Inclusion Criteria:

Eligibility is determined prior to leukapheresis. Subjects must satisfy the following criteria to be enrolled in the study:

• Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
• Documented diagnosis of multiple myeloma:
  • Must have received at least 3 prior MM treatment regimens:
    • Note: induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen.
  • Must have undergone at least 2 consecutive cycles of treatment for each regimen, unless PD was the best response to the regimen;
  • Must have received a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody;
  • Must be refractory to the last treatment regimen. Refractory is defined as documented progressive disease during or within 60 days (measured from the last dose) of completing treatment with the last anti-myeloma drug regimen before study entry.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Subjects must have measurable disease, including at least one of the criteria below:
  • Serum M-protein greater or equal to 1.0 g/dL;
  • Urine M-protein greater or equal to 200 mg/24 h;
  • Serum free light chain (FLC) assay: involved FLC level greater or equal to 10 mg/dL (100 mg/L) provided serum FLC ratio is abnormal.
• Recovery to Grade 1 or baseline of any non-hematologic toxicities due to prior treatments, excluding alopecia and Grade 2 neuropathy.
• Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
• Subject is willing and able to adhere to the study visit schedule and other protocol requirements within this protocol as well as agrees to continued follow-up for up to 15 years as mandated by the regulatory guidelines for gene therapy trials.
• Females of childbearing potential (FCBP*) must:
  • Have a negative pregnancy test as verified by the Investigator, one negative serum beta human chorionic gonadotropin [β-hCG] pregnancy test result at screening, prior to LD chemotherapy. This applies even if the subject  practices true abstinence** from heterosexual contact;
  • Either commit to true abstinence** from heterosexual contact or agree to use, and be able to comply with, effective measures of contraception without interruption, from screening through at least 1 year following last bb2121 infusion.  Contraception methods must include 1 highly effective and 1 additional effective (barrier) method of contraception from screening until at least 12 months following bb2121 infusion and until CAR T cells are no longer present by qPCR on two consecutive tests;
  • Agree to abstain from breastfeeding during study participation and for at least 1-year post-bb2121 infusion and until CAR T cells are no longer present by qPCR on two consecutive tests.
• 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 for at least 1-year post bb2121 infusion, even if he has undergone a successful vasectomy. Subjects will be followed from screening until at least 1 year following last bb2121 infusion and until CAR T cells are no longer present by qPCR on two consecutive tests.
    • 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;
    • Hormonal (birth control pill, injections, implants);
    • Tubal ligation;
    • Partner's vasectomy;
    • Male condom (additional effective method);
    • Diaphragm (additional effective method);
    • Cervical cap (additional effective method).
• * A female of childbearing potential is a female who:
  • Has achieved menarche at some point;
  • Has not undergone a hysterectomy or bilateral oophorectomy; or 
  • Has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
• ** True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

• Subjects with known central nervous system involvement with myeloma.
• History or presence of clinically relevant central nervous system (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.
  • Note: this criterion does not apply to subjects undergoing retreatment unless Grade 4 neurotoxicity was observed following prior treatment with bb2121.
• Subjects with active or history of plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or clinically significant amyloidosis.
• Subjects with solitary plasmacytomas or non-secretory myeloma without other evidence of measurable disease.
• Inadequate hepatic function defined by AST and/or ALT > 2.5 × upper limit of normal (ULN) and total bilirubin > 1.5 × ULN (unless due to Gilbert’s syndrome and direct bilirubin is ≤1.5 x ULN).
• Inadequate renal function defined by CrCl ≤45 ml/min using Cockcroft-Gault equation.
• International ratio (INR) or partial thromboplastin time (PTT) > 1.5 × ULN, or history of Grade ≥ hemorrhage within 30 days, or subject requires ongoing treatment with chronic, therapeutic dosing of anti-coagulants (eg, warfarin, low molecular weight heparin, or Factor Xa inhibitors).
• Inadequate bone marrow function defined by absolute neutrophil count (ANC) < 1000 cells/mm3 in the absence of growth factor support (filgrastim within 7 days or pegfilgrastim within 14 days of screening) and platelet count < 50,000 mm3 in the absence of transfusion support (platelet transfusion within 7 days of screening).
• Echocardiogram or MUGA with left ventricular ejection fraction < 45%.
• Inadequate pulmonary function as defined as oxygen saturation (Sa02) < 92 % on room air.
• Ongoing treatment with chronic immunosuppressants (eg, cyclosporine or systemic steroids at any dose). Intermittent topical, inhaled or intranasal corticosteroids are allowed.
• Previous history of an allogeneic hematopoietic stem cell transplantation or treatment with any gene therapy-based therapeutic for cancer or investigational cellular therapy for cancer or BCMA targeted therapy.
• Evidence of human immunodeficiency virus (HIV) infection.
• Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV):
  • Subjects who are hepatitis B surface antigen (HBsAg) negative and HBV viral DNA negative are eligible;
  • Subjects who had hepatitis B but have received an antiviral treatment and show non-detectable viral DNA for 6 months are eligible;
  • Subjects who are seropositive because of hepatitis B virus vaccine are eligible;
  • Subjects with known HBV infection should have undetectable HBV viral load and be maintained on anti-viral therapy to prevent HBV reactivation.
• Seropositive for and with active viral infection with hepatitis C virus (HCV):
  • Subjects who had hepatitis C but have received an antiviral treatment and show no detectable HCV viral RNA for 6 months are eligible.
• Subjects with a history of class III or IV congestive heart failure (CHF) or severe nonischemic cardiomyopathy, unstable or poorly controlled angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months prior to starting study treatment.
• Subjects with second malignancies in addition to myeloma if the second malignancy has required therapy in the last 3 years or is not in complete remission; exceptions to this criterion include successfully treated non-metastatic basal cell or squamous cell skin carcinoma, carcinoma in situ of the cervix, carcinoma in situ of the breast, or incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor nodes, metastasis clinical staging system]) or prostate cancer that is curative.
• Subjects who are pregnant, or who intend to become pregnant during participation in the study.
• Subject with known hypersensitivity to any component of bb2121 product, cyclophosphamide, fludarabine or tocilizumab.
• Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in 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. This includes systemic fungal, bacterial, viral, or other infection that is 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 has any condition that confounds the ability to interpret data from the study.