Inclusion Criteria:

• Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
• Subject must understand and voluntarily sign an ICF prior to any study-related assessments and procedures being conducted.
• Subject is willing and able to adhere to the study visit schedule and other protocol requirements within this protocol and subject agrees to continued follow-up for up to 15 years as mandated by the regulatory guidelines for gene therapy trials.
• Subject has documented diagnosis of MM and measurable disease, defined as:
  • M-protein (serum protein electrophoresis [sPEP] or urine protein electrophoresis [uPEP]): sPEP ≥ 0.5 g/dL or uPEP ≥ 200 mg/24 hours and/or
  • Light chain MM without measurable disease in the serum or urine: Serum immunoglobulin free light chain ≥ 10 mg/dL (100 mg/L) and abnormal serum immunoglobulin kappa lambda free light chain ratio
• Subject has received:
  • at least 3 prior MM regimens for Arm A Cohort 1 and Arm B;
  • at least 1 but no greater than 3 prior MM regimens for Arm A Cohort 2 and Arm C;
  • induction with or without hematopoietic stem cell transplant and with or without consolidation therapy and with or without maintenance therapy is considered as one regimen.

Arm A Cohort 1 and Arm B

• Subject has received prior treatment with an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody-containing regimen for at least 2 consecutive cycles.

Arm A Cohort 2 and Arm C

• Subject has received prior treatment with an immunomodulatory agent for at least 2 consecutive cycles.
• Evidence of PD during or within 6 months (measured from the last dose of any drug within the regimen) of completing treatment with the last antimyeloma regimen before study entry.
• Subject achieved a response (minimal response [MR] or better) to at least 1 prior treatment regimen.
• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Recovery to Grade 1 or baseline of any non-hematologic toxicities due to prior treatments, excluding alopecia and Grade 2 peripheral neuropathy.
• Adequate vascular access for leukapheresis.
• Females of childbearing potential (FCBP)1 must:
  • Have negative pregnancy test(s) as verified by the Investigator. This applies even if the subject practices true abstinence2 from heterosexual contact:
• All subjects who receive LD chemotherapy/bb2121:
  • One negative β-subunit of human chorionic gonadotropin(β-hCG) pregnancy test result at screening, one negative serum or urine pregnancy test within 3 days prior to LD chemotherapy. She must then agree to pregnancy testing conducted at D25, M4 and M13 after LD chemotherapy/bb2121 infusion.

Treatment of Arm A (for subjects who receive CC-220):

• Females of childbearing potential with regular or no menstrual cycle: two negative pregnancy tests prior to starting study treatment, as applicable. She must then agree to weekly pregnancy testing for the first 28 days after 1st dose of treatment and then every 28 days until at least 90 days after last dose of treatment.
• Females of childbearing potential with irregular menstrual cycles: two negative pregnancy tests prior to starting study treatment, as applicable. She must then agree to weekly pregnancy testing for the first 28 days after 1st dose of treatment and then every 28 days until at least 90 days after last dose of treatment.

Treatment Arm B (for subjects who receive BMS-986405 [JSMD194]):

• Females of childbearing potential with regular/irregular or no menstrual cycle: two negative pregnancy tests prior to starting study treatment, as applicable. She must then agree to monthly pregnancy testing until at least 90 days after last dose of treatment.

Treatment Arm C (for subjects who receive DARA, BTZ, POM or dexamethasone):

• Females of childbearing potential with regular or no menstrual cycle: Two negative pregnancy tests prior to starting study treatment, as applicable. She must then agree to weekly pregnancy testing for the first 28 days after 1st dose of treatment and then every 28 days (21 days for PVd arm) until at least 90 days after last dose of treatment.
• Females of childbearing potential with irregular menstrual cycles: Two negative pregnancy tests prior to starting treatment, as applicable. She must then agree to weekly pregnancy testing for the first 28 days after 1st dose of treatment and then every 28 days until at least 90 days after last dose of treatment
• Either practice true abstinence2 from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, effective measures of contraception without interruption. Contraception methods must include 1 highly effective and 1 additional effective (barrier) method of contraception used simultaneously from screening, during study treatment until:
  • All subjects receiving LD chemotherapy/bb2121: until at least 1 year following lymphodepleting chemotherapy. There are insufficient exposure data to provide any recommendation concerning the duration of contraception following treatment with bb2121. Any decision regarding contraception after bb2121 infusion should be discussed with the treating physician.

Treatment of Arm A or Arm B (for subjects who receive CC-220 or BMS-986405 [JSMD194]) until at least 90 days after last dose of treatment:

• Treatment Arm C subjects who receive DARA, BTZ, POM, or dexamethasone until at least 90 days after last dose of treatment.
  • Note: Highly effective methods are defined as those that result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly.
• The following are examples of highly effective and additional effective methods of contraception:
  • Intrauterine device (IUD);
  • Hormonal (birth control pill, injections, implants);
  • Bilateral tubal ligation;
  • Successful vasectomy;
  • Male condom (additional effective method);
  • Diaphragm (additional effective method);
  • Cervical cap (additional effective method).
• Agree to abstain from breastfeeding during study participation:
  • All subjects who receive LD chemotherapy/bb2121 until at least 1 year following lymphodepleting chemotherapy. There are insufficient exposure data to provide any recommendation concerning the total duration of abstaining from breastfeeding following treatment with bb2121. Any decision regarding breastfeeding after bb2121 infusion should be discussed with the treating physician;
• Treatment of Arm A or Arm B (for subjects who receive CC-220 or BMS-986405 [JSMD194]): until at least 90 days after last dose of treatment;
• Treatment Arm C subjects who receive DARA, BTZ, POM, or dexamethasone until at least 90 days after last dose of treatment.
• Refrain from tissue donation including egg cell donation or any other tissue/blood/organ donations:
  • All subjects who receive LD Chemotherapy/bb2121: Refrain from tissue donation including egg donation or any other tissue/blood/organ donations until at least 1 year following LD chemotherapy. There are insufficient exposure data to provide any recommendation concerning the duration of refraining from tissue donation following treatment with bb2121. Any decision regarding tissue donation after bb2121 infusion should be discussed with the treating physician;
• Treatment of Arm A or Arm B (for subjects who receive CC-220 or BMS-986405 [JSMD194]): until at least 90 days after last dose of treatment.
• Treatment Arm C subjects who receive DARA, BTZ, POM, or dexamethasone until at least 90 days after last dose of treatment.
• Male subjects must:
  • Practice true abstinence* or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions, even if he has undergone a successful vasectomy until:
    • All subjects who receive LD chemotherapy/bb2121: until at least 1 year following lymphodepleting chemotherapy, even if he has undergone a successful vasectomy. There are insufficient exposure data to provide any recommendation concerning the duration of contraception following treatment with bb2121. Any decision regarding contraception after bb2121 infusion should be discussed with the treating physician;
• Treatment of Arm A or Arm B (for subjects who receive CC-220 or BMS-986405 [JSMD194]): until at least 90 days after last dose of treatment, even if he has undergone a successful vasectomy;
• Treatment Arm C subjects who receive DARA, BTZ, POM, or dexamethasone until at least 90 days after last dose of treatment, even if he has undergone a successful vasectomy.
• Tissue donation including sperm or any other tissue/blood/organ donations:
• All subjects who receive LD chemotherapy/bb2121: Refrain from tissue donation including sperm or any other tissue/blood/organ donation until at least 1 year following LD chemotherapy. There are insufficient exposure data to provide any recommendation concerning the duration of refraining from tissue donation following treatment with bb2121. Any decision regarding tissue donation after bb2121 infusion should be discussed with the treating physician;
• Treatment of Arm A or Arm B (for subjects who receive CC-220 or BMS-986405 [JSMD194]): until at least 90 days after last dose of treatment;
• Treatment Arm C subjects who receive DARA, BTZ, POM, or dexamethasone until at least 90 days after last dose of treatment.

Exclusion Criteria:

• Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent participation to the study.
• Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
• Subject has any condition that confounds the ability to interpret data from the study.
• Subject has non-secretory MM or has history of or active plasma cell leukemia, Waldenstrom’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis.
• Subject has clinical evidence of pulmonary leukostasis and disseminated intravascular coagulation.
• Subject has any of the following laboratory abnormalities:
  • Treatment A Subcohorts 1a, 2a & 2adex
  • ANC < 1.0 x 10^9 /L
  • Platelets < 75 x 10^9 /L;
  • Treatment A Subcohorts 1a, 2a & 2adex;
  • ANC < 1.0 x 10^9 /L
  • Platelets < 75 x 10^9 /L;
  • Treatment B
  • ANC < 1.5 x 1^09 /L;
  • Platelets < 100 x 10^9 /L;
  • Treatment C
  • ANC < 1.0 x 10^9 /L;
  • Platelets < 75 x 10^9 /L;
  • Without growth factor support within 7 days (14 days if given pegfilgrastim) of screening;
  • Platelet transfusion is not permitted within 7 days of screening;
  • Hemoglobin < 8 g/dL (< 4.9 mmol/L) (transfusion is not permitted within 21 days of screening);
  • Creatinine clearance (CrCl) as reported below;
  • Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L);
  • Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × Upper limit of normal (ULN);
  • Serum total bilirubin > 1.5 × ULN or > 3.0 mg/dL for subjects with documented Gilbert’s syndrome;
  • International normalized ratio (INR) or activated partial thromboplastin time (aPTT) 1.5 × ULN, or history of Grade ≥ 2 hemorrhage within 30 days, or subject requires ongoing treatment with chronic, therapeutic dosing of anticoagulants (e.g., warfarin, low molecular weight heparin, Factor Xa inhibitors).
• Subject has inadequate pulmonary function defined as oxygen saturation (SaO2) < 92% on room air.
• Subject has known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) 50% of predicted normal.
• Note that forced expiratory testing (FEV1) is required for subjects suspected of having COPD and subjects must be excluded if FEV1 is < 50% of predicted normal.
• Subject has prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years with the exception of the following non-invasive malignancies:
  • Basal cell carcinoma of the skin;
  • Squamous cell carcinoma of the skin;
  • Carcinoma in situ of the cervix;
  • Carcinoma in situ of the breast;
  • Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system) or prostate cancer that can be treated with curative intent.
• Subject with known central nervous system (CNS) involvement with myeloma.
• Subject has a history or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, subarachnoid hemorrhage or other CNS bleed, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.
• Prior exposure to CC-220 (± low-dose dexamethasone) as part of their most recent antimyeloma treatment regimen (Arm A).
• Prior exposure to, BMS-986405 (JSMD194) (Arm B).
• Prior exposure to DARA in combination with POM with or without dexamethasone (DP± d) as part of their most recent antimyeloma treatment regimen (Arm C Cohort 1).
• Prior exposure to POM in combination with BTZ with or without dexamethasone (PV± d as part of their most recent antimyeloma treatment regimen (Arm C Cohort 2).
• Previous history of an allogeneic hematopoietic stem cell transplantation, treatment with any gene therapy-based therapeutic for cancer, investigational cellular therapy for cancer or BCMA targeted therapy.
• Treatment Arm A Cohort 1 and Arm B: subject has received autologous stem cell transplantation (ASCT) within 12 weeks prior to leukapheresis.
• Treatment Arms A Cohort 2 and Arm C: subject has received autologous stem cell transplantation (ASCT) within 12 months prior to leukapheresis.
• Subject has received any of the following within the last 14 days prior to leukapheresis:
  • Plasmapheresis;
  • Major surgery (as defined by the Investigator);
  • Radiation therapy other than local therapy for myeloma-associated bone lesions;
  • Use of any investigational agents and systemic antimyeloma drug therapy.
• Echocardiogram (ECHO) or multigated acquisition (MUGA) with left ventricular ejection fraction (LVEF) < 45% and for subjects in Treatment Arm A an electrocardiogram (ECG) with corrected QT interval (QTc) of > 470 milliseconds at Screening.
• Ongoing treatment with chronic immunosuppressants (eg, cyclosporine or systemic steroids at any dose). Intermittent topical, inhaled or intranasal corticosteroids are allowed.
• Subject is positive for human immunodeficiency virus (HIV), chronic or active hepatitis B or active hepatitis A or C.
• Subject has systemic and uncontrolled fungal, bacterial, viral or other infection:
  • Uncontrolled defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antimicrobial treatment) or requiring IV antimicrobials for management.
• Subject with a history of clinically significant cardiovascular disease within the past 6 months of signing the ICF: Class III or IV heart failure as defined by the New York Heart Association (NYHA), severe nonischemic cardiomyopathy, myocardial infarction, unstable or poorly controlled angina, uncontrolled severe hypertension, severe uncontrolled cardiac arrhythmias (Grade 3 or higher) or other clinically significant cardiac disease.
• Documented hypersensitivity to bb2121 combinatorial therapies and therapies intended to be part of bridging chemotherapy. This includes rash ≥ Grade 3 during prior thalidomide, POM or lenalidomide therapy.
• Subject with known hypersensitivity to any component of bb2121 product, cyclophosphamide, fludarabine, and/or tocilizumab or hypersensitivity to the excipients contained in the formulation of CC-220, BMS-986405 (JSMD194), DARA, BTZ, POM, or dexamethasone.
• Subject has taken a strong inhibitor or inducer of cytochrome (CYP)3A4/5 including grapefruit, St. John’s Wort or related products within two weeks prior to dosing and during the course of study (Arm A only).
• Subject is unable or unwilling to undergo protocol required thromboembolism prophylaxis (all Arm A and Arm C).
• Subjects with peripheral neuropathy ≥ Grade 2 within 14 days prior to Leukapheresis (all Arm A and Arm C).
• Subject is a female who is pregnant, nursing, or breastfeeding, or who intends to become pregnant during the participation in the study.

Eligibility last updated 8/19/21. Questions regarding updates should be directed to the study team contact.