A Study of Talquetamab for People with Multiple Myeloma Who Have Received BCMA CAR T-Cell Therapy

Inclusion Criteria:

• Patient with multiple myeloma who has received prior treatment with an IMID, PI, anda CD38 monoclonal antibody

• Received treatment with an FDA approved BCMA CART cell therapy ide-cel within 1-3months prior to enrollment

• Serum monoclonal protein < 0.5 gm/dL; 24-hour urine monoclonal protein < 200 mg; andserum involved free light chains < 10 mg/dL

• No evidence of disease progression based on IMWG criteria

• ≥18 years of age at the time of signing informed consent.

• ECOG performance status of 0 or 1

• Recovered to Grade 1 or baseline of any non-hematologic toxicities due to priortreatments, excluding Grade 2 neuropathy and Grade 2 alopecia.

• No evidence of ongoing, any grade cytokine release syndrome or immune effector cellmediated neurotoxicity

• No additional myeloma therapies after the CART cell therapy

• Absolute neutrophil count (ANC) ≥ 1,000/mm^3 without growth factor support for 7days for G-CSF or GM-CSF and for 14 days for pegylated GCSF prior to the laboratorytest.

• Platelet count ≥ 75,000/mm^3 (without platelet transfusion or thrombopoietinreceptor agonist use in the previous 7 before the laboratory test). Platelets ≥ 50,000/mm^3 is acceptable if the counts prior lymphodepleting chemotherapy for thepreceding CAR T cell therapy was < 75,000.

• Hemoglobin ≥ 8 g/dL (without red blood cell transfusion support or erythropoietinuse within 7 days of the laboratory test).

• Creatinine Clearance (CrCl)/estimated glomerular filtration rate (eGFR) ≥ 30 mL/min,measured by 24 hour urine assessment or estimated by CKD-EPI2021.

• Oxygen saturation ≥ 92% on room air

• Hepatic Function:

• Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5x upper limit of normal (ULN)

• Serum total bilirubin ≤ 2 x ULN; except in participants with congenitalbilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤1.5 xULN is required).

• International ratio (INR) or partial thromboplastin time (PTT) < 1.5 x ULN

• Cardiac Function: left ventricular ejection fraction ≥ 45% by echocardiogram (ECHO)or multigated acquisition scan (MUGA).

• Willing and able to adhere to the study visit schedule and other protocolrequirements

• Female patients of childbearing potential (FCBP) must:

• Have a negative highly-sensitive serum β-human chorionic gonadotropin (β-hCG)pregnancy test (<5 IU/mL) at screening and a negative urine or serum pregnancytest within 24 hours before the first dose of study drug.

• Practicing a highly effective, preferably user-independent method ofcontraception (failure rate of <1% per year when used consistently andcorrectly) and agrees to remain on a highly effective method while receivingstudy drug and until 100 days after last dose.

• Agree to pregnancy testing (serum or urine) within 100 days after the laststudy drug administration.

• Agree to use an additional contraceptive method in addition to the requirementslisted above

• Agree not to donate eggs (ova, oocytes) for the purposes of assistedreproduction during the study and for at least 100 days after the last dose ofstudy drug.

• Agree to abstain from breastfeeding from screening through at least 6 monthsafter the last dose of talquetamab

• Male patients must:

• Agree to wear a condom when engaging in any activity that allows for passage ofejaculate to another person, during the study and for 100 days after the lastdose of study drug. Male subjects should also be advised of the benefit for afemale partner to use a highly effective method of contraception as a condommay break or leak.

• Men must agree not to donate sperm for the purpose of reproduction during thestudy and for at least 100 days after receiving the last dose of study drug.

• Must sign an ICF (or their legally acceptable representative must sign) indicatingthat the participant understands the purpose of, and procedures required for, thestudy and is willing to participate in the study.

Exclusion Criteria:

• Prior or concurrent exposure to any of the following in the specified time frameprior to enrollment:

• Received any prior GRPRC5D-directed therapy

• T-cell redirection therapy (for example, antibody therapy or BiTE's) within 3months

• Investigational vaccine other than SARS CoV-2 vaccine approved/ in use underemergency approval within 4 weeks

• Live, attenuated vaccine within 4 weeks.

• Monoclonal antibody therapy within 21 days (with the exception of COVIDmonoclonal antibodies)

• Cytotoxic therapy within 21 days

• PI therapy within 14 days

• IMiD agent therapy within 14 days

• Radiotherapy within 14 days or focal radiation within 7 days

• Major surgery (as defined by the investigator) within 14 days

• Plasmapheresis within 14 days

• Received either of the following:

• An allogeneic SCT within 6 months before the first dose of study treatment.Participants who received an allogeneic transplant must be off allimmunosuppressive medications during the 6 weeks before the start of studytreatment administration without signs of graft-versus-host disease.

• An autologous SCT within 12 weeks before the start of study treatmentadministration

• A maximum cumulative dose of corticosteroids of ≥ 140 mg of prednisone or equivalentwithin 14-day period before the first dose of study drug (does not includepretreatment medications).

• Prior organ transplant requiring systemic immunosuppressive therapy

• History of ≥ Grade 2 hemorrhage within 30 days of enrollment

• Patient requiring ongoing treatment with chronic, therapeutic dosing ofanticoagulants (e.g., Warfarin, low molecular weight heparin, Factor Xa inhibitors)can be enrolled with approval of the PI.

• History or presence of clinically relevant CNS pathology such as epilepsy, seizure,paresis, aphasia, stroke, subarachnoid hemorrhage or other CNS bleed, severe braininjuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome,or psychosis. Additionally, any patients with meningeal or CNS involvement of MMwill be excluded.

• Having concurrent Waldenstrom's macroglobulinemia, POEMS (polyneuropathy,organomegaly, endocrinopathy, monoclonal protein, and skin changes), active plasmacell leukemia, or clinically significant amyloidosis

• History of Class III or IV congestive heart failure (CHF) or severe nonischemiccardiomyopathy, unstable or poorly controlled angina, myocardial infarction, orhemodynamically significant ventricular arrhythmia within the previous 6 monthsprior to enrollment

• Active clinically significant autoimmune disease, defined as a history of requiringsystemic immunosuppressive therapy and at ongoing risk for potential diseaseexacerbation. Patients with a history of autoimmune thyroid disease, asthma, orlimited skin manifestations are potentially eligible. Patients with a history ofacute or chronic GVHD are potentially eligible if on minimal immunosuppressants asdefined previously.

• Seropositive for human immunodeficiency virus (HIV-1). Acute hepatitis A.Seropositive for hepatitis B (defined by a positive test for hepatitis B surfaceantigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAgnegative with antibodies to total hepatitis B core antigen [Anti-HBc] with orwithout the presence of hepatitis B surface antibodies [Anti-HBs]) must be screenedusing real-time polymerase chain reaction (PCR) measurement of HBVDNA levels. Thosewho are PCR positive will be excluded. EXCEPTION: Subjects with serologic findingssuggestive of HBV vaccination (Anti-HBs positivity as the only serologic marker) ANDa known history of prior HBV vaccination, do not need to be tested for HBV DNA byPCR. Active hepatitis C infection as measured by positive hepatitis C virus (HCV)-RNA testing. Subjects with a history of Hepatitis C virus antibody positivitymust undergo HCV-RNA testing

• Prior malignancies except resected basal cell carcinoma or treated carcinoma insitu. Cancer treated with curative intent less than 5 years prior to enrollment willnot be allowed unless approved by the PI. Cancer treated with curative intentgreater than 5 years prior to enrollment is allowed.

• Myelodysplastic syndrome or active malignancies (ie, progressing or requiringtreatment change in the last 24 months) other than relapsed/refractory multiplemyeloma. The only allowed exceptions are:

• Non-muscle invasive bladder cancer treated within the last 24 months that isconsidered completely cured

• Skin cancer (non-melanoma or melanoma) treated within the last 24 months thatis considered completely cured.

• Noninvasive cervical cancer treated within the last 24 months that isconsidered completely cured

• Localized prostate cancer (N0M0):

• With a Gleason score of ≤6, treated within the last 24 months, or untreated andunder surveillance

• With a Gleason score of 3+4 that has been treated >6 months prior to full studyscreening and considered to have a very low risk of recurrence

• History of localized prostate cancer and receiving androgen deprivation therapyand considered to have a very low risk of recurrence.

• Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinomain situ, or history of localized breast cancer and receiving antihormonalagents and considered to have a very low risk of recurrence

• Other malignancy that is considered cured with minimal risk of recurrence.

• Female patients who are breastfeeding or who intend to become pregnant duringparticipation in the study or until 100 days after the last dose of therapy.

• Participant plans to father a child while enrolled in this study or within 100 daysafter the last dose of study treatment.

• Known allergy or hypersensitivity to any of the study medications, their analogues,or excipients in the various formulations of any agent.

• Serious medical of psychiatric illness likely to interfere with participation onthis clinical study

• Uncontrolled bacterial, viral or fungal infections (currently taking medication andwith progression or no clinical improvement) at time of enrollment.

• Acute diffuse infiltrative pulmonary disease requiring home oxygen therapy

• Unwilling or unable to provide informed consent

• Unable or unwilling to return to the center for treatment and follow up