BMS-986453 with Lymphodepletion Chemotherapy for the Treatment of Multiple Myeloma

Inclusion Criteria

• Age > 18 years with no upper age limit
• NDMM with indication for initiation of therapy diagnosed within last 12 months. Pretreatment parameters necessary for disease characterization and response assessment must be available
• Not eligible for autologous stem cell transplantation (ASCT) by institutional criteria or deferring ASCT due to personal preference
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Prior induction therapy including one proteasome inhibitor, lenalidomide, dexamethasone and an anti-CD38 monoclonal antibody in combination for a minimum of 12 and for up to 18 weeks, obtaining at least partial response (PR)
• Measurable disease documented prior to induction therapy meeting at least one of the following criteria: * Serum monoclonal (M) protein ≥ 1.0 g/dl (≥ 0.5 g/dl if IgA, IgD, IgE or IgM multiple myeloma) * ≥ 200 mg of M protein/24h in the urine * Difference between affected and unaffected free light chain ≥ 10 mg/dL with abnormal kappa to lambda ratio. * For participants with immunoglobulin class A (IgA) myeloma whose disease can only be reliably measured by quantitative immunoglobulin measurement: a serum IgA level ≥ 0.5 g/dL is required
• Have trackable clonogenic sequence using ClonoSEQ (Adaptive Biotechnology, Seattle, WA) previously identified from a high disease burden sample obtained as standard of care and enabling MRD testing
• SCREENING: Peripheral blood absolute neutrophil count (ANC) ≥ 1.0 × 10^9/L without growth factor support within 7 days (14 days if given pegfilgrastim)
• SCREENING: Hemoglobin ≥ 8 g/dL without red blood cell (RBC) transfusion within 21 days
• SCREENING: Platelet count ≥ 50 × 10^9/L without platelet transfusion within 7 days of screening
• PRE-TREATMENT (LYMPHODEPLETION) EVALUATION: Peripheral blood ANC ≥ 0.5 × 10^9/L prior to lymphodepletion (LD) chemotherapy. Growth factors and transfusions may be administered for participants who do not meet the minimum ANC count requirements at the Pre-treatment evaluation
• PRE-TREATMENT (LYMPHODEPLETION) EVALUATION: Hemoglobin ≥ 8 g/dL prior to LD chemotherapy. Growth factors and transfusions may be administered for participants who do not meet the minimum hemoglobin count requirements at the Pre-treatment evaluation
• PRE-TREATMENT (LYMPHODEPLETION) EVALUATION: Platelets ≥ 50 × 10^9 L prior to LD chemotherapy. Growth factors and transfusions may be administered for participants who do not meet the minimum platelet count requirements at the Pre-treatment evaluation
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.5 × upper limit of normal (ULN)
• Creatinine clearance (CrCl), measured in 24-hour urine collection or calculated from serum creatinine using the Cockcroft-Gault equation at screening and pre-treatment evaluation (PTE) ≥ 40 mL/minute without the support of IV hydration within 3 days of renal function assessment
• Total bilirubin ≤ 2.0 × upper limit of normal (ULN), except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤ 1.5 × ULN is required)
• Serum calcium corrected for albumin ≤ 14 mg/dL (≤ 3.5 mmol/L) or free ionized calcium ≤ 6.5 mg/dL (≤ 1.6 mmol/L)
• International normalized ratio (INR) or partial thromboplastin time (PTT) ≤ 1.5 × ULN
• Adequate pulmonary function, defined as Common Terminology Criteria for Adverse Events (CTCAE) grade ≤ 1 dyspnea and saturated oxygen (SaO2) ≥ 92% measured by pulse oximetry on room air
• Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 45% as assessed by echocardiogram (ECHO) or multi- gated acquisition (MUGA) scan performed within 8 weeks prior to screening
• Currently has central vascular access, is a candidate to receive central vascular access, or has adequate peripheral vascular access for leukapheresis procedure
• Recovered to grade ≤ 1 or baseline of any non-hematologic toxicities due to previous therapy, except alopecia (any grade acceptable) and peripheral neuropathy (grade ≤ 2 acceptable)
• Achievement of at least partial response (PR) to induction therapy, without prior progression of disease
• Reproductive Status: * BMS-986453 has not been studied in pregnant participants. BMS-986453 is a novel, experimental product and the effects on the human fetus are unknown. BMS-986453 should not be administered to pregnant persons. * The investigator or designee shall counsel individuals of childbearing potential (IOCBP) participants, and male participants who are sexually active with IOCBP, on the importance of pregnancy prevention, the implications of an unexpected pregnancy, and the potential of fetal toxicity occurring due to transmission of study intervention, present in seminal fluid, to a developing fetus, even if the participant has undergone a successful vasectomy or if the partner is pregnant. * The investigator or designee shall evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. * Local laws and regulations may require the use of alternative and/or additional contraception methods
• Female (as assigned at birth) Participants: * IOCBP must have documented proof that they are not of childbearing potential are exempt from contraceptive requirements; or * IOCBP must have a negative highly sensitive urine or serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) at screening and within 48 hours prior to the start of LD chemotherapy (pre-treatment evaluation). * Note: If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. * The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to potentially decrease the risk for inclusion of an individual with an undetected pregnancy. * IOCBP and male (assigned at birth) participants who are sexually active with IOCBP must agree to follow instructions for method(s) of contraception as described below and included in the informed consent form (ICF). * IOCBP are permitted to use hormonal contraception methods. * A female (assigned at birth) participant is eligible to participate if they are not pregnant or breastfeeding, and agrees to the following: ** Use a contraceptive method that is highly effective (with a failure rate of < 1% per year), preferably with user independent methods, during the intervention period and for at least 12 months following LD chemotherapy and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same period. There are no exposure data to provide any recommendation concerning the duration of contraception following treatment with BMS-986453. Any decision regarding contraception after BMS-986453 infusion should be discussed with the treating physician. ** Abstain from breastfeeding during study participation and through at least 1 year following LD chemotherapy, whichever is later. There are no exposure data to provide any recommendation concerning the total duration of abstaining from breastfeeding following treatment with BMS-986453. Any decision regarding breastfeeding after BMS-986453 infusion should be discussed with the treating physician. ** Refrain from organ/tissue/blood and egg cell donation while participating in the study and through at least 1 year following LD chemotherapy, whichever is later, and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same period. There are no exposure data to provide any recommendation concerning the duration of refraining from organ/tissue/blood and egg cell donation following treatment with BMS-986453. Any decision regarding organ/tissue/blood and egg cell donation after BMS-986453 infusion should be discussed with the treating physician
• Male (as assigned at birth) Participants: * Azoospermic males are not exempt from contraceptive requirements and will be required to always use a latex or other synthetic condom during any sexual activity (eg, vaginal, anal, oral) with IOCBP, even if the participant has undergone a successful vasectomy or if the partner is pregnant. * Male (as assigned at birth) participants must agree to remain abstinent from sexual activity or will be required to always use a latex or other synthetic condom during any sexual activity with IOCBP, even if the participant has undergone a successful vasectomy or if the partner is pregnant or breastfeeding. Participants should continue to use a condom during the intervention period and for at least 12 months following treatment with LD chemotherapy. There are no exposure data to provide any recommendation concerning the duration of contraception following treatment with BMS-986453. Any decision regarding contraception after BMS-986453 infusion should be discussed with the treating physician. * IOCBP partners of male (as assigned at birth) participants should be advised to use a highly effective method of contraception during the intervention period and for at least 12 months following LD chemotherapy for the participant. There are no exposure data to provide any recommendation concerning the duration of contraception following treatment with BMS-986453. Any decision regarding contraception after BMS-986453 infusion should be discussed with the treating physician. * Male (as assigned at birth) participants with a pregnant or breastfeeding partner must agree to remain abstinent from sexual activity or use a male condom during any sexual activity even if the participant has undergone a successful vasectomy, during the intervention period and for at least 12 months following LD chemotherapy. Breastfeeding partners of male participants should be advised to consult their health care provider about using appropriate highly effective contraception during the time the participant is required to use condoms. There are no exposure data to provide any recommendation concerning the duration of contraception following treatment with BMS-986453. Any decision regarding contraception after BMS-986453 infusion should be discussed with the treating physician. * Male (as assigned at birth) participants must refrain from donating sperm or any other tissue/blood/organ donation during the intervention period and for at least 12 months following LD chemotherapy. There are no exposure data to provide any recommendation concerning the duration of refraining from tissue/sperm/blood/organ donation following treatment with BMS-986453. Any decision regarding tissue/sperm/blood/organ donation after BMS-986453 infusion should be discussed with the treating physician
• Must be willing and able to adhere to the lifestyle restrictions specified in this protocol
• Participants must have signed and dated an Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)- approved written ICF in accordance with regulatory, local, and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal patient care

Exclusion Criteria

• Known active or history of central nervous system (CNS) involvement of multiple myeloma (MM)
• Active or history of plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome, or clinically significant amyloidosis
• Active autoimmune disease requiring systemic immunosuppressive therapy ≤ 4 weeks prior to BMS-986453 infusion
• Prior history of malignancies, other than MM, unless the participant has been free of the disease for ≥ 2 years, except for the following non-invasive malignancies: * Basal or squamous cell carcinoma of the skin. * Carcinoma in situ of the cervix or breast. * Incidental histologic finding of carcinoma in situ of the prostate or prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that has undergone curative therapy. * Other completely resected Stage 1 solid tumor with low risk for recurrence. Maintenance hormonal therapies are allowed in participants with a history of breast or prostate cancer. * No prior myelodysplastic syndrome
• Uncontrolled or active systemic fungal, bacterial, viral, or other infection despite appropriate anti-infective treatment at the time of leukapheresis or LD chemotherapy
• Active hepatitis B, hepatitis C, or any evidence of human immunodeficiency virus (HIV) infection
• Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection: mild or asymptomatic infection: within 10 days prior to leukapheresis or LD chemotherapy. Severe/critical illness: within 20 days prior to leukapheresis or LD chemotherapy. * Note: Acute symptoms must have been resolved and, based on investigator and sponsor assessment, there are no sequelae that would place the participant at a higher risk of receiving study treatment
• History of any one of the following cardiovascular conditions within 6 months prior to screening: Class III or IV heart failure as defined by the New York Heart Association, myocardial infarction, unstable angina, angioplasty or stenting, or other clinically significant cardiac disease
• History or presence of clinically significant central nervous system (CNS) pathology such as seizure disorder, aphasia, stroke, severe brain injury, dementia, Parkinson’s disease, or cerebellar disease, or presence of clinically active psychosis
• Deep vein thrombosis or pulmonary embolism (non-infusion line-associated) within 3 months prior to leukapheresis
• History of grade ≥ 2 hemorrhage within 30 days of screening
• Participants who are nursing or breastfeeding. * Participants who are pregnant. * Participants who intend to become pregnant during participation in the study
• Received prior treatment for MM with the following therapies, within the specified period: * Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 14 days before leukapheresis and ≥ 72 hours before LD chemotherapy. Physiologic replacement, topical, intranasal, and inhaled steroids are permitted. * Immunosuppressive therapies within 4 weeks before leukapheresis (eg, calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate, rapamycin, immunosuppressive antibodies such as anti-tumor necrosis factor [TNF], antiinterleukin 6 [IL6], or anti-IL6R). * Plasmapheresis within 14 days before leukapheresis. * Radiation that includes a large bone marrow field such as the pelvis or sternum within 14 days before leukapheresis. * Any anti-BCMA or GPRC5D directed therapy * Gene-modified adoptive cell therapy (e.g., chimeric antigen receptor modified T cells, natural killer [NK] cells) * Cytotoxic therapy within 14 days
• Received any vaccines against infectious disease: * Live vaccine: within 8 weeks prior to BMS-986453 infusion. * Approved or authorized SARS-CoV-2 vaccine: within 14 days prior to leukapheresis or initiation of lymphodepleting chemotherapy. * Note: For vaccines requiring more than one dose, the full series (eg, both doses of a two-dose series) should be completed by at least 14 days prior to leukapheresis when feasible and when a delay in leukapheresis would not put the study participant at risk
• Inability to comply with restrictions and prohibited treatments
• History of hypersensitivity to fludarabine, cyclophosphamide, tocilizumab, or known components of BMS-986453
• Prisoners or participants who are involuntarily incarcerated. * Note: Under certain specific circumstances and only in countries where local regulations permit, a person who has been imprisoned may be included or permitted to continue as a participant. Strict conditions apply
• Any uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as judged by the Investigator, or unwillingness or inability to follow the procedures required in the protocol
• Any condition, including the presence of laboratory test result abnormalities, that places the participant at unacceptable risk if they were to participate in the study
• Any condition that confounds the ability to interpret data from the study
• Participant currently in other interventional trial, including SARS-CoV-2 non-vaccine trials. If previously in another interventional trial, the participant may not have leukapheresis until the washout period of the investigational agent is ≥ 28 days or 5 half-lives, whichever is shorter (minimum 14 days)