A Study of Whether Ide-cel (bb2121) Can Be Made From People With Multiple Myeloma Who Have Had a Hematopoietic Cell Transplant

Inclusion Criteria:

Cohort 1:

• Patient with myeloma who has received at least four prior lines of treatment havingbeen exposed to an IMID, PI, and a CD38 monoclonal antibody and had measurabledisease prior to salvage high dose melphalan autoHCT done within the prior 2 - 6months. (Salvage melphalan/AutoHCT can count as the 4th line of treatment).

• Measurable disease is defined by any of the following:

• M-spike ≥ 0.5mg/dL

• Urine m-spike ≥ 200mg/dL/24 hours

• Involved Serum Free light chain ≥ 10mg/dL

• Measurable plasmacytoma on imaging (≥ 1 lesion that has a single diameter ≥ 2cm).

• Bone marrow plasma cells ≥ 30% as determined by CD138 immunohistochemistrystaining

Cohort 2:

• Patients with pathologically confirmed MM who have received at least 4 prior linesof treatment having been exposed to an IMID, PI, and a CD38 monoclonal antibody andhave undergone an allo HCT for RRMM at any time in their history and have at leastminimal residual disease by flow or NGS in the bone marrow at least 3 months afterallo HCT.

• Prior to Leukapheresis:

• Greater than age 18.

• Karnofsky performance ≥ 70.

• Recovered to Grade 1 or baseline of any non-hematologic toxicities due to priortreatments, excluding Grade 2 neuropathy

• Not receive any systemic anti-myeloma therapy for 14 days prior toleukapheresis. Therapeutic doses of corticosteroids (defined as greater than 10mg/day prednisone or equivalent) are permitted until within 72 hours prior toLeukapheresis.

• Absolute neutrophil count (ANC) ≥ 1,000/mm^3 without filgrastim use in theprior 14 days.

• Hemoglobin ≥ 8 g/dL (without red blood cell transfusion in the previous 7 days)

• Creatinine Clearance (CrCl) ≥ 45 mL/min, measured or estimated byCockcroft-Gault equation.

• Corrected serum calcium ≤ 13.5 mg/dL

• Oxygen saturation ≥ 92% on room air

• Hepatic Function:

• Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5x upper limit of normal (ULN

• Serum total bilirubin Serum total bilirubin ≤ 2 x ULN. Patients who have beendiagnosed with Gilbert's disease are permitted to exceed the defined bilirubinvalue of 2 x ULN 2 x ULN. Patients who have been diagnosed with Gilbert'sdisease are permitted to exceed the defined bilirubin value of 2 x ULN

• International ratio (INR) or partial thromboplastin time (PTT) ≤ 1.5 x ULN

• Cardiac Function: left ventricular ejection fraction ≥ 45% by echocardiogram (ECHO) or multigated acquisition scan (MUGA).

• Willing and able to adhere to the study visit schedule and other protocolrequirements including regulatory requirement of a 15 year follow up using theCIBMTR long term follow up mechanism.

• Female patients of childbearing potential (FCBP) must:

• Have a negative serum pregnancy test with a sensitivity of at least 50 mIU/mLprior to enrollment

• Agree to use, and be able to comply with, TWO acceptable methods of birthcontrol, one highly effective method and one additional effective (barrier)method AT THE SAME TIME, from screening through at least 1 year followingIde-Cel infusion

• Agree to abstain from breastfeeding from screening through at least 1 yearfollowing Ide-Cel infusion

• Male patients must:

• Agree to use a condom during sexual contact with a pregnant female or a FCBP,even if he has undergone a successful vasectomy, from screening through atleast 1 year following Ide-Cel infusion

• Must not donate sperm from screening through at least 1 year following Ide-Celinfusion

• Prior to LD Chemotherapy

• Females of childbearing potential must have a negative serum pregnancy test ≤ 7days prior to LD chemotherapy

• Platelet count ≥ 50,000/mm^3 (transfusion allowed)

• ANC ≥ 1,000/mm^3 (without filgrastim within 72 hours)

• Hepatic Function:

• Serum AST and ALT ≤ 2.5 × ULN

• Serum total bilirubin ≤ 2 × ULN. Patients who have been diagnosed withGilbert's disease are permitted to exceed the defined bilirubin value of 2 xULN

• CrCl ≥ 45 mL/min, measured or estimated by Cockcroft-Gault equation

• INR or PTT ≤ 1.5 x ULN

• No history of ≥ Grade 2 hemorrhage within 30 days

• No presence of active/uncontrolled infection requiring systemic therapy.Prophylactic antimicrobials are allowed.

• No intercurrent illness or toxicity that would place the subject at undue risk ofproceeding to LD chemotherapy

• Must not be taking therapeutic doses of corticosteroids (defined as greater than 10mg/day prednisone or equivalent) within 72 hours prior to LD chemotherapy.Physiologic replacement, topical, intranasal and inhaled steroids are permitted.Patients on calcineurin inhibitors (cyclosporine or tacrolimus) should have levelsconsidered undetectable per institutional criteria

• No active urinary outflow obstruction

• Availability of manufactured cells

• Patients not meeting these criteria may still be eligible to initiate LDchemotherapy with the approval of the Protocol PI (Principal Investigator).

• Prior to Ide-Cel or Cilta-Cel infusion

• Subjects who meet at least one of the following criteria on the day of scheduled CART cell infusion should have its administration delayed:

• Suspected or active systemic infection

• Onset of fever ≥ 38°C

• Requirement for supplemental oxygen to keep saturation greater than 91%

• Cardiac arrhythmia not controlled with medical management

• Hypotension requiring vasopressor support

• New onset or worsening of other non-hematologic organ dysfunction ≥ Grade 3

• Taking any of the prohibited medications as described in Section 15

• Significant worsening in clinical status compared to initial eligibilitycriteria that would, in the opinion of the treating physician, increase therisk of adverse events associated with Ide-Cel or Cilta-Cel infusion.

Exclusion Criteria:

• Receiving any of the following less than 14 days prior to enrollment:

• Plasmapheresis

• Major surgery (as defined by the investigator)

• Radiation therapy other than local therapy for MM-associated bone lesions

• Prior organ transplant requiring systemic immunosuppressive therapy

• History of ≥ Grade 2 hemorrhage within 30 days of enrollment

• Patient requiring ongoing treatment with chronic, therapeutic dosing ofanticoagulants (e.g., Warfarin, low molecular weight heparin, Factor Xa inhibitors)can be enrolled with approval of the PI.

• History or presence of clinically relevant CNS pathology such as epilepsy, seizure,paresis, aphasia, stroke, subarachnoid hemorrhage or other CNS bleed, severe braininjuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome,or psychosis

• Having concurrent Waldenstrom's macroglobulinemia, POEMS (polyneuropathy,organomegaly, endocrinopathy, monoclonal protein, and skin changes), or clinicallysignificant amyloidosis

• History of Class III or IV congestive heart failure (CHF) or severe nonischemiccardiomyopathy, unstable or poorly controlled angina, myocardial infarction, orhemodynamically significant ventricular arrhythmia within the previous 6 monthsprior to enrollment

• Active clinically significant autoimmune disease, defined as a history of requiringsystemic immunosuppressive therapy and at ongoing risk for potential diseaseexacerbation. Patients with a history of autoimmune thyroid disease, asthma, orlimited skin manifestations are potentially eligible. Patients with a history ofacute or chronic GVHD are potentially eligible if on minimal immunosuppressants asdefined previously.

• Seropositive for human immunodeficiency virus (HIV-1), chronic or active hepatitis Bor C, or acute hepatitis A. If any history of exposure to hepatitis B or C, then DNAPCR should be negative. If hepatitis B core Ab positive with negative DNA PCR,patients should be on prophylaxis while on study.

• Prior malignancies except resected basal cell carcinoma or treated carcinoma insitu. Cancer treated with curative intent less than 5 years prior to enrollment willnot be allowed unless approved by the PI. Cancer treated with curative intentgreater than 5 years prior to enrollment is allowed.

• Female patients who are breastfeeding or who intend to become pregnant duringparticipation in the study.

• Known allergy or hypersensitivity to any of the study medications, their analogues,or excipients in the various formulations of any agent.

• Serious medical of psychiatric illness likely to interfere with participation onthis clinical study

• Uncontrolled bacterial, viral or fungal infections (currently taking medication andwith progression or no clinical improvement) at time of enrollment.

• Unwilling or unable to provide informed consent

• Unable or unwilling to return to the center for treatment and follow up

• No systemic anti-myeloma therapy is allowed within 7 days prior to leukapheresis.Steroids are allowed, but should be tapered off by 72 hours prior to leukapheresis.

• Steroids are allowed between leukapheresis and LD chemotherapy, but should betapered off by 72 hours prior to lymphodepletion.