Mass General - Division of Clinical Research

Subjects must satisfy the following criteria to be enrolled in the study: 1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF) 2. For Cohorts 1 and 2 only, participant has 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 and abnormal serum immunoglobulin kappa lambda free light chain ratio 3. Subjects with one of the following cohort specific requirements: Cohort 1 RRMM subjects with ≥ 3 prior anti-myeloma treatment regimens: - Subject must have received at least 3 prior anti-myeloma treatment regimens. Note: induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen - Subject must have undergone at least 2 consecutive cycles of treatment for each regimen, unless PD was the best response to the regimen - Subject must have received prior treatment with a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody - Subject has evidence of PD on or within 60 days of the most recent prior treatment regimen - Subject achieved a response (minimal response [MR] or better) to at least 1 prior treatment regimen Cohort 2 subjects with 1 prior anti-myeloma treatment regimen: - Subject must have received only 1 prior anti-myeloma treatment regimen. Note: induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen - Subject must have the following HR factors: - Early relapse defined as: Cohort 2a: PD < 18 months since date of start of initial therapy. Initial therapy must contain induction, ASCT (single or tandem) and lenalidomide containing maintenance. Cohort 2b: PD < 18 months since date of start or initial therapy which must contain at minimum, a proteasome inhibitor, an immunomodulatory agent and dexamethasone Cohort 2c: Subject must have received minimum 3 cycles of induction therapy which must contain at minimum, a proteasome inhibitor, an immunomodulatory agent and dexamethasone. Subjects must have had ASCT (single or tandem AND < VGPR (excluding PD) at first assessment between 70 to 110 days after last ASCT, with initial therapy without consolidation and maintenance. Cohort 3 participants with newly diagnosed MM (NDMM) who received only induction and ASCT, without subsequent consolidation or maintenance Cohort 3 - Must have received 4 to 6 cycles of induction therapy which must contain at minimum, a proteasome inhibitor and an immunomodulatory agent and must have had single ASCT within 6 months prior to consent - Must have achieved documented PR or VGPR at first post-ASCT assessment approximately 100 days after ASCT and this response must be maintained at screening - Per Investigator's assessment, subject must be a candidate for single-agent lenalidomide maintenance 4. Subject must have Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 5. Subject must have recovery to Grade 1 or baseline of any non-hematologic toxicities due to prior treatments, excluding alopecia and Grade 2 neuropathy

The presence of any of the following will exclude a subject from enrollment: 1. Subject used any investigational agents within 14 days prior to leukapheresis or, for Cohort 3, within 14 days prior to consent 2. Subject received any of the following within the last 14 days prior to leukapheresis or, for Cohort 3, within 14 days prior to consent: 1. Plasmapheresis 2. Major surgery (as defined by the investigator) 3. Radiation therapy other than local therapy for myeloma associated bone lesions 4. Use of any systemic anti-myeloma drug therapy 3. Subject with known central nervous system involvement with myeloma 4. Subject has clinical evidence of pulmonary leukostasis and disseminated intravascular coagulation 5. History or presence of clinically relevant central nervous system (CNS) pathology 6. Subject with active or history of plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome, or clinically significant amyloidosis 7. Inadequate organ function Subject 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 8. Ongoing treatment with chronic immunosuppressants 9. 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 10. Subject has received ASCT within 12 weeks prior to leukapheresis 11. Subject has history of primary immunodeficiency 12. Subject is positive for human immunodeficiency virus (HIV-1), chronic or active hepatitis B or active hepatitis A or C 13. Subject has uncontrolled systemic fungal, bacterial, viral or other infection (including tuberculosis) despite appropriate antibiotics or other treatment 14. Subject with prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years 15. Pregnant or lactating women 16. Subject with known hypersensitivity to any component of bb2121 product, cyclophosphamide, fludarabine, and/or tocilizumab 17. Prior history of deep venous thrombosis (DVT) or pulmonary embolus (PE) within 6 months prior to consent (For Cohort 3) 18. For Cohort 1b, previous treatment with any G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D) targeted therapy or T-cell engagers 19. For Cohort 1b, known allergies, hypersensitivity, or intolerance to talquetamab or its excipients