Inclusion Criteria:
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. Subject must understand and voluntarily sign an ICF prior to any study-related
assessments/procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other protocol
requirements within this protocol and for a subject randomized to Treatment Arm A,
subject agrees to continued follow-up for up to 15 years as mandated by the regulatory
guidelines for gene therapy trials.
4. 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
5. Subject has received at least 2 but no greater than 4 prior MM regimens.
6. Subject has received prior treatment with DARA, a proteasome inhibitor- and an
immunomodulatory compound-containing regimen for at least 2 consecutive cycles.
7. Subject 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 any drug within the regimen) of completing treatment with the last anti-myeloma
regimen before study entry.
8. Subject achieved a response (minimal response [MR] or better) to at least 1 prior
treatment regimen.
9. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
10. Recovery to Grade 1 or baseline of any non-hematologic toxicities due to prior
treatments, excluding alopecia and Grade 2 peripheral neuropathy.
11. Adequate vascular access for leukapheresis
12. Females of childbearing potential (FCBP) must:
a. Have negative pregnancy test(s) as verified by the Investigator. This applies even
if the subject practices true abstinence from heterosexual contact.
b. Either practice true abstinence from heterosexual contact or agree to use, and be
able to comply with, effective measures of contraception without interruption.
c. Agree to abstain from breastfeeding during study participation. d. Refrain from
tissue donation including egg cell donation or any other tissue/blood/organ donations.
13. Male subjects must:
a. 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.
b. Refrain from tissue donation including sperm or any other tissue/blood/organ
donations.
14. Only subjects that would be considered for any of the 5 proposed standard regimens
(DPd, DVd, IRd, Kd, or EPd), as judged by the investigator, should be included in the
study.
Exclusion Criteria:
The presence of any of the following will exclude a subject from enrollment:
1. Subject has any significant medical condition, laboratory abnormality, or psychiatric
illness that would prevent the subject from participating in the study.
2. 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.
3. Subject has any condition that confounds the ability to interpret data from the study.
4. Subject has nonsecretory multiple myeloma (MM).
5. Subject has any of the following laboratory abnormalities:
a. Absolute neutrophil count (ANC) < 1,000/μL b. Platelet count: < 75,000/μL in
subjects in whom < 50% of bone marrow nucleated cells are plasma cells and platelet
count < 50,000/μL in subjects in whom ≥ 50% of bone marrow nucleated cells are plasma
cells (it is not permissible to transfuse a subject to reach this level) c. Hemoglobin
< 8 g/dL (< 4.9 mmol/L) (it is not permissible to transfuse a subject to reach this
level) d. Serum creatinine clearance (CrCl) < 45 mL/min e. Corrected serum calcium >
13.5 mg/dL (> 3.4 mmol/L) f. Serum aspartate aminotransferase (AST) or alanine
aminotransferase (ALT) > 2.5 × upper limit of normal (ULN) g. Serum total bilirubin >
1.5 × ULN or > 3.0 mg/dL for subjects with documented Gilbert's syndrome h.
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 (eg, warfarin,
low molecular weight heparin, Factor Xa inhibitors)
6. Subject has inadequate pulmonary function defined as oxygen saturation (SaO2) < 92% on
room air.
7. Subject has prior history of malignancies, other than MM, unless the subject has been
free of the disease for ≥ 5 years • 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
8. Subject has active or history of plasma cell leukemia, Waldenstrom's
macroglobulinemia, POEMS syndrome or amyloidosis.
9. Subject with known central nervous system (CNS) involvement with myeloma.
10. Subject has clinical evidence of pulmonary leukostasis and disseminated intravascular
coagulation.
11. Subject has known chronic obstructive pulmonary disease (COPD) with a forced
expiratory volume in 1 second (FEV1) 50% of predicted normal.
12. 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.
13. Subject was treated with DARA in combination with POM with or without dex (DP±d) as
part of their most recent anti-myeloma treatment regimen, cannot receive DPd as
bridging therapy but may receive DVd, IRd, Kd or EPdas bridging as per Investigator's
discretion if randomized to Treatment Arm A.
14. Subject was treated with DP±d as part of their most recent anti-myeloma treatment
regimen, cannot receive DPd if randomized to Treatment Arm B but may receive DVd, IRd,
Kd, or EPd as per Investigator's discretion.
15. Subject was treated with DARA in combination with BTZ with or without dexamethasone
(DV±d) as part of their most recent anti-myeloma treatment regimen, cannot receive DVd
as bridging therapy but may receive DPd, IRd, Kd, or EPd as bridging as per
Investigator's discretion if randomized to Treatment Arm A.
16. Subject was treated with DV±d as part of their most recent anti-myeloma treatment
regimen, cannot receive DVd if randomized to Treatment Arm B but may receive DPd, IRd,
Kd, or EPd as per Investigator's discretion.
17. Subject was treated with IXA in combination with LEN with or without dexamethasone
(IR±d) as part of their most recent anti-myeloma treatment regimen, cannot receive IRd
as bridging therapy but may receive DPd, DVd, Kd, or EPd as bridging as per
Investigator's discretion if randomized to Treatment Arm A.
18. Subject was treated with IR±d as part of their most recent anti-myeloma treatment
regimen, cannot receive IRd if randomized to Treatment Arm B but may receive DPd, DVd,
Kd, or EPd as per Investigator's discretion.
19. 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.
20. Subject has received autologous stem cell transplantation (ASCT) within 12 weeks prior
to randomization.
21. Subject has received any of the following within the last 14 days prior to
randomization:
a. Plasmapheresis b. Major surgery (as defined by the Investigator) c. Radiation
therapy other than local therapy for myeloma-associated bone lesions d. Use of any
investigational agents and systemic anti-myeloma drug therapy
22. Echocardiogram (ECHO) or multigated acquisition (MUGA) with left ventricular ejection
fraction (LVEF) < 45%.
23. Ongoing treatment with chronic immunosuppressants (eg, cyclosporine or systemic
steroids at any dose). Intermittent topical, inhaled or intranasal corticosteroids are
allowed.
24. Subject is positive for human immunodeficiency virus (HIV-1 and HIV-2), chronic or
active hepatitis B or active hepatitis A or C.
25. Subject has uncontrolled systemic fungal, bacterial, viral or other infection (defined
as exhibiting ongoing signs/symptoms related to the infection and without improvement,
despite appropriate antimicrobial treatment) or requiring IV antimicrobials for
management.
26. Subject has 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
randomization.
27. Hypersensitivity to DARA, thalidomide, lenalidomide, POM, BTZ, IXA, CFZ, ELO or
dexamathasone. This includes rash ≥ Grade 3 during prior thalidomide, POM or
lenalidomide therapy.
28. 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 DARA, POM, LEN, IXA, BTZ, CFZ, ELO or
dexamethasone.
29. Subject is a female who is pregnant, nursing, or breastfeeding
30. For a subject randomized to Treatment Arm B and will be on a POM- or LEN-containing
regimen; unable or unwilling to undergo protocol required thromboembolism prophylaxis.
28 Subject is intolerant to bortezomib, or has acute diffuse infiltrative pulmonary and
pericardial disease, subject cannot receive DVd as bridging therapy if randomized to
Treatment Arm A or cannot receive DVd if randomized to Treatment Arm B.
31. Subject was treated with K±d as part of their most recent anti-myeloma treatment
regimen, cannot receive Kd if randomized to Treatment Arm B but may receive DPd, DVd, IRd
or EPd as per Investigator's discretion.
32. Subject was treated with EP±d as part of their most recent anti-myeloma treatment
regimen, cannot receive EPd if randomized to Treatment Arm B but may receive DPd, DVd, Kd
or IRd as per Investigator's discretion.
Active, Not Recruiting
