81.8% (95% CI, 44.7–95.1) for dose level 5 at both time points. In patients (n=28) who switched from dose level 5 to monthly administration, 27 (96.4%) maintained or deepened their response.

[0590] Across all dose levels, the 12-month and 18-month progression-free survival rates were 70.7% (95% CI, 60.0–79.0) and 62.2% (95% CI, 50.8–71.7) in all patients, and 45.5% (95% CI, 27.7–61.7) and 34.1% (95% CI, 16.5–52.7) in patients with EMD. At dose level 5, the 12-month and 18-month progression-free survival rates were 73.7% (95% CI, 57.4–84.5) and 69.8% (95% CI, 52.4–81.8) in all patients, and 52.9% (95% CI, 27.6–73.0) at both time points in patients with EMD.

[0591] Pharmacokinetics, immunogenicity, and pharmacodynamics At dose level 5, talketamab and teclistamai exposure was comparable to that observed from each drug as monotherapy. No anti-talketamab or anti-teclistamai antibodies were detected post-administration across all dose levels.

[0592] T-cell activation was highly variable but consistent across all doses. At dose level 5, T-cell activation peaked before the initial total therapeutic dose and was then maintained.

[0593] Across all dose levels, the median baseline soluble BCMA concentration was 87.3 ng / ml (range, 4.708–4017) in responders and 210.1 ng / ml (range, 5.015–1224) in non-responders. A decrease in soluble BCMA concentration from baseline to day 1 of cycle 3 was observed across all dose levels in 89% (51 / 57) of responders (median change: -91%, range, -99–471%) and 50% (2 / 4) of non-responders (median change: 62%, range, approximately 98–1719%).

[0594] Consideration Talketamab plus teclistambab had a similar safety profile to that of each drug used as monotherapy. The incidence of grade 3 / 4 infection was 63.8% across all dose levels. The corresponding rates were 55.2% with teclistambab monotherapy and 19.6% and 14.5% with the 0.4 mg / kg QW and 0.8 mg / kg Q2W talketamab monotherapy schedules, respectively. Compared to initial results from this trial (data cutoff March 16, 2023; median follow-up period of 13.4 months), no further deaths due to drug-related adverse events were observed at the longer median follow-up period (20.3 months). The proportion of treatment-related adverse events leading to death or discontinuation was low, and most were due to infection. Prophylactic infection control was recommended and administered in accordance with institutional guidelines. The protocol recommended immunoglobulin supplementation to maintain serum immunoglobulin G levels above 400 mg / dL, regardless of prior or active infection, through close monitoring of hypogammaglobulinemia. Overall, these results reinforce the importance of infection screening, prevention, management, and close monitoring for hypogammaglobulinemia and neutropenia.

[0595] CRS was common and mostly low-grade (no grade 4 / 5 events were observed), and was consistent with T-cell retargeting therapy, including talketamab and teclistamag monotherapy. ICANS was rare, typically low-grade, and resolved with standard palliative care. GPRC5D-related adverse events were common, low-grade, rarely resulting in dose adjustments or discontinuation, and were managed according to protocol recommendations.

[0596] Assessments of overall response rates at previous data cutoffs, including all treated patients with one or more post-baseline disease assessments (excluding patients who died / discontinued before becoming evaluable), yielded not-too-conservative response rates. Across all doses and at the data cutoffs reported herein for dose level 5, responses were observed in 81.9% and 81.8% of patients, respectively, which is very promising. Responses with approved T-cell targeted therapies were observed in 74.1% and 71.7% of patients with talketamab 0.4 mg / kg QW and 0.8 mg / kg Q2W, respectively, 63.0% with teclistamab, 61.0% with erranatamab, 83.0% with siltacapbutane autolucel, and 67.0% with idekabutagenbicleucel. The proportion of patients achieving complete response or better was high across all doses with talketamab + teclistamai (48.9%), particularly high at dose level 5 (52.3%), and promising in the contexts of teclistamai (45.5%) and talketamab monotherapy (33.6% at 0.4 mg / kg QW and 38.7% at 0.8 mg / kg Q2W). At dose level 5, the response was very sustained, with an 85.9% probability of maintaining a response at 18 months. The 18-month duration of response was 36.7% and 48.7% for talketamab 0.4 mg / kg QW and 0.8 mg / kg Q2W monotherapy, respectively, and 57.1% for teclistamai monotherapy. The response was consistent across clinically relevant subgroups, building confidence in the usefulness of this ready-made combination across patient populations, including high-need subgroups.

[0597] BCMA-targeted CAR-T therapy showed a high response rate in patients with EMD, but the patient population included a group with paramedical lesions that had a better prognosis than patients with EMD. The duration of response and progression-free survival with CAR-T therapy were shorter in patients with EMD compared to the overall study population. Similarly, among patients with EMD treated with standard treatment regimens, the proportion of patients achieving a response was lower and progression-free survival was shorter than in patients without EMD. In patients with EMD, the response rates with talketamab monotherapy were 45.5% (0.4 mg / kg QW) and 40.0% (0.8 mg / kg Q2W), and with teclistamag monotherapy it was 37.5%. In RedirecTT-1, 66.7% of patients with EMD achieved a response at dose level 5 (33.3% achieved complete response or better), and the probability of maintaining a response at 18 months was 81.8%.

[0598] The limitations of the trial include a short follow-up period and a small overall sample size. However, this trial had a higher proportion of patients with EMD enrolled compared to other trials of antimyeloma therapy. RedirecTT-1 was an open-label, non-randomized phase 1b / 2 trial, making comparative analysis impossible.

[0599] In this first trial combining two T-cell retargeting bispecific antibodies, talketamab + tecristamag had a similar safety profile to each agent as monotherapy. Responses were observed across the dose levels investigated and were particularly deep and sustained at dose level 5, including in patients with EMD. Based on these results, this novel bitargeted off-the-shelf combination warrants further investigation at dose level 5 in patients with EMD and at other dose levels in patients without EMD.

[0600] Example 2: A study comparing talketamab + pomalidomide, talketamab + tecristamag, and elotuzumab, pomalidomide, and dexamethasone, or pomalidomide, bortezomib, and dexamethasone, in participants with relapsed or refractory myeloma who were administered anti-CD38 antibody and lenalidomide (MonumenTAL-6). This is a randomized, phase 3, active-controlled, parallel, multicenter, interventional, open-label trial in participants with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including anti-CD38 mAb and lenalidomide.

[0601] antibody Talcetamab and teclistamaib were manufactured by Janssen Pharmaceuticals. The antibody sequences are further described in Example 1 above.

[0602] the purpose This is a phase 3 randomized trial comparing investigator's choice of talketamab in combination with pomalidomide (Tal-P), talketamab in combination with tecristamab (Tal-Tec), and either elotuzumab, pomalidomide, and dexamethasone (EPd) or pomalidomide, bortezomib, and dexamethasone (PVd) in participants with relapsed or refractory myeloma who have previously received 1 to 4 lines of treatment including anti-CD38 antibody and lenalidomide.

[0603] The primary objective of this trial is to compare the efficacy of either talketamab plus pomalidomide (Tal-P) or talketamab plus tecristamag (Tal-Tec) with elotuzumab, pomalidomide, and dexamethasone (EPd) or pomalidomide, bortezomib, and dexamethasone (PVd). Secondary objectives include further comparing the efficacy of either Tal-P or Tal-Tec with EPd or PVd, and evaluating the safety and tolerance of Tal-P and Tal-Tec. The primary hypothesis is that Tal-P or Tal-Tec will improve progression-free survival (PFS) compared with EPd or PVd in participants with relapsed or refractory multiple myeloma who have previously received 1 to 4 lines of treatment including anti-CD38 mAb and lenalidomide.

[0604] Approximately 795 participants were randomized to receive Tal-P (ArmA), Tal-Tec (ArmB), or EPd or PVd (ArmC) in a 1:1:1 ratio, and stratified by the number of previous treatment lines (1 vs ≥ 2), ISS stage at screening (I vs II / III), and the investigator's intended treatment choice (EPd vs PVd).

[0605] Test arm and duration The study treatment will be administered in 28-day cycles for Tal-P (Arm A), Tal-Tec (Arm B), and EPd (Arm C). For PVd (Arm C), the study treatment will be administered in 21-day cycles. At screening, at the discretion of the principal investigator, they must declare whether the participant will be treated with EPd or PVd if randomized to Arm C.

[0606] Arm B (Tal-tec) administration schedule In Arm B, participants receive therapy with Tal / Tec (as appropriate) for up to 26 cycles, provided there are no signs of progressive disease or toxicity. The initial Arm B dosing schedule was later updated in protocol revisions as a result of building upon data from other clinical trials involving Tal and Tec. For example, an exploratory ER analysis of the RedirecTT-1 trial showed a trend towards improving the depth of response associated with Q2W talketamab administration in the initial treatment cycle. Reducing the frequency of talketamab administration after response may improve GPRC5D-specific AEs without compromising efficacy. Monthly administration of 3 mg / kg teclistamag in cycle 2 is estimated to achieve equivalent exposure to 1.5 mg / kg Q2W, based on data from trial 64007957MMY1001 (MajesTEC-1) and trial RedirecTT-1. Furthermore, tolerance may be improved with lower dosing frequencies while maintaining response.

[0607] Both the initial Arm B administration schedule and the updated Arm B administration schedule are provided below. The updated Arm B administration schedule is shown in Figure 11.

[0608] Tarketamab: Initial Arm B Dosage Schedule: In Cycle 1 (28-day cycle) of Arm B, the following doses of talketamab will be administered subcutaneously. -First dose escalation of tarketamab (SU1): 0.01 mg / kg, administered on day 1. -Second dose escalation of talketamab (SU2): 0.06 mg / kg, administered ≥2 days after SU1, on days 3-6. - Tarketamab therapeutic dose (sometimes called the third dose escalation): 0.4 mg / kg, administered ≥2 days after SU2, on days 5-10. - Tarketamab therapeutic dose: Administered ≥2 days after the first therapeutic dose (third dose escalation) of 0.8 mg / kg or 0.4 mg / kg, on days 7-15.

[0609] In the subsequent treatment cycle following Cycle 1 (a 28-day treatment cycle), a therapeutic dose of 0.8 mg / kg of talketamab is administered subcutaneously in Arm A as follows: - During cycles 2 to 4 (C2 to C4), talketamab SC is administered every other week (Q2W), i.e., 14 days (±3 days) after the previous therapeutic dose. - If a VGPR or better is confirmed from cycle 5 (C5), the schedule may be changed to Q4W administration at the discretion of the principal investigator (only on day 1 of each 28-day cycle). - Q4W from Cycle 7 (C7) for all participants.

[0610] Teclistamaib: Initial Arm B Dosage Schedule: In Cycle 1 (28-day cycle) of Arm B, the following doses of teclistamag (Tec) will be administered subcutaneously. -First dose escalation of Tec (SU1): 0.06 mg / kg, administered on day 1. -Second dose escalation of Tec (SU2): 0.3 mg / kg, administered ≥2 days after SU1, on days 3-6. -Tec therapeutic dose (sometimes called the third dose escalation): 1.5 mg / kg, administered ≥2 days after SU2, on days 5-10. -Tec therapeutic dose: Administer ≥2 days after the first therapeutic dose (third dose escalation) of 3.0 mg / kg or 1.5 mg / kg, on days 7-15.

[0611] In subsequent treatment cycles following Cycle 1 (a 28-day treatment cycle), a Tec therapeutic dose of 3.0 mg / kg is administered subcutaneously as follows: -Cycle 2 Tec is administered 14 days (±3 days) after the previous therapeutic dose. - If a partial response (PR) or better is confirmed from Cycle 3 (C3), the schedule may be changed to Q4W administration at the discretion of the principal investigator (only on day 1 of each 28-day cycle). - Q4W from Cycle 7 (C7) for all participants.

[0612] Talketamab: Updated Arm B dosing Schedule: Talcetamab is administered in a 28-day treatment cycle as follows: -In Cycle 1, the following doses of talketamab will be administered subcutaneously. ○First dose escalation of tarketamab (SU1): 0.01 mg / kg, administered on day 1. ○Second dose escalation of talketamab (SU2): 0.06 mg / kg, administered ≥2 days after SU1. ○Talketamab therapeutic dose (sometimes called the third dose escalation): 0.4 mg / kg, administered ≥2 days after SU2. ○Talketamab therapeutic dose: Administered ≥2 days after the first therapeutic dose (third dose escalation) of 0.8 mg / kg or 0.4 mg / kg, on days 7-15. -In subsequent treatment cycles following Cycle 1, administer a therapeutic dose of 0.8 mg / kg of talketamab subcutaneously as follows: ○ During cycles 2 to 4 (C2 to C4), talketamab SC is administered every other week (Q2W), i.e., 14 days (±3 days) after the previous therapeutic dose. ○If VGPR or better is confirmed from Cycle 5 (C5), the schedule can be changed to Q4W administration (only on the first day of each 28-day cycle), and the change to Q4W will occur on the first day (±3 days) of Cycle 5 or Cycle 6. ○If a partial response (PR) or better is confirmed on day 1 (±3 days) of cycle 7, the schedule must be changed to Q4W administration. ○If a partial response (PR) or better is not confirmed on day 1 (±3 days) of cycle 7, Q2W administration will be continued until a PR or better is confirmed.

[0613] Teclistamaib: Updated Arm B dosing Schedule: Teclistamaib is administered in a 28-day treatment cycle as follows: -In Cycle 1, the following doses of teclistamag are administered subcutaneously. ○First dose escalation of Tec (SU1): 0.06 mg / kg, administered on day 1. ○Second dose escalation of Tec (SU2): 0.3 mg / kg, administered ≥ 2 days after SU1. ○Tec therapeutic dose (sometimes called the third dose escalation): 1.5 mg / kg, administered ≥ 2 days after SU2. ○Tec therapeutic dose: 1.5 mg / kg, administered ≥ 2 days after the first therapeutic dose (third dose escalation) of 1.5 mg / kg, on days 7-15. -In subsequent treatment cycles following Cycle 1, administer a therapeutic dose of 3.0 mg / kg of Tec subcutaneously as follows: ○ From Cycle 2 (C2), Q4W administration (on day 1 only) was given to all participants (regardless of clinical response).

[0614] When administering talketamab SC and teclistamag SC on the same day, the two drugs should be administered at least 15 minutes apart (it is suggested that talketamab should be administered first).

[0615] Arm C (PVd) administration schedule The medication is administered in a 28-day treatment cycle as follows: - Elotuzumab IV: 10 mg / kg QW for cycles 1 and 2, and 20 mg / kg Q4W for cycle 3+. - Pomalidomide PO: 4 mg / day on days 1-21 of each cycle. There must be a maximum of 7 days between pomalidomide courses in each cycle. - Dexamethasone PO: For those under 75 years old (3-24 hours before elotuzumab), 28 mg QW for C1-C2. For C3+, 28 mg on D1, and 40 mg on D5, D15, and D22. - Dexamethasone PO:> In the case of a 75-year-old (3-24 hours before elotuzumab), For C1-C2, 8mg QW; for C3+, 8mg on D1, and 20mg on D5, D15, and D22. When elotuzumab, pomalidomide, and dexamethasone are administered on the same day, dexamethasone is administered 3 to 24 hours before elotuzumab. Pomalidomide is self-administered by participants at approximately the same time.

[0616] Effectiveness evaluation Efficacy evaluation will be performed using data from serum, urine, bone marrow, and imaging (where applicable), in accordance with IMWG criteria (2016) as defined in the protocol. Response or progression will be assessed by the principal investigator, using computerized algorithms, and by the IRC. The IRC assessment will be used as the primary analysis.

[0617] Primary evaluation criteria: ● Progression-free survival (PFS) [Time frame: up to 7 years and 2 months] PFS is defined as the period from the date of randomization to the earlier of either progressive disease or death.

[0618] Secondary evaluation criteria: ● Overall Response Rate (ORR) [Time frame: Maximum 7 years and 2 months] ORR is defined as the percentage of participants with the best overall response rate, which is partial response (PR) or better, according to the response criteria of the International Myeloma Working Group (IMWG). ● Complete response (CR) or better response rate [Time frame: up to 7 years and 2 months] A complete response (CR) or better is defined as the percentage of participants who have the best overall response (CR or better) according to the IMWG response criteria. ● Very good partial response rate (VGPR) or better [Time frame: up to 7 years and 2 months] VGPR or higher is defined as the percentage of participants who have the best overall response rate of VGPR or higher, according to the IMWG response criteria. ● Minimal Residual Disease (MRD) Negative Complete Reaction Rate [Timeframe: Up to 7 years and 2 months] MRD-negative complete response (CR) is defined as the percentage of participants who achieve both CR or better and MRD negativity at a threshold of 10^-5 at any point after the day of randomization and before disease progression or initiation of subsequent anti-myeloma therapy (SST). ● Overall Survival Time (OS) [Timeframe: Maximum 7 years and 2 months] OS is defined as the time from randomization to the participant's death. ● Progression-free survival (PFS2) in the next treatment line [Time frame: up to 7 years and 2 months] PFS2 is defined as the time from randomization to progression to the next treatment line or death, whichever comes first. ●Time to Next Treatment (TTNT) [Timeframe: Maximum 7 years and 2 months] TTNT is defined as the time from randomization to the start of SST. ● Serum concentrations of talketamab and tecristamab [Time frame: up to 7 years and 2 months] Serum concentrations of talketamab and teclistamai are reported. ● Number of participants with anti-drug antibodies (ADAs) against talketamab and tecristamab [Time frame: up to 7 years and 2 months] We report the number of participants with ADA for talketamab and tecristamag. ●Time to persistent deterioration in symptoms, function, and health-related quality of life (HRQoL) as assessed by the Multiple Myeloma Symptom and Impact Questionnaire (MySIm-Q) [Time frame: up to 7 years and 2 months] The time to sustained deterioration of symptoms, function, and HRQoL is defined as the interval from the randomization date to the onset of meaningful change. MySIm-Q is a disease-specific patient-reported outcome (PRO) assessment that complements the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC-QLQ-C30). It includes 17 items that result in symptom and impact subscales. ●Time to sustained deterioration of symptom, function, and health-related quality of life (HRQoL) as assessed by EORTC-QLQ-C30 [Time frame: up to 7 years and 2 months] The time to sustained deterioration of symptoms, function, and HRQoL is defined as the interval from the randomization date to the onset of meaningful change. The EORTC-QLQ-C30 version 3 includes 30 items comprising five function scales (physical, role, emotional, cognitive, and social), one overall health status scale, three symptom scales (pain, fatigue, and nausea or vomiting), and five single symptom items (dyspnea, insomnia, loss of appetite, constipation, and diarrhea) and one impact item (financial hardship). The recall period is 7 days ("the past week"), and responses are reported using verbal and numerical rating scales. Item and scale scores are converted to a 0-100 scale. Higher scale scores represent higher levels of response. ●Time to sustained deterioration of symptom, function, and health-related quality of life (HRQoL) as assessed by the EuroQol 5-Dimensional Questionnaire (EQ-5D-5L) [Time frame: up to 7 years and 2 months] The time to sustained deterioration of symptoms, function, and HRQoL is defined as the interval from the randomization date to the onset of meaningful change. The EQ-5D-5L consists of a five-item questionnaire that assesses five areas, including mobility, self-care, usual activity, pain or discomfort, and anxiety or depression, plus a visual analog scale that assesses "health today" with anchors ranging from 0 (worst-case scenario) to 100 (best-case scenario). ●Time to sustained deterioration of symptoms, function, and health-related quality of life (HRQoL) as assessed by Patient Global Impression - Severity (PGI-S) [Time frame: up to 7 years and 2 months] The time to sustained deterioration of symptoms, function, and HRQoL is defined as the interval from the randomization date to the onset of a meaningful change. The PGI-S is used as an anchor, external criterion for determining meaningful changes in scores for MySIm-Q and EORTC-QLQ-C30 in this population. Response options are presented as a 5-point verbal rating scale ranging from "none" to "very severe." ●Time to sustained deterioration of symptoms, function, and health-related quality of life (HRQoL) as assessed by the Epstein Taste Survey [Time frame: up to 7 years and 2 months] The time to sustained deterioration of symptoms, function, and HRQoL is defined as the interval from the randomization date to the onset of a meaningful change. The Epstein Taste Survey consists of 17 items out of a total of 71 PRO scales that are specific to changes in taste. It was developed for use in patients with head and neck cancer as a composite of the Vanderbilt Head and Neck Symptom Survey. ●Changes from baseline in symptoms, function, and health-related quality of life (HRQoL) as assessed by MySIm-Q [Time frame: up to 7 years and 2 months] This report details changes from baseline in symptoms, function, and HRQoL as assessed by MySIm-Q. MySIm-Q is a disease-specific patient-reported outcome (PRO) assessment that complements the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC-QLQ-C30). It includes 17 items that result in symptom and impact subscales. ●Changes from baseline in symptoms, function, and health-related quality of life (HRQoL) as assessed by EORTC-QLQ-C30 [Time frame: up to 7 years and 2 months] Changes from baseline in symptoms, function, and HRQoL as assessed by the EORTC-QLQ-C30 are reported. EORTC-QLQ-C30 version 3 includes 30 items comprising five function scales (physical, role, emotional, cognitive, and social), one overall health status scale, three symptom scales (pain, fatigue, and nausea or vomiting), and five single symptom items (dyspnea, insomnia, loss of appetite, constipation, and diarrhea) and one impact item (financial hardship). The recall period is 7 days ("the past week"), and responses are reported using verbal and numerical scoring scales. Item and scale scores are converted to a 0-100 scale. Higher scale scores represent higher levels of response. Therefore, high scores on function scales represent high or healthy levels of function, high scores on overall health status represent high HRQoL, while high scores on symptom scales or items represent high levels of symptoms or problems. ●Changes from baseline in symptoms, function, and health-related quality of life (HRQoL) as assessed by EQ-5D-5L [Time frame: up to 7 years and 2 months] Changes from baseline in symptoms, function, and HRQoL as assessed by the EQ-5D-5L are reported. The EQ-5D-5L is a five-item questionnaire that assesses five areas, including mobility, self-care, usual activity, pain or discomfort, and anxiety or depression, plus a visual analog scale that assesses "health today" with anchors ranging from 0 (worst-case scenario) to 100 (best-case scenario). ● Changes from baseline in symptoms, function, and health-related quality of life (HRQoL) as assessed by PGI-S [Time frame: up to 7 years and 2 months] Changes from baseline in symptoms, function, and HRQoL assessed by the PGI-S are reported. The PGI-S is used as an anchor, external criterion to determine meaningful changes in scores for MySIm-Q and EORTC-QLQ-C30 in this population. Response options are presented as a 5-point verbal rating scale ranging from "none" to "very severe." ●Changes from baseline in symptoms, function, and health-related quality of life (HRQoL) as assessed by the Epstein Taste Survey [Time frame: up to 7 years and 2 months] Changes from baseline in symptoms, function, and HRQoL as assessed by the Epstein Taste Scale are reported. The Epstein Taste Scale consists of 17 items out of a total of 71 PRO scales that are specific to changes in taste. It was developed for use in patients with head and neck cancer as a composite of the Vanderbilt Head and Neck Symptom Scale. ●Percentage of participants with significant improvement in HRQoL as assessed by EORTC-QLQ-C30 [Time frame: up to 7 years and 2 months] The percentage of participants with a significant improvement in HRQoL as assessed by the EORTC-QLQ-C30 is reported. EORTC-QLQ-C30 version 3 includes 30 items comprising five function scales (physical, role, emotional, cognitive, and social), one overall health status scale, three symptom scales (pain, fatigue, and nausea or vomiting), and five single symptom items (dyspnea, insomnia, loss of appetite, constipation, and diarrhea) and one impact item (financial hardship). The recall period is 7 days ("the past week"), and responses are reported using verbal and numerical rating scales. Item and scale scores are converted to a 0-100 scale. Higher scale scores represent higher levels of response. Therefore, high scores on function scales represent high or healthy levels of function, high scores on overall health status represent high HRQoL, while high scores on symptom scales or items represent high levels of symptoms or problems.

[0619] [Table 16]

[0620] Selection criteria: - Multiple myeloma as defined by the following criteria will be recorded: (a) Diagnosis of multiple myeloma in accordance with the International Myeloma Working Group (IMWG) diagnostic criteria; (b) Measurable disease at screening, as assessed by the central laboratory, as defined by any of the following: (i) Serum M protein level ≥ 0.5 grams / deciliter (g / dL), or (ii) Urinary M protein level ≥ 200 milligrams (mg) / 24 hours, or (iii) Light chain multiple myeloma without measurable M protein in serum or urine: Serum immunoglobulin (Ig) free light chain (FLC) ≥ 10 milligrams / deciliter (mg / dL) and abnormal serum Ig kappa-lambda FLC ratio -Relapsing or refractory diseases as defined below: a) Relapsing disease is defined when progressive disease (PD) is confirmed by IMWG criteria more than 60 days after discontinuation of treatment following an initial response to previous treatment; b) Refractory disease is defined when the decrease in M ​​protein is less than 25 percent (%) (<) during previous treatment or within 60 days (≤) of discontinuation of treatment, or when PD is confirmed by IMWG criteria. - Evidence of failure to achieve disease progression (PD) or minimum response to the final treatment line is documented, based on the response decision made by the principal investigator according to IMWG criteria at the time of the final regimen or thereafter. - Having a performance status score of 0, 1, or 2 in the Eastern Cooperative Oncology Group (ECOG) at the time of screening and immediately before the start of administration of the investigational treatment. - Participants must agree not to become pregnant, breastfeed, or plan to become pregnant during their enrollment in this study or within six months after the last dose of the study treatment.

[0621] Exclusion criteria: - Contraindications to the test drug or its excipients, or life-threatening allergies, hypersensitivity, or intolerances. - Stroke, transient ischemic attack, or seizure within 6 months prior to signing the informed consent form (ICF) - The participant has undergone major surgery or suffered a severe injury within two weeks prior to the start of administration of the study treatment, or has not fully recovered from surgery, or has scheduled major surgery during the period in which the participant is expected to be treated in the study or within two weeks of the administration of the final dose of the study treatment. - Maximum cumulative dose of ≥140 mg of prednisone or equivalent corticosteroid within the 14-day period prior to the first administration of the study drug. - The appearance of clinical signs of known central nervous system (CNS) involvement or meningeal involvement in multiple myeloma. - If either is suspected, negative whole-brain magnetic resonance imaging (MRI) and lumbar cytology are required.

Claims

1. A method for treating multiple myeloma in patients requiring treatment for multiple myeloma, A method comprising administering a combination regimen containing a therapeutically effective amount of BCMAxCD3 bispecific antibody and a therapeutically effective amount of GPRC5DxCD3 bispecific antibody to the subject.

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 2, wherein the BCMA × CD3 bispecific antibody comprises a BCMA-binding domain having 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 a CD3-binding domain having 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-specific IgG4 antibody from which the BCMA-binding arm is derived includes S228P, L234A, and L235A substitutions in the Fc region.

10. The method according to any one of claims 1 to 9, wherein the Fc region of the CD3-specific IgG4 antibody from which the CD3 binding arm is derived includes S228P, L234A, L235A, F405L, and R409K substitutions in the Fc region.

11. The method according to any one of claims 1 to 5, 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 5, 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 5, 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 5, 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 14, wherein the BCMAxCD3 bispecific antibody is tecristamag.

16. The method according to any one of claims 1 to 15, wherein the GPRC5D × CD3 bispecific antibody comprises a GPRC5D binding domain including HCDR1 of SEQ ID NO: 24, HCDR2 of SEQ ID NO: 25, HCDR3 of SEQ ID NO: 26, LCDR1 of SEQ ID NO: 27, LCDR2 of SEQ ID NO: 28, and LCDR3 of SEQ ID NO: 29, 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.

17. The method according to any one of claims 1 to 16, wherein the GPRC5D × CD3 bispecific antibody comprises a GPRC5D binding domain including a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 30 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 31, and a CD3 binding domain including 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.

18. The method according to any one of claims 1 to 17, wherein the GPRC5DxCD3 bispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.

19. The method according to any one of claims 1 to 18, wherein the GPRC5DxCD3 bispecific antibody is of the IgG4 isotype.

20. The method according to any one of claims 1 to 19, wherein the GPRC5DxCD3 bispecific antibody comprises one or more substitutions in its Fc region.

21. The method according to any one of claims 1 to 20, wherein the GPRC5DxCD3 bispecific antibody is of the IgG4 isotype and comprises S228P, F234A and L235A substitutions in its Fc region.

22. The method according to any one of claims 1 to 21, wherein the GPRC5DxCD3 bispecific antibody is of the IgG4 isotype and comprises S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region.

23. The method according to any one of claims 1 to 22, wherein the Fc region of the GPRC5D-specific IgG4 antibody from which the GPRC5D-binding arm is derived includes S228P, L234A, and L235A substitutions in the Fc region.

24. The method according to any one of claims 1 to 23, wherein the Fc region of the CD3-specific IgG4 antibody from which the CD3 binding arm is derived includes S228P, L234A, L235A, F405L, and R409K substitutions in the Fc region.

25. The method according to any one of claims 1 to 19, wherein the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 32, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 33, 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.

26. The method according to any one of claims 1 to 19, wherein the GPRC5DxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 32, a first light chain (LC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 33, 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.

27. The method according to any one of claims 1 to 19, wherein the GPRC5DxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 32, a first light chain (LC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 33, 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.

28. The method according to any one of claims 1 to 19, wherein the GPRC5DxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 32, a first light chain (LC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 33, 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.

29. The method according to any one of claims 1 to 28, wherein the GPRC5D × CD3 bispecific antibody is talketamab.

30. The method according to any one of claims 1 to 29, wherein the subject has relapsed or refractory multiple myeloma.

31. The method according to any one of claims 1 to 30, wherein the subject has previously received at least three treatment lines.

32. The method according to any one of claims 1 to 30, wherein the subject has previously received at least four treatment lines.

33. The method according to any one of claims 1 to 30, wherein the subject has previously received at least five treatment lines (five-drug exposure).

34. The method according to any one of claims 1 to 30, wherein the subject has previously received at least three lines of treatment comprising a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody.

35. The method according to any one of claims 1 to 30, wherein the subject has previously received at least four lines of treatment comprising a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody.

36. The method according to any one of claims 1 to 35, wherein the subject has an extramedullary disease (EMD).

37. The method according to any one of claims 1 to 36, comprising subcutaneously administering one or more escalating doses of the BCMAxCD3 bispecific antibody to the subject before administering a therapeutic dose of the BCMAxCD3 bispecific antibody.

38. The method according to any one of claims 1 to 37, comprising subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody to the subject weekly (QW).

39. The method according to any one of claims 1 to 37, comprising subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody to the subject every two weeks (Q2W).

40. The method according to any one of claims 1 to 37, comprising subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 750 μg / kg to approximately 1500 μg / kg on a weekly (QW) basis.

41. The method according to any one of claims 1 to 37, comprising subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 750 μg / kg every week (QW).

42. The method according to any one of claims 1 to 37, comprising subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg every week (QW).

43. The method according to any one of claims 1 to 37, comprising subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg to approximately 3000 μg / kg every two weeks (Q2W).

44. The method according to any one of claims 1 to 37, comprising subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 1500 μg / kg every two weeks (Q2W).

45. The method according to any one of claims 1 to 37, comprising subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of approximately 3000 μg / kg every two weeks (Q2W).

46. The method according to any one of claims 37 to 45, comprising subcutaneously administering two or three escalating doses of the BCMAxCD3 bispecific antibody before subcutaneously administering a therapeutic dose.

47. The method according to any one of claims 37 to 46, comprising subcutaneously administering the BCMAxCD3 bispecific antibody in gradually increasing doses of 60 μg / kg and 300 μg / kg before subcutaneously administering a therapeutic dose.

48. The method according to any one of claims 37 to 47, 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 a therapeutic dose.

49. The method according to any one of claims 37 to 48, comprising subcutaneously administering the BCMAxCD3 bispecific antibody in gradually increasing doses, with intervals of 2 to 4 days between each dose.

50. The method according to any one of claims 1 to 49, comprising subcutaneously administering one or more incremental doses of the GPRC5DxCD3 bispecific antibody to the subject before administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody.

51. The method according to any one of claims 1 to 50, comprising subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject weekly (QW).

52. The method according to any one of claims 1 to 50, comprising subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject every two weeks (Q2W).

53. The method according to any one of claims 1 to 50, comprising subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 200 μg / kg to approximately 400 μg / kg on a weekly (QW) basis.

54. The method according to any one of claims 1 to 50, comprising subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 200 μg / kg every week (QW).

55. The method according to any one of claims 1 to 50, comprising subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 400 μg / kg every week (QW).

56. The method according to any one of claims 1 to 50, comprising subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 800 μg / kg every two weeks (Q2W).

57. The method according to any one of claims 50 to 56, comprising subcutaneously administering two or three escalating doses of the GPRC5DxCD3 bispecific antibody before subcutaneously administering a therapeutic dose.

58. The method according to any one of claims 50 to 57, comprising subcutaneously administering the GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg and 60 μg / kg before subcutaneously administering a therapeutic dose.

59. The method according to any one of claims 50 to 58, comprising subcutaneously administering the GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneously administering a therapeutic dose.

60. The method according to any one of claims 50 to 59, comprising administering the GPRC5DxCD3 bispecific antibody subcutaneously in gradually increasing doses, with a gap of 2 to 4 days between doses.

61. The method according to any one of claims 1 to 36, comprising subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of 3000 μg / kg every two weeks (Q2W) and subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of 800 μg / kg every two weeks (Q2W).

62. The method according to any one of claims 1 to 36, comprising subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg every two weeks (Q2W) and subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of 800 μg / kg every two weeks (Q2W).

63. The method according to any one of claims 1 to 36, comprising subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg weekly (QW) and subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of 800 μg / kg weekly (QW).

64. The method according to any one of claims 1 to 36, comprising subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg every week (QW) and subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of 400 μg / kg every week (QW).

65. The method according to any one of claims 1 to 36, comprising subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of 1500 μg / kg weekly (QW) and subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of 200 μg / kg weekly (QW).

66. The method according to any one of claims 1 to 36, comprising subcutaneously administering the BCMAxCD3 bispecific antibody at a therapeutic dose of 750 μg / kg weekly (QW) and subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of 200 μg / kg weekly (QW).

67. The method according to any one of claims 61 to 66, comprising: subcutaneously administering one or more escalating doses of the BCMAxCD3 bispecific antibody before subcutaneously administering a therapeutic dose; and subcutaneously administering one or more escalating doses of the GPRC5DxCD3 bispecific antibody before subcutaneously administering a therapeutic dose.

68. The method according to any one of claims 61 to 67, comprising subcutaneously administering two or three escalating doses of the BCMAxCD3 bispecific antibody before subcutaneously administering a therapeutic dose, and subcutaneously administering two or three escalating doses of the GPRC5DxCD3 bispecific antibody before subcutaneously administering a therapeutic dose.

69. The method according to any one of claims 61 to 68, comprising: subcutaneously administering the BCMAxCD3 bispecific antibody in gradually increasing doses of 60 μg / kg and 300 μg / kg before subcutaneously administering the therapeutic dose; and subcutaneously administering the GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg and 60 μg / kg before subcutaneously administering the therapeutic dose.

70. The method according to any one of claims 61 to 69, 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 therapeutic dose; and subcutaneously administering the GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg and 300 μg / kg before subcutaneously administering the therapeutic dose.

71. The method according to any one of claims 61 to 69, 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 therapeutic dose; and subcutaneously administering the GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg and 400 μg / kg before subcutaneously administering the therapeutic dose.

72. The method according to any one of claims 67 to 71, wherein the escalating doses of the BCMAxCD3 bispecific antibody are administered with a gap of 2 to 4 days between each other, and the escalating doses of the GPRC5DxCD3 bispecific antibody are administered with a gap of 2 to 4 days between each other.

73. The method according to any one of claims 1 to 72, wherein each therapeutic dose of the BCMAxCD3 bispecific antibody is administered on the same day as each therapeutic dose of the GPRC5DxCD3 bispecific antibody.

74. The method according to any one of claims 1 to 73, wherein each escalating dose of the BCMAxCD3 bispecific antibody is administered on the same day as each escalating dose of the GPRC5DxCD3 bispecific antibody.

75. The first therapeutic dose of the BCMAxCD3 bispecific antibody and the first therapeutic dose of the GPRC5DxCD3 bispecific antibody are administered subcutaneously on day 1 of cycle 1 of a 28-day cycle. During Q2W, for example, on day 1 and day 15 (±3 days) of each 28-day cycle, the subsequent therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously at a dose of 800 μg / kg. The method according to any one of claims 1 to 36, wherein, for example, on day 1 and day 15 (±3 days) of a 28-day cycle during Q2W, a subsequent therapeutic dose of the BCMAxCD3 bispecific antibody is subcutaneously administered at a dose of 3000 μg / kg.

76. The method according to claim 75, 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; and subcutaneously administering the GPRC5DxCD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg and 400 μg / kg before subcutaneously administering the first therapeutic dose, wherein the first therapeutic dose is administered 2 to 4 days after the administration of the final gradually increasing dose of each bispecific antibody.

77. The method according to any one of claims 1 to 76, wherein the method achieves a partial response, a very good partial response, a complete response, or a perfect complete response in the subject, as determined by the IMWG response criteria.

78. The method according to claim 77, wherein the subject has an extramedullary disease (EMD).

79. The method according to any one of claims 1 to 77, wherein the method achieves an overall response rate of at least 70% in a target population having relapsed or refractory multiple myeloma (RRMM).

80. The method according to claim 79, wherein the subject has an extramedullary disease (EMD).

81. The method according to any one of claims 1 to 77, wherein the method achieves an overall response rate of at least 80% in a population of subjects having RRMM.

82. The method according to claim 81, wherein the subject has an extramedullary disease (EMD).

83. The method according to any one of claims 1 to 77, wherein the method achieves an overall response rate of at least 85% in a population of subjects having RRMM.

84. The method according to claim 83, wherein the subject has an extramedullary disease (EMD).

85. The method according to any one of claims 1 to 77, wherein the method achieves an overall response rate of at least 90% in a population of subjects having RRMM.

86. The method according to any one of claims 1 to 77, wherein the method achieves an overall response rate of at least 95% in a population of subjects having RRMM.

87. The method according to any one of claims 1 to 77, wherein the method achieves at least 20% complete response or a strict complete response rate in a population of subjects having RRMM.

88. The method according to claim 87, wherein the subject has an extramedullary disease (EMD).

89. The method according to any one of claims 1 to 77, wherein the method achieves at least 25% complete response or a strict complete response rate in a population of subjects having RRMM.

90. The method according to claim 89, wherein the subject has an extramedullary disease (EMD).

91. The method according to any one of claims 1 to 77, wherein the method achieves at least 30% complete response or a strict complete response rate in a population of subjects having RRMM.

92. The method according to claim 91, wherein the subject has an extramedullary disease (EMD).

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