Isatuximab in Combination With Novel Agents in RRMM - Master Protocol

Eligibility Criteria

• * Participant must be 18 years of age inclusive or older.
• * Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• * Participants with relapsed or refractory MM who have received at least 2 prior lines of therapy for MM, including PIs and IMiDs (eg, Induction regimen with autologous stem cell transplant followed by maintenance is considered one line).
• * RRMM with measurable disease:
• * Serum M protein ≥0.5 g/dL measured using serum protein immunoelectrophoresis and/or
• * Urine M protein ≥200 mg/24 hours measured using urine protein immunoelectrophoresis and/or
• * Serum free light chain (sFLC) MM without measurable M protein in serum or urine per previous criteria (serum Ig free light chain ≥10 mg/dL and abnormal serum Ig kappa lambda free light chain ratio \<0.26 or \>1.65).
• * Men or woman or childbearing potential should agree to use contraception.
• * Substudy 01, 06: Anti-CD38 therapy naïve or prior exposure to such drugs with a wash out of at least 12 months after the last dose. "Exposure" is defined as at least 2 cycles of therapy.
• * Substudies 02, 03: Anti-CD38 therapy naïve or prior exposure to such drugs without being refractory but with a wash out of at least 6 months after the last dose. "Refractory" is defined as progressing within 60 days of last dose of anti-CD38 targeting therapy.
• * Substudy 04: Anti-CD38 and anti-B cell maturation antigen (BCMA) therapy (if available) prior exposed participants with RRMM. For anti-CD38, "Exposure" is defined as at least 2 cycles of therapy. For anti-BCMA therapy if available, exposure is defined by at least 2 cycles of therapy.
• * Substudy 05: Participants with RRMM with at least 2 cycles of prior exposure to anti-CD38 therapy. For participants to whom BCMA targeted therapy is available (ie, approved in their region and can be reimbursed), at least 2 cycles of prior exposure to a BCMA targeted agent is mandatory.
• * Primary systemic amyloid light chain amyloidosis, plasma cell leukemia, monoclonal gammopathy of undetermined significance, or smoldering myeloma.
• * Uncontrolled infection within 14 days prior to first study intervention administration.
• * Clinically significant cardiac (including valvular) or vascular disease within 3 months prior to first study intervention administration., eg, myocardial infarction, unstable angina, coronary (eg, coronary artery bypass graft, percutaneous coronary intervention) or peripheral artery revascularization, left ventricular ejection fraction \<40%, heart failure New York Heart Association Classes III and IV, stroke, transient ischemic attack, pulmonary embolism, other thromboembolic event, or cardiac arrhythmia (Grade 3 or higher by NCI CTCAE Version 5.0).
• * Known acquired immunodeficiency syndrome-related illness or known human immunodeficiency virus (HIV) disease requiring antiviral treatment or active hepatitis A.
• * Uncontrolled or active hepatitis B virus (HBV) infection.
• * Active hepatitis C virus (HCV) infection.
• * Any of the following within 3 months prior to first study intervention administration: treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease.
• * Second malignancy other than basal cell or squamous cell carcinoma of the skin or in situ carcinoma, unless they are successfully treated with curative intent for more than 3 years before first study intervention administration.
• * Any anti-MM drug treatment within 14 days before first study intervention administration, including dexamethasone.
• * Participants with a contraindication to treatment.
• * Vaccination with a live vaccine 4 weeks before the start of the study.
• * Seasonal flu and COVID-19 vaccines that do not contain live virus are permitted.
• * Hemoglobin \<8 g/dL.
• * Platelets \<50 × 10\^9/L.
• * Absolute neutrophil count \<1.0 × 10\^9/L.
• * Creatinine clearance \<30 mL/min/1.73m2.
• * Total bilirubin \>1.5 × ULN, except for known Gilbert syndrome in which direct bilirubin should be ≤2.5 × ULN.
• * Aspartate aminotransferase and/or alanine aminotransferase \>3 × ULN.
• * Patients with grade 3 or 4 hypercalcemia.
• * History of resected/ablated basal or squamous cell carcinoma (SCC) of the skin or carcinoma in situ of the cervix, or other local tumors, even if considered cured by local treatment.
• * Therapeutic doses of anticoagulants or antiplatelet agents within 7 days prior to the first dose of SAR439459.
• * Prothrombin time or INR \>1.5 × upper limit of normal (ULN).
• * Current corneal epithelial disease except mild punctate keratopathy.
• * Patients who have received prior therapy with belantamab mafodotin.
• * Central nervous system or leptomeningeal disease.
• * Medical history of seizure.
• * Participants currently receiving hepatically metabolized narrow therapeutic index drugs (eg, digoxin, warfarin) if cannot be closely monitored.
• * Active, known, or suspected autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs), except controlled by replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc). The following are not exclusionary: vitiligo, childhood asthma that has resolved, psoriasis that does not require systemic treatment.
• * Prior allogeneic hematopoietic stem cell transplant (allo-HSCT).
• * History of active autoimmune disorders.
• * History of autoimmune hemolytic anemia or autoimmune. thrombocytopenia.
• * Active graft versus host disease (GVHD) or ongoing immunosuppression for GVHD.
• * Prior allogenic hematopoietic stem cell transplant (allo-HSCT).
• * Patient with chronic active EBV infection.
• * Patients with known history of HLH.
• * Hemoglobin \< 9 g/dL.
• * Prior therapy with any anti-CD47 or anti signal regulatory protein alpha agent.