Multiple Myeloma
Conditions
Keywords
Multiple Myeloma, CAR T-cells, Anti-Myeloma Agents, lenalidomide, Maintenance Therapy, Hematologic Disorders, Infusion
Brief summary
This study is designed as a Phase II, multicenter, single arm trial to assess anti-B Cell Maturation Antigen (BCMA) chimeric antigen receptor (CAR) T-cells (bb2121) to improve post autologous hematopoietic cell transplant (HCT) responses among patients with multiple myeloma (MM).
Detailed description
After meeting the eligibility criteria and enrolling on the trial, patients will undergo leukapheresis for collection of autologous lymphocytes, which will be sent to BMS/Celgene manufacturing facilities. Once cells have been manufactured, patients will then proceed to lymphodepleting chemotherapy with cyclophosphamide 300mg/m\^2 and fludarabine 30mg/m\^2 for 3 consecutive days followed by the infusion of BCMA CAR T-cells at a target dose of 450 x10\^6 cells. Maintenance lenalidomide, starting at 5mg a day for 21 days of a 28-day cycle will be initiated at a minimum of at least 30 days, but no later than 180 days after the CAR T-cell infusion and will continue until the patient reaches 12 months post CAR T-cell infusion and continue free of progression
Interventions
DRUGLenalidomide
Maintenance lenalidomide, starting at 5 mg a day for 21 days of a 28-day cycle, will be initiated at a minimum of at least 30 days, but no later than 180 days after the CAR T-cell infusion and will continue until the participant reaches 12 months post CAR T-cell infusion and continues free of progression
BIOLOGICALbb2121
Participants receive infusion of BCMA CAR T-cells at a target dose of 450 x 10\^6 cells.
DRUGCyclophosphamide
300 mg/m\^2/day for 3 consecutive days prior to the CAR T infusion
DRUGFludarabine
30 mg/m\^2/day or 3 consecutive days prior to the CAR T infusion
PROCEDUREleukapheresis
Placement of central line catheter and leukapheresis
Sponsors
Medical College of Wisconsin
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Celgene a wholly owned subsidiary of BMS
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Assess anti-B Cell Maturation Antigen(BCMA) chimeric antigen receptor (CAR) T-cells (bb2121) to improve post autologous hematopoietic cell transplant (HCT) responses among patients with multiple myeloma (MM).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age greater than or equal to 18.00 years 2. Patients must meet the criteria for symptomatic MM requiring therapy (Appendix A) prior to initiating initial systemic anti-myeloma treatment. 3. Patients must have received initial systemic anti- myeloma therapy consisting of induction therapy and consolidation with high-dose melphalan (\>140 mg/m\^2 ) followed by an auto HCT (minimum cell dose of 2x10\^6 CD34+ cells/kg (actual body weight) within 12 months from initiation of systemic anti-myeloma therapy. 4. Patient must have additional stored stem cells greater than or equal to 2x10\^6 CD34+ cells per kg actual body weight. 5. Patients must be less than or equal to 12 months after autologous HCT at the time of enrollment. 6. Patients must have initiated maintenance therapy with lenalidomide-based regimen within 6 months after the auto HCT and have received at least 3 months of maintenance prior to enrollment. 7. Patients must have tolerated a minimum dose of lenalidomide 5 mg/day for 21 days of a 28-day cycle for greater than 2 cycles without having to stop due to toxicities. 8. Patients must have a VGPR or less (Section 3.1) in reference to time time of initiation of initial systemic anti-myeloma therapy at study enrollment. 9. Patients must have Karnofsky performance greater than or equal to 70. 10. Patients must have recovered to Grade 1 or baseline of any non-hematologic toxicities due to prior treatments, excluding Grade 2 neuropathy. 11. Absolute neutrophil count (ANC) greater than or equal to 1,500/mm3 without filgrastim use in the prior 14 days. 12. Platelet count greater than 100,000/mm\^3 (without platelet transfusion in the previous 7 days or thrombopoietin mimetics in the previous 28 days). 13. Hemoglobin greater than 9 g/dL (without red blood cell transfusion in the previous 7 days). 14. Creatinine Clearance (CrCl) greater than or equal to 60 mL/min, measured or estimated by Cockcroft-Gault equation. 15. Corrected serum calcium less than or equal to 13.5 mg/dL. 16. Oxygen saturation greater than 92% on room air. 17. Hepatic Function: a. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 2.5 x upper limit of normal (ULN) b. Serum total bilirubin less than or equal to 2 x ULN. Patients who have been diagnosed with Gilbert's disease are permitted to exceed the defined bilirubin value of 2 x ULN 18. International ratio (INR) or partial thromboplastin time (PTT) less than 1.5 x ULN 19. Cardiac Function: left ventricular ejection fraction greater than 45% by echocardiogram or MUGA. 20. Patients must be willing and able to adhere to the study visit schedule and other protocol requirements including regulatory requirement of a 15 year follow up using the CIBMTR long term follow up mechanism. 21. Female patients of childbearing potential (FCBP1 ) must: a. Have a negative serum pregnancy test with a sensitivity of at least 50 mIU/mL prior to enrollment b. Agree to use, and be able to comply with, TWO acceptable methods of birth control (Appendix C), one highly effective method and one additional effective (barrier) method AT THE SAME TIME, from screening through at least 1 year following bb2121 infusion or 4 weeks following discontinuation of lenalidomide, whichever is later. c. Agree to abstain from breastfeeding from screening through at least 1 year following bb2121 infusion or 4 weeks following discontinuation of lenalidomide, whichever is later. 22. Male patients must: a. 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 at least 1 year following bb2121 infusion or 4 weeks following discontinuation of lenalidomide whichever is later b. Must not donate sperm from screening through at least 1 year following bb2121 infusion or 4 weeks following discontinuation of lenalidomide whichever is later.
Exclusion criteria
1. Patients with a prior allogeneic hematopoietic cell. 2. Female of childbearing potential (FCBP) 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). 3. Patients with disease progression (see Section 3.1.2 for disease progression definition) at any time prior to enrollment. 4. Patients receiving any of the following less than 14 days prior to enrollment: 1. Plasmapheresis 2. Major surgery (as defined by the investigator) 3. Radiation therapy other than local therapy for MM-associated bone lesions 4. Use of any systemic anti-myeloma drug therapy (with the exception of lenalidomide maintenance) 5. Any investigational agents 6. Corticosteroids (Physiologic replacement, topical, intranasal and inhaled steroids are permitted) 5. Patients with known Central Nervous System (CNS) involvement with MM. 6. Patients with a prior organ transplant requiring systemic immunosuppressive therapy. 7. Patients who previously experienced toxicities related to lenalidomide resulting in permanent treatment discontinuation. 8. Patients who experienced thromboembolic events while on full anticoagulation during prior therapy with an immunomodulatory agent (IMiD). 9. Patients unwilling to take DVT prophylaxis while on lenalidomide maintenance. 10. Patients with history of greater than or equal to Grade 2 hemorrhage within 30 days of enrollment. 11. Patient requiring ongoing treatment with chronic, therapeutic dosing of anticoagulants (e.g. Warfarin, low molecular weight heparin, Factor Xa inhibitors). 12. Patients with 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. Patients with active or history of plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or clinically significant amyloidosis. 14. Patients with purely non-secretory MM \[prior to starting systemic therapy, absence of a monoclonal protein (M protein) in serum as measured by electrophoresis and immunofixation and the absence of Bence Jones protein in the urine defined by use of conventional electrophoresis and immunofixation techniques and the absence of involved serum free light chain greater than 100mg/L\]. Patients with light chain MM detected in the serum by free light chain assay are eligible. 15. Patients with a history of Class III or IV congestive heart failure (CHF) or severe nonischemic cardiomyopathy, unstable or poorly controlled angina, myocardial infarction, or hemodynamically significant ventricular arrhythmia within the previous 6 months prior to starting study treatment. 16. Patients with ongoing treatment with chronic immunosuppressants (e.g. cyclosporine or systemic steroids at any dose). Physiologic replacement, intermittent topical, inhaled or intranasal corticosteroids are allowed. 17. Patients with active clinically significant autoimmune disease, defined as a history of requiring systemic immunosuppressive therapy and at ongoing risk for potential disease exacerbation. Patients with a history of autoimmune thyroid disease, asthma, or limited skin manifestations are potentially eligible. 18. Patients seropositive for human immunodeficiency virus (HIV-1), chronic or active hepatitis B or C, or acute hepatitis A. If any history of exposure to hepatitis B or C then DNA PCR should be negative. 19. Patients with previous history of treatment with any gene therapy-based therapeutic for cancer or investigational cellular therapy for cancer or BCMA targeted therapy. 20. Patients with prior malignancies except resected basal cell carcinoma or treated carcinoma in situ. Cancer treated with curative intent less than 5 years prior to enrollment will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs. Cancer treated with curative intent greater than 5 years prior to enrollment is allowed. 21. Female patients who are pregnant (positive beta-HCG), or breastfeeding, or who intend to become pregnant during participation in the study. 22. Patient with known allergy or hypersensitivity to any of the study medications, their analogues, or excipients in the various formulations of any agent. 23. Patient with serious medical of psychiatric illness likely to interfere with participation on this clinical study. 24. Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment. 25. Patients unwilling or unable to provide informed consent 25. Patients unable or unwilling to return to the transplant center for treatment and follow up.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of BCMA CAR-T Cell Therapy | 6 months | Achieving a complete response or better (CR or sCR) as assessed by the 6-month time point after BCMA CAR T-cell therapy in MM patients with suboptimal disease responses after an autologous HCT and lenalidomide maintenance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Incidence of Disease Progression | 1 Year | Diseases will be assessed by response categories based on the International Myeloma Working Group: Stringent Complete Response (sCR), Complete Remission (CR), Very Good Partial Remission (VGPR), Partial Remission (PR), Minimal Response (MR), Stable Disease (SD). |
| Proportion of Patients Achieving an Upgrade in Response Based on Their Best Disease Response | 1 Year | Proportion of patients achieving upgrade in response following enrollment (SD to MR or greater, MR to PR or greater, or PR to VGPR or greater) and Conversion to MRD negativity. MRD will be assessed by multi-color flow at 10-5 level |
| Number of Participants With Non Relapse Mortality | 1 Year | Non-Relapse Mortality (NRM) is defined as death occurring in a patient from causes other than disease relapse or progression. Disease progression is the competing event for NRM. |
| Kaplan-Meier of Progression Free Survival | 1 Year | Defined as progression of disease or death from any cause. Surviving patients without disease progression will be censored at the date of last contact. |
| Incidence of Cytokine Release Syndrome (CRS) | Day 4, Day 7, Day 10, Day 14, and Day 21 post-infusion | Overall incidence of CRS of any grade and grade 3 or 4 CRS post CAR T-cell infusion will be reported on all patients. |
| Incidence of Prolonged Cytopenias | 1 Year | Overall incidence of prolonged cytopenias will be reported. Prolonged cytopenia is defined as failure to achieve ANC greater than 500/mm3 or platelet count greater than 20,000/mm3(with or without support) by 30 days post CAR T-cell infusion. |
| Incidence of Neurotoxicity | 1 Year | Overall incidence of CAR T-cell related neurotoxicity per the ASBMT immune effector cell associated neurotoxicity syndrome (ICANS) Consensus Grading. |
Countries
United States
Contacts
STUDY_DIRECTORMarcelo C Pasquini, MD, MS
Medical College of Wisconsin
PRINCIPAL_INVESTIGATORAlfred Garfall, MD
University of Pennsylvannia
PRINCIPAL_INVESTIGATORSergio Giralt, MD
Memorial Sloan Kettering Cancer Center
Participant flow
Recruitment details
BMT CTN 1902's enrollment was between January 2022 and December 2023 with 40 participants enrolled from 12 centers. The study opened to accrual in February 2021. Fifteen centers were activated for enrollment. The study closed to accrual on January 09, 2024.
Pre-assignment details
There was a Safety Run-in that included the first three participants enrolled on the study with staggered enrollment to assess for excess early toxicity. These data were reviewed and enrollment was approved in the Continuing Enrollment Phase which began on October 14, 2022.
Participants by arm
| Arm | Count |
|---|---|
| Lenalidomide and bb2121 Patients complete apheresis and proceed to lymphodepleting chemotherapy with cyclophosphamide 300mg/m\^2 and fludarabine 30mg/m\^2 for 3 consecutive days followed by the infusion of BCMA CAR T-cells at a target dose of 450 x10\^6 cells. Maintenance lenalidomide, starting at 5mg a day for 21 days of a 28-day cycle will be initiated at a minimum of at least 30 days, but no later than 180 days after the CAR T-cell infusion and will continue until the patient reaches 12 months post CAR T-cell infusion and continue free of progression.
Lenalidomide: Maintenance lenalidomide, starting at 5 mg a day for 21 days of a 28-day cycle, will be initiated at a minimum of at least 30 days, but no later than 180 days after the CAR T-cell infusion and will continue until the participant reaches 12 months post CAR T-cell infusion and continues free of progression
bb2121: Participants receive infusion of BCMA CAR T-cells at a target dose of 450 x 10\^6 cells.
Cyclophosphamide: 300 mg/m\^2/day for 3 consecutive days prior to the CAR T infusion
Fludarabine: 30 mg/m\^2/day or 3 consecutive days prior to the CAR T infusion
leukapheresis: Placement of central line catheter and leukapheresis | 40 |
| Total | 40 |
Baseline characteristics
| Characteristic | Lenalidomide and bb2121 |
|---|---|
| Age, Continuous | 61.2 years STANDARD_DEVIATION 7.72 |
| Cytogenetics High risk | 9 Participants |
| Cytogenetics No abnormalities | 7 Participants |
| Cytogenetics Standard risk | 23 Participants |
| Cytogenetics Unknown | 1 Participants |
| Disease Status at LD Chemotherapy Initiation Missing | 2 Participants |
| Disease Status at LD Chemotherapy Initiation MR | 1 Participants |
| Disease Status at LD Chemotherapy Initiation No LD Chemotherapy | 2 Participants |
| Disease Status at LD Chemotherapy Initiation PR | 13 Participants |
| Disease Status at LD Chemotherapy Initiation VGPR | 22 Participants |
| Disease Status Prior to Enrollment MR | 1 Participants |
| Disease Status Prior to Enrollment PR | 17 Participants |
| Disease Status Prior to Enrollment VGPR | 22 Participants |
| Disease Status Prior to Transplant PR | 30 Participants |
| Disease Status Prior to Transplant SD | 3 Participants |
| Disease Status Prior to Transplant VGPR | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| interval from diagnosis of symptomatic Multiple Myeloma to enrollment | 16.2 months STANDARD_DEVIATION 2.77 |
| Interval from Diagnosis of Symptomatic Multiple Myeloma to Transplant | 7.1 months STANDARD_DEVIATION 2.34 |
| Interval from Transplant to Enrollment | 9.1 months STANDARD_DEVIATION 1.68 |
| ISS Stage at Diagnosis I | 14 Participants |
| ISS Stage at Diagnosis II | 18 Participants |
| ISS Stage at Diagnosis III | 6 Participants |
| ISS Stage at Diagnosis Unknown | 2 Participants |
| Karnofsky Performance Score 70 or 80 | 17 Participants |
| Karnofsky Performance Score 90 or 100 | 23 Participants |
| Multiple Myeloma Paraprotein Type IgA Kappa | 2 Participants |
| Multiple Myeloma Paraprotein Type IgA Lambda | 2 Participants |
| Multiple Myeloma Paraprotein Type IgG Kappa | 20 Participants |
| Multiple Myeloma Paraprotein Type IgG Lamda | 6 Participants |
| Multiple Myeloma Paraprotein Type Kappa light chain | 8 Participants |
| Multiple Myeloma Paraprotein Type Lambda light chain | 2 Participants |
| Myeloma Risk Status High risk | 12 Participants |
| Myeloma Risk Status Standard risk | 28 Participants |
| Number of Lines of Initial Systemic Anti-Myeloma Therapy 1 Line | 32 Participants |
| Number of Lines of Initial Systemic Anti-Myeloma Therapy 2 Lines | 6 Participants |
| Number of Lines of Initial Systemic Anti-Myeloma Therapy 3 Lines | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 29 Participants |
| R-ISS Stage at Diagnosis I | 11 Participants |
| R-ISS Stage at Diagnosis II | 20 Participants |
| R-ISS Stage at Diagnosis III | 2 Participants |
| R-ISS Stage at Diagnosis Unknown | 7 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 40 |
| other Total, other adverse events | 38 / 40 |
| serious Total, serious adverse events | 9 / 40 |
Outcome results
Primary
Efficacy of BCMA CAR-T Cell Therapy
Achieving a complete response or better (CR or sCR) as assessed by the 6-month time point after BCMA CAR T-cell therapy in MM patients with suboptimal disease responses after an autologous HCT and lenalidomide maintenance.
Time frame: 6 months
Population: Patients who received BCMA CAR T-Cell Therapy
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lenalidomide and bb2121 | Efficacy of BCMA CAR-T Cell Therapy | Acheived CR/sCR by 6 Months post Infusion | 25 Participants |
| Lenalidomide and bb2121 | Efficacy of BCMA CAR-T Cell Therapy | Did Not Acheive CR/sCR by 6 Months post Infusion | 13 Participants |
p-value: <0.000190% CI: [51.2, 78.4]Fisher Exact
Secondary
Assessment of Disease Progression
Diseases will be assessed by response categories based on the International Myeloma Working Group: Stringent Complete Response (sCR), Complete Remission (CR), Very Good Partial Remission (VGPR), Partial Remission (PR), Minimal Response (MR), Stable Disease (SD).
Time frame: 1 Year
Secondary
Best Disease Response
: Proportion of patients achieving upgrade in response following enrollment (SD to MR or greater, MR to PR or greater, or PR to VGPR or greater) and Conversion to MRD negativity. MRD will be assessed by multi-color flow at 10-5 level
Time frame: 1 Year
Secondary
Incidence of Cytokine Release Syndrome
Overall incidence of CRS of any grade and grade 3 or 4 CRS post CAR T-cell infusion will be reported on all patients.
Time frame: 1 year
Secondary
Incidence of Neurotoxicity
Overall incidence of CAR T-cell related neurotoxicity per the ASBMT immune effector cell associated neurotoxicity syndrome (ICANS) Consesus Grading.
Time frame: 1 Year
Secondary
Incidence of Prolonged Cytopenias
Overall incidence of prolonged cytopenias will be reported. Prolonged cytopenia is defined as failure to achieve ANC greater than 500/mm3 or platelet count greater than 20,000/mm3(with or without support) by 30 days post CAR T-cell ifusion.
Time frame: 1 Year
Secondary
Non Relapse Mortality
Non-Relapse Mortality (NRM) is defined as death occurring in a patient from causes other than disease relapse or progression. Disease progression is the competing event for NRM.
Time frame: 1 Year
Secondary
Progression Free Survival
Defined as progression of disease or death from any cause. Surviving patients without disease progression will be censored at the date of last contact.
Time frame: 1 Year
Other Pre-specified
Exploratory Objective 1: Incidence of Toxicities Greater Than or Equal to Grade 3 Per the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
All Grade 3 or higher toxicities will be tabulated. The proportion of patients experiencing cytokine release syndrome CRS will be reported including overall and grades 3-4 based on the ASTCT grading
Time frame: 1 Year
Other Pre-specified
Exploratory Objective 2: BCMA Expression
BCMA expression at specified timepoints will be determined by immunohistochemical staining of bone marrow biopsy specimens and/or flow cytometric analysis of bone marrow aspirate material, in order to assess for baseline expression and potential loss of expression post-treatment. Both percent of MM cells that stain positive as well as staining intensity will be reported.
Time frame: 1 Year
Other Pre-specified
Exploratory Objective 2: CAR Tcell Expansion
Quantitation of CAR T-cells in peripheral blood will be determined at specified timepoints by quantitative PCR assay, measured in copies/mcg genomic DNA. Peak CAR T-cell expansion will be compared between subjects who are and are not in CR at 12 months, and between subjects who are and are not progression-free at 12 months.
Time frame: 1 Year
Other Pre-specified
Exploratory Objective 2: CAR T-cell Persistence
Quantitation of CAR T-cells in peripheral blood will be determined at specified timepoints by quantitative PCR assay, measured in copies/mcg genomic DNA. Persistence will be measured in 2 ways: 1) as an area under the curve (AUC) over first 6 months post CAR T-cell infusion; and 2) as still having detectable CAR T-cells at 6 months post CAR T-cell infusion. AUC6mos and 6- month persistence will be compared between subjects who are and are not in CR at 12 months, and between subjects who are and are not progression-free at 12 months.
Time frame: 1 Year
Other Pre-specified
Exploratory Objective 2: Immune Reconstitution
The cellular composition of marrow (T-Cells, B-Cells, Natural Killer Cells, dendritic cells, and myeloid derived suppressor cells) will be quantified at the specified timepoints by flow cytometry.
Time frame: 1 Year
Other Pre-specified
Exploratory Objective 2: Incidence of Infections Per Protocol-specific Manual of Procedures (MOP)
incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each patient
Time frame: 1 Year
Other Pre-specified
Exploratory Objective 2: Overall Survival
The event is death from any cause. The time to this event is the time from initial enrollment to sdeath, loss to follow-up, or the end of the study, whichever comes first.
Time frame: 1 Year
Other Pre-specified
Exploratory Objective 3: Maintenance Feasibility
The feasibility of resuming maintenance following enrollment by 180 days after CAR T-cell infusion will be described. The proportion of patients initiating maintenance at 180 days following bb2121 infusion will be reported.
Time frame: 1 Year