Methods for treating multiple myeloma with car-t cells and bispecific antibodies

Abstract

Provided herein are methods of treating cancer in a subject in need thereof. In some embodiments, the method comprises administering an anti-BCMA CAR-T cell and a GPRC5DxCD3 bispecific antibody. In some embodiments, the method comprises administering an anti-BMCA CAR-T cell, a GPRC5DxCD3 bispecific antibody, and a BCMAxCD3 bispecific antibody.

Description

Docket No.258199.091802 (JBI6871WOPCT1) METHODS FOR TREATING MULTIPLE MYELOMA WITH CAR-T CELLS AND BISPECIFIC ANTIBODIES CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of United States Provisional Application Serial No.63 / 642,016, filed May 3, 2024, the entire contents of which are incorporated herein by reference in their entirety. SEQUENCE LISTING

[0002] This application contains a computer readable Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “258199091802 (JBI6871WOPCT1) Sequence Listing.xml”, was created on April 24, 2025 and is 155,648 bytes in size. BACKGROUND

[0003] Multiple myeloma is a neoplasm of plasma cells that is aggressive. Multiple myeloma is considered to be a B-cell neoplasm that proliferates uncontrollably in the bone marrow. Symptoms include one or more of hypercalcemia, renal insufficiency, anemia, bony lesions, bacterial infections, hyperviscosity and amyloidosis. Multiple myeloma is still considered to be an almost incurable disease, despite availability of new therapies that include proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies that have significantly improved patient outcomes. Because most patients will either relapse or become refractory to treatment, there is an ongoing need for new therapies for multiple myeloma. SUMMARY OF THE DISCLOSURE

[0004] Disclosed herein are methods of treating cancer in a subject in need thereof. In some embodiments, the method comprises administering an anti-BCMA CAR-T cell and a GPRC5DxCD3 bispecific antibody. In some embodiments, the method comprises administering an anti-BMCA CAR-T cell, a GPRC5DxCD3 bispecific antibody, and a BCMAxCD3 bispecific antibody. -1- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0005] Disclosed herein are a method of treating multiple myeloma in a subject in need thereof, the method comprising: administering a GPRC5DxCD3 bispecific antibody to the subject, and administering ciltacabtagene autoleucel to the subject; wherein the administration of the GPRC5DxCD3 bispecific antibody occurs before the administration of ciltacabtagene autoleucel.

[0006] In some embodiments, the subject has newly diagnosed multiple myeloma based on International Myeloma Working Group (IMWG) diagnostic criteria. In some embodiments, the subject has standard-risk multiple myeloma based on revised International Staging System (R-ISS) diagnostic criteria. In some embodiments, the subject is stem cell transplant eligible. In some embodiments, the subject is fit or intermediate-fit based on IMWG Frailty Index assessment.

[0007] In some embodiments, the GPRC5DxCD3 bispecific antibody comprises a GPRC5D binding domain comprising the HCDR1 of SEQ ID NO: 101, the HCDR2 of SEQ ID NO: 102, the HCDR3 of SEQ ID NO: 103, the LCDR1 of SEQ ID NO: 104, the LCDR2 of SEQ ID NO: 105 and the LCDR3 of SEQ ID NO: 106, and a CD3 binding domain comprising the HCDR1 of SEQ ID NO: 107, the HCDR2 of SEQ ID NO: 108, the HCDR3 of SEQ ID NO: 109, the LCDR1 of SEQ ID NO: 110, the LCDR2 of SEQ ID NO: 111 and the LCDR3 of SEQ ID NO: 112. In some embodiments, the GPRC5D binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 113 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 114, and the CD3 binding domain comprises a VH having the amino acid sequence of SEQ ID NO: 115 and a VL having the amino acid sequence of SEQ ID NO: 116. In some embodiments, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in a first heavy chain (HC1) and leucine at position 405 and lysine at position 409 in a second heavy chain (HC2), wherein residue numbering is according to the EU Index. In some embodiments the GPRC5DxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234 and alanine at position 235 in both the HC1 and the HC2. In some embodiments, the GPRC5DxCD3 bispecific antibody comprises the HC1 having the amino acid sequence of SEQ ID NO: 117, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 118, the HC2 having the amino acid sequence of SEQ ID NO: 119 and a second light chain (LC2) having the amino acid sequence -2- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) of SEQ ID NO: 120. In some embodiments, the GPRC5DxCD3 bispecific antibody is talquetamab.

[0008] In some embodiments, the administration of the GPRC5DxCD3 bispecific antibody is once every 2 weeks (Q2W) at a dosage of about 0.8 mg / kg. In some embodiments, the administration of the GPRC5DxCD3 bispecific antibody is weekly at a dosage of about 0.4 mg / kg. In some embodiments, the GPRC5D x CD3 bispecific antibody is administered subcutaneously.

[0009] In some embodiments, the subject is further administered an anti-CD38 antibody. In some embodiments, the anti-CD38 antibody is administered simultaneously with the administration of the GPRC5DxCD3 bispecific antibody. In some embodiments, the anti- CD38 antibody is co-administered with the GPRC5DxCD3 bispecific antibody. In some embodiments, the anti-CD38 antibody is administered sequentially with the administration of the GPRC5DxCD3 bispecific antibody. For example, in some embodiments, the anti-CD38 antibody is administered about 1 hour prior to the administration of the GPRC5DxCD3 bispecific antibody. In some embodiments, the anti-CD38 antibody is selected from the group consisting of daratumumab, isatuximab, and felzartamab. In some embodiments, the anti- CD38 antibody is daratumumab. In some embodiments, the administration of the anti-CD38 antibody is 1800 mg per dose. In some embodiments, the anti-CD38 antibody is administered subcutaneously.

[0010] In some embodiments, ciltacabtagene autoleucel is administered to the subject at a dose of about 0.5 to about 1.0 × 106CAR-positive viable T cells / kg. In some embodiments, ciltacabtagene autoleucel is administered to the subject at a dose of about 0.75 × 106CAR- positive viable T cells / kg.

[0011] In some embodiments, the method further comprises administering a conditioning regimen to the subject prior to administering ciltacabtagene autoleucel, wherein the conditioning regimen comprises one or more of cyclophosphamide and / or fludarabine. In some embodiments, the conditioning regimen comprises cyclophosphamide at a dosage of about 300 mg / m2. In some embodiments, the conditioning regimen comprises fludarabine at a dosage of about 30 mg / m2. In some embodiments, the conditioning regimen comprises cyclophosphamide at a dosage of about 300 mg / m2and fludarabine at a dosage of about 30 mg / m2. In some embodiments, the conditioning regimen is administered to the subject daily, for up to 3 days. In some embodiments, the ciltacabtagene autoleucel is administered to the subject 5 to 7 days after the start of the administration of the conditioning regimen. -3- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0012] In some embodiments, the method further comprises administering an induction therapy to the subject prior to administering the GPRC5DxCD3 bispecific antibody. In some embodiments, the induction therapy comprises daratumumab, bortezomib, lenalidomide, dexamethasone, or some combination thereof. In some embodiments, the induction therapy comprises 4 cycles of about 1800 mg of daratumumab, about 1.3 mg / m2of bortezomib, about 25 mg of lenalidomide, and about 40 mg of dexamethasone (DVRd). In some embodiments, each cycle of DVRd is about 28 days.

[0013] In some embodiments, the method further comprises the collection of apheresis material from the subject for the manufacturing of ciltacabtagene autoleucel. In some embodiments, the collection of apheresis material occurs prior to the administration of the GPRC5DxCD3 antibody. In some embodiments, the collection of apheresis material occurs prior to the administration of the induction therapy.

[0014] In some embodiments, the subject is administered 4 cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody. In some embodiments, each cycle of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody is about 28 days. In some embodiments,

[0015] In some embodiments, the subject receives three consecutive step-up doses of the GPRC5DxCD3 bispecific antibody of about 0.01 mg / kg, about 0.06 mg / kg, and about 0.4 mg / kg, prior to receiving the 0.8 mg / kg dose every 2 weeks. In some embodiments, the three consecutive step-up doses are administered 2, 3, 4, or 5 days apart.

[0016] In some embodiments, the first cycle of the 4 cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody comprises: the administration of a first step-up dose of 0.01 mg / kg of the GPRC5DxCD3 bispecific antibody and the administration of a first 1800 mg dose of the anti-CD38 antibody, the administration of a second step-up dose of 0.06 mg / kg of the GPRC5DxCD3 bispecific antibody 2, 3, 4, or 5 days after the administration of the first step-up dose, the administration of a third step-up dose of 0.4 mg / kg of the GPRC5DxCD3 bispecific antibody 6, 7, 8 or 9 days after the administration of the first step-up dose, and the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody two or more days after the administration of the third step-up dose, and, optionally, about 14 days after the administration of the first step-up dose, and the administration of a second 1800 mg dose of the anti-CD38 antibody. -4- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0017] In some embodiments, the second through fourth cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody each comprise the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody and the administration of 1800 mg of the anti-CD38 antibody once every 2 weeks (Q2W).

[0018] In some embodiments, the second cycle of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody comprises the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody and the administration of 1800 mg of the anti-CD38 antibody once every 2 weeks (Q2W). In some embodiments, the third and fourth cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody each comprise the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody and the administration of 1800 mg of the anti-CD38 antibody once every 4 weeks (Q4W).

[0019] In some embodiments, the method achieves a partial response (PR), very good partial response (VGPR), complete response (CR) or stringent complete response (sCR) in the subject, according to IMWG criteria. In some embodiments, the method achieves a very good partial response (VGPR), complete response (CR) or stringent complete response (sCR) in the subject, according to IMWG criteria. In some embodiments, the method achieves a complete response (CR) or stringent complete response (sCR) in the subject, according to IMWG criteria. In some embodiments, the method achieves a stringent complete response (sCR) in the subject, according to IMWG criteria. In some embodiments, the method achieves minimal residual disease (MRD) negativity at a threshold of 10-5before disease progression or start of a subsequent antimyeloma therapy. In some embodiments, the method achieves sustained MRD-negative status, as determined by next generation sequencing (NGS) with sensitivity of 10-5, for at least 6 months without examination showing MRD- positive or progressive disease (PD) in between.

[0020] Disclosed herein is a method of treating multiple myeloma in a subject in need thereof, the method comprising: administering ciltacabtagene autoleucel to the subject, administering a GPRC5DxCD3 bispecific antibody to the subject, and administering a BCMAxCD3 bispecific antibody to the subject; wherein the administration of the ciltacabtagene autoleucel occurs before the administration of GPRC5DxCD3 bispecific antibody or the BCMAxCD3 bispecific antibody. -5- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0021] In some embodiments, the subject has wherein the subject has newly diagnosed multiple myeloma based on International Myeloma Working Group (IMWG) diagnostic criteria. In some embodiments, the subject has standard-risk multiple myeloma based on revised International Staging System (R-ISS) diagnostic criteria. In some embodiments, the subject is stem cell transplant eligible. In some embodiments, the subject is fit or intermediate-fit based on IMWG Frailty Index assessment.

[0022] In some embodiments, the GPRC5DxCD3 bispecific antibody comprises a GPRC5D binding domain comprising the HCDR1 of SEQ ID NO: 101, the HCDR2 of SEQ ID NO: 102, the HCDR3 of SEQ ID NO: 103, the LCDR1 of SEQ ID NO: 104, the LCDR2 of SEQ ID NO: 105 and the LCDR3 of SEQ ID NO: 106, and a CD3 binding domain comprising the HCDR1 of SEQ ID NO: 107, the HCDR2 of SEQ ID NO: 108, the HCDR3 of SEQ ID NO: 109, the LCDR1 of SEQ ID NO: 110, the LCDR2 of SEQ ID NO: 111 and the LCDR3 of SEQ ID NO: 112. In some embodiments, the GPRC5D binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 113 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 114, and the CD3 binding domain comprises a VH having the amino acid sequence of SEQ ID NO: 115 and a VL having the amino acid sequence of SEQ ID NO: 116. In some embodiments, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in a first heavy chain (HC1) and leucine at position 405 and lysine at position 409 in a second heavy chain (HC2), wherein residue numbering is according to the EU Index. In some embodiments, the GPRC5DxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234 and alanine at position 235 in both the HC1 and the HC2. In some embodiments, the GPRC5DxCD3 bispecific antibody comprises the HC1 having the amino acid sequence of SEQ ID NO: 117, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 118, the HC2 having the amino acid sequence of SEQ ID NO: 119 and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 120. In some embodiments, the GPRC5DxCD3 bispecific antibody is talquetamab.

[0023] In some embodiments, the administration of the GPRC5DxCD3 bispecific antibody is once every 2 weeks (Q2W) at a dosage of about 0.8 mg / kg. In some embodiments, the administration of the GPRC5DxCD3 bispecific antibody is weekly at a dosage of about 0.4 mg / kg. In some embodiments, the GPRC5D x CD3 bispecific antibody is administered subcutaneously. -6- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0024] In some embodiments, the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising the HCDR1 of SEQ ID NO: 218, the HCDR2 of SEQ ID NO: 219, the HCDR3 of SEQ ID NO: 220, the LCDR1 of SEQ ID NO: 221, the LCDR2 of SEQ ID NO: 222 and the LCDR3 of SEQ ID NO: 223, and a CD3 binding domain comprising the HCDR1 of SEQ ID NO: 228, the HCDR2 of SEQ ID NO: 229, the HCDR3 of SEQ ID NO: 230, the LCDR1 of SEQ ID NO: 231, the LCDR2 of SEQ ID NO: 232 and the LCDR3 of SEQ ID NO: 233. In some embodiments, the BCMA binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 224 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 225, and the CD3 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 234 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 235. In some embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in the HC1 and leucine at position 405 and lysine at position 409 in the HC2, wherein residue numbering is according to the EU Index. In some embodiments, the BCMAxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234 and alanine at position 235 in both the HC1 and the HC2. In some embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 226, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 227, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 236 and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 237. In some embodiments, the BCMAxCD3 bispecific antibody is teclistamab.

[0025] In some embodiments, the administration of the BCMAxCD3 bispecific antibody is once every 2 weeks (Q2W) at a dosage of about 3.0 mg / kg. In some embodiments, the BCMAxCD3 bispecific antibody is administered subcutaneously.

[0026] In some embodiments, the subject is further administered an anti-CD38 antibody. In some embodiments, the anti-CD38 antibody is administered sequentially with the administration of the GPRC5DxCD3 bispecific antibody. For example, in some embodiments, the anti-CD38 antibody is administered about 1 hour before the administration of the GPRC5DxCD3 bispecific antibody. In some embodiments, the anti-CD38 antibody is administered sequentially with the administration of the BCMAxCD3 bispecific antibody. For example, in some embodiments, the anti-CD38 antibody is administered about 1 hour before the administration of the BCMAxCD3 bispecific antibody. -7- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0027] In some embodiments, the anti-CD38 antibody is selected from the group consisting of daratumumab, isatuximab, and felzartamab. In some embodiments, the anti- CD38 antibody is daratumumab.

[0028] In some embodiments, the administration of the anti-CD38 antibody is about 1800 mg per dose. In some embodiments, the anti-CD38 antibody is administered subcutaneously.

[0029] In some embodiments, ciltacabtagene autoleucel is administered to the subject at a dose of about 0.5 to about 1.0 × 106CAR-positive viable T cells / kg. In some embodiments, ciltacabtagene autoleucel is administered to the subject at a dose of about 0.75 × 106CAR- positive viable T cells / kg.

[0030] In some embodiments, the method further comprises administering a conditioning regimen to the subject prior to administering ciltacabtagene autoleucel, wherein the conditioning regimen comprises one or more of cyclophosphamide and / or fludarabine. In some embodiments, the conditioning regimen comprises cyclophosphamide at a dosage of about 300 mg / m2. In some embodiments, the conditioning regimen comprises fludarabine at a dosage of about 30 mg / m2. In some embodiments, the conditioning regimen comprises cyclophosphamide at a dosage of about 300 mg / m2and fludarabine at a dosage of about 30 mg / m2. In some embodiments, the conditioning regimen is administered to the subject daily, for up to 3 days. In some embodiments, the ciltacabtagene autoleucel is administered to the subject 5 to 7 days after the start of the administration of the conditioning regimen.

[0031] In some embodiments, the method further comprises administering an induction therapy to the subject prior to administering ciltacabtagene autoleucel. In some embodiments, the induction therapy comprises daratumumab, bortezomib, lenalidomide, dexamethasone, or some combination thereof. In some embodiments, the induction therapy comprises daratumumab, bortezomib, lenalidomide, and dexamethasone. In some embodiments, the induction therapy comprises 4 cycles of daratumumab, bortezomib, lenalidomide, and dexamethasone. In some embodiments, the induction therapy comprises 4 cycles of daratumumab, bortezomib, lenalidomide, and dexamethasone, wherein each cycle comprises about 1800 mg of daratumumab, about 1.3 mg / m2of bortezomib, about 25 mg of lenalidomide, and about 40 mg of dexamethasone (DVRd). In some embodiments, each cycle of DVRd is about 28 days.

[0032] In some embodiments, the method further comprises the collection of apheresis material from the subject for the manufacturing of ciltacabtagene autoleucel. In some -8- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) embodiments, the collection of apheresis material occurs prior to the administration of any induction therapy described herein.

[0033] In some embodiments, the subject is administered 4 cycles of antibody treatment, wherein: the first cycle comprises the administration of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody, the second cycle comprises the administration of the BCMAxCD3 bispecific antibody and the anti-CD38 antibody, the third cycle comprises the administration of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody, and the fourth cycle comprises the administration of the BCMAxCD3 bispecific antibody and the anti-CD38 antibody.

[0034] In some embodiments, each cycle of the 4 cycles is about 84 days.

[0035] In some embodiments, the first cycle comprises: the administration of an 1800 mg dose of the anti-CD38 antibody, the administration of a first step-up dose of 0.01 mg / kg of the GPRC5DxCD3 bispecific antibody about 20 hours after the administration of the anti-CD38 antibody, the administration of a second step-up dose of 0.06 mg / kg of the GPRC5DxCD3 bispecific antibody 2, 3, or 4 days after the administration of the anti-CD38 antibody, the administration of a third step-up dose of 0.4 mg / kg of the GPRC5DxCD3 bispecific antibody 7, 8, or 9 days after the administration of the anti-CD38 antibody, and the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody two or more days after the administration of the third step-up dose, and, optionally, about 14 days after the administration of the anti-CD38 antibody.

[0036] In some embodiments, the second cycle comprises: the administration of an 1800 mg dose of the anti-CD38 antibody, the administration of a first step-up dose of 0.06 mg / kg of the BCMAxCD3 bispecific antibody about 20 hours after the administration of the anti-CD38 antibody, the administration of a second step-up dose of 0.3 mg / kg of the BCMAxCD3 bispecific antibody two or more days after the administration of the first step-up dose, the administration of a third step-up dose of 1.5 mg / kg of the BCMAxCD3 bispecific antibody two or more days after the administration of the second step-up dose, and -9- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) the administration of 3.0 mg / kg of the BCMAxCD3 bispecific antibody two or more days after the administration of the third step-up dose, and, optionally, about 14 days after the administration of the anti-CD38 antibody.

[0037] In some embodiments, the third cycle comprises: the administration of an 1800 mg dose of the anti-CD38 antibody, and the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody about 1 hour after the administration of the anti-CD38 antibody.

[0038] In some embodiments, the fourth cycle comprises: the administration of an 1800 mg dose of the anti-CD38 antibody, and the administration of 3.0 mg / kg of the BCMAxCD3 bispecific antibody about 1 hour after the administration of the anti-CD38 antibody.

[0039] In some embodiments, after the fourth cycle, the subject is tested for MRD- negative status, and, if the subject is determined to be MRD-positive, the subject is administered an additional 4 cycles of any antibody treatment as defined herein.

[0040] In some embodiments, the method achieves a partial response (PR), very good partial response (VGPR), complete response (CR) or stringent complete response (sCR) in the subject, according to IMWG criteria. In some embodiments, the method achieves a very good partial response (VGPR), complete response (CR) or stringent complete response (sCR) in the subject, according to IMWG criteria. In some embodiments, the method achieves a complete response (CR) or stringent complete response (sCR) in the subject, according to IMWG criteria. In some embodiments, the method achieves a stringent complete response (sCR) in the subject, according to IMWG criteria. In some embodiments, the method achieves minimal residual disease (MRD) negativity at a threshold of 10-5before disease progression or start of a subsequent antimyeloma therapy. In some embodiments, the method achieves sustained MRD-negative status, as determined by next generation sequencing (NGS) with sensitivity of 10-5, for at least 6 months without examination showing MRD- positive or progressive disease (PD) in between. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. It should be understood that the invention is not limited to the precise embodiments shown in the drawings. -10- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0042] FIGS.1A and 1B show the treatment pathways across two cohorts in the clinical trial, starting with apheresis and varying cycles of ciltacabtagene autoleucel and talquetamab, leading to primary endpoints assessing safety and efficacy, and secondary endpoints, followed by a long-term follow-up.

[0043] FIG.2 shows the expression of BCMA antigen on the surface of GC, memory and plasmablast cells in the lymph node, long-lived plasma cells in the bone marrow LN and MALT, and on multiple myeloma cells. BAFF-R antigen is not expressed on plasmablast cells, long-lived plasma cells, or multiple myeloma cells. TACI is expressed on memory and plasmablast cells, long-lived plasma cells, and multiple myeloma cells. CD138 is expressed only on long-lived plasma cells and multiple myeloma cells.

[0044] FIG.3 shows the design of the ciltacabtagene autoleucel CAR. Ciltacabtagene autoleucel comprises two VHH domains, as opposed to a single VL domain and a single VH domain found on various other CARs. Ciltacabtagene autoleucel comprises intracellular CD137 and human CD3 zeta domains.

[0045] FIG.4 shows a schematic for preparing virus encoding ciltacabtagene autoleucel CAR, transduction of the virus into a T cell from the patient, and then preparation of CAR T cells expressing ciltacabtagene autoleucel.

[0046] FIG.5 shows bar graphs comparing the expression levels of CD28 and the distribution of T cell memory subtypes in CD3+ T cells from multiple myeloma patients, following in vitro exposure to bispecific T cell engagers talquetamab and teclistamab. The upper graphs show the percentage of CD28+ cells across different days, while the lower graphs detail the percentage of T cell subtypes, including naïve (CCR7+CD45RA+), central memory (CM, CCR7+CD45RA-), effector memory (EM, CCR7-CD45RA-), and terminally differentiated effector memory (TEMRA, CCR7-CD45RA+) cells.

[0047] FIG.6 shows scatter plots demonstrating the fold expansion and the percentage of CAR-positive T cells after ciltacabtagene autoleucel manufacturing from T cells pre-exposed to bispecific T cell engagers. Data from three donors show that previous exposure to bispecifics appears to negatively affect both the expansion capacity of CAR-T cells and the proportion of CAR-positive cells in the resulting drug product, suggesting compromised CAR-T cell manufacturing efficiency.

[0048] FIGS.7A-7B show the functional analysis of CAR-T cells derived from donor T cells pre-exposed to bispecific T cell engagers. FIG.7A indicates that CAR-T cells pre- exposed to talquetamab and teclistamab have a lower killing efficacy compared to unexposed -11- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) controls. FIG.7B displays cytokine production profiles upon stimulation, with the pre- exposed CAR-T cells demonstrating diminished secretion of key cytokines like IFNγ, TNFα, IL-2, and IL-13.

[0049] FIG.8 shows box-and-whisker plots displaying the distribution of lymphocyte counts, monocyte, and neutrophil percentages within the white blood cell (WBC) population in patients who had received CAR-T therapy, those exposed to antibody-drug conjugates (ADC), and those treated with bispecific antibodies (BsAbs).

[0050] FIG.9 shows three box-and-whisker plots analyzing T cell subsets in patients who had received CAR-T therapy, those exposed to antibody-drug conjugates (ADC), and those treated with bispecific antibodies (BsAbs). The plots illustrate the CD4:CD8 ratio, CD4+ cell counts, and CD8+ cell counts per microliter of blood.

[0051] FIG.10 shows box-and-whisker plots comparing the percentage of T cells and natural killer (NK) cells within the lymphocyte population in peripheral blood in patients who had received CAR-T therapy, those exposed to antibody-drug conjugates (ADC), and those treated with bispecific antibodies (BsAbs).

[0052] FIG.11 shows the expression of the CD38 marker on CD4+ and CD8+ T cells in patients who had received CAR-T therapy, those exposed to antibody-drug conjugates (ADC), and those treated with bispecific antibodies (BsAbs). The left plot illustrates the percentage of CD4+ T cells expressing CD38, while the right plot shows the percentage of CD8+ T cells with CD38 expression.

[0053] FIG.12 shows two box-and-whisker plots assessing baseline soluble B-cell maturation antigen (sBCMA) levels and the effector-to-target (E:T) ratio in patients who had received CAR-T therapy, those exposed to antibody-drug conjugates (ADC), and those treated with bispecific antibodies (BsAbs). The left plot shows baseline sBCMA concentrations, while the right plot illustrates the E:T ratio, which is calculated as the maximum concentration of CAR-T cells achieved post-treatment divided by the baseline sBCMA level.

[0054] FIG.13 shows the overall response rate to ciltacabtagene autoleucel therapy in patients previously treated with BCMA targeted therapies, along with the median duration of response (DOR) and progression-free survival (PFS). On the left, a stacked bar graph indicates the percentages of patients achieving partial response (PR), very good partial response (VGPR), complete response (CR), and stringent complete response (sCR). The full cohort shows a 60% PR and 5% sCR, while the ADC exposed group shows a 62% VGPR, -12- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) and the BsAb exposed group has a 57% VGPR and 14% sCR. On the right, a table compares the median DOR and PFS between the full cohort, ADC exposed, and BsAb exposed groups.

[0055] FIGS.14A-14C show the results of a cytotoxicity assay using spheroids formed from Incucyte® NucLight Green H929 cells to evaluate the effects of bispecific antibodies in combination with CAR-T cells versus MOCK cells. FIG.14A shows the relative size of spheroids over time after the addition of MOCK cells at various concentrations of talquetamab. FIG.14B illustrates the same for CAR-T cells, showing that the spheroids treated with CAR-T cells exhibit a change in size indicative of cytotoxicity across a gradient of bispecific antibody concentrations. FIG.14C shows an Area Under the Curve (AUC) analysis comparing the potency of bispecific antibody engagement between MOCK and CAR-T cells across a logarithmic concentration range

[0056] FIGS.15A-15B show flow cytometry results corresponding to of CAR-positive T cell populations and their enrichment. FIG.15A illustrates flow cytometry plots demonstrating the distinction between MOCK cells, double-positive T cells, and CAR-T cells enriched using biotinylated BCMA and anti-biotin magnetic beads. FIG.15B provides a tabulated summary of the percentage of CAR-positive cells along with the total T cell count and the absolute number of CAR-positive T cells at varying levels of dilution.

[0057] FIG.16 shows a dose-response curve, presenting the Area Under the Curve (AUC) analysis of the effect of varying log concentrations of talquetamab on spheroid size over time. Each curve represents a different dilution of CAR-positive T cells.

[0058] FIGS.17A-17B show the efficacy of talquetamab engagement with varying levels of CAR-T cell concentrations. FIG.17A presents a bar graph of the half maximal effective concentration (EC50) values for different dilutions of CAR-positive T cells, indicating the concentration of talquetamab required to achieve half of the maximum effect. Lower EC50 values suggest higher potency. FIG.17B shows the fold reduction in EC50 relative to the MOCK cells, illustrating the increased sensitivity of talquetamab in the presence of CAR-T cells.

[0059] FIGS.18A-18C show the impact of talquetamab concentration on T cell activation and expansion in the context of CAR-T cell therapy. FIG.18A and FIG.18B depict the mean fluorescence intensity (MFI) of CD25 on CD4 and CD8 T cells respectively after 48 hours, with the MFI serving as an indicator of T cell activation. FIG.18C shows the fold expansion of T cells over five days in relation to the log concentration of talquetamab. -13- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0060] FIGS.19A-19B show the effect of talquetamab on the expression of interferon- gamma (IFN-γ) by T cells at different time points post-treatment. FIG.19A, corresponding to the 48-hour mark, displays a dose-response curve where the IFN-γ concentration is plotted against the log concentration of talquetamab. FIG.19B shows the 120-hour time point.

[0061] FIG.20 shows the expression levels of the Fas ligand and CD54 molecules (ICAM-1) in H929 cells following the addition of CAR-T cells, compared to MOCK cells (T cells without CAR construct) and no T cell controls at both 24 and 48 hours after T cell addition.

[0062] FIG.21A illustrates the effect sizes and statistical significance of the interaction between CAR-T cells and Daratumumab on target cell populations, with color-coded indications of the direction and strength of these effects. FIG.21B provides a quantitative depiction of myeloma cell counts over a 7-day period.

[0063] FIG.22 shows the comparative analysis of T cell populations in an in vitro assay over a 7-day period, detailing the expansion dynamics of CD4+ and CD8+ T cells with and without the co-administration of Daratumumab. The graphs depict the counts of CAR- positive CD4+ and CD8+ T cells in the presence of Ciltacabtagene autoleucel alone (CART) versus in combination with Daratumumab (CART+Dara).

[0064] FIG.23 shows bar graphs that compare the counts of live CD38+ cells within CD4+ and CD8+ T cell subsets, cultured alone (CART) and in combination with Daratumumab (CART+Dara), over a 7-day period.

[0065] FIG.24 shows bar graphs depicting the levels of exhaustion markers on chimeric antigen receptor-positive (CAR+) CD4+ and CD8+ T cells over a 7-day culture period, both in the presence and absence of Daratumumab. The markers include PD-1, LAG3, and BTLA, individually and in combination, as indicators of T cell exhaustion.

[0066] FIG.25 shows the frequencies of regulatory T cells (Tregs), identified by the markers CD4, CD127, CD25, and CD38, in the context of chimeric antigen receptor-positive (CAR+) and negative (CAR-) T cell populations. Box plots represent the percentage of Tregs at various time points over a 7-day period under two conditions: treated with CAR-T cells alone (CART) and treated with a combination of CAR-T cells and Daratumumab (CART+Dara).

[0067] FIG.26 shows the counts of natural killer (NK) cell populations under two treatment conditions: with CAR-T cells alone (CART) and in combination with Daratumumab (CART+Dara). The bar graphs compare the numbers of early, mature, and -14- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) terminal NK cells over several days. Additionally, the box plots also assess the percentages of mature NK cells expressing activation marker CD69 and exhaustion markers NKP1D+ and NKG2A+. DETAILED DESCRIPTION

[0068] The present disclosure provides methods of treating cancer in a subject in need thereof. In some embodiments, the method comprises administering an anti-BCMA CAR-T cell and a GPRC5DxCD3 bispecific antibody. In some embodiments, the method comprises administering an anti-BMCA CAR-T cell, a GPRC5DxCD3 bispecific antibody, and a BCMAxCD3 bispecific antibody.

[0069] Several aspects and embodiments of the disclosure are described below, with reference to examples for illustrative purposes only. It should be understood that numerous specific details, relationships, and methods are set forth to provide a full understanding of the disclosure. One having ordinary skill in the relevant art, however, will readily recognize that the disclosure can be practiced without one or more of the specific details or practiced with other methods, protocols, reagents, cell lines and animals. The present disclosure is not limited by the illustrated ordering of acts or events, as some acts may occur in different orders and / or concurrently with other acts or events. Furthermore, not all illustrated acts, steps or events are required to implement a methodology in accordance with the present disclosure.

[0070] Any references in the description or in the claims to methods of treatment refer to the compounds, compositions, pharmaceutical compositions and medicaments for use in a method of treatment of the human (or animal) body by therapy (or for diagnosis).

[0071] Any references in the description or in the claims to methods of treatment refer to the use of the compounds, compositions, pharmaceutical compositions for the manufacture of a medicament for the treatment of the human (or animal) body by therapy (or for diagnosis).

[0072] In an attempt to help the reader of the present application, the description has been separated in various paragraphs or sections. These separations should not be considered as disconnecting the substance of a paragraph or section from the substance of another paragraph or section. To the contrary, the present description encompasses all the combinations of the various sections, paragraphs and sentences that can be contemplated. -15- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0073] Unless otherwise defined, all terms of art, notations and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this disclosure pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and / or as otherwise defined herein. Definitions

[0074] The terminology used herein is for the purpose of describing particular aspects or embodiments only and is not intended to be limiting. As used herein, the indefinite articles “a”, “an” and “the” should be understood to include plural reference unless the context clearly indicates otherwise.

[0075] The term “about” or “approximately” includes being within a statistically meaningful range of a value. Such a range can be within an order of magnitude, preferably within 50%, more preferably within 20%, still more preferably within 10%, and even more preferably within 5% of a given value or range. The allowable variation encompassed by the term “about” or “approximately” depends on the particular system under study, and can be readily appreciated by one of ordinary skill in the art.

[0076] Unless otherwise stated, any numerical value, such as a concentration or a concentration range described herein, are to be understood as being modified in all instances by the term “about.” Thus, a numerical value typically includes ± 10% of the recited value. For example, a dosage of 10 mg includes 9 mg to 11 mg. As used herein, the use of a numerical range expressly includes all possible subranges, all individual numerical values within that range, including integers within such ranges and fractions of the values unless the context clearly indicates otherwise.

[0077] The term “antibody” includes monoclonal antibodies (including full length 4-chain antibodies or full length heavy-chain only antibodies which have an immunoglobulin Fc region), antibody compositions with polyepitopic specificity, multispecific antibodies (e.g., bispecific antibodies, diabodies, and single-chain molecules), as well as antibody fragments (e.g., Fab, F(ab’)2, and Fv). The term “immunoglobulin” (Ig) is used interchangeably with -16- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) “antibody” herein. Antibodies contemplated herein include single-domain antibodies, such as heavy chain only antibodies. The terms “antibody” and “antibodies” refer to monoclonal antibodies, multispecific antibodies, human antibodies, humanized antibodies, chimeric antibodies, single-chain Fvs (scFv), single chain antibodies, Fab fragments, F(ab′) fragments, disulfide-linked Fvs (sdFv), intrabodies, minibodies, diabodies and anti-idiotype (anti-Id) antibodies (including, e.g., anti-Id antibodies to antigen specific TCR), and epitope-binding fragments of any of the above. The terms “antibody” and “antibodies” also refer to covalent diabodies such as those disclosed in U.S. Pat. Appl. Pub.2007 / 0004909 and Ig-DARTS such as those disclosed in U.S. Pat. Appl. Pub.2009 / 0060910. Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgM1, IgM2, IgA1 and IgA2) or subclass. “Full length antibodies” are comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g., IgM). Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CH1, hinge, CH2 and CH3). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. Antibody light chains of any vertebrate species may be assigned to one of two clearly distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains.

[0078] “Antigen binding fragment” or “antigen binding domain” refers to a portion of an immunoglobulin molecule that binds an antigen. Antigen binding fragments may be synthetic, enzymatically obtainable or genetically engineered polypeptides and include the VH, the VL, the VH and the 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, VH domains modified to function without a corresponding VL domain, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3- CDR3-FR4 portions, the HCDR1, the HCDR2 and / or the HCDR3 and the LCDR1, the LCDR2 and / or the LCDR3. VH and VL domains may be linked together via a synthetic linker to form various types of single chain antibody designs where the VH / VL domains may pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are -17- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) expressed by separate single chain antibody constructs, to form a monovalent antigen binding site, such as single chain Fv (scFv) or diabody; described for example in Int. Patent Publ. Nos. WO1998 / 44001, WO1988 / 01649, WO1994 / 13804 and WO1992 / 01047.

[0079] Suitable methods of making antibodies are known in the art. For instance, standard hybridoma methods are described in, e.g., Köhler and Milstein, Eur. J. Immunol., 5, 511-519 (1976), Harlow and Lane (eds.), Antibodies: A Laboratory Manual, CSH Press (1988), and C. A. Janeway et al. (eds.), Immunobiology, 5thEd., Garland Publishing, New York, N.Y. (2001)). Alternatively, other methods, such as EBV-hybridoma methods (Haskard and Archer, J. Immunol. Methods, 74(2), 361-67 (1984), and 18pher et al., Methods Enzymol., 121, 140-67 (1986)), and bacteriophage vector expression systems (see, e.g., Huse et al., Science, 246, 1275-81 (1989)) are known in the art. Further, methods of producing antibodies in non-human animals are described in, e.g., U.S. Pat. Nos.5,545,806, 5,569,825, and 5,714,352, and U.S. Patent Application Publication No.2002 / 0197266 A1).

[0080] Phage display can also be used to generate an antibody. In this regard, phage libraries encoding antigen-binding variable (V) domains of antibodies can be generated using standard molecular biology and recombinant DNA techniques (see, e.g., Sambrook et al., supra, and Ausubel et al., supra). Phage encoding a variable region with the desired specificity are selected for specific binding to the desired antigen, and a complete or partial antibody is reconstituted comprising the selected variable domain. Nucleic acid sequences encoding the reconstituted antibody are introduced into a suitable cell line, such as a myeloma cell used for hybridoma production, such that antibodies having the characteristics of monoclonal antibodies are secreted by the cell (see, e.g., Janeway et al., supra, Huse et al., supra, and U.S. Pat. No.6,265,150).

[0081] The antibodies, polypeptides, and proteins of embodiments of the disclosure (including functional portions and functional variants) can be subject to post-translational modifications. They can be glycosylated, esterified, N-acylated, amidated, carboxylated, phosphorylated, esterified, cyclized via, e.g., a disulfide bridge, or converted into an acid addition salt. In some embodiments, they are dimerized or polymerized, or conjugated.

[0082] The antibodies, polypeptides, and / or proteins of embodiments of the disclosure (including functional portions and functional variants thereof) can be obtained by methods known in the art. Suitable methods of de novo synthesizing polypeptides and proteins are described in references, such as Chan et al., Fmoc Solid Phase Peptide Synthesis, Oxford University Press, Oxford, United Kingdom, 2000; Peptide and Protein Drug Analysis, ed. -18- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) Reid, R., Marcel Dekker, inc., 2000; and Epitope Mapping, ed. Westwood et al., Oxford University Press, Oxford, United Kingdom, 2001. Also, polypeptides and proteins can be recombinantly produced using the nucleic acids described herein using standard recombinant methods. See, for instance, Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rded., Cold Spring Harbor Press, Cold Spring Harbor, N.Y.2001; and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, NY, 1994. Further, some of the antibodies, polypeptides, and proteins of the disclosure (including functional portions and functional variants thereof) can be isolated and / or purified from a source, such as a plant, a bacterium, an insect, a mammal, etc. Methods of isolation and purification are known in the art. Alternatively, the antibodies, polypeptides, and / or proteins described herein (including functional portions and functional variants thereof) can be commercially synthesized. In this respect, the antibodies, polypeptides, and proteins can be synthetic, recombinant, isolated, and / or purified.

[0083] The terms “B-cell maturation antigen” and “BCMA” as used herein include human B cell maturation antigen, also known as BCMA, CD269, and TNFRSF17 (UniProt Q02223), which is a member of the tumor necrosis receptor superfamily that is preferentially expressed in differentiated plasma cells. The extracellular domain of human BCMA consists, according to UniProt of amino acids 1-54 (or 5-51).

[0084] “Bispecific” refers to an antibody that specifically binds two distinct antigens or two distinct epitopes within the same antigen. The bispecific antibody may have cross- reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca cynomolgus (cynomolgus, cyno) or Pan troglodytes, or may bind an epitope that is shared between two or more distinct antigens.

[0085] “Cancer” refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth results in the formation of malignant tumors that invade neighboring tissues and may also metastasize to distant parts of the body through the lymphatic system or bloodstream. A “cancer” or “cancer tissue” can include a tumor.

[0086] “CD3” refers to a human antigen which is expressed on T cells as part of the multimolecular T cell receptor (TCR) complex and which consists of a homodimer or heterodimer formed from the association of two or four receptor chains: CD3 epsilon, CD3 -19- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) delta, CD3 zeta and CD3 gamma. Human CD3 epsilon comprises the amino acid sequence of SEQ ID NO: 122. SEQ ID NO: 123 shows the extracellular domain of CD3 epsilon.

[0087] “CD38” refers to the human CD38 protein (UniProt accession no. P28907) (synonyms: ADP-ribosyl cyclase 1, cADPr hydrolase 1, cyclic ADP-ribose hydrolase 1). CD38 is a single pass type II transmembrane protein with amino acid residues 1-21 representing the cytosolic domain, amino acid residues 22-42 representing the transmembrane domain, and residues 43-300 representing the extracellular domain.

[0088] “CH3 region” or “CH3 domain” refers to the CH3 region of an immunoglobulin. The CH3 region of human IgG1 antibody corresponds to amino acid residues 341-446. However, the CH3 region may also be any of the other antibody isotypes as described herein. The substitutions in the CH3 region are expressed as modified position(s) in the first CH3 domain of the first heavy chain / modified position(s) in the second CH3 domain of the second heavy chain. For example, F405L / K409R refers to a F405L mutation in the first CH3 region and K09R mutation in the second CH3 region. L351Y_F405A_Y407V / T394W refers to L351Y, F40FA and Y407V mutations in the first CH3 region and T394W mutation in the second CH3 region. D399FHKRQ / K409AGRH refers to mutation in which D399 may be replaced by F, H, K R or Q, and K409 may be replaced by A, G, R or H.

[0089] “Ciltacabtagene autoleucel” (“cilta-cel”) is a chimeric antigen receptor T cell (CAR-T) therapy comprising two B-cell maturation antigen (BCMA)-targeting VHH domains designed to confer avidity for BCMA. Ciltacabtagene autoleucel can comprise T lymphocytes transduced with the ciltacabtagene autoleucel CAR, a CAR encoded by a lentiviral vector. The CAR targets the human B cell maturation antigen (anti-BCMA CAR). A diagram of the lentiviral vector encoding ciltacabtagene autoleucel CAR is provided in FIG.3. The amino acid sequence of the ciltacabtagene autoleucel CAR is the amino acid sequence of SEQ ID NO: 17.

[0090] A “chimeric antigen receptor” or “CAR” is an artificially constructed hybrid protein or polypeptide containing the antigen binding domains of at least one antibody (or antibody fragment) linked to T-cell signaling domains. Characteristics of CARs can include their ability to redirect T-cell specificity and reactivity toward a selected target in a non- MHC-restricted manner, exploiting the antigen-binding properties of monoclonal antibodies. The non-MHC-restricted antigen recognition gives T cells expressing CARs the ability to recognize antigens independent of antigen processing, thus bypassing a major mechanism of tumor evasion. Moreover, when expressed in T-cells, advantageously, CARs do not dimerize -20- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) with endogenous T cell receptor (TCR) α- and β-chains. T cells expressing a CAR are referred to herein as CAR T cells, CAR-T cells or CAR modified T cells, and these terms are used interchangeably herein. The cell can be genetically modified to stably express at least one antigen-binding domain on its surface, conferring novel antigen specificity that is MHC independent. “BCMA CAR” refers to a CAR having an extracellular binding domain specific for BCMA. “Bi-epitope CAR” refers to a CAR having an extracellular binding domain specific for two different epitopes of an antigen, such as BCMA.

[0091] “Combination” means that two or more therapeutics are administered to a subject together in a mixture, concurrently as single agents or sequentially as single agents in any order.

[0092] “Complementarity determining regions” (CDR) are antibody regions that bind an antigen. CDRs may be defined using various delineations 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). The correspondence between the various delineations and variable region numbering are described (see e.g., 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 resources, http: / / www_imgt_org). Available programs such as abYsis by UCL Business PLC may be used to delineate CDRs. The term “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2” and “LCDR3” as used herein includes CDRs defined by any of the methods described supra, Kabat, Chothia, IMGT or AbM, unless otherwise explicitly stated in the specification. Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art (see, e.g., Kabat; Chothia; Martin; Lefranc et al.). Table 1. Kabat, IMGT, AbM, and Chothia numbering systems. IMGT Kabat AbM Chothia VH CDR1 27-38 31-35 26-35 26-32 VHCDR2 56-65 50-65 50-58 53-55 VH CDR3 105-117 95-102 95-102 96-101 VL CDR1 27-38 24-34 24-34 26-32 VLCDR2 56-65 50-56 50-56 50-52 VL CDR3 105-117 89-97 89-97 91-96 -21- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0093] “Comprising” is intended to include examples encompassed by the terms “consisting essentially of” and “consisting of”; similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of.” Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.

[0094] “Cycle” as used herein, refers to a recurring period of either 28 days or 84 days, depending on the phase of treatment, demarcated for the purpose of administering the prescribed interventions. Cycles during induction and during talquetamab consolidation have a 28-day duration. Cycles defined in consolidation with alternating talquetamab and teclistamab after ciltacabtagene autoleucel have an 84-day duration. Within this framework, the term “cycle” encapsulates the entire sequence of events, activities, and drug administration protocols designated for these intervals.

[0095] By “decrease” or “lower,” or “lessen,” or “reduce,” or “abate” refers generally to the ability of composition contemplated herein to produce, elicit, or cause a lesser physiological response (i.e., downstream effects) compared to the response caused by either vehicle or a control molecule / composition. In some embodiments, a “decrease” or “reduced” amount can be a “statistically significant” amount, and may include a decrease that is 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30 or more times (e.g., 500, 1000 times) (including all integers and decimal points in-between and above 1, e.g., 1.5, 1.6, 1.7.1.8, etc.) the response (reference response) produced by vehicle, a control composition, or the response in a particular cell lineage.

[0096] The terms “daratumumab” and “daratumumab SC” refers to the anti-CD38 antibody DARZALEX FASPRO® PI 2020.

[0097] The term “effective” applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a subject in need thereof. Note that when a combination of active ingredients is administered, the effective amount of the combination may or may not include amounts of each ingredient that would have been effective if administered individually. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition being treated, the particular drug or drugs employed, the mode of administration, and the like. -22- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0098] By “enhance” or “promote,” or “increase” or “expand” or “improve” refers generally to the ability of a composition contemplated herein to produce, elicit, or cause a greater physiological response (i.e., downstream effects) compared to the response caused by either vehicle or a control molecule / composition. A measurable physiological response may include an increase in T cell expansion, activation, effector function, persistence, and / or an increase in cancer cell death killing ability, among others apparent from the understanding in the art and the description herein. In some embodiments, an “increased” or “enhanced” amount can be a “statistically significant” amount, and may include an increase that is 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, or more times (e.g., 500, 1000 times) (including all integers and decimal points in-between and above 1, e.g., 1.5, 1.6, 1.7.1.8, etc.) the response produced by vehicle or a control composition. “Enhance” or “enhanced” also refers to enhancement in one or more functions of a test molecule when compared to a control molecule or a combination of test molecules when compared to one or more control molecules. Exemplary functions that can be measured are tumor cell killing, T cell activation, relative or absolute T cell number, Fc-mediated effector function (e.g., ADCC, CDC and / or ADCP) or binding to an Fc^ receptor (FcγR) or FcRn. “Enhanced” may be an enhancement of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more, or a statistically significant enhancement.

[0099] The terms “express” and “expression” mean allowing for or causing the information in a gene or DNA sequence to become produced. For example, expression can take the form of producing a protein by activating the cellular functions involved in transcription and translation of a corresponding gene or DNA sequence. A DNA sequence is expressed in or by a cell to form an “expression product” such as a protein. The expression product itself, e.g., the resulting protein, may also be said to be “expressed” by the cell. An expression product can be characterized as intracellular, extracellular or transmembrane.

[0100] “Fc gamma receptor” (Fc^R) refers to well-known Fc^RI, Fc^RIIa, Fc^RIIb or Fc^RIII. Activating Fc^R includes Fc^RI, Fc^RIIa and Fc^RIII.

[0101] The terms “fragment of an antibody”, “antibody fragment”, “functional fragment of an antibody”, and “antigen-binding portion” are used interchangeably herein to mean one or more fragments or portions of an antibody that retain the ability to specifically bind to an antigen (see, generally, Holliger et al., Nat. Biotech., 23(9): 1126-1129 (2005)). The antigen recognition moiety of the CAR encoded by the nucleic acid sequence disclosed herein can contain any BCMA-binding antibody fragment. The antibody fragment desirably comprises, -23- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) for example, one or more CDRs, the variable region (or portions thereof), the constant region (or portions thereof), or combinations thereof. Examples of antibody fragments include, but are not limited to, (i) a Fab fragment, which is a monovalent fragment consisting of the VL, VH, CL, and CHI domains; (ii) a F(ab’)2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (iv) a single chain Fv (scFv), which is a monovalent molecule consisting of the two domains of the Fv fragment (i.e., VL and VH) joined by a synthetic linker which enables the two domains to be synthesized as a single polypeptide chain (see, e.g., Bird et al., Science, 242: 423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. USA, 85: 5879-5883 (1988); and Osbourn et al., Nat. Biotechnol, 16: 778 (1998)) and (v) a diabody, which is a dimer of polypeptide chains, wherein each polypeptide chain comprises a VH connected to a VL by a peptide linker that is too short to allow pairing between the VH and VL on the same polypeptide chain, thereby driving the pairing between the complementary domains on different VH -VL polypeptide chains to generate a dimeric molecule having two functional antigen binding sites. Antibody fragments are known in the art and are described in more detail in, e.g., U.S. Patent Application Publication 2009 / 0093024 A1. Antigen binding fragments may be synthetic, enzymatically obtainable or genetically engineered polypeptides and include portions of an immunoglobulin that bind an antigen, such as the VH, the VL, the VH and the VL, Fab, Fab’, F(ab’)2, Fd and Fv fragments, domain antibodies (dAb) consisting of one VH domain or one VL domain, shark variable IgNAR domains, VH domains modified to function without a corresponding VL domain ns, VHH domains, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3-CDR3-FR4 portions, the HCDR1, the HCDR2 and / or the HCDR3 and the LCDR1, the LCDR2 and / or the LCDR3, alternative scaffolds that bind an antigen, and multispecific proteins comprising the antigen binding fragments. Antigen binding fragments (such as VH and VL) may be linked together via a synthetic linker to form various types of single antibody designs where the VH / VL domains may pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chains, to form a monovalent antigen binding domain, such as single chain Fv (scFv) or diabody. Antigen binding fragments may also be conjugated to other antibodies, proteins, antigen binding fragments or alternative scaffolds which may be monospecific or multispecific to engineer bispecific and multispecific proteins. -24- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0102] A “full length antibody” is comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g. IgM). Each heavy chain is comprised of a heavy chain variable domain (VH) and a heavy chain constant domain, the heavy chain constant domain comprised of subdomains CH1, hinge, CH2 and CH3. Each light chain is comprised of a light chain variable domain (VL) and a light chain constant domain (CL). The VH and the VL may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FW). Each VH and VL is composed of three CDRs and four FW segments, arranged from amino-to-carboxy-terminus in the following order: FW1, CDR1, FW2, CDR2, FW3, CDR3 and FW4.

[0103] “GPRC5D” refers to human G-protein coupled receptor family C group 5 member D having the amino acid sequence shown in SEQ ID NO: 121.

[0104] “GPRC5D xCD3 bispecific antibody” refers to a molecule containing two or more binding regions, wherein one of the binding regions specifically binds the cell surface antigen G Protein-Coupled Receptor Class C Group 5 Member D antigen (GPRC5D) on a target cell or tissue and wherein a second binding region of the molecule specifically binds a T cell antigen CD3. This dual / multi-target binding ability recruit T cells to the target cell or tissue leading to the eradication of the target cell or tissue.

[0105] The phrase “hazard ratio” refers to a measure of the relative rate of progression to an endpoint as compared to a control group. In outcome-based clinical trials, a reduction in the hazard ratio for a test arm as compared to the control indicates the treatment used in the test arm reduces the risk of the endpoint, in the case of the studies described herein, disease progression or death. Preferably hazard ratio is calculated per a stratified constant piecewise weighted log-rank test.

[0106] The term “heavy chain-only antibody” or “HCAb” refers to a functional antibody, which comprises heavy chains, but lacks the light chains usually found in 4-chain antibodies. Camelid animals (such as camels, llamas, or alpacas) are known to produce HCAbs.

[0107] “Human antibody” refers to an antibody that is optimized to have minimal immune response when administered to a human subject. Variable regions of human antibody are derived from human immunoglobulin sequences. If human antibody contains a constant region or a portion of the constant region, the constant region is also derived from human immunoglobulin sequences. Human antibody comprises heavy and light chain variable regions that are “derived from” sequences of human origin if the variable regions of the -25- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) human antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Such exemplary systems are human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals such as mice or rats carrying human immunoglobulin loci. “Human antibody” typically contains amino acid differences when compared to the immunoglobulins expressed in humans due to differences between the systems used to obtain the human antibody and human immunoglobulin loci, introduction of somatic mutations or intentional introduction of substitutions into the frameworks or CDRs, or both. Typically, “human antibody” is at least about 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 an amino acid sequence encoded by human germline immunoglobulin or rearranged immunoglobulin genes. In some cases, “human antibody” may contain consensus framework sequences derived from human framework sequence analyses, for example as described in Knappik et al., (2000) J Mol Biol 296:57-86, or synthetic HCDR3 incorporated into human immunoglobulin gene libraries displayed on phage, for example as described in Shi et al., (2010) J Mol Biol 397:385-96, and in Int. Patent Publ. No. WO2009 / 085462. Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of “human antibody”.

[0108] “Humanized antibody” refers to an antibody in which at least one CDR is derived from non-human species and at least one framework is derived from human immunoglobulin sequences. Humanized antibody may include substitutions in the frameworks so that the frameworks may not be exact copies of expressed human immunoglobulin or human immunoglobulin germline gene sequences.

[0109] “Isolated” refers to a homogenous population of molecules (such as synthetic polynucleotides or a protein such as an antibody) which have been substantially separated and / or purified away from other components of the system the molecules are produced in, such as a recombinant cell, as well as a protein that has been 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 chemicals and encompasses antibodies that are isolated to a higher purity, such as to 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% purity.

[0110] The term “line of therapy,” as used in connection with methods of treatment herein, refers to one or more cycles of a planned treatment program, which may have consisted of one or more planned cycles of single-agent therapy or combination therapy, as well as a -26- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) sequence of treatments administered in a planned manner. For example, a planned treatment approach of induction therapy followed by autologous stem cell transplantation followed by maintenance is one line of therapy. A new line of therapy is considered to have started when a planned course of therapy has been modified to include other treatment agents or medicaments (alone or in combination) as a result of disease progression, relapse, or toxicity. A new line of therapy is also considered to have started when a planned period of observation off therapy had been interrupted by a need for additional treatment for the disease.

[0111] “Monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of C- terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation or asparagine or glutamine deamidation. Monoclonal antibodies typically bind one antigenic epitope. A bispecific monoclonal antibody binds two distinct antigenic epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibody may be monospecific or multispecific such as bispecific, monovalent, bivalent or multivalent.

[0112] “Multispecific” refers to an antibody that specifically binds at least two distinct antigens or at least two distinct epitopes within the same antigen. Multispecific antibody may bind for example two, three, four or five distinct antigens or distinct epitopes within the same antigen.

[0113] “Mutation” refers to an engineered or naturally occurring alteration in a polypeptide or polynucleotide sequence when compared to a reference sequence. The alteration may be a substitution, insertion or deletion of one or more amino acids or polynucleotides.

[0114] “Newly diagnosed multiple myeloma” (NDMM) refers to the initial identification of multiple myeloma in a patient, which has not been previously diagnosed or treated. Diagnostic criteria for myeloma must be met when the participant was diagnosed. In some embodiments, multiple myeloma is defined as clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma-defining events, as defined by the International Myeloma Working Group (IMWG) diagnostic criteria: ^ Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: -27- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) o C: Hypercalcemia: serum calcium >0.25 mmol / L (>1 mg / dL) higher than the ULN or >2.75 mmol / L (>11 mg / dL) o R: Renal insufficiency: CrCl <40 mL / min (measured or estimated by validated equations) or serum creatinine >177 μmol / L (>2 mg / dL) o A: Anemia: hemoglobin value >20 g / L below the lower limit of normal, or hemoglobin value <100 g / L o B: Bone lesions: ≥1 osteolytic lesions on skeletal radiography, CT, or PET / CT (If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement; PET / CT=18F-fluorodeoxyglucose PET with CT) ^ Any one or more of the following biomarkers of malignancy: o Clonal bone marrow plasma cell percentage0≥60% (these values are based on the serum Freelite assay [The Binding Site Group, Birmingham, United Kingdom]; the involved FLC must be ≥100 mg / L) o Involved:uninvolved serum FLC ratio ≥100 (each focal lesion must be ≥5 mm in size) o >1 focal lesion on MRI studies (Rajkumar 2014) Clonality should be established by showing κ / λ-light chain restriction on flow cytometry, immunofluorescence, or IHC. Bone marrow plasma cell percentage should preferably be estimated from a biopsy specimen; in case of a disparity between the aspirate and biopsy, the highest value should be used.

[0115] The term “apheresis”as used herein refers to the art-recognized extracorporeal process by which the blood of a donor or patient is removed from the donor or patient and passed through an apparatus that separates out selected particular constituent(s) and returns the remainder to the circulation of the donor or patient, e.g., by retransfusion. Thus, in the context of “an 28pheresis material” refers to material obtained using apheresis.

[0116] “Non-fixed combination” refers to separate pharmaceutical compositions of the T cell redirecting therapeutic and the anti-CD38 antibody administered as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the subject.

[0117] The phrase “nonresponsive disease” refers to either failure to achieve minimal response or to development of progressive disease while on therapy. -28- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0118] The terms “nucleic acid”, “nucleotide”, and “polynucleotide” encompass both DNA and RNA unless specified otherwise. By a “nucleic acid sequence” or “nucleotide sequence” is meant the nucleic acid sequence encoding an amino acid; these terms may also refer to the nucleic acid sequence including the portion coding for any amino acids added as an artifact of cloning, including any amino acids coded for by linkers.

[0119] As used herein, the term “operatively linked,” and similar phrases, when used in reference to nucleic acids or amino acids, refer to the operational linkage of nucleic acid sequences or amino acid sequence, respectively, placed in functional relationships with each other. For example, an operatively linked promoter, enhancer elements, open reading frame, 5’ and 3’ UTR, and terminator sequences result in the accurate production of a nucleic acid molecule (e.g., RNA). In some embodiments, operatively linked nucleic acid elements result in the transcription of an open reading frame and ultimately the production of a polypeptide (i.e., expression of the open reading frame). As another example, an operatively linked peptide is one in which the functional domains are placed with appropriate distance from each other to impart the intended function of each domain.

[0120] “Pomalidomide” also termed “POMALYST®” refers to an analog of thalidomide, which is a third generation ImiD (immunomodulatory drug) with antineoplastic activity. ImiDs, such as lenalidomide and pomalidomide, form the backbone of several current multiple myeloma treatment regimens. Their exact mechanism of action is not fully understood, but ImiDs have an immunomodulatory effect on the multiple myeloma tumor microenvironment and may affect expression of tumor suppressor genes, promote apoptosis of myeloma cells, and enhance NK mediated myeloma cell lysis. The combination of daratumumab with ImiDs has been evaluated in multiple studies and demonstrated significant improvement in efficacy.

[0121] “Pharmaceutical composition” refers to composition that comprises an active ingredient and a pharmaceutically acceptable carrier.

[0122] The phrase “pharmaceutically acceptable”, as used in connection with compositions described herein, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., a human). Preferably, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans. -29- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0123] “Pharmaceutically acceptable carrier” or “excipient” refers to an ingredient in a pharmaceutical composition, other than the active ingredient, which is nontoxic to a subject.

[0124] “Philadelphia chromosome” or “Ph” refers to a well-known chromosomal translocation between chromosomes 9 and 22, resulting in the oncogenic BCR-ABL gene fusion with constitutively active tyrosine kinase activity. The translocation results in a portion of the BCR gene from chromosome 22q11 becoming fused with a portion of the ABL gene from chromosome 9q34, and is designated as t(9;22)(q34;q11) under the International System for Human Cytogenetic Nomenclature (ISCN). Depending on the precise location of the fusion, the molecular weight of the resulting fusion protein can range from 185 to 210 kDa. “Philadelphia chromosome” refers to all BCR-ABL fusion proteins formed due the (9;22)(q34;q11) translocation.

[0125] The term “protein” or “polypeptide” is used herein encompasses all kinds of naturally occurring and synthetic proteins, including protein fragments of all lengths, fusion proteins and modified proteins, including without limitation, glycoproteins, as well as all other types of modified proteins (e.g., proteins resulting from phosphorylation, acetylation, myristoylation, palmitoylation, glycosylation, oxidation, formylation, amidation, polyglutamylation, ADP-ribosylation, pegylation, biotinylation, etc.).

[0126] “Recombinant” refers to DNA, antibodies and other proteins that are prepared, expressed, created or isolated by recombinant means when segments from different sources are joined to produce recombinant DNA, antibodies or proteins.

[0127] “Reduce” or “reduced” refers to a reduction in one or more functions of a test molecule when compared to a control molecule or a combination of test molecules when compared to one or more control molecules. Exemplary functions that can be measured are tumor cell killing, T cell activation, relative or absolute T cell number, Fc-mediated effector function (e.g., ADCC, CDC and / or ADCP) or binding to an Fc^ receptor (FcγR) or FcRn. “Reduced” may be a reduction of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more, or a statistically significant enhancement.

[0128] The term “refractory,” as used in connection to treatment with a particular treatment agent or medicament or line of therapy herein, refers to diseases or disease subjects that fail to respond to said treatment agent or medicament or line of therapy. “Refractory to a therapy” refers to a cancer that is not amendable to surgical intervention and is initially unresponsive to the therapy. The phrase “refractory myeloma” refers to multiple myeloma -30- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) that is nonresponsive while on primary or salvage therapy or that has progressed within 60 days of last therapy.

[0129] “Relapsed” refers to a cancer that responded to treatment but then returns.

[0130] The term “single-domain antibody” or “sdAb” refers to a single antigen-binding polypeptide having three complementary determining regions (CDRs). The sdAb alone is capable of binding to the antigen without pairing with a corresponding CDR-containing polypeptide. In some cases, single-domain antibodies are engineered from camelid HCAbs, and their heavy chain variable domains are referred herein as “VHHs”. Some VHHs may also be known as “Nanobodies”. A camelid sdAb is one of the smallest known antigen-binding antibody fragments (see, e.g., Hamers-Casterman et al., Nature 363:446-8 (1993); Greenberg et al., Nature 374:168-73 (1995); Hassanzadeh-Ghassabeh et al., Nanomedicine (Lond), 8:1013-26 (2013)). A basic VHH has the following structure from the N-terminus to the C- terminus: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions 1 to 3.

[0131] As used herein, the terms “specifically binds”, “specifically recognizes”, or “specific for” refer to measurable and reproducible interactions such as binding between a target and an antigen binding protein (such as a CAR or a VHH), which is determinative of the presence of the target in the presence of a heterogeneous population of molecules including biological molecules.

[0132] The term “specificity” refers to selective recognition of an antigen binding protein (such as a CAR or a VHH) for a particular epitope of an antigen. Natural antibodies, for example, are monospecific. The term “multispecific” denotes that an antigen binding protein (such as a CAR or antibody) has two or more antigen-binding sites of which at least two bind different antigen-binding specificities. “Bispecific” as used herein denotes that an antigen binding protein (such as a CAR or antibody) has two different antigen-binding specificities.

[0133] As used herein, the term “subject” refers to an animal. The terms “subject” and “patient” may be used interchangeably herein in reference to a subject. As such, a “subject” includes a human that is being treated for a disease, or prevention of a disease, as a patient. The methods described herein may be used to treat an animal subject belonging to any classification. Examples of such animals include mammals. Mammals, include, but are not limited to, mammals of the order Rodentia, such as mice and hamsters, and mammals of the order Logomorpha, such as rabbits. The mammals may be of the order Carnivora, including -31- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) felines (cats) and canines (dogs). The mammals may be of the order Artiodactyla, including bovines (cows) and swines (pigs) or of the order Perssodactyla, including equines (horses). The mammals may be of the order Primates, Ceboids, or Simoids (monkeys) or of the order Anthropoids (humans and apes). In some embodiments, the mammal is a human.

[0134] The terms “T cell” and “T lymphocyte” are interchangeable and used synonymously herein. As used herein, T cell includes thymocytes, naive T lymphocytes, immature T lymphocytes, mature T lymphocytes, resting T lymphocytes, or activated T lymphocytes. A T cell can be a T helper (Th) cell, for example a T helper 1 (Th1) or a T helper 2 (Th2) cell. The T cell can be a helper T cell (HTL; CD4+ T cell) CD4+ T cell, a cytotoxic T cell (CTL; CD8+ T cell), a tumor infiltrating cytotoxic T cell (TIL; CD8+ T cell), CD4+CD8+ T cell, or any other subset of T cells. Other illustrative populations of T cells suitable for use in particular embodiments include naive T cells and memory T cells. Also included are “NKT cells”, which refer to a specialized population of T cells that express a semi-invariant αβ T-cell receptor, but also express a variety of molecular markers that are typically associated with NK cells, such as NK1.1. NKT cells include NK1.1+ and NK1.1-, as well as CD4+, CD4-, CD8+ and CD8- cells. The TCR on NKT cells is unique in that it recognizes glycolipid antigens presented by the MHC I-like molecule CD1d. NKT cells can have either protective or deleterious effects due to their abilities to produce cytokines that promote either inflammation or immune tolerance. Also included are “gamma-delta T cells (γδ T cells),” which refer to a specialized population that to a small subset of T cells possessing a distinct TCR on their surface, and unlike the majority of T cells in which the TCR is composed of two glycoprotein chains designated α- and β-TCR chains, the TCR in γδ T cells is made up of a γ-chain and a δ-chain. Γδ T cells can play a role in immunosurveillance and immunoregulation, and were found to be an important source of IL- 17 and to induce robust CD8+ cytotoxic T cell response. Also included are “regulatory T cells” or “Tregs”, which refer to T cells that suppress an abnormal or excessive immune response and play a role in immune tolerance. Tregs are typically transcription factor Foxp3- positive CD4+T cells and can also include transcription factor Foxp3-negative regulatory T cells that are IL-10-producing CD4+T cells.

[0135] “Therapeutically effective amount” refers to an amount effective, at doses and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired -32- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) response in the individual. Exemplary indicators of an effective therapeutic or combination of therapeutics that include, for example, improved well-being of the patient.

[0136] “Transplant-ineligible” means patients who, due to older age, high comorbid burden, or poor performance status, are at an increased risk of treatment-related toxicities. Grant, Shakira J et al., Journal of Geriatric Oncology, vol.12,4 (2021).

[0137] The terms “treat” or “treatment” refer to therapeutic treatment wherein the object is to slow down or lessen an undesired physiological change or disease, or provide a beneficial or desired clinical outcome during treatment. Beneficial or desired clinical outcomes include alleviation of symptoms, diminishment of extent of disease, stabilization (i.e., a cessation in the worsening) of the state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and / or remission (whether partial or total and whether detectable or undetectable). “Treatment” can also mean prolonging survival as compared to expected survival if a subject was not receiving treatment. Those in need of treatment include those subjects already with the undesired physiological change or disease as well as those subjects prone to having the physiological change or disease. Treatment may involve a treatment agent, also referred to herein as a “medicament” or “medication,” that may be intended to help achieve the beneficial or desired clinical outcome of interest by its action. Treatment agents or medicaments may be administered to a subject by many routes, including at least intravenous and oral routes. The term “intravenous,” in connection to the administration of treatment agents or medicaments, refers to the administration of said treatment agents or medicaments within one or more veins. The term “oral,” in connection to the administration of treatment agents or medicaments, refers to the administration of said treatment agents or medicaments via an oral passage such as the mouth.

[0138] “Tumor cell” or a “cancer cell” refers to a cancerous, pre-cancerous or transformed cell, either in vivo, ex vivo, or in tissue culture, that has spontaneous or induced phenotypic changes. These changes do not necessarily involve the uptake of new genetic material. Although transformation may arise from infection with a transforming virus and incorporation of new genomic nucleic acid, uptake of exogenous nucleic acid or it can also arise spontaneously or following exposure to a carcinogen, thereby mutating an endogenous gene. Transformation / cancer is exemplified by morphological changes, immortalization of cells, aberrant growth control, foci formation, proliferation, malignancy, modulation of tumor specific marker levels, invasiveness, tumor growth in suitable animal hosts such as nude mice, and the like, in vitro, in vivo, and ex vivo. -33- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0139] The term “variable” refers to the fact that certain segments of the variable domains differ extensively in sequence among antibodies. The V domain (i.e., variable domain) mediates antigen binding and defines the specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed across the entire span of the variable domains. Instead, it is concentrated in three segments called hypervariable regions (HVRs) both in the light-chain and the heavy-chain variable domains. The more highly conserved portions of variable domains are called the framework regions (FR). The variable domains of native heavy and light chains each comprise four FR regions, largely adopting a β-sheet configuration, connected by three HVRs, which form loops connecting, and in some cases forming part of, the β-sheet structure. The HVRs in each chain are held together in close proximity by the FR regions and contribute to the formation of the antigen binding site of antibodies (with the HVRs from the other chain, if the antibody is not a sdAb or HCAb) (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md. (1991)). The constant domains are not involved directly in the binding of antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity.

[0140] The “variable region” or “variable domain” of an antibody refers to the amino- terminal domains of the heavy or light chain of the antibody. The variable domains of the heavy chain and light chain may be referred to as “VH” and “VL”, respectively. These domains are generally the most variable parts of the antibody (relative to other antibodies of the same class) and contain the antigen binding sites. Heavy-chain only antibodies from the Camelid species have a single heavy chain variable region, which is referred to as “VHH” domain. VHH is thus a special type of variable region.

[0141] The dosing frequencies provided for herein are understood to be synonymous with standard terms in the art. For example, “weekly” dosing is understood to be synonymous with “QW”. For example, “biweekly” dosing is understood to be synonymous with “Q2W”. For example, “once every four weeks” is understood to be synonymous with “Q4W”. Unless explicitly stated to the contrary, “once every four weeks” and “monthly” are used interchangeably in the context of dosing frequencies. Accordingly, “monthly” or “once a month” is also understood to be synonymous with “Q4W” unless explicitly stated otherwise.

[0142] When referring to a dosage amount, “µg / kg” or “mg / kg” refers to the amount of an active agent, such as a bispecific antibody or antibody, in microgram (µg) or milligram (mg) administered to a subject per kilogram (kg) body weight of the subject. -34- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0143] Additionally, throughout this disclosure, various aspects and embodiments of the disclosure can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. As another example, a range such as 95-99 % identity, includes something with 95 %, 96 %, 97 %, 98 % or 99 % identity, and includes subranges such as 96-99 %, 96-98 %, 96-97 %, 97-99 %, 97-98 % and 98-99 % identity. This applies regardless of the breadth of the range.

[0144] The numbering of amino acid residues in the antibody constant region throughout the specification is according to the EU index as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5thEd. Public Health Service, National Institutes of Health, Bethesda, MD. (1991), unless otherwise explicitly stated. Antibody constant chain numbering can be found for example at ImMunoGeneTics website, at IMGT Web resources at IMGT Scientific charts.

[0145] The substitutions in the CH3 region are expressed as modified position(s) in the first CH3 domain of the first heavy chain / modified position(s) in the second CH3 domain of the second heavy chain. For example, F405L / K409R refers to a F405L mutation in the first CH3 region and K09R mutation in the second CH3 region. L351Y_F405A_Y407V / T394W refers to L351Y, F40FA and Y407V mutations in the first CH3 region and T394W mutation in the second CH3 region. D399FHKRQ / K409AGRH refers to mutation in which D399 may be replaced by F, H, K R or Q, and K409 may be replaced by A, G, R or H.

[0146] Conventional one and three-letter amino acid codes are used herein as shown in Table 2. Table 2. Amino acid abbreviations. Amino acid Three-letter code One-letter code Alanine Ala A Arginine Arg R Asparagine Asn N Aspartate Asp D Cysteine Cys C -35- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) Glutamate Gln E Glutamine Glu Q Glycine Gly G Histidine His H Isoleucine Ile I Leucine Leu L Lysine Lys K Methionine Met M Phenylalanine Phe F Proline Pro P Serine Ser S Threonine Thr T Tryptophan Trp W Tyrosine Tyr Y Valine Val V Chimeric Antigen Receptors and Immune Effector Cell Compositions

[0147] International Patent Publication No. WO 2018 / 028647 is incorporated by reference herein in its entirety. US Patent Publication No.2018 / 0230225 is incorporated by reference herein in its entirety. International Patent Application No. PCT / CN2020 / 133598 is incorporated by reference herein in its entirety.

[0148] The disclosure provides for methods of treating a subject with cells expressing a chimeric antigen receptor (CAR). The CAR comprises an extracellular antigen binding domain comprising one or more single-domain antibodies. In various embodiments, there is provided a CAR targeting BCMA (also referred herein as “BCMA CAR”) comprising a polypeptide comprising: (a) an extracellular antigen binding domain comprising an anti- BCMA binding moiety; (b) a transmembrane domain; and (c) an intracellular signaling domain. In some embodiments, the anti-BCMA binding moiety is camelid, chimeric, human, or humanized. In some embodiments, the intracellular signaling domain comprises a primary intracellular signaling domain of an immune effector cell (such as T cell). In some embodiments, the primary intracellular signaling domain is derived from CD4. In some embodiments, the primary intracellular signaling domain is derived from CD3-zeta. In some embodiments, the intracellular signaling domain comprises a co-stimulatory signaling domain. In some embodiments, the co-stimulatory signaling domain is derived from a co- stimulatory molecule selected from the group consisting of CD27, CD28, CD137, OX40, CD30, CD40, CD3, LFA-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, ligands of CD83 -36- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) and combinations thereof. In some embodiments, the co-stimulatory signaling domain is derived from CD137.

[0149] In some embodiments, the BCMA CAR further comprises a hinge domain (such as a CD8-alpha hinge domain) located between the C-terminus of the extracellular antigen binding domain and the N-terminus of the transmembrane domain. In some embodiments, the BCMA CAR further comprises a signal peptide (such as a CD8-alpha signal peptide) located at the N-terminus of the polypeptide. In some embodiments, the polypeptide comprises from the N-terminus to the C-terminus: a CD8-alpha signal peptide, the extracellular antigen- binding domain, a CD8-alpha hinge domain, a CD28 transmembrane domain, a first co- stimulatory signaling domain derived from CD28, a second co-stimulatory signaling domain derived from CD137, and a primary intracellular signaling domain derived from CD4. In some embodiments, the polypeptide comprises from the N-terminus to the C-terminus: a CD8-alpha signal peptide, the extracellular antigen-binding domain, a CD8-alpha hinge domain, a CD8-alpha transmembrane domain, a second co-stimulatory signaling domain derived from CD137, and a primary intracellular signaling domain derived from CD3-zeta. In some embodiments, the BCMA CAR is monospecific. In some embodiments, the BCMA CAR is monovalent.

[0150] The present application also provides CARs that have two or more (including, but not limited to, any one of 2, 3, 4, 5, 6, or more) binding moieties that specifically bind to an antigen, such as BCMA. In some embodiments, one or more of the binding moieties are antigen binding fragments. In some embodiments, one or more of the binding moieties comprise single-domain antibodies. In some embodiments, one or more of the binding moieties comprise a VHH.

[0151] In some embodiments, the CAR is a multivalent (such as bivalent, trivalent, or of higher number of valencies) CAR comprising a polypeptide comprising: (a) an extracellular antigen binding domain comprising a plurality (such as at least about any one of 2, 3, 4, 5, 6, or more) of binding moieties specifically binding to an antigen (such as a tumor antigen); (b) a transmembrane domain; and (c) an intracellular signaling domain.

[0152] In some embodiments, the binding moieties, such as VHHs (including the plurality of VHHs, or the first VHH and / or the second VHH) are camelid, chimeric, human, or humanized. In some embodiments, the binding moieties or VHHs are connected to each other via peptide bonds or peptide linkers. In some embodiments, each peptide linker is no more -37- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) than about 50 (such as no more than about any one of 35, 25, 20, 15, 10, or 5) amino acids long.

[0153] In some embodiments, the first BCMA binding moiety and / or the second BCMA binding moiety is an anti-BCMA VHH. In some embodiments, the first BCMA binding moiety is a first anti-BCMA VHH and the second BCMA binding moiety is a second anti- BCMA VHH.

[0154] In some embodiments, the first anti-BCMA binding moiety comprises a first complementarity determining region (CDR1) comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the first anti-BCMA binding moiety comprises a second complementarity determining region (CDR2) comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the first anti-BCMA binding moiety comprises a third complementarity determining region (CDR3) comprising the amino acid sequence of SEQ ID NO: 20.

[0155] In some embodiments, the first anti-BCMA binding moiety comprises a first complementarity determining region (CDR1) comprising the amino acid sequence of SEQ ID NO: 18, a second complementarity determining region (CDR2) comprising the amino acid sequence of SEQ ID NO: 19, and a third complementarity determining region (CDR3) comprising the amino acid sequence of SEQ ID NO: 20.

[0156] In some embodiments, the first BCMA binding moiety comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, the first BCMA binding moiety comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 10. In some embodiments, the first anti-BCMA binding moiety comprises one or more of, or all of, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20 and SEQ ID NO: 2. These sequences correspond to the sequences present in ciltacabtagene autoleucel.

[0157] In some embodiments, the second BCMA binding moiety comprises a first complementarity determining region (CDR1) comprising the amino acid sequence of SEQ ID NO: 21. In some embodiments, the second BCMA binding moiety comprises a second complementarity determining region (CDR2) comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the second BCMA binding moiety comprises a third complementarity determining region (CDR3) comprising the amino acid sequence of SEQ ID NO: 23.

[0158] In some embodiments, the second BCMA binding moiety comprises a first complementarity determining region (CDR1) comprising the amino acid sequence of SEQ ID -38- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) NO: 21, a second complementarity determining region (CDR2) comprising the amino acid sequence of SEQ ID NO: 22, and a third complementarity determining region (CDR3) comprising the amino acid sequence of SEQ ID NO: 23.

[0159] In some embodiments, the second BCMA binding moiety comprises the amino acid sequence of SEQ ID NO: 4. In some embodiments, the second BCMA binding moiety comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 12. In some embodiments, the second anti-BCMA binding moiety comprises one or more of, or all of, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 4. These sequences correspond to the sequences present in ciltacabtagene autoleucel.

[0160] In some embodiments, the first BCMA binding moiety and the second BCMA binding moiety are connected to each other via a peptide linker. In some embodiments, the peptide linker comprises the amino acid sequence of SEQ ID NO: 3. In some embodiments, the peptide linker comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 11.

[0161] In some embodiments, the CAR further comprises a hinge domain (such as a CD8- alpha hinge domain) located between the C-terminus of the extracellular antigen binding domain and the N-terminus of the transmembrane domain. In some embodiments, the CAR further comprises a signal peptide (such as a CD8-alpha signal peptide) located at the N- terminus of the polypeptide.

[0162] Without wishing to be bound by theory, the CARs that are multivalent, or those CARs comprising an extracellular antigen binding domain comprising a first BCMA binding moiety and a second BCMA binding moiety, may be specially suitable for targeting multimeric antigens via synergistic binding by the different antigen binding sites, or for enhancing binding affinity or avidity to the antigen. Improved avidity may allow for a substantial reduction in the dose of CAR-T cells needed to achieve a therapeutic effect, such as a dose ranging from 4.0 x 104 to 1.0 x 106 CAR-T cells per kilogram of the mass of the subject, or 3.0 x 106 to 1.0 x 108 total CAR-T expressing cells. Monovalent CARs, such as bb2121, may need to be dosed at 5 to 10 times these amounts to achieve a comparable effect. In various embodiments, reduced dosage ranges may provide for substantial reduction in cytokine release syndrome (CRS) and other potentially dangerous side-effects of CAR-T therapy.

[0163] The various binding moieties (e.g., an extracellular antigen binding domain comprising a first BCMA binding moiety and a second BCMA binding moiety) in the CARs -39- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) described herein may be connected to each other via peptide linkers. The peptide linkers connecting different binding moieties (such as VHHs) may be the same or different. Different domains of the CARs may also be connected to each other via peptide linkers. In some embodiments, the binding moieties (such as VHHs) are directly connected to each other without any peptide linkers.

[0164] The peptide linker in the CARs described herein can be of any suitable length. In some embodiments, the peptide linker is at least about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 75, 100 or more amino acids long. In some embodiments, the peptide linker is no more than about any of 100, 75, 50, 40, 35, 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5 or fewer amino acids long. In some embodiments, the length of the peptide linker is any of about 1 amino acid to about 10 amino acids, about 1 amino acids to about 20 amino acids, about 1 amino acid to about 30 amino acids, about 5 amino acids to about 15 amino acids, about 10 amino acids to about 25 amino acids, about 5 amino acids to about 30 amino acids, about 10 amino acids to about 30 amino acids long, about 30 amino acids to about 50 amino acids, about 50 amino acids to about 100 amino acids, or about 1 amino acid to about 100 amino acids.

[0165] The CARs of the present application comprise a transmembrane domain that can be directly or indirectly connected to the extracellular antigen binding domain.

[0166] The CAR may comprise a T-cell activation moiety. The T-cell activation moiety can be any suitable moiety derived or obtained from any suitable molecule. In one embodiment, for example, the T-cell activation moiety comprises a transmembrane domain. The transmembrane domain can be any transmembrane domain derived or obtained from any molecule known in the art. For example, the transmembrane domain can be obtained or derived from a CD8α molecule or a CD28 molecule. Without wishing to be bound by theory, CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T- cell receptor (TCR) and is expressed primarily on the surface of cytotoxic T-cells. The most common form of CD8 exists as a dimer composed of a CD8 alpha (CD8α) and CD8 beta (CD8β) chain. CD28 is expressed on T-cells and provides co-stimulatory signals required for T-cell activation. CD28 is the receptor for CD80 (B7.1) and CD86 (B7.2). In a preferred embodiment, the CD8α and CD28 are human.

[0167] In addition to the transmembrane domain, the T-cell activation moiety may further comprise an intracellular (i.e., cytoplasmic) T-cell signaling domain. The intercellular T- cell signaling domain can be obtained or derived from a CD28 molecule, a CD3 zeta (ζ) molecule -40- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) or modified versions thereof, a human Fc receptor gamma (FcRy) chain, a CD27 molecule, an OX40 molecule, a 4-1BB molecule, or other intracellular signaling molecules known in the art. Without wishing to be bound by theory: (1) CD28 is a T-cell marker important in T- cell co- stimulation; (2) CD3ζ associates with TCRs to produce a signal and contains immunoreceptor tyrosine-based activation motifs (ITAMs); and (3) 4-1BB, also known as CD137, transmits a potent costimulatory signal to T-cells, promoting differentiation and enhancing long-term survival of T lymphocytes. In a preferred embodiment, the CD28, CD3 zeta, 4- IBB, OX40, and CD27 are human.

[0168] The T-cell activation domain of the CAR encoded by the nucleic acid sequence disclosed herein can comprise any one of aforementioned transmembrane domains and any one or more of the aforementioned intercellular T-cell signaling domains in any combination. For example, the nucleic acid sequence disclosed herein can encode a CAR comprising a CD28 transmembrane domain and intracellular T-cell signaling domains of CD28 and CD3 zeta. Alternatively, for example, the nucleic acid sequence disclosed herein can encode a CAR comprising a CD8α transmembrane domain and intracellular T-cell signaling domains of CD28, CD3 zeta, the Fc receptor gamma (FcRy) chain, and / or 4-1 BB.

[0169] In some embodiments, the CAR polypeptide further comprises a signal peptide located at the N-terminus of the polypeptide. In some embodiments, the signal peptide is derived from CD8-alpha (CD8α SP). In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 1. In some embodiments, the signal peptide comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 9.

[0170] In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 6. In some embodiments, the transmembrane domain comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 14.

[0171] In some embodiments, the intracellular signaling domain comprises a primary intracellular signaling domain of an immune effector cell. In some embodiments, the intracellular signaling domain is derived from CD3ζ. In some embodiments, the intracellular signaling domain comprises at least one co-stimulatory signaling domains. In some embodiments, the intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the intracellular signaling domain comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 16. In some embodiments, the intracellular signaling domain comprises an amino acid sequence of SEQ ID NO: 7. In some -41- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) embodiments, the intracellular signaling domain comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 15.

[0172] In some embodiments, the CAR polypeptide further comprises a hinge domain located between the C-terminus of the extracellular antigen binding domain and the N- terminus of the transmembrane domain. In some embodiments, the hinge domain comprises the amino acid sequence of SEQ ID NO: 5. In some embodiments, the hinge domain comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 13.

[0173] In some embodiments, the CAR comprises a first and a second anti-BCMA binding moiety, wherein the first anti-BCMA binding moiety comprises a first complementarity determining region (CDR1) comprising the amino acid sequence of SEQ ID NO: 18, a second complementarity determining region (CDR2) comprising the amino acid sequence of SEQ ID NO: 19, and a third complementarity determining region (CDR3) comprising the amino acid sequence of SEQ ID NO: 20; wherein the second BCMA binding moiety comprises a first complementarity determining region (CDR1) comprising the amino acid sequence of SEQ ID NO: 21, a second complementarity determining region (CDR2) comprising the amino acid sequence of SEQ ID NO: 22, and a third complementarity determining region (CDR3) comprising the amino acid sequence of SEQ ID NO: 23; wherein the CAR further comprises: a transmembrane domain derived from CD8α, wherein optionally the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 6; a primary intracellular signaling domain derived from CD3ζ, wherein optionally the primary intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 8; a co- stimulatory signaling domain comprising a cytoplasmic domain of CD137, wherein optionally the co-stimulatory signaling domain comprises the amino acid sequence of SEQ ID NO: 7; and a hinge domain located between the C-terminus of the extracellular antigen binding domain and the N-terminus of the transmembrane domain, wherein the hinge domain is derived from CD8α, wherein optionally the hinge domain comprises the amino acid sequence of SEQ ID NO: 5. In certain such embodiments, the first VHH domain comprises the amino acid sequence of SEQ ID NO: 2 and the second VHH domain comprises the amino acid sequence of SEQ ID NO: 4.

[0174] In some embodiments, the CAR comprises one or more of, or all of, SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22 and SEQ ID NO: 23. In some embodiments, the CAR comprises SEQ ID -42- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) NO: 17. In some embodiments, the CAR comprises a polypeptide encoded by the nucleic acid sequence of one or more of, or all of, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16.

[0175] In preferred embodiments, the CAR comprises a first VHH domain comprising a CDR1, a CDR2 and a CDR3 of the VHH domain comprising the amino acid sequence of SEQ ID NO: 2, and a second VHH domain comprising a CDR1, a CDR2 and a CDR3 of the VHH domain comprising the amino acid sequence of SEQ ID NO: 4. In preferred embodiments, the first VHH domain is linked to the second VHH domain via a linker comprising the amino acid sequence of SEQ ID NO: 3. In particularly preferred embodiments, the first VHH domain comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 18, a CDR2 comprising the amino acid sequence of SEQ ID NO: 19, a CDR3 comprising the amino acid sequence of SEQ ID NO: 20, and the second VHH domain comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a CDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 23. In further preferred embodiments, the CAR comprises a first VHH domain comprising the amino acid sequence of SEQ ID NO: 2, and a second VHH domain comprising the amino acid sequence of SEQ ID NO: 4.

[0176] “Immune effector cells” are immune cells that can perform immune effector functions. In some embodiments, the immune effector cells express at least FcγRIII and perform ADCC effector function. Examples of immune effector cells which mediate ADCC include peripheral blood mononuclear cells (PBMC), natural killer (NK) cells, monocytes, cytotoxic T cells, neutrophils, and eosinophils. In some embodiments, the immune effector cells are T cells. In some embodiments, the T cells are autologous T cells. In some embodiments, the T cells are allogeneic T cells. In some embodiments, the T cells are CD4+ / CD8-, CD4- / CD8+, CD4+ / CD8+, CD4- / CD8-, or combinations thereof. In some embodiments, the T cells produce IL-2, TFN, and / or TNF upon expressing the CAR and binding to the target cells, such as CD20+ or CD19+ tumor cells. In some embodiments, the CD8+ T cells lyse antigen-specific target cells upon expressing the CAR and binding to the target cells.

[0177] Biological methods for introducing the vector into an immune effector cell include the use of DNA and RNA vectors. Viral vectors have become the most widely used method for inserting genes into mammalian, e.g., human cells. -43- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0178] Provided herein are dosage forms comprising 3.0 x 107to 1.0 x 108CAR-T cells comprising a CAR comprising a polypeptide provided herein. Provided herein are dosage forms comprising 3.0 x 107to 1.0 x 108CAR-T cells comprising a CAR comprising a polypeptide comprising: (a) an extracellular antigen binding domain comprising a first BCMA binding moiety specifically binding to a first epitope of BCMA, and a second BCMA binding moiety specifically binding to a second epitope of BCMA; (b) a transmembrane domain; and (c) an intracellular signaling domain, wherein the first epitope and the second epitope are different. In some embodiments, there are provided dosage forms comprising 3.0 x 107to 1.0 x 108engineered immune effector cells (such as T-cells) comprising a CAR comprising a polypeptide comprising: (a) an extracellular antigen binding domain comprising a first anti-BCMA VHH specifically binding to a first epitope of BCMA, and a second anti- BCMA VHH specifically binding to a second epitope of BCMA; (b) a transmembrane domain; and (c) an intracellular signaling domain, wherein the first epitope and the second epitope are different.

[0179] In some embodiments, the dosage form comprises 3.0 x 107to 4.0 x 107of the CAR-T cells. In some embodiments, the dosage form comprises 3.5 x 107to 4.5 x 107of the CAR-T cells. In some embodiments, the dosage form comprises 4.0 x 107to 5.0 x 107of the CAR-T cells. In some embodiments, the dosage form comprises 4.5 x 107to 5.5 x 107of the CAR-T cells. In some embodiments, the dosage form comprises 5.0 x 107to 6.0 x 107of the CAR-T cells. In some embodiments, the dosage form comprises 5.5 x 107to 6.5 x 107of the CAR-T cells. In some embodiments, the dosage form comprises 6.0 x 107to 7.0 x 107of the CAR-T cells. In some embodiments, the dosage form comprises 6.5 x 107to 7.5 x 107of the CAR-T cells. In some embodiments, the dosage form comprises 7.0 x 107to 8.0 x 107of the CAR-T cells. In some embodiments, the dosage form comprises 7.5 x 107to 8.5 x 107of the CAR-T cells. In some embodiments, the dosage form comprises 8.0 x 107to 9.0 x 107of the CAR-T cells. In some embodiments, the dosage form comprises 8.5 x 107to 9.5 x 107of the CAR-T cells. In some embodiments, the dosage form comprises 9.0 x 107to 1.0 x 108of the CAR-T cells.

[0180] In some embodiments, the cell population of the CAR-T dosage forms described herein comprise a T cell or population of T cells, e.g., at various stages of differentiation. Stages of T cell differentiation include naïve T cells, stem central memory T cells, central memory T cells, effector memory T cells, and terminal effector T cells, from least to most differentiated. After antigen exposure, naïve T cells proliferate and differentiate into memory -44- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) T cells, e.g., stem central memory T cells and central memory T cells, which then differentiate into effector memory T cells. Upon receiving appropriate T cell receptor, costimulatory, and inflammatory signals, memory T cells further differentiate into terminal effector T cells. See, e.g., Restifo. Blood.124.4(2014):476-77; and Joshi et al. J. Immunol. 180.3(2008):1309-15.

[0181] Naïve T cells can have the following expression pattern of cell surface markers: CCR7+, CD62L+, CD45RO−, CD95−. Stem central memory T cells (Tscm) can have the following expression pattern of cell surface markers: CCR7+, CD62L+, CD45RO−, CD95+. Central memory T cells (Tcm) can have the following expression pattern of cell surface markers: CCR7+, CD62L+, CD45RO+, CD95+. Effector memory T cells (Tem) can have the following expression pattern of cell surface markers: CCR7−, CD62L−, CD45RO+, CD95+. Terminal effector T cells (Teff) can have the following expression pattern of cell surface markers: CCR7−, CD62L−, CD45RO−, CD95+. See, e.g., Gattinoni et al. Nat. Med. 17(2011):1290-7; and Flynn et al. Clin. Translat. Immunol.3(2014):e20.

[0182] Further provided by the present application are pharmaceutical compositions comprising any one of the engineered immune effector cells comprising any one of the CARs (such as BCMA CARs) as described herein, and a pharmaceutically acceptable carrier. Pharmaceutical compositions can be prepared by mixing any of the immune effector cells described herein, having the desired degree of purity, with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. In some embodiments, a pharmaceutical composition of CAR-T cells further comprises an excipient selected from dimethylsulfoxide or dextran-40.

[0183] The compositions described herein may be administered as part of a pharmaceutical composition comprising one or more carriers. The choice of carrier will be determined in part by the particular nucleic acid sequence, vector, or host cells expressing the CAR disclosed herein, as well as by the particular method used to administer the nucleic acid sequence, vector, or host cells expressing the CAR disclosed herein. Accordingly, there are a variety of suitable formulations of the pharmaceutical composition of the disclosure.

[0184] For example, the pharmaceutical composition can contain preservatives. Suitable preservatives may include, for example, methylparaben, propylparaben, sodium benzoate, and benzalkonium chloride. A mixture of two or more preservatives optionally may be used. -45- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) The preservative or mixtures thereof are typically present in an amount of about 0.0001% to about 2% by weight of the total composition.

[0185] In addition, buffering agents may be used in the composition. Suitable buffering agents include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts. A mixture of two or more buffering agents optionally may be used. The buffering agent or mixtures thereof are typically present in an amount of about 0.001 % to about 4% by weight of the total composition.

[0186] The composition comprising the nucleic acid sequence encoding the CAR disclosed herein, or host cells expressing the CAR disclosed herein, can be formulated as an inclusion complex, such as cyclodextrin inclusion complex, or as a liposome. Liposomes can serve to target the host cells (e.g., T-cells or NK cells) or the nucleic acid sequence disclosed herein to a particular tissue. Liposomes also can be used to increase the half-life of the nucleic acid sequence disclosed herein. Many methods are available for preparing liposomes, such as those described in, for example, Szoka et al., Ann. Rev. Biophys. Bioeng., 9: 467 (1980), and U.S. Patents 4,235,871; 4,501,728; 4,837,028; and 5,019,369. The composition can employ time-released, delayed release, and sustained release delivery systems such that the delivery of the composition disclosed herein occurs prior to, and with sufficient time to cause, sensitization of the site to be treated. Many types of release delivery systems are available and known to those of ordinary skill in the art. Such systems can avoid repeated administrations of the composition, thereby increasing convenience to the subject and the physician, and may be particularly suitable for certain composition embodiments of the disclosure.

[0187] In some embodiments, the CAR-T cells are formulated at a dose of about 0.5 x 106cells / kg to about 1.0 x 106cells / kg, of about 0.55 x 106cells / kg to about 0.95 x 106cells / kg, of about 0.6 x 106cells / kg to about 0.90 x 106cells / kg, of about 0.65 x 106cells / kg to about 0.85 x 106cells / kg, and of about 0.7 x 106cells / kg to about 0.80 x 106cells / kg. In some embodiments, the dosage form comprises 0.75 x 106cells / kg. In a preferred embodiment, the dose is formulated at approximately 0.75 x 106cells / kg. In some embodiments, the CAR-T cells are formulated at a dose of less than 1.0 x 108CAR-T cells per subject. GPRC5DxCD3 Bispecific Antibodies

[0188] G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D) is a 7 transmembrane receptor protein that is classified as a type C G protein-coupled receptor -46- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) based on the sequence homology score, and is an orphan receptor whose ligand and signaling mechanisms are yet to be identified. GPRC5D messenger ribonucleic acid (mRNA) is predominantly expressed in cells with a plasma cell phenotype and also expressed in all malignant plasma cells from patients with multiple myeloma. The expression of GPRC5D on the plasma cell lineage makes it a target for T cell mediated therapy to treat plasma cell disorders like multiple myeloma. A GPRC5D xCD3 bispecific antibody targets the CD3 receptor complex on T cells and GPRC5D on plasma cells. The dual binding sites allow the GPRC5DxCD3 bispecific antibody to draw CD3+ T cells in close proximity to myeloma cells, without regard to T cell receptor specificity or reliance on MHC Class 1 molecules on the surface of antigen presenting cells for activation, leading to cell death of the GPRC5D- positive cells.

[0189] Any suitable GPRC5D xCD3 bispecific antibody can be used in a method of the application. Exemplary multispecific and / or bispecific formats include dual targeting molecules include Dual Targeting (DT)-Ig (GSK / Domantis), Two-in-one Antibody (Genentech) and mAb2 (F-Star), Dual Variable Domain (DVD)-Ig (Abbott), 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 (Fc- DART) (MacroGenics), F(ab)2 (Medarex / AMGEN), Dual-Action or Bis-Fab (Genentech), Dock-and-Lock (DNL) (ImmunoMedics), Bivalent Bispecific (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 Antibodies (AIT, ReceptorLogics), Human Serum Albumin ScFv Fusion (Merrimack) and COMBODY (Epigen Biotech), dual targeting nanobodies (Ablynx), dual targeting heavy chain only domain antibodies. Various formats of bispecific antibodies have been described, for example in Chames and Baty (2009) Curr Opin Drug Disc Dev 12: 276 and in Nunez-Prado et al., (2015) Drug Discovery Today 20(5):588-594.

[0190] In some embodiments, the GPRC5D xCD3 bispecific antibody and the anti-CD38 antibody are antigen binding fragments. Exemplary antigen binding fragments are Fab, F(ab’)2, Fd and Fv fragments.

[0191] In some embodiments, the GPRC5DxCD3 bispecific antibody is chimeric, humanized or human. -47- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0192] In some embodiments, the GPRC5D xCD3 bispecific antibody comprises a GPRC5D binding domain comprising a VH having the HCDR1 of SEQ ID NO: 101, the HCDR2 of SEQ ID NO: 102, the HCDR3 of SEQ ID NO: 103, and a VL having the LCDR1 of SEQ ID NO: 104, the LCDR2 of SEQ ID NO: 105 and the LCDR3 of SEQ ID NO: 106, and a CD3 binding domain comprising a VH having the HCDR1 of SEQ ID NO: 107, the HCDR2 of SEQ ID NO: 108, the HCDR3 of SEQ ID NO: 109, and a VL having the LCDR1 of SEQ ID NO: 110, the LCDR2 of SEQ ID NO: 111 and the LCDR3 of SEQ ID NO: 112. The HCDRs and LCDRs of the GPRC5D x CD3 bispecific antibody are recited in Table 3 below: Table 3: Exemplary CDRs of GPRC5D x CD3 bispecific antibody Region Sequence SEQ ID NO: Binding Arm HCDR1 GYTMN 101 GPRC5D HCDR2 LINPYNSDTNYAQKLQG 102 HCDR3 VALRVALDY 103 LCDR1 KASQNVATHVG 104 LCDR2 SASYRYS 105 LCDR3 QQYNRYPYT 106 HCDR1 TYAMN 107 CD3 HCDR2 RIRSKYNNYATYYAASVKG 108 HCDR3 HGNFGNSYVSWFAY 109 LCDR1 RSSTGAVTTSNYAN 110 LCDR2 GTNKRAP 111 LCDR3 ALWYSNLWV 112

[0193] The CDRs recited in the table above are of the Kabat numbering system. However, as provided for herein, the CDRs of the present disclosure may be provided by any appropriate numbering system, such as any of the Kabat, Chothia, IMGT, or AbM numbering systems. Tables 4-6 below provide exemplary CDRs utilizing the Chothia, AbM, and IMGT numbering systems: Table 4: Exemplary CDRs of GPRC5D x CD3 bispecific antibody – Chothia numbering system: -48- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) Binding Arm Region Sequence SEQ ID NO: GPRC5D HCDR1 GYSFTGY 124 HCDR2 NPYNSD 125 HCDR3 VALRVALDY 103 LCDR1 KASQNVATHVG 104 LCDR2 SASYRYS 105 LCDR3 QQYNRYPYT 106 CD3 HCDR1 GFTFNTY 126 HCDR2 RSKYNNYA 127 HCDR3 HGNFGNSYVSWFAY 109 LCDR1 RSSTGAVTTSNYAN 110 LCDR2 GTNKRAP 111 LCDR3 ALWYSNLWV 112 Table 5: Exemplary CDRs of GPRC5D x CD3 bispecific antibody – AbM numbering system: Binding Arm Region Sequence SEQ ID NO: GPRC5D HCDR1 GYSFTGYTMN 128 HCDR2 LINPYNSDTN 129 HCDR3 VALRVALDY 103 LCDR1 KASQNVATHVG 104 LCDR2 SASYRYS 105 LCDR3 QQYNRYPYT 106 CD3 HCDR1 GFTFNTYAMN 130 HCDR2 RIRSKYNNYATY 131 HCDR3 HGNFGNSYVSWFAY 109 LCDR1 RSSTGAVTTSNYAN 110 LCDR2 GTNKRAP 111 LCDR3 ALWYSNLWV 112 Table 6: Exemplary CDRs of GPRC5D x CD3 bispecific antibody – IMGT numbering system: -49- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) Binding Arm Region Sequence SEQ ID NO: GPRC5D HCDR1 GYSFTGYT 132 HCDR2 INPYNSDT 133 HCDR3 ARVALRVALDY 134 LCDR1 QNVATH 135 LCDR2 SAS NA LCDR3 QQYNRYPYT 106 CD3 HCDR1 GFTFNTYA 136 HCDR2 IRSKYNNYAT 137 HCDR3 ARHGNFGNSYVSWFAY 138 LCDR1 TGAVTTSNY 139 LCDR2 GTN NA LCDR3 ALWYSNLWV 112

[0194] In some embodiments, the GPRC5D xCD3 bispecific antibody comprises a GPRC5D binding domain comprising a VH having the HCDR1 of SEQ ID NO: 101, the HCDR2 of SEQ ID NO: 102, the HCDR3 of SEQ ID NO: 103, and a VL having the LCDR1 of SEQ ID NO: 104, the LCDR2 of SEQ ID NO: 105 and the LCDR3 of SEQ ID NO: 106, and a CD3 binding domain comprising a VH having the HCDR1 of SEQ ID NO: 107, the HCDR2 of SEQ ID NO: 108, the HCDR3 of SEQ ID NO: 109, and a VL having the LCDR1 of SEQ ID NO: 110, the LCDR2 of SEQ ID NO: 111 and the LCDR3 of SEQ ID NO: 112.

[0195] In some embodiments, the GPRC5D xCD3 bispecific antibody comprises a GPRC5D binding domain comprising a VH having the HCDR1 of SEQ ID NO: 124, the HCDR2 of SEQ ID NO: 125, the HCDR3 of SEQ ID NO: 103, and a VL having the LCDR1 of SEQ ID NO: 104, the LCDR2 of SEQ ID NO: 105 and the LCDR3 of SEQ ID NO: 106, and a CD3 binding domain comprising a VH having the HCDR1 of SEQ ID NO: 126, the HCDR2 of SEQ ID NO: 127, the HCDR3 of SEQ ID NO: 109, and a VL having the LCDR1 of SEQ ID NO: 110, the LCDR2 of SEQ ID NO: 111 and the LCDR3 of SEQ ID NO: 112.

[0196] In some embodiments, the GPRC5D xCD3 bispecific antibody comprises a GPRC5D binding domain comprising a VH having the HCDR1 of SEQ ID NO: 128, the HCDR2 of SEQ ID NO: 129, the HCDR3 of SEQ ID NO: 103, and a VL having the LCDR1 of SEQ ID NO: 104, the LCDR2 of SEQ ID NO: 105 and the LCDR3 of SEQ ID NO: 106, and a CD3 binding domain comprising a VH having the HCDR1 of SEQ ID NO: 130, the HCDR2 of SEQ ID NO: 131, the HCDR3 of SEQ ID NO: 109, and a VL having the LCDR1 of SEQ ID NO: 110, the LCDR2 of SEQ ID NO: 111 and the LCDR3 of SEQ ID NO: 112.

[0197] In some embodiments, the GPRC5D xCD3 bispecific antibody comprises a GPRC5D binding domain comprising a VH having the HCDR1 of SEQ ID NO: 132, the HCDR2 of SEQ ID NO: 133, the HCDR3 of SEQ ID NO: 134, and a VL having the LCDR1 -50- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) of SEQ ID NO: 135, a LCDR2 having the amino acid sequence SAS, and the LCDR3 of SEQ ID NO: 106, and a CD3 binding domain comprising a VH having the HCDR1 of SEQ ID NO: 136, the HCDR2 of SEQ ID NO: 137 the HCDR3 of SEQ ID NO: 138, and a VL having the LCDR1 of SEQ ID NO: 139, a LCDR2 having the amino acid sequence GTN, and the LCDR3 of SEQ ID NO: 112.

[0198] In some embodiments, the GPRC5D xCD3 bispecific antibody comprises a GPRC5D binding domain comprising the VH of SEQ ID NO: 113 and the VL of SEQ ID NO: 114, and a CD3 binding domain comprising the VH of SEQ ID NO: 115 and the VL of SEQ ID NO: 116.

[0199] In some embodiments, the GPRC5D xCD3 bispecific antibody that binds GPRC5D comprises a first heavy chain (HC1) of SEQ ID NO: 117, a first light chain (LC1) of SEQ ID NO: 118, a second heavy chain (HC2) of SEQ ID NO: 119, and a second light chain (LC2) of SEQ ID NO: 120.

[0200] In some embodiments, the CD3 binding arm of the GPRC5DxCD3 bispecific antibody and the GPRC5D binding arm of the GPRC5DxCD3 bispecific antibody comprise the amino acid sequences as provided for in Tables 7A-7B. Table 7A. Sequences of GPRC5D binding arm of a GPRC5DxCD3 bispecific antibody. Region Sequence SEQ ID NO: HCDR1 GYTMN 101 HCDR2 LINPYNSDTNYAQKLQG 102 HCDR3 VALRVALDY 103 LCDR1 KASQNVATHVG 104 LCDR2 SASYRYS 105 LCDR3 QQYNRYPYT 106 QVQLVQSGAEVKKPGASVKVSCKASGYSFT 113 VH GYTMNWVRQAPGQGLEWMGLINPYNSDTN YAQKLQGRVTMTTDTSTSTAYMELRSLRSD DTAVYYCARVALRVALDYWGQGTLVTVSS  DIQMTQSPSSLSASVGDRVTITCKASQNVAT 114 VL HVGWYQQKPGKAPKRLIYSASYRYSGVPSR FSGSGSGTEFTLTISNLQPEDFATYYCQQYNR YPYTFGQGTKLEIK QVQLVQSGAEVKKPGASVKVSCKASGYSFT 117 GYTMNWVRQAPGQGLEWMGLINPYNSDTN YAQKLQGRVTMTTDTSTSTAYMELRSLRSD HC DTAVYYCARVALRVALDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTKTYTCNVDHKPSNTK VDKRVESKYGPPCPPCPAPEAAGGPSVFLFPP -51- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) KPKDTLMISRTPEVTCVVVDVSQEDPEVQFN WYVDGVEVHNAKTKPREEQFNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS KAKGQPREPQVYTLPPSQEEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMH EALHNHYTQKSLSLSLGK DIQMTQSPSSLSASVGDRVTITCKASQNVAT 118 HVGWYQQKPGKAPKRLIYSASYRYSGVPSR FSGSGSGTEFTLTISNLQPEDFATYYCQQYNR LC YPYTFGQGTKLEIKKAAPSVTLFPPSSEELQA NKATLVCLISDFYPGAVTVAWKGDSSPVKA GVETTTPSKQSNNKYAASSYLSLTPEQWKSH RSYSCQVTHEGSTVEKTVAPTECS Table 7B. Sequences of CD3 binding arm of a GPRC5DxCD3 bispecific antibody. Region Sequence SEQ ID NO: HCDR1 TYAMN 107 HCDR2 RIRSKYNNYATYYAASVKG 108 HCDR3 HGNFGNSYVSWFAY 109 LCDR1 RSSTGAVTTSNYAN 110 LCDR2 GTNKRAP 111 LCDR3 ALWYSNLWV 112 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFNT 115 YAMNWVRQAPGKGLEWVARIRSKYNNYAT YYAASVKGRFTISRDDSKNSLYLQMNSLKTE DTAVYYCARHGNFGNSYVSWFAYWGQGTL VTVSS VL QTVVTQEPSLTVSPGGTVTLTCRSSTGAVTT 116 SNYANWVQQKPGQAPRGLIGGTNKRAPGTP ARFSGSLLGGKAALTLSGVQPEDEAEYYCAL WYSNLWVFGGGTKLTVLGQP HC EVQLVESGGGLVQPGGSLRLSCAASGFTFNT 119 YAMNWVRQAPGKGLEWVARIRSKYNNYAT YYAASVKGRFTISRDDSKNSLYLQMNSLKTE DTAVYYCARHGNFGNSYVSWFAYWGQGTL VTVSSASTKGPSVFPLAPCSRSTSESTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTKTYTCNVDHK PSNTKVDKRVESKYGPPCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ -52- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) VSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFLLYSKLTVDKSRWQEGNVFS CSVMHEALHNHYTQKSLSLSLGK LC QTVVTQEPSLTVSPGGTVTLTCRSSTGAVTT 120 SNYANWVQQKPGQAPRGLIGGTNKRAPGTP ARFSGSLLGGKAALTLSGVQPEDEAEYYCAL WYSNLWVFGGGTKLTVLGQPKAAPSVTLFP PSSEELQANKATLVCLISDFYPGAVTVAWKA DSSPVKAGVETTTPSKQSNNKYAASSYLSLT PEQWKSHRSYSCQVTHEGSTVEKTVAPTECS

[0201] In some embodiments, the GPRC5DxCD3 bispecific antibody can be, but are not limited to, talquetamab (also named JNJ-564 or JNJ-64407564), a GPRC5DxCD3 bispecific antibody described in Kodama et al. Mol Cancer Ther.2019.18(9): 1555-1564, the entire content of which is incorporated herein by reference, or a bispecific antibody that uses a human GPRC5D binding domain described in US Patent No.10,590,196, the entire content of which is incorporated herein by reference, or a GPRC5D binding domain that competes with talquetamab or the human GPRC5D binding domain described in US Patent No.10,590,196 for binding to human GPRC5D.

[0202] In some embodiments, talquetamab comprises a first heavy chain (HC1), a first light chain (LC1), a second heavy chain (HC2), and a second light chain (LC2), wherein the HC1 is associated with LC1 and the HC2 is associated with LC2, wherein HC1 and LC1 form a first antigen-binding site that immunospecifically binds to GPRC5D and wherein HC2 and LC2 form a second antigen-binding site that immunospecifically binds to CD3. In some embodiments, talquetamab comprises a HC1 of SEQ ID NO: 117, a LC1 of SEQ ID NO: 118, a HC2 of SEQ ID NO: 119, and a LC2 of SEQ ID NO: 120. In some embodiments, the CD3 arm and the GPRC5D arm of talquetamab form a functional bispecific antibody through an interaction between their respective Fc domains.

[0203] In some embodiments, the GPRC5DxCD3 bispecific antibody comprises any one of GPRC5D binding domains described in US Patent No.10,906,956 or WO2020 / 092854 the entire content of which is incorporated herein by reference, or a GPRC5D binding domain that competes with such GPRC5D binding domain for binding to human GPRC5D.

[0204] In some embodiments, the GPRC5DxCD3 bispecific antibody is an IgG1, an IgG2, an IgG3 or an IgG4 isotype.

[0205] In some embodiments, the GPRC5DxCD3 bispecific antibody is an IgG1 isotype.

[0206] In some embodiments, the GPRC5DxCD3 bispecific antibody is an IgG2 isotype.

[0207] In some embodiments, the GPRC5DxCD3 bispecific antibody is an IgG3 isotype. -53- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0208] In some embodiments, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype.

[0209] The GPRC5DxCD3 bispecific antibody can be of any allotype. Immunogenicity of therapeutic antibodies is associated with increased risk of infusion reactions and decreased duration of therapeutic response (Baert et al., (2003) N Engl J Med 348:602-08). The extent to which therapeutic antibodies induce an immune response in the host may be determined in part by the allotype of the antibody (Stickler et al., (2011) Genes and Immunity 12:213-21). Antibody allotype is related to amino acid sequence variations at specific locations in the constant region sequences of the antibody. Table 8 shows select IgG1, IgG2 and IgG4 allotypes. Table 8. IgG1, IgG2 and IgG4 allotypes. Allotype Amino acid residue at position of diversity (residue numbering: EU Index) IgG2 IgG4 IgG1 189 282 309 422 214 356 358 431 G2m(n) T M G2m(n-) P V G2m(n) / (n- T VnG4m(a) L R G1m(17) K E M A G1m(17,1) K D L A

[0210] In some embodiments, the one or more Fc substitutions is selected from the group consisting of F234A / L235A on IgG4, 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-deleted / A327G / P331A / D365E / L358M on IgG1, 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- deleted / G237A / P238S on IgG4, wherein residue numbering is according to the EU index.

[0211] In some embodiments, the one or more Fc substitutions is F234A / L235A on IgG4.

[0212] In some embodiments, the one or more Fc substitutions is L234A / L235A on IgG1.

[0213] In some embodiments, the one or more Fc substitutions is V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2.

[0214] In some embodiments, the one or more Fc substitutions is F234A / L235A on IgG4.

[0215] In some embodiments, the one or more Fc substitutions is S228P / F234A / L235A on IgG4. -54- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0216] In some embodiments, the one or more Fc substitutions is N297A on all Ig isotypes.

[0217] In some embodiments, the one or more Fc substitutions is V234A / G237A on IgG2.

[0218] In some embodiments, the one or more Fc substitutions is K214T / E233P / L234V / L235A / G236-deleted / A327G / P331A / D365E / L358M on IgG1.

[0219] In some embodiments, the one or more Fc substitutions is H268Q / V309L / A330S / P331S on IgG2.

[0220] In some embodiments, the one or more Fc substitutions is S267E / L328F on IgG1. In some embodiments, the one or more Fc substitutions is L234F / L235E / D265A on IgG1.

[0221] In some embodiments, the one or more Fc substitutions is L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1.

[0222] In some embodiments, the one or more Fc substitutions is S228P / F234A / L235A / G237A / P238S on IgG4 and S228P / F234A / L235A / G236- deleted / G237A / P238S on IgG4.

[0223] In some embodiments, the multispecific antibody further comprises a S228P substitution.

[0224] In some embodiments, the multispecific antibody comprises one or more asymmetric substitutions in a first CH3 domain or in a second CH3 domain, or in both the first CH3 domain and the second CH3 domain.

[0225] In some embodiments, the one or more asymmetric substitutions is selected from the group consisting of F450L / K409R, wild-type / F409L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S and T366W / T366S_L368A_Y407V, L351Y_F405A_Y407V / T394W, T366I_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.

[0226] In some embodiments, the one or more asymmetric substitutions is F450L / K409R.

[0227] In some embodiments, the one or more asymmetric substitutions is wild- type / F409L_R409K.

[0228] In some embodiments, the one or more asymmetric substitutions is T366Y / F405A.

[0229] In some embodiments, the one or more asymmetric substitutions is T366W / F405W. -55- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0230] In some embodiments, the one or more asymmetric substitutions is F405W / Y407A.

[0231] In some embodiments, the one or more asymmetric substitutions is T394W / Y407T.

[0232] In some embodiments, the one or more asymmetric substitutions is T394S / Y407A.

[0233] In some embodiments, the one or more asymmetric substitutions is T366W / T394S.

[0234] In some embodiments, the one or more asymmetric substitutions is F405W / T394S.

[0235] In some embodiments, the one or more asymmetric substitutions is T366W / T366S_L368A_Y407V.

[0236] In some embodiments, the one or more asymmetric substitutions is L351Y_F405A_Y407V / T394W.

[0237] In some embodiments, the one or more asymmetric substitutions is T366I_K392M_T394W / F405A_Y407V.

[0238] In some embodiments, the one or more asymmetric substitutions is T366L_K392M_T394W / F405A_Y407V.

[0239] In some embodiments, the one or more asymmetric substitutions is L351Y_Y407A / T366A_K409F.

[0240] In some embodiments, the one or more asymmetric substitutions is L351Y_Y407A / T366V_K409F.

[0241] In some embodiments, the one or more asymmetric substitutions is Y407A / T366A_K409F.

[0242] In some embodiments, the one or more asymmetric substitutions is T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0243] In some embodiments, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in a first heavy chain (HC1) and leucine at position 405 and lysine at position 409 in a second heavy chain (HC2), wherein residue numbering is according to the EU Index.

[0244] In some embodiments, the GPRC5DxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234 and alanine at position 235 in both the HC1 and the HC2, wherein residue numbering is according to the EU Index.

[0245] The antibodies used in the methods of the invention binding specific antigens may be selected de novo from, for example, a phage display library, where the phage is engineered to express human immunoglobulins or portions thereof such as Fabs, single chain antibodies (scFv), or unpaired or paired antibody variable regions (Knappik et al., J Mol Biol 296:57-86, -56- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 2000; Krebs et al., J Immunol Meth 254:67-84, 2001; Vaughan et al., Nature Biotechnology 14:309-14, 1996; Sheets et al., PITAS (USA) 95:6157-62, 1998; Hoogenboom and Winter, J Mol Biol 227:381, 1991; Marks et al., J Mol Biol 222:581, 1991). Phage display libraries expressing antibody heavy and light chain variable regions as fusion proteins with bacteriophage pIX coat protein as described in Shi et al (2010) J. Mol. Biol.397:385-96 and Int’l Pat. Pub. No. WO2009 / 085462. The antibody libraries may be screened for binding to the desired antigen, such as GPRC5D and the obtained positive clones may be further characterized and the Fabs isolated from the clone lysates, and subsequently cloned as full- length antibodies. Such phage display methods for isolating human antibodies are established in the art. See for example: U.S. Pat. No.5,223,409; U.S. Pat. No.5,403,484; U.S. Pat. No. 5,571,698; U.S. Pat. No.5,427,908; U.S. Pat. No.5,580,717; U.S. Pat. No.5,969,108; U.S. Pat. No.6,172,197; U.S. Pat. No.5,885,793; U.S. Pat. No.6,521,404; U.S. Pat. No. 6,544,731; U.S. Pat. No.6,555,313; U.S. Pat. No.6,582,915; and U.S. Pat. No.6,593,081.

[0246] T cell redirecting bispecific antibodies may be generated in vitro in a cell-free environment by introducing asymmetrical mutations in the CH3 regions of two monospecific homodimeric antibodies and forming the bispecific heterodimeric antibody from two parent monospecific homodimeric antibodies in reducing conditions to allow disulfide bond isomerization according to methods described in Intl. Pat. Publ. No. WO2011 / 131746. In the methods, two monospecific bivalent antibodies are engineered to have certain substitutions at the CH3 domain that promote heterodimer stability; the antibodies are incubated together under reducing conditions sufficient to allow the cysteines in the hinge region to undergo disulfide bond isomerization; thereby generating the bispecific antibody by Fab arm exchange. The incubation conditions may optimally be restored to non-reducing. Exemplary reducing agents that may be used are 2- mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cysteine and beta-mercaptoethanol, preferably a reducing agent selected from the group consisting of: 2- mercaptoethylamine, dithiothreitol and tris(2-carboxyethyl)phosphine. For example, incubation for at least 90 min at a temperature of at least 20°C in the presence of at least 25 mM 2-MEA or in the presence of at least 0.5 mM dithiothreitol at a pH of from 5-8, for example at pH of 7.0 or at pH of 7.4 may be used.

[0247] Exemplary CH3 mutations that may be used in a first heavy chain and in a second heavy chain of the bispecific antibody are K409R and / or F405L. -57- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0248] Additional CH3 mutations that may be used include technologies such as Duobody® mutations (Genmab), Knob-in-Hole mutations (Genentech), electrostatically- matched mutations (Chugai, Amgen, NovoNordisk, Oncomed), the Strand Exchange Engineered Domain body (SEEDbody) (EMD Serono), and other asymmetric mutations (e.g., Zymeworks).

[0249] Duobody® mutations (Genmab) are disclosed for example in US9150663 and US2014 / 0303356 and include mutations F405L / K409R, wild-type / F405L_R409K, T350I_K370T_F405L / K409R, K370W / K409R, D399AFGHILMNRSTVWY / K409R, T366ADEFGHILMQVY / K409R, L368ADEGHNRSTVQ / K409AGRH, D399FHKRQ / K409AGRH, F405IKLSTVW / K409AGRH and Y407LWQ / K409AGRH.

[0250] Knob-in-hole mutations are disclosed for example in WO1996 / 027011 and include mutations on the interface of CH3 region in which an amino acid with a small side chain (hole) is introduced into the first CH3 region and an amino acid with a large side chain (knob) is introduced into the second CH3 region, resulting in preferential interaction between the first CH3 region and the second CH3 region. Exemplary CH3 region mutations forming a knob and a hole are T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S and T366W / T366S_L368A_Y407V.

[0251] Heavy chain heterodimer formation may be promoted by using electrostatic interactions by substituting positively charged residues on the first CH3 region and negatively charged residues on the second CH3 region as described in US2010 / 0015133, US2009 / 0182127, US2010 / 028637 or US2011 / 0123532.

[0252] Other asymmetric mutations that can be used to promote heavy chain heterodimerization are L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W as described in US2012 / 0149876 or US2013 / 0195849.

[0253] SEEDbody mutations involve substituting select IgG residues with IgA residues to promote heavy chai heterodimerization as described in US20070287170.

[0254] Other exemplary mutations that may be used are R409D_K370E / D399K_E357K, S354C_T366W / Y349C_ T366S_L368A_Y407V, Y349C_T366W / S354C_T366S_L368A_Y407V, T366K / L351D, L351K / Y349E, L351K / Y349D, L351K / L368E, L351Y_Y407A / T366A_K409F, -58- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) L351Y_Y407A / T366V_K409F, K392D / D399K, K392D / E356K, K253E_D282K_K322D / D239K_E240K_K292D, K392D_K409D / D356K_D399K as described in WO2007 / 147901, WO 2011 / 143545, WO2013157954, WO2013096291 and US2018 / 0118849.

[0255] Additional bispecific or multispecific structures that can be used as GPRC5DxCD3 bispecific antibodies include Dual Variable Domain Immunoglobulins (DVD) (Int. Pat. Publ. No. WO2009 / 134776; DVDs are full length antibodies comprising the heavy chain having a structure VH1-linker-VH2-CH and the light chain having the structure VL1-linker-VL2-CL; linker being optional), structures that include various dimerization domains to connect the two antibody arms with different specificity, such as leucine zipper or collagen dimerization domains (Int. Pat. Publ. No. WO2012 / 022811, U.S. Pat. No.5,932,448; U.S. Pat. No. 6,833,441), two or more domain antibodies (dAbs) conjugated together, diabodies, heavy chain only antibodies such as camelid antibodies and engineered camelid antibodies, Dual Targeting (DT)-Ig (GSK / Domantis), Two-in-one Antibody (Genentech), Cross-linked Mabs (Karmanos Cancer Center), mAb2 (F-Star) and CovX-body (CovX / Pfizer), IgG-like Bispecific (InnClone / Eli Lilly), Ts2Ab (MedImmune / AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idec) and TvAb (Roche), ScFv / Fc Fusions (Academic Institution), SCORPION (Emergent BioSolutions / Trubion, Zymogenetics / BMS), Dual Affinity Retargeting Technology (Fc-DART) (MacroGenics) and Dual(ScFv)2-Fab (National Research Center for Antibody Medicine—China), Dual-Action or Bis-Fab (Genentech), Dock-and-Lock (DNL) (ImmunoMedics), Bivalent Bispecific (Biotecnol) and Fab-Fv (UCB- Celltech). ScFv-, diabody-based, and domain antibodies, include but are not limited to, Bispecific T Cell Engager (BiTE) (Micromet), Tandem Diabody (Tandab) (Affimed), Dual Affinity Retargeting Technology (DART) (MacroGenics), Single-chain Diabody (Academic), TCR-like Antibodies (AIT, ReceptorLogics), Human Serum Albumin ScFv Fusion (Merrimack) and COMBODY (Epigen Biotech), dual targeting nanobodies (Ablynx), dual targeting heavy chain only domain antibodies.

[0256] The Fc region of the GPRC5DxCD3 bispecific antibodies such as bispecific or multispecific antibodies or the anti-CD38 antibodies may comprise at least one substitution in the Fc region that reduces binding of the GPRC5DxCD3 bispecific antibodies to an activating Fc^ receptor (Fc^R) and / or reduces Fc effector functions such as C1q binding, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) or phagocytosis (ADCP). -59- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0257] Fc positions that may be substituted to reduce binding of the Fc to the activating Fc^R and subsequently to reduce effector function are substitutions 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-deleted / A327G / P331A / D365E / L358M on IgG1, 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- deleted / G237A / P238S on IgG4.

[0258] Fc substitutions that may be used to reduce CDC is a K322A substitution.

[0259] Well-known S228P substitution may further be made in IgG4 antibodies to enhance IgG4 stability.

[0260] “Antibody-dependent cellular cytotoxicity”, “antibody-dependent cell-mediated cytotoxicity” or “ADCC” is a mechanism for inducing cell death that depends upon the interaction of antibody-coated target cells with effector cells possessing lytic activity, such as natural killer cells (NK), monocytes, macrophages and neutrophils via Fc gamma receptors (Fc^R) expressed on effector cells. For example, NK cells express Fc^RIIIa, whereas monocytes express Fc^RI, Fc^RII and Fc^RIIIa. ADCC activity of the antibodies may be assessed using an in vitro assay using cells expressing the protein the antibody binds to as target cells and NK cells as effector cells. Cytolysis may be detected by the release of label (e.g., radioactive substrates, fluorescent dyes or natural intracellular proteins) from the lysed cells. In an exemplary assay, target cells are used with a ratio of 1 target cell to 4 effector cells. Target cells are pre-labeled with BATDA and combined with effector cells and the test antibody. The samples are incubated for 2 hours and cell lysis measured by measuring released BATDA into the supernatant. Data is normalized to maximal cytotoxicity with 0.67% Triton X-100 (Sigma Aldrich) and minimal control determined by spontaneous release of BATDA from target cells in the absence of any antibody.

[0261] “Antibody-dependent cellular phagocytosis” (“ADCP”) refers to a mechanism of elimination of antibody-coated target cells by internalization by phagocytic cells, such as macrophages or dendritic cells. ADCP may be evaluated by using monocyte-derived macrophages as effector cells and cells that express the protein the antibody binds to as target cells also engineered to express GFP or another labeled molecule. In an exemplary assay, effector:target cell ratio may be for example 4:1. Effector cells may be incubated with target -60- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) cells for 4 hours with or without the antibody of the invention. After incubation, cells may be detached using accutase. Macrophages may be identified with anti-CD11b and anti-CD14 antibodies coupled to a fluorescent label, and percent phagocytosis may be determined based on % GFP fluorescence in the CD11+CD14+macrophages using standard methods.

[0262] “Complement-dependent cytotoxicity”, or “CDC”, refers to a mechanism for inducing cell death in which the Fc effector domain of a target-bound antibody binds and activates complement component C1q which in turn activates the complement cascade leading to target cell death. Activation of complement may also result in deposition of complement components on the target cell surface that facilitate CDC by binding complement receptors (e.g., CR3) on leukocytes. CDC of cells may be measured for example by plating Daudi cells at 1×105cells / well (50 μL / well) in RPMI-B (RPMI supplemented with 1% BSA), adding 50 μL of test antibodies to the wells at final concentration between 0-100 μg / mL, incubating the reaction for 15 min at room temperature, adding 11 μL of pooled human serum to the wells, and incubation the reaction for 45 min at 37° C. Percentage (%) lysed cells may be detected as % propidium iodide stained cells in FACS assay using standard methods.

[0263] Binding of the antibody to Fc^R or FcRn may be assessed on cells engineered to express each receptor using flow cytometry. In an exemplary binding assay, 2x105cells per well are seeded in 96-well plate and blocked in BSA Stain Buffer (BD Biosciences, San Jose, USA) for 30 min at 4°C. Cells are incubated with a test antibody on ice for 1.5 hour at 4°C. After being washed twice with BSA stain buffer, the cells are incubated with R-PE labeled anti-human IgG secondary antibody (Jackson Immunoresearch Laboratories) for 45 min at 4°C. The cells are washed twice in stain buffer and then resuspended in 150 μL of Stain Buffer containing 1:200 diluted DRAQ7 live / dead stain (Cell Signaling Technology, Danvers, USA). PE and DRAQ7 signals of the stained cells are detected by Miltenyi MACSQuant flow cytometer (Miltenyi Biotec, Auburn, USA) using B2 and B4 channel, respectively. Live cells are gated on DRAQ7 exclusion and the geometric mean fluorescence signals are determined for at least 10,000 live events collected. FlowJo software (Tree Star) is used for analysis. Data is plotted as the logarithm of antibody concentration versus mean fluorescence signals. Nonlinear regression analysis is performed. BCMAxCD3 Bispecific Antibodies -61- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0264] Any suitable BCMAxCD3 bispecific antibody can be used in a method of the application. Exemplary multispecific and / or bispecific formats include dual targeting molecules include Dual Targeting (DT)-Ig (GSK / Domantis), Two-in-one Antibody (Genentech) and mAb2 (F-Star), Dual Variable Domain (DVD)-Ig (Abbott), 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 (Fc- DART) (MacroGenics), F(ab)2 (Medarex / AMGEN), Dual-Action or Bis-Fab (Genentech), Dock-and-Lock (DNL) (ImmunoMedics), Bivalent Bispecific (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 Antibodies (AIT, ReceptorLogics), Human Serum Albumin ScFv Fusion (Merrimack) and COMBODY (Epigen Biotech), dual targeting nanobodies (Ablynx), dual targeting heavy chain only domain antibodies. Various formats of bispecific antibodies have been described, for example in Chames and Baty (2009) Curr Opin Drug Disc Dev 12: 276 and in Nunez-Prado et al., (2015) Drug Discovery Today 20(5):588-594.

[0265] In some embodiments, the BCMAxCD3 bispecific antibody and the anti-CD38 antibody are antigen binding fragments. Exemplary antigen binding fragments are Fab, F(ab’)2, Fd and Fv fragments.

[0266] In some embodiments, the BCMAxCD3 bispecific antibody is chimeric, humanized or human.

[0267] In some embodiments, the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising a VH having the HCDR1 of SEQ ID NO: 218, the HCDR2 of SEQ ID NO: 219, the HCDR3 of SEQ ID NO: 220, and a VL having the LCDR1 of SEQ ID NO: 221, the LCDR2 of SEQ ID NO: 222 and the LCDR3 of SEQ ID NO: 223, and a CD3 binding domain comprising a VH having the HCDR1 of SEQ ID NO: 228, the HCDR2 of SEQ ID NO: 229, the HCDR3 of SEQ ID NO: 230, and a VL having the LCDR1 of SEQ ID NO: 231, the LCDR2 of SEQ ID NO: 232 and the LCDR3 of SEQ ID NO: 233. The HCDRs and LCDRs of the BCMA x CD3 bispecific antibody are recited in Table 9 below: Table 9: Exemplary CDRs of BCMA x CD3 bispecific antibody Binding Arm Region Sequence SEQ ID NO: BCMA HCDR1 SGSYFWG 218 HCDR2 SIYYSGITYYNPSLKS 219 -62- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) Binding Arm Region Sequence SEQ ID NO: HCDR3 HDGAVAGLFDY 220 LCDR1 GGNNIGSKSVH 221 LCDR2 DDSDRPS 222 LCDR3 QVWDSSSDHVV 223 CD3 HCDR1 TYAMN 228 HCDR2 RIRSKYNNYATYYAASVKG 229 HCDR3 HGNFGNSYVSWFAY 230 LCDR1 RSSTGAVTTSNYAN 231 LCDR2 GTNKRAP 232 LCDR3 ALWYSNLWV 233

[0268] The CDRs recited in the table above are of the Kabat numbering system. However, as provided for herein, the CDRs of the present disclosure may be provided by any appropriate numbering system, such as any of the Kabat, Chothia, IMGT, or AbM numbering systems. Tables 10-12 below provide exemplary CDRs utilizing the Chothia, AbM, and IMGT numbering systems: Table 10: Exemplary CDRs of BCMA x CD3 bispecific antibody – Chothia numbering system: Binding Arm Region Sequence SEQ ID NO: BCMA HCDR1 GGSISSGSY 254 HCDR2 YYSGI 255 HCDR3 HDGAVAGLFDY 220 LCDR1 GGNNIGSKSVH 221 LCDR2 DDSDRPS 222 LCDR3 QVWDSSSDHVV 223 CD3 HCDR1 GFTFNTY 256 HCDR2 RSKYNNYA 257 HCDR3 HGNFGNSYVSWFAY 230 LCDR1 RSSTGAVTTSNYAN 231 LCDR2 GTNKRAP 232 LCDR3 ALWYSNLWV 233 -63- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) Table 11: Exemplary CDRs of BCMA x CD3 bispecific antibody – AbM numbering system: Binding Arm Region Sequence SEQ ID NO: BCMA HCDR1 GGSISSGSYFWG 258 HCDR2 SIYYSGITY 259 HCDR3 HDGAVAGLFDY 220 LCDR1 GGNNIGSKSVH 221 LCDR2 DDSDRPS 222 LCDR3 QVWDSSSDHVV 223 CD3 HCDR1 GFTFNTYAMN 260 HCDR2 RIRSKYNNYATY 261 HCDR3 HGNFGNSYVSWFAY 230 LCDR1 RSSTGAVTTSNYAN 231 LCDR2 GTNKRAP 232 LCDR3 ALWYSNLWV 233 Table 12: Exemplary CDRs of BCMA x CD3 bispecific antibody – IMGT numbering system: Binding Arm Region Sequence SEQ ID NO: CBMA HCDR1 GGSISSGSYF 262 HCDR2 IYYSGIT 263 HCDR3 ARHDGAVAGLFDY 264 LCDR1 NIGSKS 265 LCDR2 DDS NA LCDR3 QVWDSSSDHVV 223 CD3 HCDR1 GFTFNTYA 266 HCDR2 IRSKYNNYAT 267 HCDR3 ARHGNFGNSYVSWFAY 268 LCDR1 TGAVTTSNY 269 LCDR2 GTN NA LCDR3 ALWYSNLWV 233

[0269] In some embodiments, the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising a VH having the HCDR1 of SEQ ID NO: 218, the HCDR2 of -64- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) SEQ ID NO: 219, the HCDR3 of SEQ ID NO: 220, and a VL having the LCDR1 of SEQ ID NO: 221, the LCDR2 of SEQ ID NO: 222 and the LCDR3 of SEQ ID NO: 223, and a CD3 binding domain comprising a VH having the HCDR1 of SEQ ID NO: 228, the HCDR2 of SEQ ID NO: 229, the HCDR3 of SEQ ID NO: 230, and a VL having the LCDR1 of SEQ ID NO: 231, the LCDR2 of SEQ ID NO: 232 and the LCDR3 of SEQ ID NO: 233.

[0270] In some embodiments, the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising a VH having the HCDR1 of SEQ ID NO: 254, the HCDR2 of SEQ ID NO: 255, the HCDR3 of SEQ ID NO: 220, and a VL having the LCDR1 of SEQ ID NO: 221, the LCDR2 of SEQ ID NO: 222 and the LCDR3 of SEQ ID NO: 223, and a CD3 binding domain comprising a VH having the HCDR1 of SEQ ID NO: 256, the HCDR2 of SEQ ID NO: 257, the HCDR3 of SEQ ID NO: 230, and a VL having the LCDR1 of SEQ ID NO: 231, the LCDR2 of SEQ ID NO: 232 and the LCDR3 of SEQ ID NO: 233.

[0271] In some embodiments, the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising a VH having the HCDR1 of SEQ ID NO: 258, the HCDR2 of SEQ ID NO: 259, the HCDR3 of SEQ ID NO: 220, and a VL having the LCDR1 of SEQ ID NO: 221, the LCDR2 of SEQ ID NO: 222 and the LCDR3 of SEQ ID NO: 223, and a CD3 binding domain comprising a VH having the HCDR1 of SEQ ID NO: 260, the HCDR2 of SEQ ID NO: 261, the HCDR3 of SEQ ID NO: 230, and a VL having the LCDR1 of SEQ ID NO: 231, the LCDR2 of SEQ ID NO: 232 and the LCDR3 of SEQ ID NO: 233.

[0272] In some embodiments, the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising a VH having the HCDR1 of SEQ ID NO: 262, the HCDR2 of SEQ ID NO: 263, the HCDR3 of SEQ ID NO: 264, and a VL having the LCDR1 of SEQ ID NO: 265, a LCDR2 having the amino acid sequence of DDS, and the LCDR3 of SEQ ID NO: 223, and a CD3 binding domain comprising a VH having the HCDR1 of SEQ ID NO: 266, the HCDR2 of SEQ ID NO: 267, the HCDR3 of SEQ ID NO: 268, and a VL having the LCDR1 of SEQ ID NO: 269, a LCDR2 having the amino acid sequence of GTN, and the LCDR3 of SEQ ID NO: 233.

[0273] In some embodiments, the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising the VH of SEQ ID NO: 224 and the VL of SEQ ID NO: 225, and a CD3 binding domain comprising the VH of SEQ ID NO: 234 and the VL of SEQ ID NO: 235.

[0274] In some embodiments, the BCMAxCD3 bispecific antibody that binds BCMA comprises a first heavy chain (HC1) of SEQ ID NO: 226, a first light chain (LC1) of SEQ ID -65- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) NO: 227, a second heavy chain (HC2) of SEQ ID NO: 236, and a second light chain (LC2) of SEQ ID NO: 237.

[0275] In some embodiments, the BCMA binding arm of the BCMA x CD3 bispecific antibody and the CD3 binding arm of the BCMA x CD3 bispecific antibody comprise the amino acid sequences as provided for in Tables 13A-13B. Table 13A: Sequences of the BCMA binding arm of a BCMA x CD3 bispecific antibody. Region Sequence SEQ ID NO: BCMB69 HCDR1 SGSYFWG 218 HCDR2 SIYYSGITYYNPSLKS 219 HCDR3 HDGAVAGLFDY 220 LCDR1 GGNNIGSKSVH 221 LCDR2 DDSDRPS 222 LCDR3 QVWDSSSDHVV 223 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSGSY 224 FWGWIRQPPGKGLEWIGSIYYSGITYYNPSLKS RVTISVDTSKNQFSLKLSSVTAADTAVYYCAR HDGAVAGLFDYWGQGTLVTVSS VL SYVLTQPPSVSVAPGQTARITCGGNNIGSKSVH 225 WYQQPPGQAPVVVVYDDSDRPSGIPERFSGSN SGNTATLTISRVEAGDEAVYYCQVWDSSSDHV VFGGGTKLTVLGQP HC QLQLQESGPGLVKPSETLSLTCTVSGGSISSGSY 226 FWGWIRQPPGKGLEWIGSIYYSGITYYNPSLKS RVTISVDTSKNQFSLKLSSVTAADTAVYYCAR HDGAVAGLFDYWGQGTLVTVSSASTKGPSVFP LAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTKTYTCNVDHKPSNTKVDKRVESKYGPPCPP CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV FSCSVMHEALHNHYTQKSLSLSLGK -66- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) Region Sequence SEQ ID NO: LC SYVLTQPPSVSVAPGQTARITCGGNNIGSKSVH 227 WYQQPPGQAPVVVVYDDSDRPSGIPERFSGSN SGNTATLTISRVEAGDEAVYYCQVWDSSSDHV VFGGGTKLTVLGQPKAAPSVTLFPPSSEELQAN KATLVCLISDFYPGAVTVAWKGDSSPVKAGVE TTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSC QVTHEGSTVEKTVAPTECS Table 13B: Sequences of the CD3 binding arm of a BCMA x CD3 bispecific antibody. Region Sequence SEQ ID NO: CD3B219 HCDR1 TYAMN 228 HCDR2 RIRSKYNNYATYYAASVKG 229 HCDR3 HGNFGNSYVSWFAY 230 LCDR1 RSSTGAVTTSNYAN 231 LCDR2 GTNKRAP 232 LCDR3 ALWYSNLWV 233 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFNT 234 YAMNWVRQAPGKGLEWVARIRSKYNNYAT YYAASVKGRFTISRDDSKNSLYLQMNSLKTE DTAVYYCARHGNFGNSYVSWFAYWGQGTL VTVSS VL QTVVTQEPSLTVSPGGTVTLTCRSSTGAVTT 235 SNYANWVQQKPGQAPRGLIGGTNKRAPGTP ARFSGSLLGGKAALTLSGVQPEDEAEYYCAL WYSNLWVFGGGTKLTVLGQP HC EVQLVESGGGLVQPGGSLRLSCAASGFTFNT 236 YAMNWVRQAPGKGLEWVARIRSKYNNYAT YYAASVKGRFTISRDDSKNSLYLQMNSLKTE DTAVYYCARHGNFGNSYVSWFAYWGQGTL VTVSSASTKGPSVFPLAPCSRSTSESTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTKTYTCNVDHK PSNTKVDKRVESKYGPPCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFLLYSKLTVDKSRWQEGNVFS CSVMHEALHNHYTQKSLSLSLGK -67- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) Region Sequence SEQ ID NO: LC QTVVTQEPSLTVSPGGTVTLTCRSSTGAVTT 237 SNYANWVQQKPGQAPRGLIGGTNKRAPGTP ARFSGSLLGGKAALTLSGVQPEDEAEYYCAL WYSNLWVFGGGTKLTVLGQPKAAPSVTLFP PSSEELQANKATLVCLISDFYPGAVTVAWKA DSSPVKAGVETTTPSKQSNNKYAASSYLSLT PEQWKSHRSYSCQVTHEGSTVEKTVAPTECS

[0276] In some embodiments, the BCMAxCD3 bispecific antibody comprises a BCMA binding domain that binds BCMA selected from the group consisting of the BCMA binding domain of ACTR cancer therapy by Seattle Genetics, AFM-26, ALLO-715, anti-BCMA allogenic CAR-T cell therapy by CRISPR Therapeutics, anti-BCMA CAR-T therapy by Sorrento Therapeutics, anti-CD19 / BCMA CAR-T cell therapy by Hrain Biotechnology, BCMA CAR-T therapy by Chineo Med (Beijing), BCMA TAC-T cell therapy by Triumvira Immunologics, BCMA-CAR T cell therapy by Shanghai Unicar-Therapy Biomed, BCMA / CD3 antibody by Regeneron, CAR-NK cell therapies by NantKwest, CC-93629, CMD-505, CTX-4419, CYAD-211, HDP-101, HPN-217, P-BCMA-ALLO1, TNB-383B, bb- 2121, AUTO-2, BCMA chimeric antigen receptor therapy by Pregene, BCMA-CAR T cells by Shanghai Bioray Laboratory, BCMA-CAR-T cells by CARsgen Therapeutics, CAR- T / TCR-T cell immunotherapy by Shenzhen BinDeBio, ET-140, P-BCMA-101, REGN-5458, AMG-701, anti BCMA CAR-T cell therapy by Cellular Biomedicine Group, bb-21217, BI- 836909, CC-93269, Descartes-08, IM-21, JNJ-64007957, MEDI-2228 or PF-06863135.

[0277] In some embodiments, the BCMAxCD3 bispecific antibody can be, but is not limited to, elranatamab (also named PF-06863135), teneobio (also named TNB-383B), REGN5458, REGN5459, pavurutamab (also named AMG-701), BI 836909, CC-93269, WVT078 or teclistamab (also named JNJ-957 or JNJ-64007957).

[0278] In some embodiments, teclistamab comprises a first heavy chain (HC1), a first light chain (LC1), a second heavy chain (HC2), and a second light chain (LC2), wherein the HC1 is associated with LC1 and the HC2 is associated with LC2, wherein HC1 and LC1 form a first antigen-binding site that immunospecifically binds to BCMA and wherein HC2 and LC2 form a second antigen-binding site that immunospecifically binds to CD3. In some embodiments, teclistamab comprises a HC1 of SEQ ID NO: 226, a LC1 of SEQ ID NO: 227, a HC2 of SEQ ID NO: 236, and a LC2 of SEQ ID NO: 237. In some embodiments, the -68- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) BCMA arm and the CD3 arm of teclistamab form a functional bispecific antibody through an interaction between their respective Fc domains.

[0279] In some embodiments, the BCMAxCD3 bispecific antibody comprises any one of the BCMA binding domains described in Int. Pat. Publ. No. WO2017 / 031104.

[0280] In some embodiments, the BCMAxCD3 bispecific antibody is an IgG1, an IgG2, an IgG3, or an IgG4 isotype.

[0281] In some embodiments, the BCMAxCD3 bispecific antibody is an IgG1 isotype.

[0282] In some embodiments, the BCMAxCD3 bispecific antibody is an IgG2 isotype.

[0283] In some embodiments, the BCMAxCD3 bispecific antibody is an IgG3 isotype.

[0284] In some embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype.

[0285] The BCMAxCD3 bispecific antibody can be of any allotype. It is expected that allotype has no influence on properties of the BCMAxCD3 bispecific antibodies, such as binding or Fc-mediated effector functions. Immunogenicity of therapeutic antibodies is associated with increased risk of infusion reactions and decreased duration of therapeutic response (Baert et al., (2003) N Engl J Med 348:602-08). The extent to which therapeutic antibodies induce an immune response in the host may be determined in part by the allotype of the antibody (Stickler et al., (2011) Genes and Immunity 12:213-21). Antibody allotype is related to amino acid sequence variations at specific locations in the constant region sequences of the antibody. Table 14 shows select IgG1, IgG2, and IgG4 allotypes. Table 14. IgG1, IgG2 and IgG4 allotypes. Allotype Amino acid residue at position of diversity (residue numbering: EU Index) IgG2 IgG4 IgG1 189 282 309 422 214 356 358 431 G2m(n) T M G2m(n-) P V G2m(n) / (n- T VnG4m(a) L R G1m(17) K E M A G1m(17,1) K D L A

[0286] In some embodiments, the one or more Fc substitutions is selected from the group consisting of F234A / L235A on IgG4, 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-deleted / A327G / P331A / D365E / L358M on IgG1, -69- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 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- deleted / G237A / P238S on IgG4, wherein residue numbering is according to the EU index.

[0287] In some embodiments, the one or more Fc substitutions is F234A / L235A on IgG4.

[0288] In some embodiments, the one or more Fc substitutions is L234A / L235A on IgG1.

[0289] In some embodiments, the one or more Fc substitutions is V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2.

[0290] In some embodiments, the one or more Fc substitutions is F234A / L235A on IgG4.

[0291] In some embodiments, the one or more Fc substitutions is S228P / F234A / L235A on IgG4.

[0292] In some embodiments, the one or more Fc substitutions is N297A on all Ig isotypes.

[0293] In some embodiments, the one or more Fc substitutions is V234A / G237A on IgG2.

[0294] In some embodiments, the one or more Fc substitutions is K214T / E233P / L234V / L235A / G236-deleted / A327G / P331A / D365E / L358M on IgG1.

[0295] In some embodiments, the one or more Fc substitutions is H268Q / V309L / A330S / P331S on IgG2.

[0296] In some embodiments, the one or more Fc substitutions is S267E / L328F on IgG1. In some embodiments, the one or more Fc substitutions is L234F / L235E / D265A on IgG1.

[0297] In some embodiments, the one or more Fc substitutions is L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1.

[0298] In some embodiments, the one or more Fc substitutions is S228P / F234A / L235A / G237A / P238S on IgG4 and S228P / F234A / L235A / G236-deleted / G237A / P238S on IgG4.

[0299] In some embodiments, the multispecific antibody further comprises a S228P substitution.

[0300] In some embodiments, the multispecific antibody comprises one or more asymmetric substitutions in a first CH3 domain or in a second CH3 domain, or in both the first CH3 domain and the second CH3 domain.

[0301] In some embodiments, the one or more asymmetric substitutions is selected from the group consisting of F450L / K409R, wild-type / F409L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S and T366W / T366S_L368A_Y407V, L351Y_F405A_Y407V / T394W, -70- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) T366I_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.

[0302] In some embodiments, the one or more asymmetric substitutions is F450L / K409R. In some embodiments, the one or more asymmetric substitutions is wild-type / F409L_R409K. In some embodiments, the one or more asymmetric substitutions is T366Y / F405A. In some embodiments, the one or more asymmetric substitutions is T366W / F405W. In some embodiments, the one or more asymmetric substitutions is F405W / Y407A. In some embodiments, the one or more asymmetric substitutions is T394W / Y407T. In some embodiments, the one or more asymmetric substitutions is T394S / Y407A. In some embodiments, the one or more asymmetric substitutions is T366W / T394S. In some embodiments, the one or more asymmetric substitutions is F405W / T394S. In some embodiments, the one or more asymmetric substitutions is T366W / T366S_L368A_Y407V. In some embodiments, the one or more asymmetric substitutions is L351Y_F405A_Y407V / T394W. In some embodiments, the one or more asymmetric substitutions is T366I_K392M_T394W / F405A_Y407V. In some embodiments, the one or more asymmetric substitutions is T366L_K392M_T394W / F405A_Y407V. In some embodiments, the one or more asymmetric substitutions is L351Y_Y407A / T366A_K409F. In some embodiments, the one or more asymmetric substitutions is L351Y_Y407A / T366V_K409F. In some embodiments, the one or more asymmetric substitutions is Y407A / T366A_K409F. In some embodiments, the one or more asymmetric substitutions is T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0303] In some embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in a first heavy chain (HC1) and leucine at position 405 and lysine at position 409 in a second heavy chain (HC2), wherein residue numbering is according to the EU Index.

[0304] In some embodiments, the BCMAxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234 and alanine at position 235 in both the HC1 and the HC2. Anti-CD38 Antibodies

[0305] CD38 is a multifunctional protein having function in receptor-mediated adhesion and signaling as well as mediating calcium mobilization via its ecto-enzymatic activity, -71- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) catalyzing formation of cyclic ADP-ribose (cADPR) and ADPR. CD38 mediates cytokine secretion and activation and proliferation of lymphocytes (Funaro et al., J Immunol 145:2390-6, 1990; Terhorst et al., Cell 771-80, 1981; Guse et al., Nature 398:70-3, 1999). CD38, via its NAD glycohydrolase activity, also regulates extracellular NAD+ levels, which have been implicated in modulating the regulatory T-cell compartment (Adriouch et al., Microbes infect 14:1284-92, 2012; Chiarugi et al., Nature Reviews 12:741-52, 2012). In addition to signaling via Ca2+, CD38 signaling occurs via cross-talk with antigen-receptor complexes on T- and B-cells or other types of receptor complexes, e.g., major histocompatibility complex (MHC) molecules, involving CD38 in several cellular responses, but also in switching and secretion of IgG1.

[0306] Any suitable anti-CD38 antibody can be used in a method of the application.

[0307] In some embodiments, the anti-CD38 antibody comprises the HCDR1 of SEQ ID NO: 308, the HCDR2 of SEQ ID NO: 309, the HCDR3 of SEQ ID NO: 310, the LCDR1 of SEQ ID NO: 311, the LCDR2 of SEQ ID NO: 312 and the LCDR3 of SEQ ID NO: 313.

[0308] The CDRs recited above are of the Kabat numbering system. However, as provided for herein, the CDRs of the present disclosure may be provided by any appropriate numbering system, such as Kabat, Chothia, IMGT, or AbM numbering systems. Table 15 provides exemplary CDRs utilizing the Kabat, Chothia, IMGT, and AbM numbering systems: Table 15: Exemplary CDRs of the anti-CD38 antibody Region Kabat Chothia AbM IMGT HCDR SFAMS GFTFNS GFTFNSFAM GFTFNSFA 1 (SEQ ID NO: 308) F S (SEQ ID (SEQ ID NO: 350) (SEQ ID NO: 348) NO: 346) HCDR AISGSGGGTYYADSVK SGSGGG AISGSGGGT ISGSGGGT 2 G (SEQ ID NO: 309) (SEQ ID Y (SEQ ID (SEQ ID NO: 351) NO: 347) NO: 349) HCDR DKILWFGEPVFDY SEQ ID SEQ ID NO: AKDKILWFGEPVFD 3 (SEQ ID NO: 310) NO: 310 310 Y (SEQ ID NO: 352) LCDR RASQSVSSYLA SEQ ID SEQ ID NO: QSVSSY 1 (SEQ ID NO: 311) NO: 311 311 (SEQ ID NO: 353) LCDR DASNRAT SEQ ID SEQ ID NO: DAS 2 (SEQ ID NO: 312) NO: 312 312 -72- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) Region Kabat Chothia AbM IMGT LCDR QQRSNWPPT SEQ ID SEQ ID NO: SEQ ID NO: 313 3 (SEQ ID NO: 313) NO: 313 313

[0309] In some embodiments, the anti-CD38 antibody comprises the HCDR1 of SEQ ID NO: 308, the HCDR2 of SEQ ID NO: 309, the HCDR3 of SEQ ID NO: 310, the LCDR1 of SEQ ID NO: 311, the LCDR2 of SEQ ID NO: 312 and the LCDR3 of SEQ ID NO: 313.

[0310] In some embodiments, the anti-CD38 antibody comprises the HCDR1 of SEQ ID NO: 346, the HCDR2 of SEQ ID NO: 347, the HCDR3 of SEQ ID NO: 310, the LCDR1 of SEQ ID NO: 311, the LCDR2 of SEQ ID NO: 312 and the LCDR3 of SEQ ID NO: 313.

[0311] In some embodiments, the anti-CD38 antibody comprises the HCDR1 of SEQ ID NO: 348, the HCDR2 of SEQ ID NO: 349, the HCDR3 of SEQ ID NO:310, the LCDR1 of SEQ ID NO: 311, the LCDR2 of SEQ ID NO: 312 and the LCDR3 of SEQ ID NO: 313.

[0312] In some embodiments, the anti-CD38 antibody comprises the HCDR1 of SEQ ID NO: 350, the HCDR2 of SEQ ID NO: 351, the HCDR3 of SEQ ID NO: 352, the LCDR1 of SEQ ID NO: 353, a LCDR2 having the amino acid sequence of DAS, and the LCDR3 of SEQ ID NO: 313.

[0313] In some embodiments, the anti-CD38 antibody comprises the VH of SEQ ID NO: 306 and the VL of SEQ ID NO: 307.

[0314] In some embodiments, the anti-CD38 antibody comprises the HC of SEQ ID NO: 312 and the LC of SEQ ID NO: 313.

[0315] Other anti-CD38 antibodies used in the methods of the invention may be known antibodies, such as mAb003 described in U.S. Pat. No.7,829,673. The VH and the VL of mAb003 may be expressed as IgG1 / κ; mAb024 described in U.S. Pat. No.7,829,673. The VH and the VL of mAb024 may be expressed as IgG1 / κ; MOR-202 (MOR-03087) comprising described in US. Pat. No.8,088,896. The VH and the VL of MOR-202 may be expressed as IgG1 / κ; or isatuximab; described in U.S. Pat. No.8,153,765. The VH and the VL of isatuximab may be expressed as IgG1 / κ. In some embodiments, the anti-CD38 antibody comprises a) the VH of SEQ ID NO: 338 and the VL of SEQ ID NO: 339; b) the VH of SEQ ID NO: 340 and the VL of SEQ ID NO: 341; c) the VH of SEQ ID NO: 342 and the VL of SEQ ID NO: 343; or d) the VH of SEQ ID NO: 344 and the VL of SEQ ID NO: 345. -73- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0316] In some embodiments, daratumumab comprises the VH of SEQ ID NO: 306 and the VL of SEQ ID NO: 307.

[0317] In some embodiments, daratumumab comprises the HC of SEQ ID NO: 312 and the LC of SEQ ID NO: 313.

[0318] In some embodiments, the anti-CD38 antibody is chimeric, humanized, or human.

[0319] In some embodiments, the anti-CD38 antibody is an IgG1, an IgG2, an IgG3, or an IgG4 isotype.

[0320] In some embodiments, the anti-CD38 antibody is an IgG1 isotype. Methods

[0321] The present application further relates to methods and compositions for use in cell immunotherapy. In particular, disclosed herein are methods of treating cancer in a subject in need thereof comprising administering an anti-BCMA CAR-T cell and a GPRC5DxCD3 bispecific antibody to the subject. In some embodiments, the method comprises administering an anti-BMCA CAR-T cell, a GPRC5DxCD3 bispecific antibody, and a BCMAxCD3 bispecific antibody to the subject.

[0322] In some embodiments, the cell immunotherapy is for treating cancer in a subject, including but not limited to hematological malignancies and solid tumors. In some embodiments, the cell immunotherapy is for treating multiple myeloma in a subject. In some embodiments, the subject is human. In some embodiments, the methods are suitable for treatment of adults and pediatric population, including all subsets of age, and can be used as any line of treatment, including first line or subsequent lines.

[0323] The methods described herein may be used for treating various cancers, including both solid cancer and liquid cancer. In some embodiments, the methods are used to treat multiple myeloma. The methods described herein may be used as a combination therapy with other types of cancer therapies known in the art, such as chemotherapy, surgery, radiation, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, targeted therapy, cryotherapy, ultrasound therapy, photodynamic therapy, radio-frequency ablation or the like, in an adjuvant setting or a neoadjuvant setting.

[0324] In some embodiments, the cancer is stage I, stage II or stage III, and / or stage A or stage B multiple myeloma based on the Durie-Salmon staging system. In some embodiments, the cancer is stage I, stage II or stage III multiple myeloma based on the International staging -74- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) system published by the International Myeloma Working Group (IMWG). In some embodiments, the multiple myeloma is progressive.

[0325] In some embodiments, the subject has newly diagnosed multiple myeloma based on the International staging system published by the International Myeloma Working Group (IMWG). In some embodiments, the subject has standard-risk multiple myeloma based on revised International Staging System (R-ISS) diagnostic criteria. In some embodiments, the subject is stem cell transplant-eligible. In some embodiments, the subject is fit based on IMWG Frailty Index assessment. In some embodiments, the subject is intermediate-fit based on IMWG Frailty Index assessment.

[0326] Any of the anti-BCMA VHHs, CARs, and engineered immune effector cells (such as CAR-T cells) described herein may be used in the method of treating cancer. In some embodiments, the immune effector cells are autologous. In some embodiments, the immune effector cells are allogeneic. In a preferred embodiment, cilcacabtagene autoleucel (“cilta- cel”) CAR-T cells are administered to the subject.

[0327] In some embodiments, apheresis material is collected from the subject for the production of CAR-T cells. In some embodiments, apheresis material is collected from the subject for the production of ciltacabtagene autoleucel.

[0328] In some embodiments, the CAR-T cells are administered at a dose of about 1.0 x 105to 2.0 x 105cells / kg, 1.5 x 105to 2.5 x 105cells / kg, 2.0 x 105to 3.0 x 105cells / kg, 2.5 x 105to 3.5 x 105cells / kg, 3.0 x 105to 4.0 x 105cells / kg, 3.5 x 105to 4.5 x 105cells / kg, 4.0 x 105to 5.0 x 105cells / kg, 4.5 x 105to 5.5 x 105cells / kg, 5.0 x 105to 6.0 x 105cells / kg, 5.5 x 105to 6.5 x 105cells / kg, 6.0 x 105to 7.0 x 105cells / kg, 6.5 x 105to 7.5 x 105cells / kg, 7.0 x 105to 8.0 x 105cells / kg, 7.5 x 105to 8.5 x 105cells / kg, 8.0 x 105to 9.0 x 105cells / kg, 8.5 x 105to 9.5 x 105cells / kg, 9.0 x 105to 1.0 x 106cells / kg, 1.0 x 106to 2.0 x 106cells / kg, 1.5 x 106to 2.5 x 106cells / kg, 2.0 x 106to 3.0 x 106cells / kg, 2.5 x 106to 3.5 x 106cells / kg, 3.0 x 106to 4.0 x 106cells / kg, 3.5 x 106to 4.5 x 106cells / kg, 4.0 x 106to 5.0 x 106cells / kg, 4.5 x 106to 5.5 x 106cells / kg, or 5.0 x 106to 6.0 x 106cells / kg. In some embodiments, the dose comprises approximately 0.75 x 106cells / kg. In some embodiments, the dose comprises approximately 0.68 x 106cells / kg. In some embodiments, the CAR-T cells are administered at a dose of about 1.0 x 108cells per subject.

[0329] In some embodiments, the CAR-T cells are administered at a dose of less than 1.0 x 108cells per subject. In some embodiments, the CAR-T cells are administered at a dose of about 3.0 to 4.0 x 107cells. In some embodiments, the CAR-T cells are administered at a -75- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) dose of about 3.5 to 4.5 x 107cells. In some embodiments, the CAR-T cells are administered at a dose of about 4.0 to 5.0 x 107cells. In some embodiments, the CAR-T cells are administered at a dose of about 4.5 to 5.5 x 107cells. In some embodiments, the CAR-T cells are administered at a dose of about 5.0 to 6.0 x 107cells. In some embodiments, the CAR-T cells are administered at a dose of about 5.5 to 6.5 x 107cells. In some embodiments, the CAR-T cells are administered at a dose of about 6.0 to 7.0 x 107cells. In some embodiments, the CAR-T cells are administered at a dose of about 6.5 to 7.5 x 107cells. In some embodiments, the CAR-T cells are administered at a dose of about 7.0 to 8.0 x 107cells. In some embodiments, the CAR-T cells are administered at a dose of about 7.5 to 8.5 x 107cells. In some embodiments, the CAR-T cells are administered at a dose of about 8.0 to 9.0 x 107cells. In some embodiments, the CAR-T cells are administered at a dose of about 8.5 to 9.5 x 107cells. In some embodiments, the CAR-T cells are administered at a dose of about 9.0 x 107to 1.0 x 108cells.

[0330] In some embodiments, the CAR-T cells are administered at a dose of about 0.693 x 106CAR-positive viable T-cells / kg. In some embodiments, the CAR-T cells are administered at a dose of about 0.52 x 106CAR-positive viable T-cells / kg. In some embodiments, the CAR-T cells are administered at a dose of about 0.94 x 106CAR-positive viable T-cells / kg. In some embodiments, the CAR-T cells are administered at a dose of about 0.709 x 106CAR- positive viable T-cells / kg. In some embodiments, the CAR-T cells are administered at a dose of about 0.51 x 106CAR-positive viable T-cells / kg. In some embodiments, the CAR-T cells are administered at a dose of about 0.95 x 106CAR-positive viable T-cells / kg. In some embodiments, the CAR-T cells are administered in an outpatient setting.

[0331] In some embodiments, the CAR-T cells (e.g., at any of the foregoing doses) are administered in one or more intravenous infusions. In some embodiments, said administration of said CAR-T cells is via a single intravenous infusion. In some embodiments, said single intravenous infusion is administered using a single bag of said CAR-T cells. In some embodiments, said administration of said single bag of said CAR-T cells is completed between the time at which said single bag of CAR-T cells is thawed and three hours after said single bag of CAR-T cells is thawed. In some embodiments, single intravenous administration is administered using two bags of said CAR-T cells. In some embodiments, said administration of each of said two bags of said CAR-T cells is completed between the time at which a first bag of said two bags of CAR-T cells is thawed and three hours after said first bag of CAR-T cells is thawed. -76- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0332] The composition comprising the host cells expressing the CAR-encoding nucleic acid sequence disclosed herein, or a vector comprising the CAR-encoding nucleic acid sequence disclosed herein, can be administered to a mammal using standard administration techniques, including oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration. The composition preferably is suitable for parenteral administration. The term “parenteral”, as used herein, includes intravenous, intramuscular, subcutaneous, rectal, vaginal, and intraperitoneal administration. More preferably, the composition is administered to a mammal using peripheral systemic delivery by intravenous, intraperitoneal, or subcutaneous injection. Most preferably, the composition is administered by intravenous infusion.

[0333] In some embodiments, prior to the administration of CAR-T cells, subjects may be administered a conditioning regimen.

[0334] Patients undergoing a CAR-T cell therapy may be prepared with a so- called conditioning regimen that can suppress the patient’s immune system and improve the efficacy of CAR-T cell therapy (Blood (2019) 133 (17): 1799–1800).

[0335] The intensity of conventional conditioning regimens can vary significantly. Description of the regimens can refer to genotoxic or non-genotoxic regimens, which may overlap with reference to myeloablative or non-myeloablative regimens. See, for example, Bacigalupo et al. (2009) Biol Blood Marrow Transplant.15(12):1628-1633, herein specifically incorporated by reference.

[0336] Myeloablative conditioning regimens are combination of agents expected to produce profound pancytopenia and myeloablation within 1-3 weeks from administration; pancytopenia is long lasting, usually irreversible and in most instances fatal, unless hematopoiesis is restored by hemopoietic stem cell infusion. Examples include total body irradiation and / or administration of high doses of alkylating agents; busulfan, melphalan, cyclophosphamide; etc.

[0337] Non-myeloablative conditioning regiments typically cause minimal cytopenia, and little early toxicity, but are immunosuppressive to the extent that, when followed by administration of an effective dose of HSPC, will result in engraftment of donor lympho- hemopoietic stem cells.

[0338] In certain embodiments the conditioning regimens provided herein are non- myeloablative. -77- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0339] In some embodiments, the conditioning regimen comprises one or more of cyclophosphamide and / or fludarabine.

[0340] In some embodiments, the conditioning regimen comprises cyclophosphamide administered at a dosage of 300 mg / m2. In some embodiments, the conditioning regimen comprises fludarabine administered at a dosage of 30 mg / m2. In some embodiments, the conditioning regimen comprises cyclophosphamide administered at a dosage of 300 mg / m2 and fludarabine at a dosage of 30 mg / m2.

[0341] In some embodiments, the conditioning regimen is administered to the subject daily, for up to 3 days. In some embodiments, the CAR-T therapy is administered to the subject 5 to 7 days after the start of the administration of the conditioning regimen.

[0342] In some embodiments, the collection of apheresis material collected for the production of CAR-T cells, including ciltacabtagene autoleucel, occurs after the administration of the GPRC5DxCD3 bispecific antibody. In some embodiments, the collection of apheresis material collected for the production of CAR-T cells, including ciltacabtagene autoleucel, occurs before the administration of the GPRC5DxCD3 bispecific antibody. In some embodiments, the collection of apheresis material collected for the production of CAR-T cells, including ciltacabtagene autoleucel, occurs after the administration of the BCMAxCD3 bispecific antibody. In some embodiments, the collection of apheresis material collected for the production of CAR-T cells, including ciltacabtagene autoleucel, occurs before the administration of the BCMAxCD3 bispecific antibody. In some embodiments, the collection of apheresis material collected for the production of CAR-T cells, including ciltacabtagene autoleucel, occurs after the administration of the induction therapy. In some embodiments, the collection of apheresis material collected for the production of CAR-T cells, including ciltacabtagene autoleucel, occurs before the administration of the induction therapy.

[0343] Any of the GPRCD5xCD3 bispecific antibodies described herein may be used in the method of treating cancer.

[0344] In some embodiments, the GPRC5DxCD3 bispecific antibody comprises a GPRC5D binding domain comprising the HCDR1 of SEQ ID NO: 101, the HCDR2 of SEQ ID NO: 102, the HCDR3 of SEQ ID NO: 103, the LCDR1 of SEQ ID NO: 104 the LCDR2 of SEQ ID NO: 105 and the LCDR3 of SEQ ID NO: 106, and a CD3 binding domain comprising the HCDR1 of SEQ ID NO: 107, the HCDR2 of SEQ ID NO: 108, the HCDR3 of SEQ ID NO: 109, the LCDR1 of SEQ ID NO: 110, the LCDR2 of SEQ ID NO: 111 and the -78- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) LCDR3 of SEQ ID NO: 112. In some embodiments, the GPRC5D binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 113 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 114, and the CD3 binding domain comprises a VH having the amino acid sequence of SEQ ID NO: 115 and a VL having the amino acid sequence of SEQ ID NO: 116. In some embodiments, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in a first heavy chain (HC1) and leucine at position 405 and lysine at position 409 in a second heavy chain (HC2), wherein residue numbering is according to the EU Index. In some embodiments, the GPRC5DxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234 and alanine at position 235 in both the HC1 and the HC2. In some embodiments, the GPRC5DxCD3 bispecific antibody comprises the HC1 having the amino acid sequence of SEQ ID NO: 117, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 118, the HC2 having the amino acid sequence of SEQ ID NO: 119 and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 120. In some embodiments, the GPRC5DxCD3 bispecific antibody is talquetamab.

[0345] In some embodiments, the GPRC5DxCD3 bispecific antibody is administered weekly or once every 2 weeks (Q2W).

[0346] In some embodiments, the GPRC5DxCD3 bispecific antibody is administered in an amount sufficient to alleviate or at least partially arrest the disease being treated (“therapeutically effective amount”).

[0347] In some embodiments, the GPRC5DxCD3 bispecific antibody is subcutaneously administered.

[0348] In some embodiments, the GPRC5DxCD3 bispecific antibody is administered at a dose of 0.4 mg / kg to 0.8 mg / kg weekly or once every 2 weeks (Q2W), or any frequency in- between.

[0349] In some embodiments, an induction therapy is administered to the subject prior to administering the GPRC5DxCD3 bispecific antibody. In some embodiments, an induction therapy is administered to the subject prior to the administration of ciltacabtagene autoleucel. The term “induction” or “induction therapy” refers to treatment regimens in the initial therapy to achieve adequate disease control, allow adequate stem-cell harvest, induce the deepest possible response, and minimize toxicity (Bazarbachi et al., Blood Cancer Journal, 12(47): 1-8 (2022)). In some embodiments, the induction therapy comprises a proteasomal -79- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) inhibitor (PI) or an immunomodulatory drug (IMiD). In some embodiments, the induction therapy comprises a proteasomal inhibitor (PI) and an immunomodulatory drug (ImiD). In some embodiments, the PI is bortezomib, carfilzomib, or ixazomib. In some embodiments, the ImiD is lenalidomide, pomalidomide, thalidomide, or a cereblon E3 ligase modulatory drug (CELMoD), such as iberdomine or mezigdomide. In some embodiments, the induction therapy further comprises dexamethasone. In some embodiments, the induction therapy further comprises an anti-CD38 antibody. In some embodiments, the anti-CD38 antibody is daratumumab.

[0350] In some embodiments, the induction therapy comprises daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd). In some embodiments, the dose of daratumumab can be administered subcutaneously at a dose of 1200 to 2400 mg, or any value in between. In some embodiments, the bortezomib can be administered at a dose of 0.1 mg / m2 to 5 mg / m2, or any value in between. In some embodiments, the lenalidomide can be administered at a dose of 5 to 50 mg, or any value in between, in some embodiments, the dexamethasone can be administered at a dose of 4 to 100 mg, or any value in between.

[0351] In some embodiments, the induction therapy comprises 4, 28-day cycles of DVRd.

[0352] In some embodiments, the administration of the GPRC5DxCD3 bispecific antibody occurs before the administration of ciltacabtagene autoleucel.

[0353] Any of the anti-CD38 antibodies described herein may be used in the method of treating cancer.

[0354] In some embodiments, the anti-CD38 antibody is selected from the group consisting of daratumumab, isatuximab, and felzartamab. In some embodiments, the anti- CD38 antibody is daratumumab.

[0355] In some embodiments, the anti-CD38 antibody is administered subcutaneously in a fixed dose of 1200 to 2400 mg. For example, the anti-CD38 antibody can be administered subcutaneously at a dose of 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, or any value in-between. In some embodiments, the anti-CD38 antibody is administered subcutaneously at a dose of 1800 mg.

[0356] In certain embodiments, the anti-CD38 antibody and the GPRC5DxCD3 bispecific antibody are administered on the same day. -80- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0357] In certain embodiments, the anti-CD38 antibody and the GPRC5DxCD3 bispecific antibody are administered simultaneously. In some embodiments, the anti-CD38 antibody is co-administered with the GPRC5DxCD3 bispecific antibody.

[0358] In some embodiments, the anti-CD38 antibody is administered sequentially with the GPRC5DxCD3 bispecific antibody. In some embodiments, the anti-CD38 antibody is administered prior to the administration of the GPRC5DxCD3 bispecific antibody. For example, in some embodiments, the GPRC5DxCD3 bispecific antibody is administered within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 hours after the administration of the anti-CD38 antibody. For example, in some embodiments, the anti-CD38 antibody is administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 hours prior to administering the GPRC5DxCD3 bispecific antibody. In some embodiments, the anti-CD38 antibody is administered 1 hour prior to the administration of the GPRC5DxCD3 bispecific antibody.

[0359] In some embodiments, each cycle of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody is about 28 days. In some embodiments, the subject is administered three consecutive step-up doses of the GPRC5DxCD3 bispecific in the first cycle. In some embodiments, the step-up doses of the GPRC5DxCD3 bispecific antibody are 0.01 mg / kg, 0.06 mg / kg, and 0.4 mg / kg. In some embodiments, the step-up doses are administered prior to the administration of the 0.8 mg / kg weekly or once every 2 weeks (Q2W) dose. In some embodiments, the step-up doses may be administered between 2-5 days apart, inclusive. For example, in cycle 1, a 0.01 mg / kg dose may be administered on day 1, a 0.06 mg / kg dose may be administered on day 4, a 0.4 mg / kg dose may be administered on day 8, and a 0.8 mg / kg once every 2 weeks (Q2W) dose may be started on day 15. In some embodiments, the anti-CD38 antibody is administered on day 1 and day 15 of the first cycle.

[0360] In some embodiments, the subject is administered 4 cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody.

[0361] In some embodiments, the first cycle of the 4 cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody comprises the administration of a first step- up dose of 0.01 mg / kg of the GPRC5DxCD3 bispecific antibody and the administration of a first 1800 mg dose of the anti-CD38 antibody, the administration of a second step-up dose of 0.06 mg / kg of the GPRC5DxCD3 bispecific antibody 2, 3, 4, or 5 days after the administration of the first step-up dose, the administration of a third step-up dose of 0.4 mg / kg of the GPRC5DxCD3 bispecific antibody 6, 7, 8 or 9 days after the administration of the first step-up dose, and the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific -81- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) antibody two or more days after the administration of the third step-up dose, and, optionally, about 14 days after the administration of the first step-up dose, and the administration of a second 1800 mg dose of the anti-CD38 antibody

[0362] In some embodiments, the second through fourth cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody each comprise the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody and the administration of 1800 mg of the anti-CD38 antibody once every 2 weeks (Q2W).

[0363] In some embodiments, prior to ciltacabtagene autoleucel infusion subjects will receive 4 cycles of 1800 mg of daratumumab with 0.8 mg / kg talquetamab given every 2 weeks in Cycles 1 and 2 and given every 4 weeks in Cycles 3 and 4.

[0364] Any of the BCMAxCD3 bispecific antibodies described herein may be used in the method of treating cancer.

[0365] In some embodiments, the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising the HCDR1 of SEQ ID NO: 218, the HCDR2 of SEQ ID NO: 219, the HCDR3 of SEQ ID NO: 220, the LCDR1 of SEQ ID NO: 221, the LCDR2 of SEQ ID NO: 222 and the LCDR3 of SEQ ID NO: 223, and a CD3 binding domain comprising the HCDR1 of SEQ ID NO: 228, the HCDR2 of SEQ ID NO: 229, the HCDR3 of SEQ ID NO: 230, the LCDR1 of SEQ ID NO: 231, the LCDR2 of SEQ ID NO: 232 and the LCDR3 of SEQ ID NO: 233. In some embodiments, the BCMA binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 224 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 225, and the CD3 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 234 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 235. In some embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in the HC1 and leucine at position 405 and lysine at position 409 in the HC2, wherein residue numbering is according to the EU Index. In some embodiments, the BCMAxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234 and alanine at position 235 in both the HC1 and the HC2. In some embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 226, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 227, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 236 and a -82- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) second light chain (LC2) having the amino acid sequence of SEQ ID NO: 237. In some embodiments, the BCMAxCD3 bispecific antibody is teclistamab.

[0366] In some embodiments, the BCMAxCD3 bispecific antibody is administered at a dose of 2.0 mg / kg to 4.0 mg / kg weekly or once every 2 weeks (Q2W), or any frequency in- between. In some embodiments, the BCMAxCD3 bispecific antibody is administered subcutaneously.

[0367] In certain embodiments, the anti-CD38 antibody and the BCMAxCD3 bispecific antibody are administered on the same day.

[0368] In certain embodiments, the anti-CD38 antibody and the BCMAxCD3 bispecific antibody are administered simultaneously. In some embodiments, the anti-CD38 antibody is co-administered with the BCMAxCD3 bispecific antibody.

[0369] In some embodiments, the anti-CD38 antibody is administered sequentially with the BCMAxCD3 bispecific antibody. In some embodiments, the anti-CD38 antibody is administered prior to the administration of the BCMAxCD3 bispecific antibody. For example, in some embodiments, the BCMAxCD3 bispecific antibody is administered within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 hours after the administration of the anti-CD38 antibody. For example, in some embodiments, the anti-CD38 antibody is administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 hours prior to administering the BCMAxCD3 bispecific antibody. In some embodiments, the anti-CD38 antibody is administered 1 hour prior to the administration of the BCMAxCD3 bispecific antibody.

[0370] In some embodiments, the administration of the GPRC5DxCD3 bispecific antibody and the BCMAxCD3 bispecific antibody occurs after the administration of ciltacabtagene autoleucel. In some embodiments, the administration of the GPRC5DxCD3 bispecific antibody and the BCMAxCD3 bispecific antibody begins between about 84 to 168 days after the administration of ciltacabtagene autoleucel.

[0371] In some embodiments, the subject is administered 4 cycles of antibody treatment. In some embodiments, each cycle of the 4 cycles is about 84 days. In some embodiments, the first cycle comprises the administration of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody. In some embodiments, the second cycle comprises the administration of the BCMAxCD3 bispecific antibody and the anti-CD38 antibody. In some embodiments, the third cycle comprises the administration of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody. In some embodiments, the fourth cycle comprises the administration of the BCMAxCD3 bispecific antibody and the anti-CD38 antibody. -83- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0372] In some embodiments, the first cycle comprises the administration of an 1800 mg dose the anti-CD38 antibody, the administration of a first step-up dose of 0.01 mg / kg of the GPRC5DxCD3 bispecific antibody about 20 hours after the administration of the anti-CD38 antibody, the administration of a second step-up dose of 0.06 mg / kg of the GPRC5DxCD3 bispecific antibody 2, 3, or 4 days after the administration of the anti-CD38 antibody, the administration of a third step-up dose of 0.4 mg / kg of the GPRC5DxCD3 bispecific antibody 7, 8, or 9 days after the administration of the anti-CD38 antibody, and the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody two or more days after the administration of the third step-up dose, and, optionally, about 14 days after the administration of the anti-CD38 antibody.

[0373] In some embodiments, second cycle comprises the administration of an 1800 mg dose of the anti-CD38 antibody, the administration of a first step-up dose of 0.06 mg / kg of the BCMAxCD3 bispecific antibody about 20 hours after the administration of the anti-CD38 antibody, the administration of a second step-up dose of 0.3 mg / kg of the BCMAxCD3 bispecific antibody two or more days after the administration of the first step-up dose, the administration of a third step-up dose of 1.5 mg / kg of the BCMAxCD3 bispecific antibody two or more days after the administration of the second step-up dose, and the administration of 3.0 mg / kg of the BCMAxCD3 bispecific antibody two or more days after the administration of the third step-up dose, and, optionally, about 14 days after the administration of the anti-CD38 antibody

[0374] In some embodiments, the third cycle comprises the administration of an 1800 mg dose of the anti-CD38 antibody, and the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody about 1 hour after the administration of the anti-CD38 antibody.

[0375] In some embodiments, the fourth cycle comprises the administration of an 1800 mg dose of the anti-CD38 antibody, and the administration of 3.0 mg / kg of the BCMAxCD3 bispecific antibody about 1 hour after the administration of the anti-CD38 antibody.

[0376] In some embodiments, after the fourth cycle, the subject is tested for MRD- negative status, and, if the subject is determined to be MRD-positive, the subject is administered an additional 4 cycles of antibody treatment.

[0377] In some embodiments, participants will receive daratumumab SC 1800 mg along with talquetamab SC 0.8 mg / kg given on Day 1 on Cycles 3, 5 and 7, alternating with teclistamab SC 3.0 mg / kg given on Day 1 on cycles 4, 6 and 8. -84- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0378] In some embodiments, a subject’s response to the method of treatment is assessed using the International Myeloma Working Group (IMWG)-based response criteria, which are summarized in Table 9. In some embodiments, the response may be classified as a stringent complete response (sCR). In some embodiments, the response may be classified as a complete response (CR), which is worse than a stringent complete response (sCR). In some embodiments, the response may be classified as a very good partial response (VGPR), which is worse than a complete response (CR). In some embodiments, the response may be classified as a partial response (PR), which is worse than a very good partial response (VGPR). In some embodiments, the response may be classified as a minimal response (MR), which is worse than a partial response (PR). In some embodiments, the response may be classified as a stable disease (SD), which is worse than a minimal response (MR). In some embodiments, the response may be classified as a progressive disease (PD), which is worse than a stable disease.

[0379] In some embodiments, the method achieves an overall response rate of about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% of treated subjects. The overall response rate may be deciphered by calculating the proportion of patients who achieve a partial response, a very good partial response, a complete response, or a stringent complete response.

[0380] In some embodiments, the tests used to assess International Myeloma Working Group (IMWG)-based response criteria are Myeloma protein (M-protein) measurements in serum and urine, serum calcium corrected for albumin, bone marrow examination, skeletal survey and documentation of extramedullary plasmacytomas.

[0381] Non-limiting examples of tests for M-protein measurement in blood and urine are known to one of ordinary skill in the art and comprise serum quantitative Ig, serum protein electrophoresis (SPEP), serum immunofixation electrophoresis, serum FLC assay, 24-hour urine M-protein quantitation by electrophoresis (UPEP), urine immunofixation electrophoresis, and serum β2-microglobulin.

[0382] Calculating serum calcium corrected for albumin in blood samples for detection of hypercalcemia is known to one of ordinary skill in the art. Without wishing to be bound by theory, calcium binds to albumin and only the unbound (free) calcium is biologically active; therefore, the serum calcium level must be adjusted for abnormal albumin levels (“corrected serum calcium”). -85- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0383] In some embodiments, a skeletal survey of any one of, or all of, the skull, the entire vertebral column, the pelvis, the chest, the humeri, the femora, and any other bones, may be performed and evaluated by either roentgenography (“Xrays”) or low-dose computed tomography (CT) diagnostic quality scans without the use of IV contras, both of which are known to one of ordinary skill in the art. In some embodiments, following T cell administration and before disease progression is confirmed, X-rays or CT scans may be performed locally, whenever clinically indicated based on symptoms, to document response or progression. In some embodiments, magnetic resonance imaging (MRI) may be used for evaluating bone disease but does not replace a skeletal survey. MRI is known to one of ordinary skill in the art. In some embodiments, if a radionuclide bone scan is used at screening, in addition to the complete skeletal survey, both methods may be used to document disease status. Radionuclide bone scans are known to one of ordinary skill in the art. In some embodiments, the radionuclide bone scan and complete skeletal survey may be performed at the same time. In some embodiments, a radionuclide bone scan may not replace a complete skeletal survey. In some embodiments, if a subject presents with disease progression manifested by symptoms of pain due to bone changes, then disease progression may be documented by skeletal survey or other radiographs, depending on the symptoms that the subject experiences.

[0384] In some embodiments, extramedullary plasmacytomas may be documented by clinical examination or MRI. In some embodiments, if there was no contraindication to the use of IV contrast, extramedullary plasmacytomas may be documented by CT scan. In some embodiments, extramedullary plasmacytomas may be documented by a fusion of positron emission tomography (PET) and CT scans if the CT component is of sufficient diagnostic quality. In some embodiments, assessment of measurable sites of extramedullary disease may be performed, measured, or evaluated locally every 4 weeks for subjects until development of confirmed CR or confirmed disease progression. In some embodiments, evaluation of extramedullary plasmacytomas may be done every 12 weeks.

[0385] In some embodiments, to qualify for VGPR or PR or MR, the sum of products of the perpendicular diameters of the existing extramedullary plasmacytomas may have decreased by over 90% or at least 50%, respectively. In some embodiments, to qualify for disease progression, either the sum of products of the perpendicular diameters of the existing extramedullary plasmacytomas must have increased by at least 50%, or the longest diameter of previous lesion >1 cm in short axis must have increased at least 50%, or a new -86- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) plasmacytoma must have developed. In some embodiments, to qualify for disease progression when not all existing extramedullary plasmacytomas are reported, the sum of products of the perpendicular diameters of the reported plasmacytomas had increased by at least 50%. In some embodiments, if the study treatment interferes with the immunofixation assay, CR may be defined as the disappearance of the original M-protein associated with multiple myeloma on immunofixation.

[0386] In some embodiments, a subject’s response to the method of treatment is assessed in terms of change in disease burden or tumor burden. Disease burden or tumor burden represents the type of measurable disease in the subject. In some embodiments, the change in tumor burden may be assessed in terms of paraprotein level changes upon treatment. In some embodiments, the paraprotein is an M-protein in the serum. In some embodiments, the paraprotein is an M-protein in the serum. In some embodiments, the change in tumor burden is assessed in terms of the difference between involved and uninvolved free light chain (dFLC). In some embodiments, the change in tumor burden is assessed in terms of the maximum paraprotein reduction from baseline, i.e., from prior to the administration of the CAR-T cells. In some embodiments, the change in tumor burden is assessed at a median follow-up time of greater than or equal to 28 days following the administration of CAR-T cells. In some embodiments, the change in tumor burden is assessed at a median follow-up time of greater than or equal to 1 month following the administration of CAR-T cells. In some embodiments, the change in tumor burden is assessed at a median follow-up time of greater than or equal to 3 months following the administration of CAR-T cells. In some embodiments, the change in tumor burden is assessed at a median follow-up time of greater than or equal to 6 months following the administration of CAR-T cells. In some embodiments, the change in tumor burden is assessed at a median follow-up time of greater than or equal to 9 months following the administration of CAR-T cells. In some embodiments, the change in tumor burden is assessed at a median follow-up time of greater than or equal to 12 months following the administration of CAR-T cells.

[0387] In some embodiments, bone marrow aspirate or biopsy may be performed for clinical assessments or bone marrow aspirate may be performed for biomarker evaluations. In some embodiments, clinical staging (morphology, cytogenetics, and immunohistochemistry or immunofluorescence or flow cytometry) may be done. In some embodiments, a portion of the bone marrow aspirate may be immunophenotyped and monitored for BCMA, checkpoint ligand expression in CD138-positive multiple myeloma cells, and checkpoint expression on T -87- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) cells. In some embodiments, minimal residual disease (MRD) may be monitored in subjects using next generation sequencing (NGS) of bone marrow aspirate DNA. The NGS of bone marrow aspirate DNA is known to one of ordinary skill in the art. In some embodiments, the NGS is performed via clonoSEQ. In some embodiments, baseline bone marrow aspirates may be used to define the myeloma clones, and post-treatment samples may be used to evaluate MRD negativity. In some embodiments, the MRD negativity status may be based on samples that are evaluable. In some embodiments, evaluable samples are those that passed one or more of, or all of, calibration, quality control, and sufficiency of cells evaluable at a particular sensitivity level. In some embodiments, the sensitivity level is 10-6. In some embodiments, the sensitivity level is 10-5. In some embodiments, the sensitivity level is 10-4. In some embodiments, the sensitivity level is 10-3.

[0388] In some embodiments, the method achieves MRD-negativity at a threshold of 10-5before disease progression or start of a subsequent antimyeloma therapy. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-5, for at least 6 months without examination showing MRD-positive or PD in between. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-5, for at least 12 months without examination showing MRD-positive or PD in between. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-5, for at least 18 months without examination showing MRD-positive or PD in between. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-5, for at least 24 months without examination showing MRD-positive or PD in between. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-5, for at least 30 months without examination showing MRD-positive or PD in between. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-5, for at least 36 months without examination showing MRD-positive or PD in between. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-5, for at least 42 months without examination showing MRD-positive or PD in between. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-5, for at least 48 months without examination showing MRD-positive or PD in between. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-5, for at least 54 -88- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) months without examination showing MRD-positive or PD in between. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-5, for at least 60 months without examination showing MRD-positive or PD in between.

[0389] In some embodiments, the method achieves MRD-negativity at a threshold of 10-6before disease progression or start of a subsequent antimyeloma therapy. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-6, for at least 6 months without examination showing MRD-positive or PD in between. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-6, for at least 12 months without examination showing MRD-positive or PD in between. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-6, for at least 18 months without examination showing MRD-positive or PD in between. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-6, for at least 24 months without examination showing MRD-positive or PD in between. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-6, for at least 30 months without examination showing MRD-positive or PD in between. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-6, for at least 36 months without examination showing MRD-positive or PD in between. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-6, for at least 42 months without examination showing MRD-positive or PD in between. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-6, for at least 48 months without examination showing MRD-positive or PD in between. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-6, for at least 54 months without examination showing MRD-positive or PD in between. In some embodiments, the method achieves sustained MRD-negative status, as determined by NGS with sensitivity of 10-6, for at least 60 months without examination showing MRD-positive or PD in between.

[0390] Also provided in further embodiments is the medical use of the therapies (including CARs, CAR T cells, and antibodies) provided herein for use in the methods of treatment disclosed herein. Also provided in further embodiments is the use of the therapies -89- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) (including CARs, and CAR T cells), and antibodies provided herein for use in the manufacture of a medicament for the use in the methods of treatment disclosed herein. Enumerated Embodiments

[0391] The following examples are illustrative, but not limiting, of the compounds, compositions and methods described herein. Other suitable modifications and adaptations known to those skilled in the art are within the scope of the following embodiments. 1. A method of treating multiple myeloma in a subject in need thereof, the method comprising: administering a GPRC5DxCD3 bispecific antibody to the subject, and administering ciltacabtagene autoleucel to the subject; wherein the administration of the GPRC5DxCD3 bispecific antibody occurs before the administration of ciltacabtagene autoleucel. 2. The method of embodiment 1, wherein the subject has newly diagnosed multiple myeloma based on International Myeloma Working Group (IMWG) diagnostic criteria. 3. The method of embodiments 1 or 2, wherein the subject has standard-risk multiple myeloma based on revised International Staging System (R-ISS) diagnostic criteria. 4. The method of any preceding embodiment, wherein the subject is stem cell transplant eligible. 5. The method of any preceding embodiment, wherein the subject is fit or intermediate- fit based on IMWG Frailty Index assessment. 6. The method of any preceding embodiment, wherein the GPRC5DxCD3 bispecific antibody comprises a GPRC5D binding domain comprising the HCDR1 of SEQ ID NO: 101, the HCDR2 of SEQ ID NO: 102, the HCDR3 of SEQ ID NO: 103, the LCDR1 of SEQ ID NO: 104, the LCDR2 of SEQ ID NO: 105 and the LCDR3 of SEQ ID NO: 106, and a CD3 binding domain comprising the HCDR1 of SEQ ID NO: 107, the HCDR2 of SEQ ID NO: -90- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 108, the HCDR3 of SEQ ID NO: 109, the LCDR1 of SEQ ID NO: 110, the LCDR2 of SEQ ID NO: 111 and the LCDR3 of SEQ ID NO: 112. 7. The method of embodiment 1 to 6, wherein the GPRC5D binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 113 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 114, and the CD3 binding domain comprises a VH having the amino acid sequence of SEQ ID NO: 115 and a VL having the amino acid sequence of SEQ ID NO: 116. 8. The method of any preceding embodiment, wherein the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in a first heavy chain (HC1) and leucine at position 405 and lysine at position 409 in a second heavy chain (HC2), wherein residue numbering is according to the EU Index. 9. The method of embodiment 8, wherein the GPRC5DxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234 and alanine at position 235 in both the HC1 and the HC2. 10. The method of embodiments 1 to 9, wherein the GPRC5DxCD3 bispecific antibody comprises the HC1 having the amino acid sequence of SEQ ID NO: 117, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 118, the HC2 having the amino acid sequence of SEQ ID NO: 119 and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 120. 11. The method of any preceding embodiment, wherein the GPRC5DxCD3 bispecific antibody is talquetamab. 12. The method of any one of embodiments 1 to 11, wherein the administration of the GPRC5DxCD3 bispecific antibody is once every 2 weeks (Q2W) at a dosage of about 0.8 mg / kg. 13. The method of any one of embodiments 1 to 11, wherein the administration of the GPRC5DxCD3 bispecific antibody is weekly at a dosage of about 0.4 mg / kg. -91- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 14. The method of any preceding embodiment, wherein the GPRC5D x CD3 bispecific antibody is administered subcutaneously. 15. The method of any preceding embodiment, wherein the subject is further administered an anti-CD38 antibody. 16. The method of embodiment 15, wherein the anti-CD38 antibody is administered simultaneously with the administration of the GPRC5DxCD3 bispecific antibody. 17. The method of embodiment 15, wherein the anti-CD38 antibody is administered sequentially with the administration of the GPRC5DxCD3 bispecific antibody. 18. The method of embodiment 15, wherein the anti-CD38 antibody is administered about 1 hour before the administration of the GPRC5DxCD3 bispecific antibody. 19. The method of any one of embodiments 15 to 18, wherein the anti-CD38 antibody is selected from the group consisting of daratumumab, isatuximab, and felzartamab. 20. The method of any one of embodiments 15 to 19, wherein the anti-CD38 antibody is daratumumab. 21. The method of any one of embodiments 15 to 20, wherein the administration of the anti-CD38 antibody is 1800 mg per dose. 22. The method of any one of embodiments 15 to 21, wherein the anti-CD38 antibody is administered subcutaneously. 23. The method of any preceding embodiment, ciltacabtagene autoleucel is administered to the subject at a dose of about 0.5 to about 1.0 × 106CAR-positive viable T cells / kg 24. The method of embodiment 23, wherein ciltacabtagene autoleucel is administered to the subject at a dose of about 0.75 × 106CAR-positive viable T cells / kg. -92- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 25. The method of any preceding embodiment, further comprising administering a conditioning regimen to the subject prior to administering ciltacabtagene autoleucel, wherein the conditioning regimen comprises one or more of cyclophosphamide and / or fludarabine. 26. The method of embodiment 25, wherein the conditioning regimen comprises cyclophosphamide at a dosage of about 300 mg / m2. 27. The method of embodiment 25, wherein the conditioning regimen comprises fludarabine at a dosage of about 30 mg / m2. 28. The method of embodiment 25, wherein the conditioning regimen comprises cyclophosphamide at a dosage of about 300 mg / m2and fludarabine at a dosage of about 30 mg / m2. 29. The method of any one of embodiments 25 to 28, wherein the conditioning regimen is administered to the subject daily, for up to 3 days. 30. The method of any one of embodiments 25 to 29, wherein the ciltacabtagene autoleucel is administered to the subject 5 to 7 days after the start of the administration of the conditioning regimen. 31. The method of any preceding embodiment, further comprising administering an induction therapy to the subject prior to administering the GPRC5DxCD3 bispecific antibody. 32. The method of embodiment 31, wherein the induction therapy comprises daratumumab, bortezomib, lenalidomide, dexamethasone, or some combination thereof. 33. The method of embodiment 31 or 32, wherein the induction therapy comprises 4 cycles daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd). -93- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 34. The method of embodiment 33, wherein each cycle of DVRd is about 28 days and comprises about 1800 mg of daratumumab, about 1.3 mg / m2of bortezomib, about 25 mg of lenalidomide, and about 40 mg of dexamethasone. 35. The method of any proceeding embodiment, wherein the method further comprises the collection of apheresis material from the subject for the manufacturing of ciltacabtagene autoleucel. 36. The method of embodiment 35, wherein the collection of apheresis material occurs prior to the administration of the GPRC5DxCD3 antibody. 37. The method of embodiments 35 or 36, wherein the collection of apheresis material occurs prior to the administration of the induction therapy of embodiments 31 to 34. 38. The method of any one of embodiments 15 to 37, wherein the subject is administered 4 cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody. 39. The method of embodiment 38, wherein each cycle of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody is about 28 days. 40. The method of embodiment 38 or 39, wherein in the first cycle of the 4 cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody the subject receives three consecutive step-up doses of the GPRC5DxCD3 bispecific antibody of about 0.01 mg / kg, about 0.06 mg / kg, and about 0.4 mg / kg, prior to receiving the 0.8 mg / kg once every 2 weeks (Q2W) dose. 41. The method of embodiment 40, wherein the three consecutive step-up doses are administered 2, 3, 4, or 5 days apart. 42. The method of any one of embodiments 38 to 41, wherein the first cycle of the 4 cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody comprises: the administration of a first step-up dose of 0.01 mg / kg of the GPRC5DxCD3 bispecific antibody and the administration of a first 1800 mg dose of the anti-CD38 antibody, -94- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) the administration of a second step-up dose of 0.06 mg / kg of the GPRC5DxCD3 bispecific antibody 2, 3, 4, or 5 days after the administration of the first step-up dose, the administration of a third step-up dose of 0.4 mg / kg of the GPRC5DxCD3 bispecific antibody 6, 7, 8 or 9 days after the administration of the first step-up dose, and the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody two or more days after the administration of the third step-up dose, and, optionally, about 14 days after the administration of the first step-up dose, and the administration of a second 1800 mg dose of the anti-CD38 antibody. 43. The method of embodiment 42, wherein the second through fourth cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody each comprise the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody and the administration of 1800 mg of the anti-CD38 antibody once every 2 weeks (Q2W). 44. The method of embodiment 42, where the second cycle of the 4 cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody comprises the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody and the administration of 1800 mg of the anti-CD38 antibody once every 2 weeks (Q2W), and wherein the third and fourth cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody comprises the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody and the administration of 1800 mg of the anti-CD38 antibody once every 4 weeks (Q4W). 45. The method of any proceeding embodiment, wherein the method achieves a partial response (PR), very good partial response (VGPR), complete response (CR) or stringent complete response (sCR) in the subject, according to IMWG criteria. 46. The method of any proceeding embodiment, wherein the method achieves a very good partial response (VGPR), complete response (CR) or stringent complete response (sCR) in the subject, according to IMWG criteria. 47. The method of any proceeding embodiment, wherein the method achieves a complete response (CR) or stringent complete response (sCR) in the subject, according to IMWG criteria. -95- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 48. The method of any proceeding embodiment, wherein the method achieves a stringent complete response (sCR) in the subject, according to IMWG criteria. 49. The method of any proceeding embodiments, wherein the method achieves minimal residual disease (MRD) negativity at a threshold of 10-5before disease progression or start of a subsequent antimyeloma therapy. 50. The method of any proceeding embodiment, wherein the method achieves sustained MRD-negative status, as determined by next generation sequencing (NGS) with sensitivity of 10-5, for at least 6 months without examination showing MRD-positive or progressive disease (PD) in between. 51. A method of treating multiple myeloma in a subject in need thereof, the method comprising: administering ciltacabtagene autoleucel to the subject, administering a GPRC5DxCD3 bispecific antibody to the subject, and administering a BCMAxCD3 bispecific antibody to the subject; wherein the administration of the ciltacabtagene autoleucel occurs before the administration of GPRC5DxCD3 bispecific antibody or the BCMAxCD3 bispecific antibody. 52. The method of embodiment 51, wherein the subject has wherein the subject has newly diagnosed multiple myeloma based on International Myeloma Working Group (IMWG) diagnostic criteria. 53. The method of embodiments 51 or 52, wherein the subject has standard-risk multiple myeloma based on revised International Staging System (R-ISS) diagnostic criteria. 54. The method of any one of embodiments 51 to 53, wherein the subject is stem cell transplant eligible. 55. The method of any one of embodiments 51 to 54, wherein the subject is fit or intermediate-fit based on IMWG Frailty Index assessment. -96- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 56. The method of any one of embodiments 51 to 55, wherein the GPRC5DxCD3 bispecific antibody comprises a GPRC5D binding domain comprising the HCDR1 of SEQ ID NO: 101, the HCDR2 of SEQ ID NO: 102, the HCDR3 of SEQ ID NO: 103, the LCDR1 of SEQ ID NO: 104, the LCDR2 of SEQ ID NO: 105 and the LCDR3 of SEQ ID NO: 106, and a CD3 binding domain comprising the HCDR1 of SEQ ID NO: 107, the HCDR2 of SEQ ID NO: 108, the HCDR3 of SEQ ID NO: 109, the LCDR1 of SEQ ID NO: 110, the LCDR2 of SEQ ID NO: 111 and the LCDR3 of SEQ ID NO: 112. 57. The method of any one of embodiments 51 to 56, wherein the GPRC5D binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 113 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 114, and the CD3 binding domain comprises a VH having the amino acid sequence of SEQ ID NO: 115 and a VL having the amino acid sequence of SEQ ID NO: 116. 58. The method of any one of embodiments 51 to 57, wherein the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in a first heavy chain (HC1) and leucine at position 405 and lysine at position 409 in a second heavy chain (HC2), wherein residue numbering is according to the EU Index. 59. The method of embodiment 58, wherein the GPRC5DxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234 and alanine at position 235 in both the HC1 and the HC2. 60. The method of any one of embodiments 51 to 59, wherein the GPRC5DxCD3 bispecific antibody comprises the HC1 having the amino acid sequence of SEQ ID NO: 117, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 118, the HC2 having the amino acid sequence of SEQ ID NO: 119 and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 120. 61. The method of any one of embodiments 51 to 60, wherein the GPRC5DxCD3 bispecific antibody is talquetamab. -97- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 62. The method of any one of embodiments 51 to 61, wherein the administration of the GPRC5DxCD3 bispecific antibody is once every 2 weeks (Q2W) at a dosage of about 0.8 mg / kg. 63. The method of any one of embodiments 51 to 61, wherein the administration of the GPRC5DxCD3 bispecific antibody is weekly at a dosage of about 0.4 mg / kg. 64. The method of any one of embodiments 51 to 63, wherein the GPRC5D x CD3 bispecific antibody is administered subcutaneously. 65. The method of any one of embodiments 51 to 64, wherein the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising the HCDR1 of SEQ ID NO: 218, the HCDR2 of SEQ ID NO: 219, the HCDR3 of SEQ ID NO: 220, the LCDR1 of SEQ ID NO: 221, the LCDR2 of SEQ ID NO: 222 and the LCDR3 of SEQ ID NO: 223, and a CD3 binding domain comprising the HCDR1 of SEQ ID NO: 228, the HCDR2 of SEQ ID NO: 229, the HCDR3 of SEQ ID NO: 230, the LCDR1 of SEQ ID NO: 231, the LCDR2 of SEQ ID NO: 232 and the LCDR3 of SEQ ID NO: 233. 66. The method of any one of embodiments 51 to 65, wherein the BCMA binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 224 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 225, and the CD3 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 234 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 235. 67. The method of embodiment 65 or 66, wherein the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in the HC1 and leucine at position 405 and lysine at position 409 in the HC2, wherein residue numbering is according to the EU Index. 68. The method of embodiment 67, wherein the BCMAxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234 and alanine at position 235 in both the HC1 and the HC2. -98- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 69. The method of any one of embodiments 51 to 68, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 226, the a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 227, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 236 and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 237. 70. The method of any one of embodiments 51 to 69, wherein the BCMAxCD3 bispecific antibody is teclistamab. 71. The method of any one of embodiments 51 to 70, wherein the administration of the BCMAxCD3 bispecific antibody is once every 2 weeks (Q2W) at a dosage of about 3.0 mg / kg. 72. The method of any one of embodiments 51 to 71, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously. 73. The method of any one of embodiments 51 to 72, wherein the subject is further administered an anti-CD38 antibody. 74. The method of embodiment 73, wherein the anti-CD38 antibody is administered sequentially with the administration of the GPRC5DxCD3 bispecific antibody. 75. The method of embodiment 73 or 74, wherein the anti-CD38 antibody is administered about 1 hour before the administration of the GPRC5DxCD3 bispecific antibody. 76. The method of any one of embodiments 73 to 75, wherein the anti-CD38 antibody is administered sequentially with the administration of the BCMAxCD3 bispecific antibody. 77. The method of any one of embodiments 73 to 76, wherein the anti-CD38 antibody is administered about 1 hour before the administration of the BCMAxCD3 bispecific antibody. -99- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 78. The method of any one of embodiments 73 to 77, wherein the anti-CD38 antibody is selected from the group consisting of daratumumab, isatuximab, and felzartamab. 79. The method of any one of embodiments 73 to 78, wherein the anti-CD38 antibody is daratumumab. 80. The method of any one of embodiments 73 to 79, wherein the administration of the anti-CD38 antibody is about 1800 mg per dose. 81. The method of any one of embodiments 73 to 80, wherein the anti-CD38 antibody is administered subcutaneously. 82. The method of any one of embodiments 51 to 81, ciltacabtagene autoleucel is administered to the subject at a dose of about 0.5 to about 1.0 × 106CAR-positive viable T cells / kg 83. The method of embodiment 82, wherein ciltacabtagene autoleucel is administered to the subject at a dose of about 0.75 × 106CAR-positive viable T cells / kg. 84. The method of any one of embodiments 51 to 83, further comprising administering a conditioning regimen to the subject prior to administering ciltacabtagene autoleucel, wherein the conditioning regimen comprises one or more of cyclophosphamide and / or fludarabine. 85. The method of embodiment 84, wherein the conditioning regimen comprises cyclophosphamide at a dosage of about 300 mg / m2. 86. The method of embodiment 84, wherein the conditioning regimen comprises fludarabine at a dosage of about 30 mg / m2. 87. The method of embodiment 84, wherein the conditioning regimen comprises cyclophosphamide at a dosage of about 300 mg / m2and fludarabine at a dosage of about 30 mg / m2. -100- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 88. The method of any one of embodiments 84 to 87, wherein the conditioning regimen is administered to the subject daily, for up to 3 days. 89. The method of any one of embodiments 84 to 88, wherein the ciltacabtagene autoleucel is administered to the subject 5 to 7 days after the start of the administration of the conditioning regimen. 90. The method of any one of embodiments 51 to 89, further comprising administering an induction therapy to the subject prior to administering ciltacabtagene autoleucel. 91. The method of embodiment 90, wherein the induction therapy comprises daratumumab, bortezomib, lenalidomide, dexamethasone, or some combination thereof. 92. The method of embodiment 90 or 91, wherein the induction therapy comprises 4 cycles of daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd). 93. The method of embodiment 92, wherein each cycle of DVRd is about 28 days, and comprises about 1800 mg of daratumumab, about 1.3 mg / m2of bortezomib, about 25 mg of lenalidomide, and about 40 mg of dexamethasone. 94. The method of any one of embodiments 51 to 93, wherein the method further comprises the collection of apheresis material from the subject for the manufacturing of ciltacabtagene autoleucel. 95. The method of embodiments 94, wherein the collection of apheresis material occurs prior to the administration of the induction therapy of embodiments 90 to 93. 96. The method of any one of embodiments 73 to 95, wherein the subject is administered 4 cycles of antibody treatment, wherein: the first cycle comprises the administration of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody, the second cycle comprises the administration of the BCMAxCD3 bispecific antibody and the anti-CD38 antibody, -101- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) the third cycle comprises the administration of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody, and the fourth cycle comprises the administration of the BCMAxCD3 bispecific antibody and the anti-CD38 antibody. 97. The method of embodiment 96, wherein each cycle of the 4 cycles is about 84 days. 98. The method of embodiments 96 or 97, wherein the first cycle comprises: the administration of an 1800 mg dose of the anti-CD38 antibody, the administration of a first step-up dose of 0.01 mg / kg of the GPRC5DxCD3 bispecific antibody about 20 hours after the administration of the anti-CD38 antibody, the administration of a second step-up dose of 0.06 mg / kg of the GPRC5DxCD3 bispecific antibody 2, 3, or 4 days after the administration of the anti-CD38 antibody, the administration of a third step-up dose of 0.4 mg / kg of the GPRC5DxCD3 bispecific antibody 7, 8, or 9 days after the administration of the anti-CD38 antibody, and the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody two or more days after the administration of the third step-up dose, and, optionally, about 14 days after the administration of the anti-CD38 antibody. 99. The method of any one of embodiments 96 to 98, wherein the second cycle comprises: the administration of an 1800 mg dose of the anti-CD38 antibody, the administration of a first step-up dose of 0.06 mg / kg of the BCMAxCD3 bispecific antibody about 20 hours after the administration of the anti-CD38 antibody, the administration of a second step-up dose of 0.3 mg / kg of the BCMAxCD3 bispecific antibody two or more days after the administration of the first step-up dose, the administration of a third step-up dose of 1.5 mg / kg of the BCMAxCD3 bispecific antibody two or more days after the administration of the second step-up dose, and the administration of 3.0 mg / kg of the BCMAxCD3 bispecific antibody two or more days after the administration of the third step-up dose, and, optionally, about 14 days after the administration of the anti-CD38 antibody. 100. The method of any one of embodiments 96 to 99, wherein the third cycle comprises: -102- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) the administration of an 1800 mg dose of the anti-CD38 antibody, and the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody about 1 hour after the administration of the anti-CD38 antibody. 101. The method of any one of embodiments 96 to 99, wherein the fourth cycle comprises: the administration of an 1800 mg dose of the anti-CD38 antibody, and the administration of 3.0 mg / kg of the BCMAxCD3 bispecific antibody about 1 hour after the administration of the anti-CD38 antibody. 102. The method of any one of embodiments 96 to 101, wherein, after the fourth cycle, the subject is tested for MRD-negative status, and, if the subject is determined to be MRD- positive, the subject is administered an additional 4 cycles of antibody treatment, wherein: the fifth cycle comprises the administration of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody as defined in embodiment 100, the sixth cycle comprises the administration of the BCMAxCD3 bispecific antibody and the anti-CD38 antibody as defined in embodiment 101, the seventh cycle comprises the administration of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody as defined in embodiment 100, and the eighth cycle comprises the administration of the BCMAxCD3 bispecific antibody and the anti-CD38 antibody as defined in embodiment 101. 103. The method of any proceeding embodiment, wherein the method achieves a partial response (PR), very good partial response (VGPR), complete response (CR) or stringent complete response (sCR) in the subject, according to IMWG criteria. 104. The method of any one of embodiments 51 to 103, wherein the method achieves a very good partial response (VGPR), complete response (CR) or stringent complete response (sCR) in the subject, according to IMWG criteria. 105. The method of any one of embodiments 51 to 104, wherein the method achieves a complete response (CR) or stringent complete response (sCR) in the subject, according to IMWG criteria. -103- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 106. The method of any one of embodiments 51 to 105, wherein the method achieves a stringent complete response (sCR) in the subject, according to IMWG criteria. 107. The method of any one of embodiments 51 to 106, wherein the method achieves minimal residual disease (MRD) negativity at a threshold of 10-5before disease progression or start of a subsequent antimyeloma therapy. 108. The method of any one of embodiments 51 to 107, wherein the method achieves sustained MRD-negative status, as determined by next generation sequencing (NGS) with sensitivity of 10-5, for at least 6 months without examination showing MRD-positive or progressive disease (PD) in between. 109. A method of treating multiple myeloma in a subject in need thereof, the method comprising: administering a GPRC5DxCD3 bispecific antibody to the subject, wherein the method further comprises administering an induction therapy to the subject prior to administering the GPRC5DxCD3 bispecific antibody, wherein the induction therapy comprises 4 cycles of about 1800 mg of daratumumab, about 1.3 mg / m2of bortezomib, about 25 mg of lenalidomide, and about 40 mg of dexamethasone (DVRd), wherein each cycle of DVRd is about 28 days, wherein the subject is further administered daratumumab, wherein the daratumumab, when administered, is administered simultaneously with the administration of the GPRC5DxCD3 bispecific antibody, wherein the GPRC5DxCD3 bispecific antibody comprises a GPRC5D binding domain, which comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 113 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 114, and comprises a CD3 binding domain which comprises a VH having the amino acid sequence of SEQ ID NO: 115 and a VL having the amino acid sequence of SEQ ID NO: 116, wherein the subject is administered 4 cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody, -104- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) wherein the first cycle of the 4 cycles of the GPRC5DxCD3 bispecific antibody and the anti- CD38 antibody comprises: the administration of a first step-up dose of 0.01 mg / kg of the GPRC5DxCD3 bispecific antibody and the administration of a first 1800 mg dose of the anti-CD38 antibody, the administration of a second step-up dose of 0.06 mg / kg of the GPRC5DxCD3 bispecific antibody 2, 3, or 4 days after the administration of the anti-CD38 antibody, the administration of a third step-up dose of 0.4 mg / kg of the GPRC5DxCD3 bispecific antibody 7, 8, or 9 days after the administration of the anti-CD38 antibody, and the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody two or more days after the administration of the third step-up dose, and, optionally, about 14 days after the administration of the anti-CD38 antibody, wherein the second through fourth cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody each comprise the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody and the administration of 1800 mg of the anti-CD38 antibody once every 2 weeks (Q2W), and administering ciltacabtagene autoleucel to the subject; wherein ciltacabtagene autoleucel is administered to the subject at a dose of about 0.75 × 106CAR-positive viable T cells / kg, wherein the administration of the GPRC5DxCD3 bispecific antibody occurs before the administration of ciltacabtagene autoleucel. 110. A method of treating multiple myeloma in a subject in need thereof, the method comprising: administering ciltacabtagene autoleucel to the subject, administering a GPRC5DxCD3 bispecific antibody to the subject wherein the GPRC5DxCD3 bispecific antibody comprises a GPRC5D binding domain which comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 113 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 114, and comprises a CD3 binding domain which comprises a VH having the amino acid sequence of SEQ ID NO: 115 and a VL having the amino acid sequence of SEQ ID NO: 116, and administering a BCMAxCD3 bispecific antibody to the subject; -105- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) wherein the BCMAxCD3 bispecific antibody comprises a BCMA binding domain which comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 224 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 225, and comprises a CD3 binding domain which comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 234 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 235, wherein the subject is further administered daratumumab, wherein the daratumumab, when administered, is administered simultaneously with the administration of the GPRC5DxCD3 bispecific antibody, wherein the daratumumab, when administered, is administered simultaneously with the administration of the BCMAxCD3 bispecific antibody, wherein the subject is administered 4 cycles of antibody treatment, wherein each cycle of the 4 cycles is about 84 days, wherein the first cycle comprises: the administration of an 1800 mg dose of the anti-CD38 antibody, the administration of a first step-up dose of 0.01 mg / kg of the GPRC5DxCD3 bispecific antibody about 20 hours after the administration of the anti-CD38 antibody, the administration of a second step-up dose of 0.06 mg / kg of the GPRC5DxCD3 bispecific antibody 2, 3, or 4 days after the administration of the anti-CD38 antibody, the administration of a third step-up dose of 0.4 mg / kg of the GPRC5DxCD3 bispecific antibody 7, 8, or 9 days after the administration of the anti-CD38 antibody, and the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody two or more days after the administration of the third step-up dose, and, optionally, about 14 days after the administration of the anti-CD38 antibody; wherein the second cycle comprises: the administration of an 1800 mg dose of the anti-CD38 antibody, the administration of a first step-up dose of 0.06 mg / kg of the BCMAxCD3 bispecific antibody about 20 hours after the administration of the anti-CD38 antibody, the administration of a second step-up dose of 0.3 mg / kg of the BCMAxCD3 bispecific antibody two or more days after the administration of the first step-up dose, the administration of a third step-up dose of 1.5 mg / kg of the BCMAxCD3 bispecific antibody two or more days after the administration of the second step-up dose, and -106- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) the administration of 3.0 mg / kg of the BCMAxCD3 bispecific antibody two or more days after the administration of the third step-up dose, and, optionally, about 14 days after the administration of the anti-CD38 antibody; wherein the third cycle comprises: the administration of an 1800 mg dose of the anti-CD38 antibody, and the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody about 1 hour after the administration of the anti-CD38 antibody; wherein the fourth cycle comprises: the administration of an 1800 mg dose of the anti-CD38 antibody, and the administration of 3.0 mg / kg of the BCMAxCD3 bispecific antibody about 1 hour after the administration of the anti-CD38 antibody, wherein the administration of the ciltacabtagene autoleucel occurs before the administration of GPRC5DxCD3 bispecific antibody and before the BCMAxCD3 bispecific antibody, wherein ciltacabtagene autoleucel is administered to the subject at a dose of about 0.75 × 106CAR-positive viable T cells / kg, wherein the method further comprises administering an induction therapy to the subject prior to administering ciltacabtagene autoleucel, wherein the induction therapy comprises 4 cycles of daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd), wherein each cycle of DVRd is about 28 days and comprises about 1800 mg of daratumumab, about 1.3 mg / m2of bortezomib, about 25 mg of lenalidomide, and about 40 mg of dexamethasone. EXAMPLES

[0392] The following examples are provided to further describe some of the aspects and embodiments disclosed herein. The examples are intended to illustrate, not to limit, the disclosed aspects or embodiments. Example 1: Ciltacabtagene and Teclistamab

[0393] B-cell maturation antigen (BCMA, also known as CD269 and TNFRSF17) is a 20 kilodalton, type III membrane protein that is part of the tumor necrosis receptor superfamily. BCMA is a cell surface antigen that is predominantly expressed in B-lineage cells at high levels. FIG.2 shows the expression of BCMA on various immune-derived cells. Comparative -107- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) studies have shown a lack of BCMA in most normal tissues and absence of expression on CD34-positive hematopoietic stem cells. BCMA binds 2 ligands that induce B cell proliferation and plays a critical role in B cell maturation and subsequent differentiation into plasma cells. The selective expression and the biological importance for the proliferation and survival of myeloma cells makes BCMA a promising target for CAR-T based immunotherapy.

[0394] Ciltacabtagene autoleucel (also known as cilta-cel) is an autologous chimeric antigen receptor T-cell (CAR-T) therapy that targets BCMA. The ciltacabtagene autoleucel chimeric antigen receptor (CAR) comprises to BCMA-targeting VHH domains designed to confer avidity. A map of the construct is depicted in FIG.3 and a schematic of the CAR-T cell production is shown in FIG.4. Ciltacabtagene autoleucel includes a VHH domain comprising the amino acid sequence set forth in SEQ ID NO: 102 and a VHH domain comprising the amino acid sequence set forth in SEQ ID NO: 104.

[0395] Anti-BCMA / anti-CD3 antibody JNJ-64007957 (referred to as teclistamab or JNJ- 957) (described in WO2017031104A1) and daratumumab were made by Janssen Pharmaceuticals. CNTO7008 (CD3xnull), BC3B4 (BCMAxnull) and 3930 (IgG isotype control), all made by Janssen Pharmaceuticals, were used as control antibodies.

[0396] Talquetamab is a novel, humanized IgG4 bispecific antibody designed to target the CD3 receptor complex on T-cells and GPRC5D-expressing multiple myeloma cells, resulting in T-cell activation and subsequent lysis of GPRC5D-expressing cells. As a stable bispecific IgG molecule generated through controlled fragment antigen binding arm exchange following the method reported by Labrijn et al (2013), talquetamab is able to draw T-cells in close proximity to myeloma cells, without regard to T-cell receptor specificity or reliance on major histocompatibility complex Class 1 molecules on the surface of antigen presenting cells for activation, leading to activation of T-cells and subsequent lysis of GPRC5D-expressing cells. Multiple studies are ongoing and planned to evaluate talquetamab in combinations and to evaluate it in earlier lines of therapy. Talquetamab comprises a CD3 binding arm CD3B219 and a GPRC5d binding arm GC5B596, the amino acid sequences of which are shown in Table 7A and Table 7B, respectively.

[0397] Teclistamab is a full-size, IgG4-PAA bispecific antibody that targets the CD3 receptor expressed on the surface of T-cells and BCMA, which is expressed on the surface of malignant multiple myeloma B lineage cells, as well as late-stage B cells and plasma cells. With its dual binding sites, teclistamab is able to draw CD3+ T-cells in close proximity to -108- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) BCMA+ cells, resulting in T-cell activation and subsequent lysis of BCMA+ cells which is mediated by secreted perforin and various granzymes stored in the secretory vesicles of cytotoxic T-cells. This effect occurs without regard to T-cell receptor specificity or reliance on MHC Class 1 molecules on the surface of antigen presenting cells for activation, leading to cell death of the BCMA+ cells. Multiple studies are ongoing and planned to evaluate teclistamab in combinations and to evaluate it in earlier lines of therapy. Teclistamab comprises a BCMA binding arm BCMB69 and a CD3 binding arm CD3B219, the amino acid sequences of which are shown in Table 13A and Table 13B, respectively.

[0398] Daratumumab is a first-in-class, human IgG1ĸ mAb that binds with high affinity to CD38-expressing cells, inducing tumor cell death through diverse mechanisms of immune- mediated actions CDC, ADCC, and ADCP, as well as induction of apoptosis and modulation of CD38 enzyme activities. CD38 is overexpressed on myeloma cells but is expressed at relatively low levels on normal lymphoid and myeloid cells and in some tissues of non- hematopoietic origin, making it a relevant target for the treatment of multiple myeloma (MM). Example 2: Considerations for optimal sequencing and / or combination of CAR-T and CD3 Bispecifics

[0399] Recent advancements in multiple myeloma therapy have shown significant clinical responses in their respective trials. Carvykti™ (cilta-cel) was approved in February 2022 with a 97.9% response rate as observed in CARTITUDE-1 and a median duration of response about 21.8 months. Tecvayli® (teclistamab) was approved in October 2022, with a 63% overall response rate (ORR) registered in the MajesTEC-1 trial and a median response duration of approximately 22 months. Talvey™ (talquetamab) was approved in August 2022 and saw a response rate of 73% in the MonumenTAL-1 trial with the median response duration for the .4mg / kg group measuring at 9.5 months.

[0400] These drugs show a similarity in their mode of action (MOA), functioning through direct cytotoxicity (examples include perforin, granzyme, Fas / FasL) and cytokine production (which include agents like IFN-γ, TNF-α, IL-2, etc.). This group of drugs, as a franchise, addresses various multiple myeloma therapy lines and patient segments.

[0401] To optimize patient outcomes with ciltacabtagene autoleucel, it is hypothesized that T cell fitness and CAR-T outcomes are influenced by previous exposure to bispecific T cell redirectors. This informs an intervention strategy that may involve therapy sequencing -109- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) (for instance, administering ciltacabtagene autoleucel earlier and / or performing aphaeresis prior to Tec / Tal and suchlike), screening patients for T cell fitness and addressing this prior to aphaeresis, and potentially aiming for synergy through adjuvant / combination therapies as opposed to rudimentary sequential therapies. Still, the sequencing and / or combination of CAR-T and CD3 bispecifics, specifically ciltacabtagene autoleucel, teclistamab, and talquetamab, calls for careful considerations. One of the most crucial aspects to consider is whether treating with one or more of these drugs affects the potential for subsequent treatment with another. To decide an optimal course of action, considerations of safety, efficacy, and timing need to be factored into whether these drugs are treated together or in close succession. This involves seeking ways to enhance efficacy by combining or sequencing these drugs without compromising safety.

[0402] Clinical data, based on the CARTITUDE-1 study, indicates that ciltacabtagene autoleucel patients previously treated with BCMA targeted bispecifics show responses far below expectations. T-cell analyses from these patients exhibit a decreased CD4:CD8 ratio and increase in CD38 expression, potentially indicating a lower level of “fitness”. Preclinical data, too, suggests that exposure to bispecifics may reduce T cell “fitness.” However, preclinical data also suggests that CAR-T can enhance bispecific responses. Thus, it is vital to take a closer look at how prior exposure to bispecific antibodies influences CAR-T cell manufacturing and function. The following section offers an examination of in vitro assessments regarding this interplay, to elucidate the potential effects and thus, enhance therapeutic strategies in multiple myeloma treatment. Example 3: Effect of Prior Exposure of Bispecific Antibodies to CAR-T Cell Manufacturing and Function

[0403] Target cell-mediated T cell bispecific activation influences T cell fitness. As an explanation of this effect, it was hypothesized that extended activation could potentially lead to alterations in T cell fitness within the apheresis material, resulting in sub-optimum CAR-T manufacturing and compromised efficacy. To study this, the effects of prior exposure to T cell redirectors, or bispecific antibodies (BsAbs) on CAR-T manufacturing and functionality were examined through in vitro assessments.

[0404] An experiment was performed to assess the impact of prior exposure to T cell redirectors on the manufacturing and functionality of CAR-T cells. T cells from multiple myeloma patients were exposed to bispecific T cell engagers, either talquetamab or -110- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) teclistamab, for 12 days in vitro. Results depicted in FIG.5 indicate that T cells pre-exposed to bispecifics saw a decrease in CD28+ cells, while also leading to an increase in the proportion of effector memory population. These T cells were subsequently processed through ciltacabtagene autoleucel manufacturing. Results depicted in FIG.6 indicate that such pre-exposure also negatively impacted CAR-T production, reducing the amount of CAR-T drug product that could be manufactured, subsequently decreasing the level of CAR positivity within said drug product. Finally, the resulting CAR-T cells were subjected to functional analysis to evaluate their effectiveness. FIGS.7A-7B depict that CAR-T cells derived from these pre-exposed cells yielded reduced cytotoxicity and cytokine production when compared to control groups.

[0405] Collectively, these results indicate that T cells with prior exposure to teclistamab / talquetamab bispecifics show decreased CD28 expression as well as an enriched fraction of Effector memory cells. This means that teclistamab or talquetamab pretreatment decreases CAR-T manufacturing efficacy. Further, the noted reduction in cytokine production and killing efficacy, as well as the reduced CAR+ expansion indicates that CAR-T made from teclistamab and / or talquetamab pre-treated T cells exhibit decreased functionality. Overall, treatment with bispecifics before ciltacabtagene autoleucel may hinder T cell fitness, reduce CAR-T production, and limit CAR-T functionality. Thus, these results indicate that it may be best to perform apheresis before administering bispecific treatment to achieve optimal CAR-T production and functionality. Example 4 – CARTITUDE-2 Cohort C: T Cell Fitness in Patients with Prior Exposure to BCMA Targeted Therapy

[0406] The CARTITUDE-2 study (MMY2003), specifically with respect to Cohort C, focused on T cell fitness in patients who had previous exposure to BCMA targeted therapy. Patients were monitored for a median duration of 18 months, ranging from 0.6 to 22.7 months. Among these, 13 patients had previously undergone BCMA antibody-drug conjugate (ADC) therapy and seven had undergone bispecific antibody (BsAb) therapy. One patient from the ADC group had prior exposure to BsAb therapy. Approximately 3% of the patients (comprising six individuals) had anti-BCMA therapy as their last line of therapy (LOT), which included four patients from the ADC group and two from the BsAb group.

[0407] Baseline patient characteristics were first assessed: the median age was 62.5 years (range 44-81 years); 15% had high-risk cytogenetics (all del17p); 25% had extramedullary -111- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) disease; patients had previously received a median of 8 LOTs (ranging between 4 and 13); and 90% were diagnosed as anti-BCMA refractory. The median time from the last anti- BCMA treatment to ciltacabtagene autoleucel infusion was 180 days (range, 62-749 days) for ADC-exposed patients and 227 days (range, 84-329 days) for BsAb-exposed patients. The median ciltacabtagene autoleucel dose that was administered was 0.61 x 10^6 CAR viable T cells / kg (range between 0.21 x 10^6 – 0.83 x 10^6). Notably, one patient received a dose below the target level. Patients treated with BCMA ADC and BsAbs demonstrated comparable baseline demographics and disease characteristics.

[0408] The data from MMY2003 (cohort C) was compared against data from patients enrolled in the CARTITUDE-1 (MMY2001) study. The levels of lymphocytes, monocytes, and neutrophils in peripheral blood were found to be comparable between the ADC and BsAb groups, as indicated in the MMY2001 and MMY2003 (Cohort C) studies (FIG.8). Patients with prior BsAb exposure displayed a lower CD4:CD8 ratio at apheresis (FIG.9). These patients also exhibited lower CD4+ T cell count in the peripheral blood, while CD8+ T cell counts remained similar to patients without BsAb exposure (FIG.9). Patients from the MMY2001 study showed similar CD4 and CD8 counts as compared to the ADC group. The observed decrease in CD4+ cells and the CD4:CD8 ratio points toward potentially suboptimal T cell fitness. Patients with prior BsAb exposure had higher levels of circulating natural killer (NK) compared to the ADC and MMY2001 groups, while showing a comparable T cell count (FIG.10). The expression of CD38 in CD4+ / CD8+ T cells was shown to be associated with a decrease in CD4+ T cells in cellular immunity; this expression was found to negatively correlate with treatment-free survival in male chronic lymphocytic leukemia (CLL) patients (FIG.11). These results align with the observed increase in CD38+ T cells following teclistamab treatment (MajesTEC-1 study). See Deeksha et al., ASH 2003. While the ADC group also showed elevated CD38+ T cells, it remains unclear whether this effect is a consequence of BCMA targeting therapies due to a lack of specific reports on the issue. Finally, there was no substantial difference in baseline tumor burden and effector-to- target (E:T) ratio between the ADC and BsAb groups, according to (FIG.12).

[0409] To summarize, patients previously exposed to BsAb exhibited higher levels of NK cells, lower levels of CD4+ T cells, and a lower CD4:CD8 ratio, potentially pointing towards suboptimal T cell fitness. No difference was found in lymphocytes, monocytes, and neutrophils in peripheral blood between patients with prior exposure to targeted ADC vs. BsAb or none of the two before ciltacabtagene autoleucel administration. Furthermore, these -112- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) patients showed similar levels of CD25+, CD28+ T cells, and T cell memory subsets but higher levels of CD38+ T cells compared to those in the ADC group. Comparing ADC and BsAb groups, no significant difference was found in baseline tumor burden (sBCMA) or E:T ratio (Cmax(CAR-T) / sBCMA), and no substantial difference was detected in baseline pro- inflammatory cytokines. Generally, the results, as depicted in FIG.13, demonstrated that the efficacy of ciltacabtagene autoleucel was compromised in patients previously treated with BCMA bispecific antibodies (BsAb), compared to those exposed to BCMA antibody-drug conjugates (ADC) therapies.

[0410] Overall, efficacy of ciltacabtagene autoleucel in patients with prior BCMA BsAb is compromised compared to prior BCMA ADC therapies or no BCMA directed therapy. These results support the preclinical data presented in Example 3 and further suggest that clinical efficacy may be compromised in ciltacabtagene autoleucel patients previously treated with bispecifics. Example 5: Preclinical Data Supporting Combinations of Ciltacabtagene autoleucel with Talquetamab

[0411] Preclinical research was conducted to study the effects of administering teclistamab or talquetamab simultaneously with or after the administration of ciltacabtagene autoleucel, assessing whether their application in this order augments or diminishes the therapeutic efficacy of the individual treatments. Methodologically, the study involved conducting cytotoxicity assays and cytokine profiling on ciltacabtagene autoleucel, both in isolation and in conjunction with teclistamab and talquetamab. The primary aim of these assays was to evaluate the relative efficacy of the different treatment combinations and to ascertain the survival rates of T cells under varying conditions. These approaches aimed to help elucidate the therapeutic viability of the combination, specifically focused on addressing treatment scenarios envisioned in the aMMbition study design, as presented in Example 7, below.

[0412] Suboptimal Quantity of CAR-T can Medicate Enhanced Killing via Bispecific Engagement

[0413] First, an assay was designed to utilize Incucyte-based spheroid formation to provide real-time kinetic data on the cytotoxic effects of CAR-T cell therapy. This assay began on Day 0 with the seeding of Incucyte® NucLight Green H929 cells into uncoated round-bottom wells. During the initial three days, these cells proliferated and coalesced to -113- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) form spheroid structures. On Day 3, bispecific antibodies were introduced into the wells. This was followed by the addition of T cells, which were genetically modified to express CARs, enabling the targeted destruction of the cancer cell spheroids. MOCK cells were used as a comparator and as effectors in the bispecific killing assay; these cells were activated and expanded according to the manufacturing protocol with the exception that lentiviral transduction was not performed.

[0414] Comparisons were then made between untreated spheroids and those treated with the combination of CAR-T cells and bispecific antibodies. FIGS.14A-14B depict the change in relative spheroid size over time following T cell addition, at varying concentrations of talquetamab, with FIG.14A comparing the responses of MOCK cells and FIG.14B comparing the responses of CAR-T cells. FIG.14C depicts an Area Under the Curve (AUC) analysis, depicting the responses of MOCK cells against CAR-T cells over a log-transformed range of bispecific antibody concentrations. The findings indicate a marked difference in the potency of bispecific engagement in the presence of CAR-T cells (EC50 = 0.0014) as compared to MOCK cells (EC50 = 0.050), underscoring an enhanced effect of the bispecific antibodies when used in tandem with CAR-T cells.

[0415] Overall, these results show that even relatively low quantities of CAR-T cells can significantly bolster the killing of cancer cells when combined with bispecific antibodies. Further, coculturing ciltacabtagene autoleucel with teclistamab or talquetamab results in greater in vitro killing capacity, such that maximal killing can be achieved via a combination of doses that provide no monotherapeutic efficacy. This observation implies a synergistic interaction between these therapeutic agents, potentially enabling a greater efficacy of CAR- T cell therapy. Similar results were observed, though not depicted in the figures, with teclistamab.

[0416] Next, experiments were performed to determine the minimum threshold of CAR positivity required for achieving the desired therapeutic effect in CAR-T cell treatments. Flow cytometry was performed to differentiate between various T cell populations: MOCK cells, double positive (DP) T cells expressing both CD4 and CD8, and T cells enriched used biotinylated BCMA and anti-biotin magnetic beads.

[0417] FIG.15A depicts flow cytometry plots, illustrating the proportion of CAR-positive cells in relation to the total T cell population. FIG.15B presents the percentage of CAR- positive cells and the absolute numbers of both T cells and CAR-positive T cells at different dilution levels. Overall, the results indicate that even a diluted presence of CAR-positive T -114- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) cells within a population of non-modified cells can amplify the cytotoxic effect when engaged by bispecific antibodies. This supports the emerging understanding that bispecific antibodies can lower the threshold of CAR-T cells needed to observe a therapeutic effect. FIG.16 depicts the relationship between the log concentration of talquetamab and the AUC, which is indicative of the overall effect of the drug over time. Each curve on the graph corresponds to a different dilution of CAR positive T cells, showing that as the proportion of CAR-positive T cells decreases, the AUC generally decreases, indicating a lesser effect. FIG. 17A compares the half maximal effective concentration (EC50) values for each dilution level of CAR-positive T cells while FIG.17B compares the fold reduction in EC50 for each dilution level. The results indicate that although the magnitude of the cytotoxic effect decreases with lower levels of CAR-positive T cells, even as few as 1% of remaining CAR- positive cells can significantly enhance the killing effect when engaged by talquetamab, further suggesting that talquetamab retain substantial therapeutic efficacy across a range of CAR-T cell concentrations.

[0418] Activation of CAR- Cells in the Tumor Microenvironment

[0419] CAR-T cell therapy has been shown to exert a wider therapeutic impact beyond their direct cytolytic activity by recruiting and activating a diverse array of immune effector cells. Evidence from post-infusion biopsies of diffuse large B cell lymphoma (DLBCL) patients treated with axicabtagene ciloleucel, a CAR-T cell therapy, supports the hypothesis that CAR-T cells, upon engagement with the target antigen on DLBCL cells, can trigger an activation cascade. See JCI Insight, June 18, 5(12), 3134612. Latent T cells recognize the CD19 antigen on DLBCL cells, leading to their transformation into CAR-T cells. Once activated, these CAR-T cells release interferon gamma (IFN-γ). This release activates macrophages and induces activation of non-CAR T cells, which subsequently exhibit markers such as PD1, Ki67, and Granzyme B (GsmB), signaling their readiness to participate in the immune response. In sum, this upregulation implies that CAR-cell cell infusion not only directly targets cancer cells but also broadly primes the immune system, potentially enhancing the overall antitumor response.

[0420] Experiments were conducted to evaluate the activation and proliferation of CAR- negative (CAR-) T cells in the presence of CAR-positive (CAR+) T cells and the impact of talquetamab on the process. FIGS.18A-18B provide an analysis of CD25 Mean Fluorescence Intensity (MFI) on both CD4 and CD8 T cells after 48 hours, in relation to the log concentration of talquetamab. CD25 is a subunit of the IL-2 receptor, and its upregulation is a -115- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) marker of T cell activation. The graphs depict three curves each, representing MOCK cells (T cells without CAR construct), CAR- cells (T cells without the CAR construct in the drug product sample), and CAR+ cells (T cells with the CAR construct in the drug product sample). The MFI levels of CD25 increase with the concentration of talquetamab, indicating heightened T cell activation. FIG.18C depicts T cell expansion over five days, again in relation to the log concentration of talquetamab. These results indicate that the presence of talquetamab facilitates the early activation and expansion of CAR- T cells. This finding is significant as it indicates a bispecific antibody-mediated cross-talk between CAR+ and CAR- T cells, leading to an amplified immune response against the tumor cells. Moreover, while both CAR- and CAR+ cells expand, the presence of the bispecific antibody appears necessary for the expansion of CAR- cells in a dose-dependent manner, suggesting that talquetamab may play a crucial role in the broader activation of the immune system, beyond the direct effects of CAR-T cell therapy.

[0421] Experiments were conducted to determine the effect of bispecific antibodies on the expression of inflammatory cytokines. FIGS.19A-19B depict the concentration of interferon- gamma (IFN-γ), a mediator in the immune response against tumors, against the logarithmic concentration of talquetamab. FIG.19A, representing the 48-hour time point, demonstrates a clear dose-response relationship, with increasing talquetamab levels correlating to a higher expression of IFN-γ, notably more pronounced in the sample containing the CAR-T drug product. At the 120-hour mark, as depicted in FIG.19B, the IFN-γ levels remained elevated in the presence of talquetamab, with the CAR-T drug product continuing to exhibit a higher cytokine expression compared to the MOCK T cells. These results indicate the potential of bispecific antibodies to enhance cytokine responses beyond the levels typically observed with single-agent therapy, suggesting that bispecific antibodies like talquetamab not only engage tumor cells directly but also amplify the release of cytokines, further stimulating the immune system. Additional results not depicted indicate that similar trends were observed with other cytokines, such as IL-2, TNF-α, and IL-13, pointing to a more extensive influence of bispecific antibody treatment on the cytokine environment within the tumor microenvironment.

[0422] There exist two primary pathways by which BCMA CAR-T cells mediate the destruction of cancer cells: 1) directing targeting, or redirected lysis of Tumor-Associated Antigen (TAA) positive target cells and 2) indirect effects, or bystander lysis of TAA- negative cells. See pLoS One.2017; 12(8): e1083390. Concerning the direct targeting -116- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) pathway, CAR-T cells, engineered to target specific Tumor-Associated Antigens (TAA) on the surface of cancer cells, bind to these antigens via their CARs. Upon engagement, the CAR-T cells become activated and release cytotoxic molecules, such as IFN-γ and TNF-α. These molecules induce apoptosis in the target cells. Furthermore, the interaction between the CAR-T cell and the cancer cell upregulates certain molecules on the T cell surface, specifically the Fas ligand, which is involved in the strengthening the cell-to-cell interaction and enhancing the cytotoxic response. CAR-T cells can also indirectly cause the death of neighboring cancer cells that do not express the targeted antigen (TAA-negative). This occurs through the interaction of adhesion molecules, specifically ICAM-1 on the cancer cells and LFA-1 on the T cells, and the Fas / Fas Ligand pathway, which can trigger pseudo-synapse, referring to the formation of an immune synapse-like structure that facilitates cell killing without the TAA being present on the bystander cell.

[0423] In vitro experiments were conducted to study the impact of a suboptimal dose of anti-BCMA CAR-T cells on the expression of cell adhesion molecules and cell death receptors in H929 cells. Incucyte ® NucLight Green H929 cells were plated in an uncoated round-bottom well until they formed into a spheroid structure on Day 3, at which time T cells were added to the culture. FIG.20 depicts expression levels of two specific markers at 24- and 48-hours post T cell addition: the Fas ligand and the CD54 molecule (also known as ICAM-1), an intercellular adhesion molecule. The graphs indicate that both Fas and CD54 expression levels were significantly higher in the presence of CAR-T cells compared to the MOCK and no treatment controls. These results indicate that the presence of CAR-T cells, even at suboptimal doses, leads to the upregulation of markers associated with cell susceptibility to killing and bystander T cell killing. This suggests that suboptimal doses of CAR-T cells can alter the tumor microenvironment in a manner that increases the susceptibility of cancer cells to immune-mediated killing, thereby potentially enhancing the overall efficacy of the therapy.

[0424] Summary

[0425] To summarize, these results indicate that both teclistamab and talquetamab have demonstrated an ability to enhance the cytotoxicity of the CAR-T cell drug product. The level of CAR-positive T cell necessary for effective monotherapy was found to be significantly lower than the threshold required to see notable increase in cytokine levels. This implies that even low concentrations of CAR+ cells can exert a substantial therapeutic impact. No notable adverse or beneficial effects were observed on the number or activation status of CAR- -117- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) positive cells when combined with the bispecific antibodies. Additionally, the presence of CAR-positive cells in the culture environment was shown to increase the vulnerability of tumor cells to killing by CAR-negative cells, suggesting a synergistic interaction. Finally, an increase in the activation of CAR-T cells and the upregulation of cell adhesion molecules like ICAM-1 and death receptors, such as Fas, on target cells were observed. Overall, bispecific antibodies demonstrate a potential to amplify the cytokine response beyond that typically seen with single-agent therapy, indicating that a combination of these agents with CAR-T cells could offer a more dynamic and potent therapeutic approach against multiple myeloma. Overall, these results indicate that bispecifics may synergistically enhance tumor cell killing, outpacing either monotherapy. Combining these modalities in patients with high disease burden and suboptimal drug product attributes could further enhance curative potential. Example 6: Preclinical Data Supporting Combinations of Ciltacabtagene autoleucel with Dara

[0426] The effect of a therapeutic combination of daratumumab and ciltacabtagene autoleucel on multiple myeloma (MM) therapy was investigated. Daratumumab is included in the standard of care (SOC) for MM treatment and is also being considered as a potential bridging and maintenance therapy in conjunction with ciltacabtagene autoleucel. Understanding the interactions between Daratumumab and ciltacabtagene autoleucel is critical for the design of effective treatment strategies.

[0427] To this end, a set of in vitro experiments were employed to evaluate the impact of the daratumumab / ciltacabtagene autoleucel combination on myeloma cells, as well as on chimeric antigen receptor-positive and negative (CAR+ / -) T cells. Flow cytometry was utilized as an analytical technique to discern the effects.

[0428] Three specific objectives formed the basis of this investigation:

[0429] Determination of any synergistic benefit of combining daratumumab with ciltacabtagene autoleucel.

[0430] Assessment of whether daratumumab exerts a direct cytotoxic effect on CAR T- cells.

[0431] Evaluation of the influence of daratumumab on the expansion of CAR+ T cells.

[0432] These objectives aimed to address whether the combination of daratumumab with ciltacabtagene autoleucel could enhance the current SOC for MM and inform the design of novel treatment regimens. -118- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1)

[0433] First, NK cells and T cells were purified from a selected pool of healthy donors. CAR-T cells were then generated through the process of LCAR lentivirus transduction in a controlled laboratory setting.

[0434] Prior to initiation of the assay, the frequencies of CAR expression among T cells from the various donors were equalized to ensure consistency across the experimental conditions. The target myeloma cells were then co-cultured with either CAR-T cells alone or in conjunction with NK cells and daratumumab, which was administered at a concentration of 6.45 nM, equivalent to 1 µg / mL, representing a 320-fold higher dose than EC50. The co- cultures were sustained over durations of 7 or 14 days, with the effector to target cell ratio maintained at 5:0.4:1, correlating to NK cells, CAR+ T cells, and target myeloma cells respectively.

[0435] Flow cytometry was employed to evaluate the cytotoxic impact on myeloma cells and to conduct a detailed phenotypic characterization of both T and NK cells. The Cytokine Bead Array (CBA) method was utilized for an in-depth analysis of the secreted cytokines.

[0436] FIG.21A depicts the effect sizes for the Chimeric Antigen Receptor T (CAR-T) cells and Daratumumab combination, with the direction of the effects and the maximum R p- values being highlighted in a color-coded fashion, utilizing a stratified null model for statistical analysis.

[0437] FIG.21B provides a quantitative assessment of myeloma cell counts over a period of 7 days. It was observed that the combination of CAR-T cells with daratumumab significantly enhanced the clearance of myeloma cells, with a noticeable effect on day 1 and day 2 post-treatment, as compared to the CAR-T cells alone. The myeloma cell counts are indicated by live CD38+CD138+ cells in the culture, with the number of viable myeloma cells decreasing in the presence of the combined therapy. The data underscore the enhanced efficacy of the combination therapy in the early stages of treatment, suggesting a potential for improved therapeutic outcomes in the context of myeloma management.

[0438] Next, CAR+ T cells were subjected to expansion in the presence of daratumumab. The data demonstrate that CAR+ T cells, inclusive of both CD4+ and CD8+ subpopulations, were capable of expansion when treated with daratumumab; however, a lower recovery rate was observed in comparison to the control group without daratumumab.

[0439] FIG.22 depicts bar graphs that compare the proliferation of CAR+CD4+ and CAR+CD8+ T cells over a 7-day period with and without daratumumab treatment. The graphs illustrate that while CAR+CD4+ and CAR+CD8+ T cells exhibited growth under both -119- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) conditions, the presence of Daratumumab was associated with reduced expansion rates of these T cells. Conversely, the CAR-negative CD8+ T cells (CAR-CD8+) experienced an increase in expansion following exposure to Daratumumab. This finding suggests a differential impact of Daratumumab on CAR+ and CAR- T cell subpopulations, with the latter showing a more robust expansion in response to the monoclonal antibody.

[0440] Additional data indicates that the combination of Daratumumab with CAR+ T cells results in a reduction of cells expressing the CD38 marker. Over a 7-day period, both CAR+CD4+CD38+ and CAR+CD8+CD38+ T cell populations were quantified to assess the effect of daratumumab on cell expansion. FIG.23 shows the counts of live CD38+ cells among both CD4+ and CD8+ T cell subsets when cultured alone (denoted as CART) or in combination with daratumumab (denoted as CART+Dara). It is observed that the presence of daratumumab leads to a significant decrease in the expansion of CD38+ expressing CAR+ cells across both T cell subsets. This reduction in cell counts is noted to be specific to the CAR+ cells, as opposed to any reduction in the CAR-negative (CAR-) cells. This reduction is restricted to the cells expressing the CD38 antigen, which is a target of the daratumumab monoclonal antibody. The data suggest that daratumumab selectively impacts the expansion of CD38+ expressing CAR+ cells, potentially due to the antibody's mechanism of action which includes direct antitumor activity and immunomodulatory effects through the depletion of CD38+ immune cells.

[0441] A reduction in exhaustion marker expression on CAR+ T cells was observed upon the addition of daratumumab to a Ciltacabtagene autoleucel (CAR-T) treatment regimen. The interactions between co-stimulatory and inhibitory receptors, which are known to regulate T cell responses, were assessed by measuring the cell counts of exhausted CAR+ T cells across several exhaustion markers.

[0442] Exhaustion markers including PD-1, LAG3, and BTLA were quantified on both CD4+ and CD8+ CAR+ T cell populations over a time course. Bar graphs presented in FIG. 24 display the cell counts of CAR+ / CD4+ and CAR+ / CD8+ T cells expressing each of these exhaustion markers individually, as well as combinations thereof. The counts were measured when the CAR+ T cells were cultured alone (indicated as CART) and in combination with daratumumab (indicated as CART+Dara).

[0443] A reduction in the counts of exhausted cells was observed in the CAR+ populations treated with the combination of daratumumab and ciltacabtagene autoleucel when compared to treatment with CAR-T cells alone. This effect was specific to the CAR+ cells, as no -120- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) change was reported in the CAR- exhausted cells, although the data for the latter were not shown on the slide. This finding indicates that the addition of daratumumab to the ciltacabtagene autoleucel regimen has a modulatory effect on the exhaustion phenotype of CAR+ T cells, which could potentially improve the functional capacity and persistence of CAR-T cells in therapeutic applications.

[0444] The effects of daratumumab treatment on regulatory T cells (Tregs) expressing CD38 within a population of CAR+ cells were next evaluated. The experiment analyzed the frequency of Tregs exhibiting the CD38+ phenotype in the context of CAR+ cells over a period of seven days.

[0445] The data depicted in the box plots as presented in FIG.25 depict the percentage of CAR+ / CD4+ / CD127- / CD25+ / CD38+ Tregs on days 0, 1, 2, 4, and 7, comparing the frequencies between samples treated solely with CAR-T cells (CART) and those treated with a combination of CAR-T cells and daratumumab (CART+Dara). Similarly, the frequencies of CAR- / CD4+ / CD127- / CD25+ / CD38+ Tregs were measured to determine the influence of daratumumab on the non-genetically modified T cell subset within the same time frame. Results showed a reduction in the proportion of CD38+ Tregs in the CAR+ cell population by day 7 when daratumumab was added to the culture. This decrease was not observed in the CAR- T cell population, suggesting that the presence of daratumumab specifically influences the immunosuppressive phenotype within the genetically modified T cell subset. The findings imply that daratumumab, when combined with CAR-T cell therapy, may mitigate the immunosuppressive effects commonly attributed to Tregs in the tumor microenvironment, potentially enhancing the efficacy of CAR-T cell-mediated anti-tumor responses. By day 7, daratumumab treatment results in a decreased frequency of CD38+ Tregs-like phenotype within the CAR+ cell milieu.

[0446] Another experiment assessed whether a reduction in early NK cell counts would affect the cytotoxic activity when used in conjunction with the cilta+dara combination therapy. Additionally, the study evaluated changes in activation markers, particularly CD69, and the expression of exhaustion markers on NK cells. Quantitative analyses were carried out over a specified time course to measure the counts of early, mature, and terminal NK cell populations in samples treated with daratumumab alone and in combination with Ciltacabtagene autoleucel (CART+Dara). The results, as depicted in FIG.26, demonstrated that, although there was a decrease in NK cell counts with increasing exposure to daratumumab, this did not compromise the cytotoxic activity of the remaining cells. The -121- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) capability of the remaining peripheral blood mononuclear cell (PBMC) fraction to mediate Antibody-Dependent Cellular Cytotoxicity (ADCC), a mechanism of action for daratumumab, was retained.

[0447] This experiment provided evidence that the daratumumab and ciltacabtagene autoleucel combination therapy could reduce early NK cell numbers without affecting the cytotoxic potential of the remaining cells. This was accompanied by increased expression of the activation marker CD69 and reduced expression of exhaustion markers, suggesting sustained NK cell functionality despite the reduction in cell numbers.

[0448] Conclusion

[0449] In sum, the results presented in this Example highlight the enhanced cytotoxicity against myeloma cells when ciltacabtagene autoleucel and daratumumab are used in conjunction. It was observed that the concurrent administration of both agents resulted in increased lysis of myeloma cells, indicative of a synergistic effect.

[0450] The results also present an initial decrease in the number of CAR-positive (CAR+) T-cells after treatment with daratumumab, followed by a lower recovery rate of these cells post-treatment. Furthermore, a reduction was reported in the population of CAR T-cells expressing the CD38 marker as well as in the number of immunosuppressive regulatory T cells (Tregs) that express CD38.

[0451] Notably, despite these changes, there was no observed alteration in the activation profile of the remaining T-cells. However, there was a reduction in the exhausted phenotype among the T-cell population, which suggests an improved functional status of T-cells.

[0452] In terms of cytokine production, the study reported a decrease in B-cell stimulating and proinflammatory cytokines, while anti-inflammatory cytokine levels were increased. This alteration in cytokine profile could have implications for the overall inflammatory environment and immune response regulation in the context of CAR T-cell therapy. Example 7: Combination Approach to Evaluate the Safety and Efficacy of Optimal Sequencing of Bispecific Antibody-Daratumumab Combinations and Ciltacabtagene autoleucel Following DVRd Induction

[0453] Treatment for multiple myeloma (MM) has substantially improved over time and varies depending on the aggressiveness of the disease, underlying prognostic factors, physical condition of the patient, and existing co-morbidities, however MM is still an incurable disease. Transplant has been the standard of care for the younger and more fit MM patient, -122- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) but novel therapies now offer the potential for greater survival benefit with improved quality of life. T-cell engaging (TCE) therapeutics directed at novel targets such as BCMA and GPRC5D demonstrate high response rates and durability of responses even in patients with relapsed and refractory MM (RRMM) who have received multiple lines of therapy. Furthermore, TCE therapies offer the potential to reprogram the immune microenvironment in the bone marrow niche to restore immune function. Chimeric antigen receptor T-cell (CAR-T) therapies replace a dysfunctional T-cell compartment with highly activated effector cells designed to recognize a tumor-associated surface target, achieving unprecedented therapeutic outcomes in the RRMM population. Despite the efficacy of these novel agents, there is a lack of knowledge to guide design of optimal combinations of these agents to achieve superior or even curative potential. Developing highly effective treatment strategies combining and sequencing ciltacabtagene autoleucel, teclistamab, talquetamab and daratumumab in the newly diagnosed patient may be able to achieve the curative goal rarely attained with transplant. This addresses a significant and critical unmet need for incorporating novel therapeutic options directed at alternative mechanisms of action that can better control the disease, provide deeper, more sustained responses, and yield better long-term outcomes including maintenance of HRQoL (Usmani 2016).

[0454] With the availability of these novel drugs, cure for the younger and more fit, newly diagnosed, standard risk patients may be an achievable goal. These immunotherapeutic modalities engage and modulate the endogenous immune response to achieve therapeutic benefit (Friedrich 2023; van de Donk 2018). Sequential combinations offer the potential to condition the tumor immune microenvironment for optimal efficacy of a subsequent immune- directed therapeutic agent to attain a synergistic effect capable of translating into a curative combination. Furthermore, cure implies a permanent remission after a fixed duration of therapy not requiring indefinite maintenance treatment.

[0455] This study is designed to assess the safety and tolerability as well as to generate early efficacy data for 2 fixed-duration sequential combinations developed for use in newly diagnosed myeloma participants. This study focuses on the standard-risk population where integration of multiple immune-directed therapies around ciltacabtagene autoleucel should improve upon therapeutic efficacy rates achieved with ciltacabtagene autoleucel alone. Following a standard induction regimen consisting of DVRd, patients will undergo consolidation with one of 2 treatment combinations. Participants in cohort A will receive 4 cycles of Tal-D prior to ciltacabtagene autoleucel infusion to assess whether brief exposure to -123- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) a non-BCMA-targeting TCE can condition a more permissive tumor microenvironment for the subsequent introduction of ciltacabtagene autoleucel. Participants in cohort B will receive a consolidation plan beginning with ciltacabtagene autoleucel infusion and followed by up to 2 years of treatment consisting of brief 1-month pulses of alternating Tal-D and Tec-D with intervening 2-month treatment-free intervals testing the hypothesis that short interval exposure to TCE agents can perpetuate the anti-myeloma activity of ciltacabtagene autoleucel.

[0456] The potential efficacy of these and other current treatment regimens, with life- expectancy approaching 10 years in standard risk myeloma patients, establishes a need for a surrogat...

Claims

Docket No.258199.091802 (JBI6871WOPCT1) What is claimed is:

1. A method of treating multiple myeloma in a subject in need thereof, the method comprising: administering a GPRC5DxCD3 bispecific antibody to the subject, and administering ciltacabtagene autoleucel to the subject; wherein the administration of the GPRC5DxCD3 bispecific antibody occurs before the administration of ciltacabtagene autoleucel.

2. The method of claim 1, wherein the subject has newly diagnosed multiple myeloma based on International Myeloma Working Group (IMWG) diagnostic criteria.

3. The method of claims 1 or 2, wherein the subject has standard-risk multiple myeloma based on revised International Staging System (R-ISS) diagnostic criteria.

4. The method of any preceding claim, wherein the subject is stem cell transplant eligible.

5. The method of any preceding claim, wherein the subject is fit or intermediate-fit based on IMWG Frailty Index assessment.

6. The method of any preceding claim, wherein the GPRC5DxCD3 bispecific antibody comprises a GPRC5D binding domain comprising the HCDR1 of SEQ ID NO: 101, the HCDR2 of SEQ ID NO: 102, the HCDR3 of SEQ ID NO: 103, the LCDR1 of SEQ ID NO: 104, the LCDR2 of SEQ ID NO: 105 and the LCDR3 of SEQ ID NO: 106, and a CD3 binding domain comprising the HCDR1 of SEQ ID NO: 107, the HCDR2 of SEQ ID NO: 108, the HCDR3 of SEQ ID NO: 109, the LCDR1 of SEQ ID NO: 110, the LCDR2 of SEQ ID NO: 111 and the LCDR3 of SEQ ID NO:

112.

7. The method of claim 1 to 6, wherein the GPRC5D binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 113 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 114, and the CD3 -250- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) binding domain comprises a VH having the amino acid sequence of SEQ ID NO: 115 and a VL having the amino acid sequence of SEQ ID NO:

116.

8. The method of any preceding claim, wherein the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in a first heavy chain (HC1) and leucine at position 405 and lysine at position 409 in a second heavy chain (HC2), wherein residue numbering is according to the EU Index.

9. The method of claim 8, wherein the GPRC5DxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234 and alanine at position 235 in both the HC1 and the HC2.

10. The method of claims 1 to 9, wherein the GPRC5DxCD3 bispecific antibody comprises the HC1 having the amino acid sequence of SEQ ID NO: 117, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 118, the HC2 having the amino acid sequence of SEQ ID NO: 119 and a second light chain (LC2) having the amino acid sequence of SEQ ID NO:

120.

11. The method of any preceding claim, wherein the GPRC5DxCD3 bispecific antibody is talquetamab.

12. The method of any one of claims 1 to 11, wherein the administration of the GPRC5DxCD3 bispecific antibody is once every 2 weeks (Q2W) at a dosage of about 0.8 mg / kg.

13. The method of any one of claims 1 to 11, wherein the administration of the GPRC5DxCD3 bispecific antibody is weekly at a dosage of about 0.4 mg / kg.

14. The method of any preceding claim, wherein the GPRC5D x CD3 bispecific antibody is administered subcutaneously.

15. The method of any preceding claim, wherein the subject is further administered an anti-CD38 antibody. -251- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 16. The method of claim 15, wherein the anti-CD38 antibody is administered simultaneously with the administration of the GPRC5DxCD3 bispecific antibody.

17. The method of claim 15, wherein the anti-CD38 antibody is administered sequentially with the administration of the GPRC5DxCD3 bispecific antibody.

18. The method of claim 15, wherein the anti-CD38 antibody is administered about 1 hour before the administration of the GPRC5DxCD3 bispecific antibody.

19. The method of any one of claims 15 to 18, wherein the anti-CD38 antibody is selected from the group consisting of daratumumab, isatuximab, and felzartamab.

20. The method of any one of claims 15 to 19, wherein the anti-CD38 antibody is daratumumab.

21. The method of any one of claims 15 to 20, wherein the administration of the anti- CD38 antibody is 1800 mg per dose.

22. The method of any one of claims 15 to 21, wherein the anti-CD38 antibody is administered subcutaneously.

23. The method of any preceding claim, ciltacabtagene autoleucel is administered to the subject at a dose of about 0.5 to about 1.0 × 106CAR-positive viable T cells / kg 24. The method of claim 23, wherein ciltacabtagene autoleucel is administered to the subject at a dose of about 0.75 × 106CAR-positive viable T cells / kg.

25. The method of any preceding claim, further comprising administering a conditioning regimen to the subject prior to administering ciltacabtagene autoleucel, wherein the conditioning regimen comprises one or more of cyclophosphamide and / or fludarabine. -252- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 26. The method of claim 25, wherein the conditioning regimen comprises cyclophosphamide at a dosage of about 300 mg / m2.

27. The method of claim 25, wherein the conditioning regimen comprises fludarabine at a dosage of about 30 mg / m2.

28. The method of claim 25, wherein the conditioning regimen comprises cyclophosphamide at a dosage of about 300 mg / m2and fludarabine at a dosage of about 30 mg / m2.

29. The method of any one of claims 25 to 28, wherein the conditioning regimen is administered to the subject daily, for up to 3 days.

30. The method of any one of claims 25 to 29, wherein the ciltacabtagene autoleucel is administered to the subject 5 to 7 days after the start of the administration of the conditioning regimen.

31. The method of any preceding claim, further comprising administering an induction therapy to the subject prior to administering the GPRC5DxCD3 bispecific antibody.

32. The method of claim 31, wherein the induction therapy comprises daratumumab, bortezomib, lenalidomide, dexamethasone, or some combination thereof.

33. The method of claim 31 or 32, wherein the induction therapy comprises 4 cycles daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd).

34. The method of claim 33, wherein each cycle of DVRd is about 28 days and comprises about 1800 mg of daratumumab, about 1.3 mg / m2of bortezomib, about 25 mg of lenalidomide, and about 40 mg of dexamethasone.

35. The method of any proceeding claim, wherein the method further comprises the collection of apheresis material from the subject for the manufacturing of ciltacabtagene autoleucel. -253- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 36. The method of claim 35, wherein the collection of apheresis material occurs prior to the administration of the GPRC5DxCD3 antibody.

37. The method of claims 35 or 36, wherein the collection of apheresis material occurs prior to the administration of the induction therapy of claims 31 to 34.

38. The method of any one of claims 15 to 37, wherein the subject is administered 4 cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody.

39. The method of claim 38, wherein each cycle of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody is about 28 days.

40. The method of claim 38 or 39, wherein in the first cycle of the 4 cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody the subject receives three consecutive step-up doses of the GPRC5DxCD3 bispecific antibody of about 0.01 mg / kg, about 0.06 mg / kg, and about 0.4 mg / kg, prior to receiving the 0.8 mg / kg dose once every 2 weeks.

41. The method of claim 40, wherein the three consecutive step-up doses are administered 2, 3, 4, or 5 days apart.

42. The method of any one of claims 38 to 41, wherein the first cycle of the 4 cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody comprises: the administration of a first step-up dose of 0.01 mg / kg of the GPRC5DxCD3 bispecific antibody and the administration of a first 1800 mg dose of the anti-CD38 antibody, the administration of a second step-up dose of 0.06 mg / kg of the GPRC5DxCD3 bispecific antibody 2, 3, 4, or 5 days after the administration of the first step-up dose, the administration of a third step-up dose of 0.4 mg / kg of the GPRC5DxCD3 bispecific antibody 6, 7, 8 or 9 days after the administration of the first step-up dose, and the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody two or more days after the administration of the third step-up dose, and, optionally, about 14 days -254- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) after the administration of the first step-up dose, and the administration of a second 1800 mg dose of the anti-CD38 antibody.

43. The method of claim 42, wherein the second through fourth cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody each comprise the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody and the administration of 1800 mg of the anti-CD38 antibody once every 2 weeks (Q2W).

44. The method of claim 42, where the second cycle of the 4 cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody comprises the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody and the administration of 1800 mg of the anti-CD38 antibody once every 2 weeks (Q2W), and wherein the third and fourth cycles of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody comprises the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody and the administration of 1800 mg of the anti-CD38 antibody once every 4 weeks (Q4W).

45. The method of any proceeding claim, wherein the method achieves a partial response (PR), very good partial response (VGPR), complete response (CR) or stringent complete response (sCR) in the subject, according to IMWG criteria.

46. The method of any proceeding claim, wherein the method achieves a very good partial response (VGPR), complete response (CR) or stringent complete response (sCR) in the subject, according to IMWG criteria.

47. The method of any proceeding claim, wherein the method achieves a complete response (CR) or stringent complete response (sCR) in the subject, according to IMWG criteria.

48. The method of any proceeding claim, wherein the method achieves a stringent complete response (sCR) in the subject, according to IMWG criteria. -255- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 49. The method of any proceeding claims, wherein the method achieves minimal residual disease (MRD) negativity at a threshold of 10-5before disease progression or start of a subsequent antimyeloma therapy.

50. The method of any proceeding claim, wherein the method achieves sustained MRD- negative status, as determined by next generation sequencing (NGS) with sensitivity of 10-5, for at least 6 months without examination showing MRD-positive or progressive disease (PD) in between.

51. A method of treating multiple myeloma in a subject in need thereof, the method comprising: administering ciltacabtagene autoleucel to the subject, administering a GPRC5DxCD3 bispecific antibody to the subject, and administering a BCMAxCD3 bispecific antibody to the subject; wherein the administration of the ciltacabtagene autoleucel occurs before the administration of GPRC5DxCD3 bispecific antibody or the BCMAxCD3 bispecific antibody.

52. The method of claim 51, wherein the subject has wherein the subject has newly diagnosed multiple myeloma based on International Myeloma Working Group (IMWG) diagnostic criteria.

53. The method of claims 51 or 52, wherein the subject has standard-risk multiple myeloma based on revised International Staging System (R-ISS) diagnostic criteria.

54. The method of any one of claims 51 to 53, wherein the subject is stem cell transplant eligible.

55. The method of any one of claims 51 to 54, wherein the subject is fit or intermediate- fit based on IMWG Frailty Index assessment.

56. The method of any one of claims 51 to 55, wherein the GPRC5DxCD3 bispecific antibody comprises a GPRC5D binding domain comprising the HCDR1 of SEQ ID NO: 101, the HCDR2 of SEQ ID NO: 102, the HCDR3 of SEQ ID NO: 103, the LCDR1 of SEQ ID NO: 104, the LCDR2 of SEQ ID NO: 105 and the LCDR3 of SEQ ID NO: 106, and a CD3 -256- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) binding domain comprising the HCDR1 of SEQ ID NO: 107, the HCDR2 of SEQ ID NO: 108, the HCDR3 of SEQ ID NO: 109, the LCDR1 of SEQ ID NO: 110, the LCDR2 of SEQ ID NO: 111 and the LCDR3 of SEQ ID NO:

112.

57. The method of any one of claims 51 to 56, wherein the GPRC5D binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 113 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 114, and the CD3 binding domain comprises a VH having the amino acid sequence of SEQ ID NO: 115 and a VL having the amino acid sequence of SEQ ID NO:

116.

58. The method of any one of claims 51 to 57, wherein the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in a first heavy chain (HC1) and leucine at position 405 and lysine at position 409 in a second heavy chain (HC2), wherein residue numbering is according to the EU Index.

59. The method of claim 58, wherein the GPRC5DxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234 and alanine at position 235 in both the HC1 and the HC2.

60. The method of any one of claims 51 to 59, wherein the GPRC5DxCD3 bispecific antibody comprises the HC1 having the amino acid sequence of SEQ ID NO: 117, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 118, the HC2 having the amino acid sequence of SEQ ID NO: 119 and a second light chain (LC2) having the amino acid sequence of SEQ ID NO:

120.

61. The method of any one of claims 51 to 60, wherein the GPRC5DxCD3 bispecific antibody is talquetamab.

62. The method of any one of claims 51 to 61, wherein the administration of the GPRC5DxCD3 bispecific antibody is once every 2 weeks (Q2W) at a dosage of about 0.8 mg / kg. -257- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 63. The method of any one of claims 51 to 61, wherein the administration of the GPRC5DxCD3 bispecific antibody is weekly at a dosage of about 0.4 mg / kg.

64. The method of any one of claims 51 to 63, wherein the GPRC5D x CD3 bispecific antibody is administered subcutaneously.

65. The method of any one of claims 51 to 64, wherein the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising the HCDR1 of SEQ ID NO: 218, the HCDR2 of SEQ ID NO: 219, the HCDR3 of SEQ ID NO: 220, the LCDR1 of SEQ ID NO: 221, the LCDR2 of SEQ ID NO: 222 and the LCDR3 of SEQ ID NO: 223, and a CD3 binding domain comprising the HCDR1 of SEQ ID NO: 228, the HCDR2 of SEQ ID NO: 229, the HCDR3 of SEQ ID NO: 230, the LCDR1 of SEQ ID NO: 231, the LCDR2 of SEQ ID NO: 232 and the LCDR3 of SEQ ID NO:

233.

66. The method of any one of claims 51 to 65, wherein the BCMA binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 224 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 225, and the CD3 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 234 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO:

235.

67. The method of claim 65 or 66, wherein the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in the HC1 and leucine at position 405 and lysine at position 409 in the HC2, wherein residue numbering is according to the EU Index.

68. The method of claim 67, wherein the BCMAxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234 and alanine at position 235 in both the HC1 and the HC2.

69. The method of any one of claims 51 to 68, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 226, the a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 227, a -258- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 236 and a second light chain (LC2) having the amino acid sequence of SEQ ID NO:

237.

70. The method of any one of claims 51 to 69, wherein the BCMAxCD3 bispecific antibody is teclistamab.

71. The method of any one of claims 51 to 70, wherein the administration of the BCMAxCD3 bispecific antibody is once every 2 weeks (Q2W) at a dosage of about 3.0 mg / kg.

72. The method of any one of claims 51 to 71, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously.

73. The method of any one of claims 51 to 72, wherein the subject is further administered an anti-CD38 antibody.

74. The method of claim 73, wherein the anti-CD38 antibody is administered sequentially with the administration of the GPRC5DxCD3 bispecific antibody.

75. The method of claim 73 or 74, wherein the anti-CD38 antibody is administered about 1 hour before the administration of the GPRC5DxCD3 bispecific antibody.

76. The method of any one of claims 73 to 75, wherein the anti-CD38 antibody is administered sequentially with the administration of the BCMAxCD3 bispecific antibody.

77. The method of any one of claims 73 to 76, wherein the anti-CD38 antibody is administered about 1 hour before the administration of the BCMAxCD3 bispecific antibody.

78. The method of any one of claims 73 to 77, wherein the anti-CD38 antibody is selected from the group consisting of daratumumab, isatuximab, and felzartamab.

79. The method of any one of claims 73 to 78, wherein the anti-CD38 antibody is daratumumab. -259- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 80. The method of any one of claims 73 to 79, wherein the administration of the anti- CD38 antibody is about 1800 mg per dose.

81. The method of any one of claims 73 to 80, wherein the anti-CD38 antibody is administered subcutaneously.

82. The method of any one of claims 51 to 81, ciltacabtagene autoleucel is administered to the subject at a dose of about 0.5 to about 1.0 × 106CAR-positive viable T cells / kg 83. The method of claim 82, wherein ciltacabtagene autoleucel is administered to the subject at a dose of about 0.75 × 106CAR-positive viable T cells / kg.

84. The method of any one of claims 51 to 83, further comprising administering a conditioning regimen to the subject prior to administering ciltacabtagene autoleucel, wherein the conditioning regimen comprises one or more of cyclophosphamide and / or fludarabine.

85. The method of claim 84, wherein the conditioning regimen comprises cyclophosphamide at a dosage of about 300 mg / m2.

86. The method of claim 84, wherein the conditioning regimen comprises fludarabine at a dosage of about 30 mg / m2.

87. The method of claim 84, wherein the conditioning regimen comprises cyclophosphamide at a dosage of about 300 mg / m2and fludarabine at a dosage of about 30 mg / m2.

88. The method of any one of claims 84 to 87, wherein the conditioning regimen is administered to the subject daily, for up to 3 days.

89. The method of any one of claims 84 to 88, wherein the ciltacabtagene autoleucel is administered to the subject 5 to 7 days after the start of the administration of the conditioning regimen. -260- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 90. The method of any one of claims 51 to 89, further comprising administering an induction therapy to the subject prior to administering ciltacabtagene autoleucel.

91. The method of claim 90, wherein the induction therapy comprises daratumumab, bortezomib, lenalidomide, dexamethasone, or some combination thereof.

92. The method of claim 90 or 91, wherein the induction therapy comprises 4 cycles of daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd).

93. The method of claim 92, wherein each cycle of DVRd is about 28 days, and comprises about 1800 mg of daratumumab, about 1.3 mg / m2of bortezomib, about 25 mg of lenalidomide, and about 40 mg of dexamethasone.

94. The method of any one of claims 51 to 93, wherein the method further comprises the collection of apheresis material from the subject for the manufacturing of ciltacabtagene autoleucel.

95. The method of claims 94, wherein the collection of apheresis material occurs prior to the administration of the induction therapy of claims 90 to 93.

96. The method of any one of claims 73 to 95, wherein the subject is administered 4 cycles of antibody treatment, wherein: the first cycle comprises the administration of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody, the second cycle comprises the administration of the BCMAxCD3 bispecific antibody and the anti-CD38 antibody, the third cycle comprises the administration of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody, and the fourth cycle comprises the administration of the BCMAxCD3 bispecific antibody and the anti-CD38 antibody.

97. The method of claim 96, wherein each cycle of the 4 cycles is about 84 days. -261- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 98. The method of claims 96 or 97, wherein the first cycle comprises: the administration of an 1800 mg dose of the anti-CD38 antibody, the administration of a first step-up dose of 0.01 mg / kg of the GPRC5DxCD3 bispecific antibody about 20 hours after the administration of the anti-CD38 antibody, the administration of a second step-up dose of 0.06 mg / kg of the GPRC5DxCD3 bispecific antibody 2, 3, or 4 days after the administration of the anti-CD38 antibody, the administration of a third step-up dose of 0.4 mg / kg of the GPRC5DxCD3 bispecific antibody 7, 8, or 9 days after the administration of the anti-CD38 antibody, and the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody two or more days after the administration of the third step-up dose, and, optionally, about 14 days after the administration of the anti-CD38 antibody.

99. The method of any one of claims 96 to 98, wherein the second cycle comprises: the administration of an 1800 mg dose of the anti-CD38 antibody, the administration of a first step-up dose of 0.06 mg / kg of the BCMAxCD3 bispecific antibody about 20 hours after the administration of the anti-CD38 antibody, the administration of a second step-up dose of 0.3 mg / kg of the BCMAxCD3 bispecific antibody two or more days after the administration of the first step-up dose, the administration of a third step-up dose of 1.5 mg / kg of the BCMAxCD3 bispecific antibody two or more days after the administration of the second step-up dose, and the administration of 3.0 mg / kg of the BCMAxCD3 bispecific antibody two or more days after the administration of the third step-up dose, and, optionally, about 14 days after the administration of the anti-CD38 antibody.

100. The method of any one of claims 96 to 99, wherein the third cycle comprises: the administration of an 1800 mg dose of the anti-CD38 antibody, and the administration of 0.8 mg / kg of the GPRC5DxCD3 bispecific antibody about 1 hour after the administration of the anti-CD38 antibody.

101. The method of any one of claims 96 to 99, wherein the fourth cycle comprises: the administration of an 1800 mg dose of the anti-CD38 antibody, and -262- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) the administration of 3.0 mg / kg of the BCMAxCD3 bispecific antibody about 1 hour after the administration of the anti-CD38 antibody.

102. The method of any one of claims 96 to 101, wherein, after the fourth cycle, the subject is tested for MRD-negative status, and, if the subject is determined to be MRD- positive, the subject is administered an additional 4 cycles of antibody treatment, wherein: the fifth cycle comprises the administration of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody as defined in claim 100, the sixth cycle comprises the administration of the BCMAxCD3 bispecific antibody and the anti-CD38 antibody as defined in claim 101, the seventh cycle comprises the administration of the GPRC5DxCD3 bispecific antibody and the anti-CD38 antibody as defined in claim 100, and the eighth cycle comprises the administration of the BCMAxCD3 bispecific antibody and the anti-CD38 antibody as defined in claim 101.

103. The method of any proceeding claim, wherein the method achieves a partial response (PR), very good partial response (VGPR), complete response (CR) or stringent complete response (sCR) in the subject, according to IMWG criteria.

104. The method of any one of claims 51 to 103, wherein the method achieves a very good partial response (VGPR), complete response (CR) or stringent complete response (sCR) in the subject, according to IMWG criteria.

105. The method of any one of claims 51 to 104, wherein the method achieves a complete response (CR) or stringent complete response (sCR) in the subject, according to IMWG criteria.

106. The method of any one of claims 51 to 105, wherein the method achieves a stringent complete response (sCR) in the subject, according to IMWG criteria.

107. The method of any one of claims 51 to 106, wherein the method achieves minimal residual disease (MRD) negativity at a threshold of 10-5before disease progression or start of a subsequent antimyeloma therapy. -263- 313215418v1Docket No.258199.091802 (JBI6871WOPCT1) 108. The method of any one of claims 51 to 107, wherein the method achieves sustained MRD-negative status, as determined by next generation sequencing (NGS) with sensitivity of 10-5, for at least 6 months without examination showing MRD-positive or progressive disease (PD) in between. -264- 313215418v1

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