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Phase II Multicenter Trial of anti-B Cell Maturation  
  
Antigen Chimeric Antigen Receptor T Cell Therapy for Multiple Myeloma Patients with Sub-Optimal Response After Autologous Hematopoietic Cell Transplantation and Maintenance Lenalidomide NCT 05032820 Version 3.0 Study Chairpersons Alfred Garfall, MD1, Sergio Giralt, MD2 IND Sponsor Medical College of Wisconsin Marcelo C Pasquini Protocol Team:
Anderson, Erica, MA8 Avigan, David, MD3 Callander, Natalie, MD4 Choi, Taewoong, MD5 Cohen, Adam, MD1 Dhakal, Binod, MD6 Geller, Nancy L. PhD14 Varadarajan, Indumathy, MD9 Logan, Brent, PhD7 Richard, Shambavi, MD10 Nishihori, Taiga, MD11 Pasquini, Marcelo, MD6 Boyd, Megan, MPH8 Scott, Megan, BS8 Shah, Nina, MD12 Sidana, Surbhi, MD13 Usmani, Saad, MD 2 Sponsored by the National Institutes of Health National Heart, Lung, and Blood Institute National Cancer Institute 1University of Pennsylvania 2Memorial Sloan-Kettering Cancer Center 3Beth Israel Deaconess Medical Center 4University of Wisconsin Carbone Cancer Center 5Duke University 6Medical College of Wisconsin 7Medical College of Wisconsin Alfred Garfall, MD
Sergio Giralt, MD I am approving this document.  
27/Apr/2022 09:36 AM EDT
Sergio Giralt, MD 22/Apr/2022 09:34 PM EDT
Alfred Garfall, MD I am approving this document.  
___________________________________ ___________________________________
Approval Signature (Protocol Chair) Approval Signature (Protocol Chair)
8The Emmes Company  
  
  
9University of Virginia 10Mount Sinai Medical Center 11Moffitt Cancer Center 12University of California, San Francisco 13 Stanford University 14 National Heart, Lung, and Blood Institute Marcelo Pasquini, MD, MS  
  
  
25/Apr/2022 08:42 AM EDT
I am approving this document.  
Marcelo Pasquini, MD, MS
___________________________________ *Approval Signature (Protocol Sponsor)*
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core study participants

Baylor College of Medicine City of Hope Duke University Medical Center H. Lee Moffitt Cancer Center Loyola University Medical College of Wisconsin Memorial Sloan-Kettering Mount Sinai Medical Center Roswell Park Stanford Hospital and Clinics University of California San Francisco University of Pennsylvania University of Virginia
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affiliate study participants

Beth Israel Deaconess Medical Center University of Wisconsin Carbone Cancer Center
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protocol synopsis - bmt ctn

Phase II Multicenter Trial of anti-B Cell Maturation Antigen Chimeric Antigen Receptor T Cell Therapy for Multiple Myeloma Patients with Sub-Optimal Response After Autologous Hematopoietic Cell Transplantation and Maintenance Lenalidomide Co-Principal Investigators: Alfred Garfall, MD Sergio Giralt, MD  
| Study Design:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | 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).                                                                            |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Primary Objectives:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | The primary objective is to evaluate the efficacy of BCMA CAR  T cell therapy to improve the response in patients who received  an upfront autologous HCT and lenalidomide maintenance.                                                                                                                                                                                 |
| Secondary Objectives:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | The secondary objectives include assessment of disease  progression, response to treatment as determined by improved  response and conversion to minimal residual disease (MRD)  negativity, non-relapse mortality, progression free survival  (PFS), incidence of cytokine release syndrome (CRS),  incidence of prolonged cytopenias, and incidence of  neurotoxicity |
| Exploratory Objectives: Exploratory objectives to be described include incidence of  toxicities greater than or equal to grade 3 per the Common  Terminology Criteria for Adverse Events (CTCAE) version 5.0,  incidence of infections per protocol-specific Manual of  Procedures (MOP), maintenance feasibility, overall survival,  disease response, CAR T-cell expansion, CAR T-cell  persistence, BCMA expression, immune reconstitution  Eligibility Criteria: Eligible patients are greater than or equal to 18.00 years of age  with MM with very good partial response (VGPR) or less, within  12 months after an autologous HCT with melphalan >  140mg/m2, have initiated lenalidomide-based maintenance at  least 3 months ago, and have not experienced disease  progression since initiation of initial systemic anti-myeloma  therapy.  Treatment 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/m2/day and fludarabine  30mg/m2/day for 3 consecutive days followed by the infusion |                                                                                                                                                                                                                                                                                                                                                                         |  
of BCMA CAR T-cells at a target dose of 450 x106 cells.  
Maintenance lenalidomide, starting at 5 mg daily 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, will increase if applicable to subjects' previously tolerated dose, and will continue until the patient reaches 12 months post CAR T-cell infusion and continue free of progression.  
| Accrual Objective:                                       | 40 patients   |
|----------------------------------------------------------|---------------|
| Accrual Period:                                          | 22 months     |
| Target Number of Sites: 15 sites  CIBMTR infrastructure. |               |  
Long Term Follow Up: All patients will be followed for 15 years to meet regulatory  
requirements through a long term follow up protocol using the CIBMTR infrastructure.  
Study Duration: Patients will be followed for 12 months after bb2121 infusion
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bmt ctn 1902 study schema

| 1     | OVERVIEW 1-9                                                                                                             |
|-------|--------------------------------------------------------------------------------------------------------------------------|
| 1.1   | Background 1-9                                                                                                           |
| 1.1.1 | Autologous Stem Cell Transplantation in MM 1-9                                                                           |
| 1.1.2 | The Role of Maintenance Therapy after Autologous HCT 1-9                                                                 |
| 1.1.3 | Depth of Response Correlates to PFS and OS 1-11                                                                          |
| 1.1.4 | Dynamics of Response While on Lenalidomide Maintenance Therapy ... 1-11                                                  |
| 1.1.5 | CAR T-Cell Therapy 1-13                                                                                                  |
| 1.1.6 | Anti-B Cell Maturation Antigen CAR T-Cell Therapy for MM 1-14                                                            |
| 1.1.7 | Rationale for CAR T-Cells as a Component of First-Line MM Therapy ... 1-15                                               |
| 1.1.8 | Idecabtagene Vicleucel (Ide-cel) 1-15                                                                                    |
| 1.2   | Study Specific Information 1-17                                                                                          |
| 1.3   | Rationale for Study 1-17                                                                                                 |
| 2     | STUDY DESIGN 2-1                                                                                                         |
| 2.1   | Study Overview 2-1                                                                                                       |
| 2.2   | Hypothesis and Study Objectives 2-1                                                                                      |
| 2.2.1 | Hypothesis 2-1                                                                                                           |
| 2.2.2 | Primary Objective 2-1                                                                                                    |
| 2.2.3 | Clinical Secondary Objective 2-1                                                                                         |
| 2.2.4 | Exploratory Objectives 2-1                                                                                               |
| 2.3   | Patient Eligibility 2-2                                                                                                  |
| 2.3.1 | Initial Inclusion Criteria 2-2                                                                                           |
| 2.3.2 | Initial Exclusion Criteria 2-4                                                                                           |
| 2.3.3 | Patient Eligibility Criteria for LD Chemotherapy 2-6                                                                     |
| 2.3.4 | Patient Eligibility Criteria for CAR T-Cell (bb2121) Infusion 2-7                                                        |
| 2.3.5 | Patient Eligibility Criteria for Maintenance Therapy After bb2121 Infusion  between Day 30 and Prior to or on Day 90 2-7 |
| 2.3.6 | Patient Eligibility Criteria for Maintenance Therapy After bb2121 Infusion  after Day 90 and Prior to Day 180 2-8        |
| 2.4   | Treatment Plan 2-8                                                                                                       |
| 2.4.1 | Treatment Prior to Enrollment 2-8                                                                                        |
| 2.4.2 | Leukapheresis 2-9                                                                                                        |
| 2.4.3 | CAR T-Cell (bb2121) Manufacturing 2-9                                                                                    |
| 2.4.4 | LD Chemotherapy 2-10                                                                                                     |  
| Blood and Marrow Transplant Clinical Trials Network   | BMT CTN 1902                                                                |
|-------------------------------------------------------|-----------------------------------------------------------------------------|
| Version 3.0 dated March 10, 2022                      |                                                                             |
| 2.4.5                                                 | CAR T-Cell (bb2121) Infusion: 2-10                                          |
| 2.4.6                                                 | Maintenance Treatment 2-11                                                  |
| 2.5                                                   | Risks and Toxicities 2-14                                                   |
| 2.5.1                                                 | Leukapheresis Risks 2-14                                                    |
| 2.5.2                                                 | LD Chemotherapy Risks 2-14                                                  |
| 2.5.3                                                 | CAR T Therapy (bb2121) Toxicities 2-15                                      |
| 2.5.4                                                 | Lenalidomide Related Toxicities 2-18                                        |
| 2.5.5                                                 | Subsequent Neoplasms and Long Term Follow up 2-19                           |
| 2.6                                                   | Supportive Care and Toxicity Management 2-19                                |
| 2.6.1                                                 | LD Chemotherapy Supportive Care and Toxicity Management 2-19                |
| 2.6.2                                                 | CAR T-cell (bb2121) Infusion Supportive Care and Toxicity  Management… 2-20 |
| 2.6.3                                                 | Lenalidomide Supportive Care 2-21                                           |
| 2.7                                                   | Concomitant Medications 2-21                                                |
| 2.7.1                                                 | Permitted Concomitant Medication and Procedures 2-21                        |
| 2.7.2                                                 | Prohibited Concomitant Medications and Procedures 2-22                      |
| 2.8                                                   | Study Drug Supply 2-23                                                      |
| 2.8.1                                                 | Lenalidomide 2-23                                                           |
| 2.9                                                   | Patient Withdrawal from Study and Off Study Criteria 2-25                   |
| 2.10                                                  | Study Conduct 2-25                                                          |
| 3                                                     | STUDY ENDPOINTS AND DEFINITIONS 3-1                                         |
| 3.1                                                   | Definition of Disease Status 3-1                                            |
| 3.1.1                                                 | Response Categories 3-1                                                     |
| 3.1.2                                                 | Disease Progression Definitions 3-3                                         |
| 3.2                                                   | Primary Endpoint 3-3                                                        |
| 3.3                                                   | Clinical Secondary Endpoints 3-4                                            |
| 3.3.1                                                 | Disease Progression 3-4                                                     |
| 3.3.2                                                 | Disease Response 3-4                                                        |
| 3.3.3                                                 | Non-Relapse Mortality 3-4                                                   |
| 3.3.4                                                 | Incidence of Cytokine Release Syndrome (CRS) 3-4                            |
| 3.3.5                                                 | Incidence of Prolonged Cytopenias 3-4                                       |
| 3.3.6                                                 | Incidence of Neurotoxicity 3-4                                              |
| 3.3.7                                                 | Progression Free Survival 3-4                                               |
| 3.3.8                                                 | Feasibility of Re-Initiation of Lenalidomide Maintenance 3-5                |
| 3.4                                                   | Exploratory Endpoints 3-5                                                   |  
| Version 3.0 dated March 10, 2022   |                                                                                             |
|------------------------------------|---------------------------------------------------------------------------------------------|
| 3.4.1                              | Incidence of Toxicities Grade > 3 per CTCAE Version 5.0 3-5                                 |
| 3.4.2                              | Incidence of Infections per Protocol-Specific MOP 3-5                                       |
| 3.4.3                              | Maintenance Feasibility 3-5                                                                 |
| 3.4.4                              | Overall Survival 3-5                                                                        |
| 3.4.5                              | CAR T-Cell Expansion 3-5                                                                    |
| 3.4.6                              | CAR T-Cell Persistence 3-5                                                                  |
| 3.4.7                              | BCMA Expression 3-6                                                                         |
| 3.4.8                              | Immune Reconstitution 3-6                                                                   |
| 4                                  | PATIENT REGISTRATION, ENROLLMENT AND EVALUATION 4-1                                         |
| 4.1                                | Enrollment Procedures 4-1                                                                   |
| 4.1.1                              | Product Manufacturing, Release and Infusion 4-1                                             |
| 4.1.2                              | Long Term Follow-up 4-2                                                                     |
| 4.2                                | Study Monitoring 4-2                                                                        |
| 4.2.1                              | Follow-Up Schedule 4-2                                                                      |
| 4.3                                | Patient Evaluations 4-3                                                                     |
| 4.3.1                              | Pre-Enrollment Evaluations and Requirements 4-3                                             |
| 4.3.2                              | Evaluations Required Following Initial Study Enrollment: 4-3                                |
| 4.3.3                              | Evaluations Required Prior to Initiating LD Chemotherapy 4-4                                |
| 4.3.4                              | Evaluations and Requirements Prior to CAR T-Cell Infusion 4-4                               |
| 4.3.5                              | Evaluations and Requirements Following CAR T-Cell Infusion 4-5                              |
| 4.3.6                              | Pre-Maintenance Evaluations and Requirements 4-6                                            |
| 4.3.7                              | Evaluations at the Time of Disease Progression 4-7                                          |
| 4.4                                | Data Reporting 4-11                                                                         |
| 4.4.1                              | Criteria for Forms Submission 4-11                                                          |
| 4.4.2                              | Reporting Patient Deaths 4-11                                                               |
| 4.4.3                              | Center for International Blood and Marrow Transplant Research  (CIBMTR) Data Reporting 4-11 |
| 4.5                                | Adverse Event Reporting 4-12                                                                |
| 4.5.1                              | Definitions 4-13                                                                            |
| 4.5.2                              | Classification of Adverse Events by Severity 4-15                                           |
| 4.5.3                              | Classification of Adverse Events by Relationship to Investigational  Product 4-15           |
| 4.5.4                              | Required Adverse Event Reporting 4-15                                                       |
| 4.5.5                              | Reporting of Special Situations 4-18                                                        |
| 5                                  | STATISTICAL CONSIDERATIONS 5-1                                                              |
| 5.1                                | Study Design 5-1                                                                            |  
| Blood and Marrow Transplant Clinical Trials Network   | BMT CTN 1902                                                                                    |
|-------------------------------------------------------|-------------------------------------------------------------------------------------------------|
| Version 3.0 dated March 10, 2022                      |                                                                                                 |
| 5.1.1                                                 | Study Duration 5-1                                                                              |
| 5.1.2                                                 | Randomization and Blinding 5-1                                                                  |
| 5.1.3                                                 | Safety Run-In and Staggered Enrollment 5-1                                                      |
| 5.1.4                                                 | Primary Endpoint 5-2                                                                            |
| 5.2                                                   | Sample Size Considerations 5-3                                                                  |
| 5.3                                                   | Interim Analysis and Stopping Guidelines 5-3                                                    |
| 5.4                                                   | Demographic and Baseline Characteristics 5-4                                                    |
| 5.5                                                   | Analysis Populations and General Analysis Guidelines 5-4                                        |
| 5.5.1                                                 | Primary Analysis Population 5-4                                                                 |
| 5.5.2                                                 | General Analysis Guidelines 5-4                                                                 |
| 5.5.3                                                 | As Treated Analysis 5-5                                                                         |
| 5.6                                                   | Analysis of Primary Endpoint 5-5                                                                |
| 5.7                                                   | Analysis of Secondary Endpoints 5-5                                                             |
| 5.7.1                                                 | Response to Treatment 5-5                                                                       |
| 5.7.2                                                 | Progression-Free Survival (PFS) 5-5                                                             |
| 5.7.3                                                 | Non-Relapse Mortality (NRM) 5-6                                                                 |
| 5.7.4                                                 | Progression of Disease 5-6                                                                      |
| 5.7.5                                                 | Incidence of Cytokine Release Syndrome (CRS) 5-6                                                |
| 5.7.6                                                 | Incidence of Prolonged Cytopenias 5-6                                                           |
| 5.7.7                                                 | Incidence of Neurotoxicity (ICANS) 5-6                                                          |
| 5.7.8                                                 | Feasibility of Reinitiation of Lenalidomide Maintenance 5-6                                     |
| 5.8                                                   | Analysis of Exploratory Endpoints 5-6                                                           |
| 5.8.1                                                 | CAR T-Cell Expansion 5-6                                                                        |
| 5.8.2                                                 | CAR T-Cell Persistence 5-6                                                                      |
| 5.8.3                                                 | BCMA Expression 5-7                                                                             |
| 5.8.4                                                 | Immune Reconstitution 5-7                                                                       |
| 5.8.5                                                 | Overall Survival 5-7                                                                            |
| 5.8.6                                                 | Overall Toxicity 5-7                                                                            |
| 5.8.7                                                 | Infections 5-7                                                                                  |
| APPENDIX A                                            | CRITERIA FOR SYMPTOMATIC MULTIPLE MYELOMA A-1                                                   |
| APPENDIX B                                            | LABORATORY PROCEDURES B-1                                                                       |
| APPENDIX C                                            | RISKS OF FETAL EXPOSURE, PREGNANCY TESTING GUIDELINES  AND ACCEPTABLE BIRTH CONTROL METHODS C-1 |
| APPENDIX D                                            | REVLIMID® (LENALIDOMIDE) OVERVIEW D-1                                                           |
| APPENDIX E                                            | HUMAN SUBJECTS E-1                                                                              |  
| APPENDIX F   | KARNOFSKY PERFORMANCE STATUS SCALE F-1                                                   |
|--------------|------------------------------------------------------------------------------------------|
| APPENDIX G   | BB2121 INFUSION PROCESS G-1                                                              |
| APPENDIX H   | MANAGEMENT GUIDELINES FOR CYTOKINE RELEASE  SYNDROME (CRS) AND NEUROLOGIC TOXICITIES H-1 |
| APPENDIX I   | MANAGEMENT GUIDELINES FOR CYTOPENIAS I-1                                                 |
| APPENDIX J   | REFERENCES J-1                                                                           |
| APPENDIX K   | INVESTIGATOR'S SIGNATURE J-1                                                             |
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chapter 1 1 overview 1.1

Multiple myeloma (MM), is a plasma cell malignancy that affects approximately 31,000 new patients in the US yearly.[1] Treatment includes induction therapy with proteasome inhibitors (PIs), immune-modulatory drugs (IMIDs) and steroids. Eligible patients receive consolidation with high dose melphalan and autologous hematopoietic cell transplantation (HCT) followed by maintenance therapy. Treatment results in complete remission (CR) rates of 50% with median progression free survival (PFS) between 48 and 60 months. Disease recurrence is common and only a small percentage of patients are potentially cured.[2] Once patients relapse after first-line therapy, salvage therapies combining IMIDs, PIs, cytotoxic chemotherapy and monoclonal antibodies are effective in inducing remissions that last on average 12 to 24 months. Eventually MM becomes resistant to standard therapies and most patients will succumb from their disease.[3]
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1.1.1 autologous stem cell transplantation

Autologous HCT remains a cornerstone of MM therapy. Autologous HCT is safe with nonrelapse mortality (NRM) rates of less than 2% in patients with a low comorbidity index score.[4] Several trials have shown a benefit in overall survival (OS) and PFS in MM
patients.[5-10] The benefit of autologous HCT is maintained in patients treated with PI and IMIDs. In one study, patients were treated with lenalidomide and dexamethasone induction therapy and then randomized to receive either 6 cycles of oral melphalan based consolidation therapy or two 4-month cycles of high dose melphalan and autologous stem cell rescue (tandem transplants).[10] Patients were additionally randomized to receive maintenance therapy with lenalidomide or observation in a 2 by 2 overall design. Both PFS and 4-year OS were improved with autologous HCT compared to melphalan based consolidation therapy (43.0 months vs. 22.4 months and 81.6% vs. 65.3% respectively). Most recently, results from the French arm of the IFM/DFCI 2009 clinical trial became available.[6] The significance of this trial is that induction therapy included the best-known standard of care using both proteasome inhibitors as well as lenalidomide. A 3-year PFS of 61% was observed in the transplant arm compared to 48% in the non-transplant arm (stratified p value for log-rank test < 0.0002; HR= 1.5, 95% CI= 1.2-1.9). Even among patients achieving MRD-negative responses, PFS still trended in favor of transplantation.[11]
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1.1.2 the role of maintenance

Therapy following autologous HCT remains controversial particularly in patients who achieve a complete response (CR). In the aforementioned trial where patients were randomized to receive autologous HCT followed by maintenance in a 2 by 2 design, median PFS was significantly increased with lenalidomide maintenance (41.9 months vs.  
21.6 months) but 3-year OS was not significantly improved (88.0% vs. 79.2%).[12] The benefit of lenalidomide maintenance was further evaluated in a phase 3 trial of 614 patients with newly diagnosed MM to randomly receive lenalidomide if they had non-progressive disease after autologous HSCT.[12] Patients in the lenalidomide arm had a longer median PFS (41 versus 23 months), although OS was similar at four years (73 versus 75 percent). Lenalidomide treatment resulted in higher toxicity and incidence of second primary malignancies (3.1 versus 1.2 per 100 patient-years). In another phase 3 randomized study of patients with stable disease or better after autologous HCT, the study was unblinded after interim analysis showed decreased rates of disease progression in the lenalidomide treated group (20 % versus 44%).[13] Mortality was higher in the placebo group with a trend toward significance (10% vs 5%, HR of 0.52, 95% CI 0.26 - 1.02). A higher benefit appeared to occur in patients who were not in CR after autologous HSCT. A recent metaanalysis of the published randomized trials showed a survival benefit for patients receiving lenalidomide maintenance.[14]
The initial target population for this study was subjects who failed to achieve at least VGPR (i.e., <VGPR) after full first-line therapy (multi-agent induction, autologous HSCT, and lenalidomide maintenance). In an amendment, the target population was modified to include patients achieving VGPR but failing to achieve CR (i.e., <CR). The original target population was estimated to represent approximately 15-20% of patients based on results from STAMINA [ref stadtmauer jco 2019] and IFM-09 [ref Attal NEJM 2017]. Since initial design of this study, data emerged supporting the safety and efficacy of more intensive induction regimens such as daratumumab + bortezomib + lenalidomide + dexamethasone (dara-VRd) and carfilzomib + lenalidomide + dexamethasone (KRd). Though phase-three studies have not yet demonstrated superior overall survival with these more intensive regimens in the general myeloma population, single-arm safety and efficacy data have led many clinicians to switch to these more intensive regimens in patients with high-risk baseline features or those not exhibiting at least VGPR to standard VRd. This practice change resulted in fewer patients arriving at the entry-point for this study (i.e., after transplant and several months of maintenance therapy) in <VGPR, as illustrated in the following datasets:
x Among subjects in the GRIFFIN study of dara-VRd vs VRd in the transplant-eligible population, <10% of patients exhibited <VGPR with dara-VRd vs 27% with VRd at the analogous post-transplant timepoints we are targeting entry for this study [Ref Voorhees Blood (2020) 136 (8): 936–945.] whereas 49% were <CR.  
x In the FORTE study, only 6% of patients who received KRd + autologous HSCT +
lenalidomide maintenance exhibited <VGPR [Ref Gay et al., ASH 2020 abstract \#141] whereas 41% exhibited <CR.
These practice changes narrowed our eligible population under the original inclusion criteria. Available data, however, suggest continuous risk of disease progression even in subjects treated with more potent first-line regimens, even those achieving MRD-negative responses [ref Kazandjian et al., JAMA oncology 2018, 4(12):1781]. In addition, as described in section 1.1.3 below, depth-of-response continues to be a powerful predictor of survival outcomes, with patients with <CR after modern first-line therapy experiencing inferior outcomes compared to those in CR/sCR. Therefore, the changes to eligibility criteria to include patients achieving VGPR but failing to achieve CR are consistent with the objective to evaluate CAR T cell therapy in the subset of MM patients with sub-optimal responses to first-line therapy, and the revised target population remains one with significant unmet need in whom risk of participation is justified by continuous risk of disease progression and inferior outcomes compared to those who achieve CR.
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1.1.3 depth of response correlates

Depth of response has been universally associated with treatment outcomes in MM.[17-22]
Extensive evidence from trials incorporating autologous HCT show that CR, or maximal response after transplant, is associated with improved PFS and OS.[17, 18, 20-22] This benefit remains true when newer agents are incorporated into therapy as shown by the Arkansas group in the total therapy 2 and 3 trials incorporating thalidomide or thalidomide with bortezomib respectively.[17, 18, 21] More recently, Joseph et al. reported long-term outcomes of ~1000 non-trial patients receiving VRd-based induction, transplant where applicable, and lenalidomide-based maintenance [ref Joseph et al., Journal of Clinical Oncology 38, no. 17 (June 10, 2020) 1928-1937). There was significantly poorer PFS in the group achieving best response of VGPR (median 49.9 months, 95% CI 39.1-60.7) vs CR (median 72.2 months, 95% CI 61.0-83.4) and sCR (median 89.9 months, 95% CI 64.2-115.6). Thus, a VGPR patient can expect nearly 2 years less PFS compared to a CR patient and over 3 years less PFS compared to a sCR patient; these findings support studying interventions to improve response in the VGPR population. Durability of CR is also important, as patients who remained in CR for 3 years after the start of treatment had significantly superior survival when compared to patients who never achieved a CR or who relapsed within 3 years.[21] The use of multiparametric flow cytometry and polymerase chain reaction based gene sequencing led to more sensitive disease detection and the identification of minimal residual disease (MRD) even in patients who meet criteria for CR. MRD assessments have now been incorporated into the response criteria of the International Myeloma Working Group (IMWG).[23] MRD eradication was shown to have a prognostic significance on OS in patients with immunofixation based CR in patients treated on the GEM2000 protocol.[24] The impact of MRD negativity at a level of 10-5 and 10-6 either by multiparameter flow cytometry (MFC) or Next Generation Sequencing (NGS) as a surrogate for long-term disease control has been confirmed by other investigators. 1.1.4 Dynamics of Response While on Lenalidomide Maintenance Therapy  
Data describing response kinetics  
 to lenalidomide maintenance therapy is lacking outside of what is reported as PFS or OS in the lenalidomide maintenance trials. Some patients experience a plateau in the disease response that never quite reaches CR without frank progression. These patients linger in near CR, VGPR, or PR despite initial therapy, autologous HSCT and lenalidomide maintenance. In data describing the Memorial Sloan Kettering Cancer Center experience with lenalidomide maintenance in MM,[25] it was noted that patients continue to respond after starting lenalidomide  
  
Maintenance from Shah, Gunjan L. et al.
maintenance with a median time to response of 132 days and median duration of therapy of 21.5 months. Furthermore, lenalidomide maintenance increased the number of patients in CR from 38% to 60%. 40% of patients however remained in a VGPR or PR. Though not statistically significant (p=0.11), a clear trend or separation in the Kaplan-Meier curves measuring PFS was noted between patients who were in CR, patients not in CR but responded to lenalidomide maintenance, and non-responding patients (Figure 1.1.4).  
Twelve-month PFS was highest in patients who deepened their response on lenalidomide maintenance (93%) compared to patients already in CR (12-month PFS of 72%) or patients without a response to lenalidomide maintenance (12-month PFS of 63%). What these data suggest is that further deepening the response in MM patients, even during the maintenance stage of therapy, may impact survival. Adding a second agent in this particular setting, in patients without CR despite upfront therapy, is an attractive strategy to convert patients with residual disease into a CR and perhaps prolong their survival. The MSKCC data detailed above is the first to objectively describe this patient population, the group of patients who plateau their response to myeloma therapy, and this proposed study would be one of the first to recommend an intervention in this patient population.[25]
Table 1.1.4 demonstrates the kinetics of response during maintenance therapy for patients registered on BMT CTN 0702. Note that 19.9% (n=29) of patients on the single autologous HCT followed by lenalidomide maintenance arm had achieved a CR by 12 months. At 24 months the percentage of patients achieving a CR had risen to 29.5% (n=43) but only a few patients had further increases in their depth of response between 24 and 36 months. [15]  
| Auto/Auto                                             | Auto/RVD               | Auto/Maint   |          |                             |          |        |     |     |      |
|-------------------------------------------------------|------------------------|--------------|----------|-----------------------------|----------|--------|-----|-----|------|
| N                                                     | N                      | N            |          |                             |          |        |     |     |      |
| N                                                     | Evaluable              | N            | valuab   | N                           | valuable |        |     |     |      |
| Events                                                | Pts                    | %            | Events   | Pts                         | %        | Events | Pts | %   |      |
| nd in the content of the content.                     | 125                    | 100.0        | 12       | 100.0                       | 146      | 100.0  |     |     |      |
| and evaluable for conversion to CR                    |                        |              |          |                             |          |        |     |     |      |
| Achieving CR by 3 mos post maintenance 1              | 8                      | 125          | 6.4      | 8                           | 12       | 7.1    | 10  | 146 | 6.8  |
| Achieving CR by 6 mos post maintenance 1              | 15                     | 125          | 12.0     | 16                          | 12       | 14.3   | 21  | 146 | 14.4 |
| Achieving CR by 12 mos post maintenance 1             | 25                     | 125          | 20.0     | 30                          | 12       | 26.8   | 29  | 146 | 19.9 |
| Achieving CR by 24 mos post maintenance 1             | 35                     | 125          | 2.0      | 37                          | 12       | 3.0    | .43 | 146 | 29.5 |
| Achieving CR by 36 mos post maintenance 1             | 39                     | 125          | 31.2     | 38                          | 12       | 3.9    | .48 | 146 | 32.9 |
| ce a participant has achieved CR post ma              | nce by a given time pe | , the partic | nt is in | I as an event at all future |          |        |     |     |      |
| also had to occur within 38 months post randomization |                        |              |          |                             |          |        |     |     |      |  
An ancillary study, PRIMeR, used MFC to conduct MRD assessments on the BMT CTN
0702 study. Patients were enrolled on a national 3-arm RCT[15] comparing 1) tandem autologous HCT, 2) single autologous HCT and 3) single autologous HCT, 4 cycles of lenalidomide, bortezomib, dexamethasone consolidation (auto+RVD); all 3 treatment arms included continuous lenalidomide maintenance until MM progression. A total of 437 of 758 patients enrolled in STAMiNA provided consent and had at least one analyzable sample for MRD by MFC. The MFC panel included 10 monoclonal antibodies (CD38, CD138, CD45, CD56, CD19, CD20, CD27, CD28, kappa, lambda) measured via 3 tubes of 6 colors each with a target of analyzing 2.5 × 10e5-1.5 × 10e6 events, depending on sample quality and quantity, yielding a sensitivity of 10e-5 to 10e-6. At a median follow-up of 38 months, there was no significant difference in PFS or OS by treatment arm in the subset of PRIMeR patients. Multivariate analysis of time to progression or death, adjusting for disease risk, demonstrated hazard ratios (HR) in MRD negative patients compared to MRD positive patients at baseline, premaintenance and at 1 year to be 0.66 (p=0.07), 0.48 (0<0.001) and 0.22 (p<0.001) respectively. Corresponding HRs for overall mortality were 0.81 (p=0.50), 0.77 (p=0.52) and 0.10 (0<0.001). The proportion of MRD negative patients at 1 year was highest (odds ratio 1.2) among patients randomized to the tandem autologous HCT arm. Despite better outcomes, patients with MRD negative MM at 1 year still experienced disease progression (23% vs. 56% at 38 months after autologous HCT) despite continuous lenalidomide maintenance. Data from the PRIMeR study confirms that achievement of MRD negativity at 1 year is associated with improved outcomes.[26] We hypothesize that BCMA directed chimeric antigen receptor (CAR) T-cell therapy will be successful in converting a significant proportion of patients who have had a suboptimal response to autologous HCT and maintenance into a CR and that a large proportion of them will become MRD negative.
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1.1.5 car t-cell therapy

In CAR T cell therapy for cancer, autologous T cells are genetically modified *ex vivo* to express a receptor that artificially redirects T cell specificity towards a cell-surface target specific for malignant cells.[27] Modified cells are reinfused, typically after a cycle of cytotoxic chemotherapy to deplete endogenous lymphocytes and promote *in vivo* proliferation of infused cells. The clinically active receptors developed over the last decade incorporate costimulatory signaling domains on the intracellular components, typically CD28 or 4-1BB. Multiple phase 1 studies of anti-CD19 CAR T cells demonstrated durable responses in highly refractory patients with B cell malignancies. These results led to pivotal multisite studies for two products that are now FDA-approved, tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel); Table 1.1.5 summarizes results of these key studies in pediatric/young-adult B cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). Remarkably, a substantial portion of patients with initial CR remain disease-free with long-term follow-up and may be cured. Often patients have longstanding aplasia of normal B cells, suggesting durable anti-CD19 immune surveillance. Notable toxicities observed across CAR T cell products include cytokine release syndrome (CRS)
and neurotoxicity.[28] These toxicities are typically manageable and short-lived but can be severe and life-threatening.  
| Product   | Study           | Population               | N   | ORR   | Durability                         | Ref  [29] Maude et  al. NEJM  2018   |
|-----------|-----------------|--------------------------|-----|-------|------------------------------------|--------------------------------------|
| Tisa-cel  | ELIANA          | Rel/ref ALL, age 3-23    | 75  | 81%   | 59% of responders in  rem @ M9-M12 |                                      |
| Tisa-cel  | JULIET          | rel/ref DLBCL            | 93  | 40%   | 79% of CRs in                      | [30] Schuster                        |
| CR        | remission @12m  | NEJM 2019                |     |       |                                    |                                      |
| Axi-cel   | ZUMA-1          | rel/ref  DLBCL/PMBCL/tFL | 101 | 40%   | ~70% of CRs in                     | [31] Neelapu                         |
| CR        | remission @ 12m | NEJM 2017                |     |       |                                    |                                      |  
These promising results in heavily relapsed/refractory patients have led to trials incorporating CAR T cells into earlier lines of therapy in patients with poor prognosis and inadequate response to standard first-line therapy. The ZUMA-7 study is randomizing NHL patients who fail to achieve CR to standard first-line chemoimmunotherapy to axi-cel or standard salvage chemoimmunotherapy (NCT03391466). Similarly, in the upcoming BELINDA study, patients with aggressive B cell lymphoma who relapse after first-line therapy will be randomized to standard salvage therapy and auto-SCT or tisa-cel (NCT03570892) Gill et al. recently presented preliminary results of a Penn/Novartis study of anti-CD19 CARs in CLL patients responding to ibrutinib but who failed to achieve CR,
which is a marker of poor prognosis.[32] CR was achieved in 94% of patients, which compares favorably to ~25% ORR seen in several studies of anti-CD19 CARs in heavily relapsed/refractory patients.[33, 34] In addition to more favorable responses, toxicity was also less severe, likely due to the lower disease burden leading to less cytokine release syndrome. These results provide evidence in support of this protocol's design to evaluate CAR T cells in MM patients who fail to achieve CR to standard first-line therapy.
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1.1.6 anti-b cell maturation antigen

Initial studies of CAR T cell therapy for MM have targeted B cell maturation antigen (BCMA), a TNF receptor superfamily member that mediates plasma cell homeostasis through interaction with ligands in the bone marrow microenvironment. BCMA is expressed in most MM cases and on normal plasma cells but has little expression in other normal tissues.[35] Safety of targeting BCMA has been established in numerous CAR T cell studies, along with a recently published phase 1 study of an anti-BCMA antibody-drug conjugate and recently presented results with an anti-BCMA bispecific antibody.[36] No clinically significant on-target/off-myeloma toxicity has been identified in studies reported so far. Initial studies of anti-BCMA CAR T cells focused on relapsed/refractory MM patients. Three phase-1 studies have presented or published mature follow-up data, which are summarized in Table 1.1.6. Additional clinical data on bb2121, which will be utilized in this study, are provided in a subsequent section. Collectively, data from these phase-1 studies demonstrate ability of anti-BCMA CAR T cells to induce cytoreductive responses, including some MRD-negative responses, in patients with advanced and heavily treated MM (median 7-8 prior lines of therapy). With longer follow-up, however, it appears even the patients with best initial responses remain likely to progress.  
| Median                                             |                         |                         |                       |                           |                                |     |
|----------------------------------------------------|-------------------------|-------------------------|-----------------------|---------------------------|--------------------------------|-----|
| Trial                                              | N                       | prior lines  of therapy | ORR at  optimal  dose | VGPR/CR  at optimal  dose | Durability (at  optimal doses) | Ref |
| [37, 38] Ali, S.A., et  al.; Brudno, J.N., et  al. |                         |                         |                       |                           |                                |     |
| Novartis                                           | 25                      | 7                       | 64%                   |                           |                                |     |
| Penn/                                              | 36%                     | Median PFS 4.1          | [39] Cohen, A.D., et  |                           |                                |     |
| (7/11)                                             | (4/11)                  | months                  | al.                   |                           |                                |     |
| Bluebird/                                          | 43                      | 7.5                     | 96%                   | 86%                       | Median PFS 11.8                |     |
| BMS/Cel                                            | [40] Raje, N.S., et al. |                         |                       |                           |                                |     |
| (21/22)                                            | (19/22)                 | months                  |                       |                           |                                |     |
| gene  NCI                                          | 26                      | 7.5                     | 81%                   | 63%                       | Median PFS 7.1                 |     |
| (13/16)                                            | (10/16)                 | months                  |                       |                           |                                |     |
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1.1.7 rationale for car t-cells

Emerging evidence suggests that the health of the T cells used in CAR T cell manufacturing is the main determinant of response. In an analysis of relapsed/refractory CLL patients treated with anti-CD19 CAR T cells, the phenotype of the T cells obtained at leukapheresis was the only pre-treatment patient- or disease-specific parameter associated with response. Specifically, higher frequency of a memory T cell subset defined by the CD8+ CD45RO- CD27+ phenotype was most strongly associated with favorable clinical response and more potent manufactured product.[41] Similarly, in MM patients treated on the Penn/Novartis anti-BCMA CAR study, both higher CD8+ CD45RO- CD27+ frequency and higher CD4/CD8 ratio were strongly associated with favorable response, and no other clinical features were identified as predictive of response.[42] A subsequent analysis by the Penn group showed that CD8+ CD45RO- CD27+ frequency, CD4/CD8 ratio, and proliferative response to ex vivo stimulation were all significantly higher in leukapheresis products obtained after first-line therapy compared with those obtained from the heavily relapsed/refractory treated on their phase 1 anti-BCMA CAR T cell study.[43]
The MSKCC group has shown that CD4/CD8 ratio inverts at early post-transplant time points but approaches normal in the 6-12 months after autologous stem cell transplant,[44]
which is the window for intervention targeted by this study. Based on these data, CAR T cells manufactured from products obtained after completion of first line therapy may enable more durable responses than were observed in the heavily relapsed/refractory patients treated on the phase 1 studies. The association between disease burden and toxicity observed by several groups,[38, 45] along with experience of Gill et al. cited above with antiCD19 CARs in CLL patients responding to ibrutinib, suggests that safety of CAR T cells may also be optimized if used as consolidation of early-line therapy rather than as salvage for refractory disease.
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1.1.8 idecabtagene vicleucel (ide-cel)

bb2121 is defined as an autologous T lymphocyte-enriched population that contains cells transduced with an anti-BCMA CAR lentiviral vector encoding a CAR targeting human BCMA. Anti-BCMA CAR lentiviral vector is used to transduce autologous T cells. This vector uses the murine leukemia virus-derived myeloproliferative sarcoma virus enhanced promoter to drive expression of the chimeric receptor, a multi-domain protein consisting of the extracellular antigen recognition domain (VL and VH), the CD8α hinge domain, a transmembrane domain (CD8 TM), and the intracellular CD137 co-stimulatory (4-1BB) and CD3zeta chain signaling domains. Preclinical pharmacology of bb2121 showed desirable specificity against BCMA and potent activity of the CAR T cells leading to rapid and complete elimination of BCMA expressing tumors. In vitro, bb2121 was cytotoxic against a range of MM cell lines with varying levels of BCMA expression and this activity was not inhibited by soluble BCMA at physiologic concentrations in the cultures. There was no tonic signaling of bb2121 in the absence of BCMA target engagement and no in vitro cytotoxicity induced in cell lines lacking BCMA, underscoring the specificity of bb2121 for BCMA-expressing target cells. In vivo models showed a selective and higher antitumor activity of bb2121 in comparison to bortezomib in treatment of immune- deficient mice with large established BCMA- expressing tumors with complete remission and survival rates as high as 100% in mice after a single dose of bb2121. In Phase 1 first-in-human clinical trial of bb2121 (CRB-401) in relapsed or refractory subjects, efficacy results have been observed with an acceptable safety profile. In this study, subjects with heavily pretreated relapsed or refractory (with high [>50%] BCMA expression) were treated with escalating doses (50, 150, 450, 800 x 106 CAR+ T cells) of bb2121 following lymphodepletion with fludarabine and cyclophosphamide. , Forty-three pts received bb2121 in the dose escalation and expansion phase of CRB-401. No doselimiting toxicities were observed during dose escalation. Cytokine release syndrome
(CRS) occurred in 27 of 43 (63%) treated subjects which was mild to moderate in the majority of subjects with only two cases of transient Grade 3 CRS. Neurotoxicity of any grade was observed in 14 of 43 (33%) using the System-Organ-Class (SOC) terms of dizziness, bradyphrenia, somnolence, confusional state, nystagmus, insomnia, memory impairment, depressed level of consciousness, neurotoxicity, lethargy, tremor and hallucination. Most neurologic events were grade 1/2 and likely multifactorial in nature but did include one reversible grade 4 event (2.3%) with a finding of cerebral edema and no grade 3 events. There were 5 deaths on study, 3 due to disease progression at the 50 ×
106 dose and 2 in patients treated at active doses (both were in CR from myeloma at the time of death; cardiac arrest and myelodysplasia following discontinuation). Overall response rate in 36 evaluable subjects in subjects treated at ≥ 150 × 106 CAR T-cells was 81% with a CR rate of 47% and a median duration of response of 10.9 months. Among 16 responding subjects evaluable for MRD status, all 16 subjects (100%) were MRD
negative.[46] Based on these results, a target dose of 450 x 106 CAR T-cells with a minimum acceptable dose of 150 x 106 CAR T-cells is planned for this study based on the consistent efficacy and acceptable tolerability in this dose range. Cytopenias have been observed after bb2121. As reported by Raje et al., in the recently completed phase 1 study, grade 3-4 neutropenia occurred in 32/33 subjects and grade 34 thrombocytopenia in 17/33 subjects[40]. Among those with grade 3-4 neutropenia, 31 recovered to ANC ≥ 1000/μl by week 4. Among those with grade 3-4 thrombocytopenia, 11 recovered to platelet counts ≥50,000/μl by week 4. Almost all patients had recovered to these thresholds by week 12 (Figure 1.1.8). Possible etiologies for the prolonged cytopenias include cyclophosphamide + fludarabine in the setting of weak marrow reserve from relapsed/refractory myeloma and extensive prior therapy and myelosuppressive effects of cytokine release syndrome. Refer to the bb2121 Investigator's Brochure (IB) for detailed information concerning the available pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) profile of the investigational product (IP).
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1.2 study specific information

Based on the efficacy data of bb2121 in the setting of relapsed refractory MM, we hypothesize that this agent will be effective in improving the response of patients with myeloma that have not achieved a VGPR or better despite post-transplant maintenance. We propose to conduct a multicenter phase II study of bb2121 therapy in patients with myeloma who have failed to achieve a VGPR after high dose melphalan and autologous HCT followed by at least 6 months of lenalidomide maintenance. The primary objective is to assess the impact of bb2121 therapy on improving the depth of response in these patients. Secondary endpoints include determining the effect of therapy on PFS, MRD, incidence of cytokine release syndrome (CRS), incidence of prolonged cytopenias, incidence of neurotoxicity, non-relapse mortality, overall survival. Additionally, this study includes several immunologic endpoints to understand the effect of bb2121 and the impact of expansion and persistence on outcomes.
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1.3 rationale for study

Depth of response is an important surrogate marker for PFS and OS in patients with MM. With the currently available 4 drug induction therapy of daratumumab, bortezomib, lenalidomide and dexamethasone only 60% of patients achieve a CR of which 70 to 80% are MRD negative. Yet, patients who do not achieve this level of response after transplantation experience a higher rate of treatment failure. The BCMA targeted CAR genetically modified T cell bb2121 has shown dramatic responses in patients with relapsed refractory MM. Thus, it is logical to explore this agent to upgrade the response for patients with myeloma that have failed to achieve a complete response to primary therapy (i.e., VGPR or less). We postulate that treatment with bb2121 will result in further major responses in this patient population. The results of this study will allow us to plan a larger more definitive trial.
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chapter 2 2 study design

This is a single-arm, phase II multi-center clinical trial to assess the ability of BCMA directed CAR-T therapy to improve response in MM patients who have failed to achieve at least VGPR after first-line therapy (induction followed by high-dose melphalan, autologous stem cell transplant and maintenance lenalidomide). Prior to enrollment, patients must have had an autologous HCT and initiated lenalidomide-based maintenance with a response of less than CR (i.e., VGPR or less) (in comparison to preinduction status). Eligible patients will undergo leukapheresis, receive lymphodepleting
(LD) chemotherapy followed by infusion of BCMA directed CAR-T cell therapy. Subjects will resume maintenance lenalidomide beginning at least 30 days after CAR-T cell infusion assuming they have recovered from the infusion and certain hematologic criteria have been met. Subjects will be followed on this protocol for one year.
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2.2 hypothesis and study objectives

Infusion of bb2121 will result in a significant reduction in myeloma tumor burden as documented by the achievement of a complete response in patients who failed to achieve a CR after high dose melphalan and maintenance therapy.
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2.2.2 primary objective

The primary objective of this trial is to evaluate the efficacy of BCMA CAR T cell therapy to improve the response in patients who received an upfront autologous HCT and lenalidomide maintenance . The primary endpoint is 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.
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2.2.3 clinical secondary objective

Clinical secondary objectives include: Assessment of disease progression, best disease response as described by conversion to MRD negativity and upgrade in clinical disease response, non-relapse mortality, progression free survival, incidence of CRS, incidence of prolonged cytopenias, and incidence of neurotoxicity.
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2.2.4 exploratory objectives

Exploratory objectives to be described include: Incidence of toxicities greater than or equal to grade 3 per CTCAE version 5.0, incidence of infections per protocol-specific MOP, feasibility of reinitiating maintenance, overall survival, disease response, CAR Tcell Expansion, CAR T-cell persistence, BCMA expression, immune reconstitution
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2.3 patient eligibility

Patients must meet specified eligibility criteria outlined in section 2.3.1 and 2.3.2 prior to initial enrollment. Additional criteria must also be met to continue to successive stages of the protocol. 2.3.1 Initial Inclusion Criteria Patients must meet the following eligibility criteria prior to enrollment on the study and proceeding with leukapheresis:  
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 treatment1.  
3. Patients must have received initial systemic anti- myeloma therapy consisting of induction therapy and consolidation with high-dose melphalan (>140 mg/m2) followed by an auto HCT (minimum cell dose of 2x106 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 2x106 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.  
a. For patients who were receiving maintenance containing lenalidomide, they 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.  
7. Patients must have a VGPR or less (Section 3.1) in reference to time of initiation of initial systemic anti-myeloma therapy1 at study enrollment.  
8. Patients must have Karnofsky performance greater than or equal to 70. 9. Patients must have recovered to Grade 1 or baseline of any non-hematologic toxicities due to prior treatments, excluding Grade 2 neuropathy.  
10. Absolute neutrophil count (ANC) greater than or equal to 1,500/mm3 without filgrastim use in the prior 14 days.  
11. Platelet count greater than 100,000/mm3 (without platelet transfusion in the previous 7 days or thrombopoietin mimetics in the previous 28 days)
12. Hemoglobin greater than 9 g/dL (without red blood cell transfusion in the previous 7 days)
13. Creatinine Clearance (CrCl) greater than or equal to 60 mL/min, measured or estimated by Cockcroft-Gault equation.
14. Corrected serum calcium less than or equal to 13.5 mg/dL 15. Oxygen saturation greater than 92% on room air 16. 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.
17. International ratio (INR) or partial thromboplastin time (PTT) less than 1.5 x ULN.  
18. Cardiac Function: left ventricular ejection fraction greater than 45% by echocardiogram or MUGA.  
19. 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.
20. 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.
21. 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.  
2.3.2 Initial Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:  
1. Patients with a prior allogeneic hematopoietic cell transplant 2. Patients with disease progression (see Section 3.1.2 for disease progression definition) at any time prior to enrollment 3. Patients receiving any of the following less than 14 days prior to enrollment a. Plasmapheresis b. Major surgery (as defined by the investigator) c. Radiation therapy other than local therapy for MM-associated bone lesions d. Use of any systemic anti-myeloma drug therapy1 (with the exception of lenalidomide maintenance)
e. Any investigational agents f. Corticosteroids (Physiologic replacement, topical, intranasal and inhaled steroids are permitted)
4. Patients with known Central Nervous System (CNS) involvement with MM 5. Patients with a prior organ transplant requiring systemic immunosuppressive therapy 6. Patients who previously experienced toxicities related to lenalidomide resulting in permanent treatment discontinuation 7. Patients who experienced thromboembolic events while on full anticoagulation during prior therapy with an immunomodulatory agent (IMiD)
8. Patients unwilling to take DVT prophylaxis while on lenalidomide maintenance 9. Patients with history of greater than or equal to Grade 2 hemorrhage within 30 days of enrollment 10. Patient requiring ongoing treatment with chronic, therapeutic dosing of anticoagulants (e.g., Warfarin, low molecular weight heparin, Factor Xa inhibitors)
11. 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 12. 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 13. 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.  
14. 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 15. 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 16. 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.  
17. 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.  
18. Patients with previous history of treatment with any gene therapy-based therapeutic for cancer or investigational cellular therapy for cancer or BCMA targeted therapy 19. 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.  
20. Female patients who are pregnant (positive beta-HCG), or breastfeeding, or who intend to become pregnant during participation in the study 21. Patient with known allergy or hypersensitivity to any of the study medications, their analogues, or excipients in the various formulations of any agent.  
22. Patient with serious medical of psychiatric illness likely to interfere with participation on this clinical study 23. Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment.
24. Patients unwilling or unable to provide informed consent 25. Patients unable or unwilling to return to the transplant center for treatment and follow up.  
2.3.3 Patient Eligibility Criteria for LD Chemotherapy
To be eligible to start LD chemotherapy, patients must meet the following criteria:  
1. Females of childbearing potential (FCBP) must have a negative serum pregnancy test less than 7 days prior to LD chemotherapy 2. Platelet count greater than or equal to 100,000/mm3 (without platelet transfusion within 7 days or thrombopoietin mimetics within 28 days)
3. Absolute neutrophil count (ANC) greater than or equal to 1,500/mm3 (without filgrastim within 72 hours)
4. Hepatic function:
a. Serum aspartate aminotransferase (AST) and alanine aminotransferase
(ALT) less than AND equal to 2.5 × upper limit of normal (ULN)
b. Serum total bilirubin less than or equal to 2 × ULN. Patients who have been diagnosed with Gilbert's disease are permitted to exceed the defined bilirubin value of 2 x ULN
5. Creatinine Clearance (CrCl) greater than or equal to 45 mL/min, measured or estimated by Cockcroft-Gault equation.
6. International ratio (INR) or partial thromboplastin time (PTT) less than 1.5 x ULN 7. No history of greater than or equal to Grade 2 hemorrhage within 30 days  
8. Not receiving ongoing treatment with chronic, therapeutic dosing of anticoagulants
(e.g., Warfarin, low molecular weight heparin, Factor Xa inhibitors)
a. Patients not meeting this criterion may still be eligible to initiate LD
chemotherapy with the approval of the Protocol Chairs and/or Officer
9. Patient must have no presence of active/uncontrolled infection requiring systemic therapy. Prophylactic antimicrobials are allowed.  
10. No intercurrent illness or toxicity that would place the subject at undue risk of proceeding to LD chemotherapy  
11. Patients must not be taking any of the prohibited medications as described in Section 2.7.2 including therapeutic doses of corticosteroids (defined as greater than 20
mg/day prednisone or equivalent) within 72 hours prior to LD chemotherapy. Physiologic replacement, topical, intranasal and inhaled steroids are permitted 12. No active urinary outflow obstruction  
13. No evidence of disease progression since enrollment
14. Availability of manufactured cells 2.3.4 Patient Eligibility Criteria for CAR T-Cell (bb2121) Infusion Administration will be delayed if a subject meets at least one of the following criteria on the day of scheduled CAR T-cell infusion1:  
1. Suspected or active systemic infection 2. Onset of fever greater than or equal to 38°C/100.4°F 3. Requirement for supplemental oxygen to keep saturation greater than 91% 4. Cardiac arrhythmia not controlled with medical management 5. Hypotension requiring vasopressor support 6. New onset or worsening of other non-hematologic organ dysfunction greater than or equal to Grade 3 7. Taking any of the prohibited medications as described in (Section 2.7.2)
8. Significant worsening in clinical status compared to initial eligibility criteria that would, in the opinion of the treating physician, increase the risk of adverse events associated with CAR T-cell infusion.  
2.3.5 Patient Eligibility Criteria for Maintenance Therapy After bb2121 Infusion between Day 30 and Prior to or on Day 90
Patients must have sufficiently recovered from CAR T-cell therapy at the time of initiation of maintenance therapy. Patients will be initiated on lenalidomide maintenance if they meet the following criteria:  
1. Platelet count greater than or equal to 75,000/mm3 (without platelet transfusion in prior 7 days or use of thrombopoietin mimetics within 28 days)
2. ANC greater than 1,000/mm3 without growth factor support in the last 14 days.  
3. Must have recovery from CAR T-cell toxicities (specifically cytokine release syndrome and neurotoxicity to Grade 1 or baseline of non-hematologic CART related toxicities, with the exception of Grade 2 neuropathy)
4. No active, uncontrolled infections 5. No evidence of disease progression since initial enrollment on the study 6. Patient must be registered into the mandatory Lenalidomide REMS program and be willing and able to comply with the requirements of the REMS® program.  
7. Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Lenalidomide REMS program.  
2.3.6 Patient Eligibility Criteria for Maintenance Therapy After bb2121 Infusion after Day 90 and Prior to Day 180 1. Platelet count greater than or equal to 50,000/mm3 (without platelet transfusion within 7 days or thrombopoietin mimetics within 28 days).  
2. ANC greater than 1000/mm3 (filgrastim allowed) 3. Must have recovery from CAR T-cell toxicities (specifically cytokine release syndrome and neurotoxicity to Grade 1 or baseline of non-hematologic CAR-T related toxicities, with the exception of Grade 2 neuropathy)
4. No active, uncontrolled infections 5. No evidence of disease progression since initial enrollment on the study 6. Patient must be registered into the mandatory Lenalidomide REMS program and be willing and able to comply with the requirements of the REMS® program.  
7. Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Lenalidomide REMS program.
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2.4 treatment plan 2.4.1 treatment

Patients must have received initial systemic anti- myeloma therapy consisting of induction therapy and consolidation with high-dose melphalan (>140 mg/m2) followed by an auto HCT (minimum cell dose of 2x106 CD34+ cells/kg (actual body weight) within 12 months from initiation of systemic anti-myeloma therapy. Patients also must have initiated posttransplant maintenance therapy with lenalidomide for 3 months and have achieved less than CR (i.e., VGPR or less) to this prior sequence of therapies at the time of enrollment. Patients must discontinue lenalidomide maintenance at least two weeks (14 days) prior to leukapheresis on BMT CTN 1902. Lenalidomide maintenance will be held from two weeks prior to leukapheresis until after CAR T-Cell infusion. Maintenance will be reinitiated per section 2.4.6 once the patient meets criteria in section 2.3.5 or 2.3.6.
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2.4.2 leukapheresis

Following the screening assessments and enrollment, if the subject is eligible to participate in the study, subjects will undergo a leukapheresis collection to obtain a sufficient quantity of peripheral blood mononuclear cells (PBMCs) for the production of the bb2121 investigational product. Should a technical issue arise during the procedure or in the processing of the product, the subject may have a second collection procedure performed. More than one bb2121 product lot may be combined to meet the protocol target dose range. Subjects must continue to meet screening eligibility requirements for repeat leukapheresis. Leukapheresis should occur approximately 14 days after initial enrollment. The BMT CTN should be notified if leukapheresis cannot occur within approximately 14 days of initial enrollment. The leukapheresis product must be shipped in a sterile container to BMS/Celgene's manufacturing facility. CAR-T manufacturing will be initiated upon receipt of patient apheresis material; no notification to proceed with manufacturing is required. Treatment with the following therapies after enrollment and prior to leukapheresis is not permitted:
x Any prior systemic therapy1, including experimental agents, for MM  
x Corticosteroids. Physiologic replacement topical, intranasal and inhaled steroids are permitted.  
x Localized radiation therapy to control pain is permitted.
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2.4.3 car t-cell (bb2121) manufacturing

All bb2121 for this clinical trial will be manufactured by BMS/Celgene and are required to meet pre-defined release criteria. Any out of specification product must be communicated to the BMT CTN DCC to be escalated per the designated review pathway and addressed. In the event any lot release criteria is out of specification, the event must be reported to the BMT CTN via the Adverse Event Form per the instructions in section 4.5.5. The product will be reviewed by an independent non-conforming product monitor and escalated to the FDA by the BMT CTN in order to decide whether the product can be administered or whether a new manufacturing procedure will be performed. The product must not be infused until FDA approval is received and communicated by the BMT CTN to the site. CAR T-Cell (bb2121) manufacturing will be initiated at BMS/Celgene following leukapheresis. If there is any reason that the investigator feels that the patient will NOT be eligible for LD chemotherapy or bb2121 infusion within the allotted study window, he/she should notify the study team immediately.
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2.4.4 ld chemotherapy

LD chemotherapy will be initiated 5 days prior to planned bb2121 infusion (refer to Table 2.4.4 for LD treatment plan). Timing of LD chemotherapy will also be coordinated with BMS/Celgene in order to confirm that the bb2121 product is ready. The patient must meet criteria in section 2.3.3 in order to initiate LD Chemotherapy. Chemotherapy will be administered per institutional guidelines. Patients will receive cyclophosphamide 300 mg/m2/day from Day -5 to Day -3 via intravenous infusion over 30 minutes (Table 2.4.4) and fludarabine 30 mg/m2/day from Day -5 to Day -3 via infusion over 30 minutes. The order of daily dose of fludarabine and cyclophosphamide administration during LD chemotherapy can be reversed according to institutional practices. On Day 0, patients will receive the bb2121 infusion.
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2.4.4.1 renal insufficiency dose adjustment

Fludarabine will be dose reduced based on renal function. Patients with creatinine clearance 50 to 70 mL/min should receive a 20% dose reduction (fludarabine 24 mg/m2) of each daily fludarabine dose. Patients with creatinine clearance (CrCl) of 45 to 49 mL/min should receive a 40% dose reduction (fludarabine 18 mg/m2) of each daily fludarabine dose. Fludarabine should not be administered to patients with severely impaired renal function (creatinine clearance less than 45 mL/min).  
| Drug                                                                                   | Dose                                           | Day -   | Day -   | Day -   | Day   |
|----------------------------------------------------------------------------------------|------------------------------------------------|---------|---------|---------|-------|
| 5                                                                                      | 4                                              | 3       | 0       |         |       |
| Cyclophosphamide                                                                       | 300 mg/m2/day IV infusion over 30 min          | X       | X       | X       |       |
| Fludarabine                                                                            | 30 mg/m2/day IV infusion over 30 minutes       |         |         |         |       |
| administered immediately after cyclophosphamide*                                       | X                                              | X       | X       |         |       |
| bb2121 Infusion                                                                        | Minimum dose of 150 × 106 CAR-T cells/infusion | X       |         |         |       |
| *See section 2.4.4.1 for dose reduction guidelines in the event of renal insufficiency |                                                |         |         |         |       |
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2.4.5 car t-cell (bb2121) infusion

All bb2121 cellular products must meet pre-defined release criteria. Upon completion of LD chemotherapy, subjects will be infused with bb2121 on Day 0 at a target dose of 450
× 106 CAR-T cells/infusion or, in the event of dose-de-escalation per Section 5.1, 300 x 106 CAR T cells. Products that are safe to infuse but out of specification will be escalated for review as included in section 2.4.3. The product must not be infused until FDA approval is received and communicated by the BMT CTN to the site. However, considerations of a second leukapheresis for a second course of manufacturing will be made on a case by case basis. See Appendix G for additional details regarding bb2121 infusion process.
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2.4.5.1 delay in bb2121 infusion

Subjects who do not meet eligibility to receive bb2121 (section 2.3.4) on the scheduled Day 0 will delay infusion until all criteria in section 2.3.4 are met. The patient should be re-assessed for eligibility to receive bb2121 daily until the criteria are met. Infusion may be delayed up to 14 days. If subjects do not meet criteria to receive bb2121 within 7 days of the originally planned infusion day, the BMT CTN DCC must be notified in order to escalate per the designated review pathway. However, infusion may continue without approval. For delays beyond 14 days, the BMT CTN 1902 protocol chairs and/or officer will decide whether bb2121 infusion is permitted and whether LD chemotherapy must be readministered. Final decision on such delayed bb2121 infusion will rest with the BMT CTN
1902 protocol chairs and/or protocol officer.
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2.4.5.2 pre-medication

Pre-medication will occur approximately 30 minutes prior to the infusion of bb2121 and will include acetaminophen 650 mg orally and diphenhydramine 12.5 mg IV or 25 to 50 mg orally (or equivalent). Subjects should not receive corticosteroids as pre-medication. 2.4.5.3 Infusion Modifications for Infusion Reaction Patients should not receive steroids after infusion. The following guidelines should be followed for infusion reactions:  
x Grade 1: administer symptomatic treatment; continue bb2121 infusion at the same dose and rate x Grade 2: administer symptomatic treatment; continue bb2121 with a reduced rate of administration x Grade 3: stop administration of bb2121, administer symptomatic treatment, and resume at a reduced rate of administration only after symptoms resolve. If Grade 3 reaction recurs, discontinue bb2121 infusion.  
x Grade 4: discontinue administration of bb2121 and administer symptomatic treatment as necessary; no further bb2121 should be administered.
2.4.6 Maintenance Treatment All patients who meet the eligibility criteria to proceed with maintenance in sections 2.3.5 or 2.3.6 will re-start maintenance therapy with lenalidomide between 30 and 180 days after CAR T-cell infusion. Initiating maintenance therapy outside of this range may be permitted with prior approval from the Protocol Chairs and/or Officer. The BMT CTN DCC must be notified in advance in order to escalate per the designated review pathway. Eligibility criteria for initiation of maintenance therapy and corresponding starting dose requirements are summarized in Table 2.4.6A. All subjects who start maintenance therapy will receive lenalidomide monotherapy; subjects who had received posttransplant lenalidomide maintenance/consolidation in combination with other agents prior to enrollment will not resume the prior combination regimen after CAR T cell infusion. For patients that initiate maintenance between Day 30 and 90 post CAR T-cell infusion, Lenalidomide will be administered initially at a dose of 5 mg per day for 21 days every 28 days; dose will be increased to 10 mg daily with cycle 2 if patients previously tolerated this dose prior to enrollment and if no significant hematologic toxicity (as determined by investigator) developed on the 5 mg dose. Patients will continue lenalidomide until they reach 12 months from initiation of therapy or until one of the criteria in section 2.4.6.1 applies. For patients that initiate maintenance between Day 91 and 180 post CAR T-cell infusion, Lenalidomide will be administered initially at a dose of 5 mg per day for 21 days every 28 days and continue at this dose for minimum of 3 cycles before dose increase to 10 mg will be considered. Patients that require stem cell reinfusion may continue with maintenance therapy 30-60 days after the reinfusion, provided they meet eligibility criteria to proceed with maintenance therapy by Day 180 post CAR T-cell infusion. DVT prophylaxis for patients will be given per institutional guidelines. Patients who stop maintenance therapy for any reason prior to 12 months from initiation of maintenance will continue to be followed per protocol for 12 months post bb2121infusion. Upon completion of protocol specified maintenance therapy, patients will be treated at the investigator's discretion. However, it is recommended that patients continue receiving lenalidomide as per standard of care.  
| Eligibility and Dosing Requirements for Initiation of Maintenance Therapy Post CAR-T Infusion  Days post CAR T Infusion ≥ 30 and ≤ 90 > 90 and ≤ 1801 > 180  Hematologic Eligibility Requirements2  Platelet Count3 > 75,000/mm3 > 50,000 /mm3 > 50,000/mm3  ANC4 > 1000/mm3 > 1000/mm3 > 1000/mm3  10mg daily for 21  of 28-day cycles  (first cycle at 5  mg)5 5mg daily for 21 of  Cannot initiate  28-day cycles6 maintenance7 Starting Lenalidomide Dose 1 Stem cell re-infusion may be performed per the cytopenia management guidelines in Appendix I prior to day 180 to   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
2.4.6.1 Lenalidomide Maintenance Dose Modifications and Holds Lenalidomide dose will be adjusted for toxicity. Table 2.4.6C describes the dose reduction steps to be utilized during maintenance therapy. In the presence of lenalidomide-related toxicities (Table 2.4.6B), the study drug will be held until the toxicity resolves then restarted at a reduced dose as described in Table 2.4.6D. If lenalidomide is held for greater than 8 weeks for any reason, the BMT CTN DCC must be notified in order to escalate per the designated review pathway. Approval must be obtained prior to re-starting lenalidomide. If lenalidomide is held for greater than or equal to 14 days for any reason, it will be considered a Protocol Deviation (PD) and will be reported following the BMT CTN DCC PD process.  
| Maintenance Therapy for Non-Hematologic Toxicities                                                                    |                                                                                                                                                                                                                                                                                                                                              |
|-----------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade by NCI CTCAE v5.0 1                                                                                             | Action                                                                                                                                                                                                                                                                                                                                       |
| Grade 3 neutropenia  associated with fever                                                                            |                                                                                                                                                                                                                                                                                                                                              |
| (temperature ≥ 38. 5º C)  or Grade 4 neutropenia                                                                      | Hold lenalidomide. Follow CBC weekly.  If the toxicity resolves to <grade 2 restart lenalidomide at next lower  dose level.  If neutropenia is the only toxicity for which a dose reduction is  required, granulocyte growth factors could be considered at the  discretion of the treating physician and the lenalidomide dose  maintained. |
| Thrombocytopenia                                                                                                      | Hold lenalidomide. Follow CBC weekly.                                                                                                                                                                                                                                                                                                        |
| (platelet count < 30,000/mm³)                                                                                         | If the toxicity resolves to ≤ grade 2 restart lenalidomide at next lower  dose level.                                                                                                                                                                                                                                                        |
| Non-blistering rash  Grade 3                                                                                          |                                                                                                                                                                                                                                                                                                                                              |
| (Generalized rash ≥ 25% BSA)                                                                                          | Hold lenalidomide: Follow weekly. Treatment with antihistamine  may be initiated at the discretion of the investigator.  If the toxicity resolves to ≤ grade 1 restart lenalidomide at next lower  dose level.                                                                                                                               |
| Non-blistering rash                                                                                                   | Discontinue lenalidomide permanently. Continue to follow the                                                                                                                                                                                                                                                                                 |
| Grade 4                                                                                                               | patient per-protocol                                                                                                                                                                                                                                                                                                                         |
| Desquamating (blistering) rash                                                                                        | Discontinue lenalidomide permanently. Continue to follow the                                                                                                                                                                                                                                                                                 |
| any Grade                                                                                                             | patient per-protocol                                                                                                                                                                                                                                                                                                                         |
| Venous thrombosis/embolism  ≥ Grade 3 (DVT or cardiac thrombosis;  intervention indicated)                            | Hold lenalidomide and start anticoagulation per institutional  guidelines. Restart therapy and maintain dose level.                                                                                                                                                                                                                          |
| Other non-hematologic toxicity  assessed as Lenalidomiderelated  ≥ Grade 3                                                                                                                       | Hold lenalidomide.  If the toxicity resolves to ≤ grade 2 restart lenalidomide at next lower  dose level.                                                                                                                                                                                                                                    |
| Hyperthyroidism or                                                                                                    | Hold lenalidomide.                                                                                                                                                                                                                                                                                                                           |
| Hypothyroidism                                                                                                        | Evaluate etiology and initiate appropriate therapy. Restart lenalidomide at next lower dose level.                                                                                                                                                                                                                                           |
| Pregnancy2                                                                                                            | Discontinue lenalidomide study drug.                                                                                                                                                                                                                                                                                                         |
| 1Please consult NCI CTCAE version 5.0 for Grade descriptions. The "≥ Grade 3" descriptions listed above are  minimums |                                                                                                                                                                                                                                                                                                                                              |
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table 2.4.6c lenalidomide dose reduction

| Lenalidomide Dose Reduction Steps for Non-Hematologic Toxicity   |                                        |
|------------------------------------------------------------------|----------------------------------------|
| Dose at Time of Toxicity                                         | Dose reduction                         |
| 10 mg daily for 21 days every 28 days                            | 5 mg daily for 21 days every 28 days   |
| 5 mg daily for 21 days every 28 days                             | 2.5 mg daily for 21 days every 28 days |
| 2.5 mg daily for 21 days every 28 days                           | Discontinue Lenalidomide               |  
2.4.6.2 Lenalidomide Maintenance Dose Re-Escalation Patients that initiate lenalidomide at a dose of 5mg daily for 21 days every 28 days may be re-escalated as shown in Table 2.4.6D to a maximum of 10 mg daily for 21 days every 28 days. If a dose reduction has occurred and ANC ≥ 1000/μL and platelet count is ≥ 75,000/μL, the study drug dose may be re-escalated as shown in Table 2.4.8D, one step per cycle to a maximum of 10 mg daily for 21 days every 28 days.
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table 2.4.6d lenalidomide dose re-escalation

Current Patient Dose Dose Re-Escalation  
2.5 mg daily for 21 days every 28 days 5 mg daily for 21 days every 28 days 5 mg daily for 21 days every 28 days 10 mg daily for 21 days every 28 days 10 mg daily for 21 days every 28 days No more dose escalations permitted
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2.5 risks and toxicities

All organ toxicities will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. CRS and neurotoxicities will be graded according to the ASTCT consensus grading criteria (Appendix H). 2.5.1 Leukapheresis Risks Risks of this collection are related to placement of an intravenous leukapheresis catheter that can be associated with bleeding and pain. The leukapheresis procedure has a risk of hypocalcemia, thrombocytopenia, anemia, leukopenia and bleeding diathesis. 2.5.2 LD Chemotherapy Risks Common side effects of fludarabine and cyclophosphamide include bone marrow cytopenias and immune suppression which increase the risk of bleeding and infection and may be exacerbated by bb2121 treatment.
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2.5.2.1 cyclophosphamide risks

Cyclophosphamide side effects include:  
x Cardiac and vascular: heart failure (which can result in edema, effusion, dyspnea x Cutaneous: alopecia, rash, hyperpigmentation of skin and nails x Gastrointestinal: nausea, vomiting, diarrhea, anorexia, abdominal pain, mucositis, stomatitis x General: lethargy x Hematologic: leukopenia, thrombocytopenia, anemia x Pulmonary: pulmonary fibrosis x Endocrine: amenorrhea, gonadal function impairment, sterility, Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) - with associated cerebral edema x Genitourinary: hemorrhagic cystitis x Miscellaneous: infection, allergic reaction including anaphylaxis, secondary malignancy
2.5.2.2 Fludarabine Risks Fludarabine side effects include:  
x Gastrointestinal: vomiting, anorexia, nausea, mucositis x General: fatigue, fever, chills x Hematologic: anemia, thrombocytopenia, neutropenia x Hepatic: increased liver function tests x Neurologic: paresthesia, confusion, seizure, agitation, visual disturbances, pain x Pulmonary: cough, shortness of breath x Renal: renal impairment, hematuria x Miscellaneous: infection, general organ damage
2.5.3 CAR T Therapy (bb2121) Toxicities Administration of bb2121 may cause infusion reactions, such as fever, rigors, rash, urticaria, dyspnea, hypotension, and/or nausea.
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2.5.3.1 cytokine release syndrome (crs)

Administration of CAR T cells is associated with CRS and it has been reported frequently following treatment with bb2121. CRS is a potentially serious disorder associated with uncontrolled activation and proliferation of CAR T cells and associated cytokine secretion. CRS is characterized by high fever, fatigue, nausea, headache, dyspnea, tachycardia, rigors, hypotension, hypoxia, myalgia/arthralgia, anorexia, and neurologic abnormalities (e.g., altered mental status, aphasia, altered level of consciousness, and seizures or seizure-like activity). Laboratory abnormalities may include cytopenias, coagulopathy, electrolyte, renal and liver function abnormalities as well as C-reactive protein (CRP), ferritin and cytokine elevations. Organ dysfunction, in particular, cardiac, pulmonary and neurologic dysfunction, can be observed as part of CRS. Refer to Appendix H for CRS grading and management guidelines.
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2.5.3.2 neurologic toxicities

CAR T-cell therapy is associated with potentially serious neurologic toxicities and lifethreatening neurotoxicity has been reported with bb2121. The etiology and optimal management of neurologic toxicities remains unclear. Neurologic symptoms may include altered mental status, aphasia, altered level of consciousness, and seizures or seizurelike activity, and can accompany CRS (precede or follow other CRS symptoms) or can occur in isolation. Refer to Appendix H for neurotoxicity management guidelines.
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2.5.3.3 macrophage activation syndrome

Macrophage activation syndrome (MAS) is a potentially serious disorder associated with uncontrolled activation and proliferation of CAR T cells and subsequent activation of macrophages. MAS is typically characterized by high-grade, non-remitting fever, cytopenias, and hepatosplenomegaly. Laboratory abnormalities found in MAS include elevated inflammatory cytokine levels, serum ferritin, soluble IL-2 receptor (sCD25), triglycerides, and decreased circulating natural killer (NK) cells. Other findings include variable levels of transaminases, signs of acute liver failure, coagulopathy, and disseminated intravascular coagulopathy. There are no definitive diagnostic criteria for MAS; it is typically diagnosed using published criteria for hemophagocytic lymphohistiocytosis.[47] While there is considerable overlap in clinical manifestations and laboratory findings between MAS and CRS, other distinguishing MAS physical findings such as hepatosplenomegaly and lymphadenopathy are not common in adult subjects treated with activated T cell therapies.
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2.5.3.4 tumor lysis syndrome

Both LD chemotherapy and bb2121 may cause tumor lysis syndrome (TLS) in subjects with high disease burden. Subjects should be closely monitored for laboratory evidence of TLS.
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2.5.3.5 plasma cell aplasia and

Plasma cell aplasia is an expected off-tumor, on-target toxicity of bb2121. The expected duration of plasma cell aplasia is unknown but may persist as long as bb2121 CAR T cells remain in the body. Prolonged plasma cell aplasia is expected to result in hypogammaglobulinemia which can also be observed as a manifestation of myeloma itself. Hypogammaglobulinemia may increase the risk of bacterial and other infections including opportunistic infections and viral reactivation. Serum immunoglobulin levels will be obtained from all subjects prior to and at regular time points following bb2121 treatment. 2.5.3.6 Replication Competent Lentivirus, Clonality and Insertional Oncogenesis Lentiviral vectors used in gene transfer are engineered to be replication-defective; however, generation of replication competent lentivirus (RCL) during manufacturing is still a possibility. Modern vector production systems have been improved to reduce the risk of RCL generation. To date, there have been no reports of RCL generated during lentiviral vector manufacturing, which may be due, at least in part, to the use of self-inactivating vectors such as the lentiviral vector used in the production of bb2121.[48]
Concern for possible neoplastic transformation due to the location of the vector integration into the host genome has arisen due to preclinical studies that have shown retrovirusmediated malignant transformation in mice[49, 50] and monkeys[51] and a single clinical study reporting development of leukemia in subjects with X-linked severe combined immunodeficiency (SCID) who received retroviral-modified CD34+ hematopoietic stem cells,[52] including one subject who died.[53] Of note, no instances of RCL generation during production or lentivirus-mediated malignant transformation in animals or subjects treated in trials of gene-modified T cells have been reported to date. Data has recently been published on the integration sites of retroviral and lentiviral vectors used for T cell modification in clinical trials.[54-56] No clonality of integration sites was observed with exception of a single case recently reported by Fraietta et al. in which the vast majority (94%) of CAR T cells at peak expansion were derived from a single transduced cell [57]. Further study on this case revealed disruption of the TET2 gene and a hypomorphic mutation in the patient's second TET2 allele. Importantly, this clonal T cell expansion seemed to be antigen-driven as the population contracted with elimination of the patients CLL and thus did not represent an oncologic transformation. Further studies identified epigenetic reprogramming instigated by TET2 disruption as the likely mechanism for the proliferative advantage exhibited by this clone[57]. Though this event did not result in malignant transformation, it supports the rationale for long-term follow-up of patients treated with genetically modified cellular therapies.
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2.5.3.7 infections

Administration of CAR T cells following LD chemotherapy is associated with risk of bacterial and opportunistic infections, and infections have been reported following treatment with bb2121. Risk factors for infection include immune dysfunction from myeloma, LD chemotherapy (i.e., fludarabine and cyclophosphamide) and associated lymphopenia and myelosuppression, and bb2121 treatment-associated toxicities. CRS may exacerbate and delay recovery from cytopenias, and treatment of CRS and neurotoxicity with corticosteroids may also increase infection risk. Finally, plasma cell aplasia following bb2121 treatment is an expected on-target toxicity of BCMA targeted CAR T cell therapies and may result in chronic hypogammaglobulinemia. Infections may include bacterial, fungal, pneumocystis, viral reactivation and symptomatic viral infections (e.g., cytomegalovirus (CMV), hepatitis B virus, respiratory viruses and other viruses). Infections may be life threatening or fatal. Death from CMV pneumonia (with low level concurrent pneumocystis infection) following treatment with bb2121 has occurred. bb2121 treated subjects will undergo frequent monitoring for recovery from cytopenias and lymphopenia for at least 6 months following bb2121 infusion.
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2.5.3.8 prolonged cytopenias

Prolonged cytopenias have been observed in MM patients after CAR T cell therapy in prior studies of bb2121 and other CAR T cell products. The etiology is likely multifactorial, with the following contributing factors: (1) myelosuppressive effects of LD chemotherapy, (2) low bone marrow reserve from prior myeloma therapy, (3) high MM disease burden in the relapsed/refractory population studied in these prior trials, and (4) CAR T cell activation and cytokine release syndrome, including macrophage activation (i.e., hemophagocytosis). In this trial, the recent myeloablative chemotherapy and AHCT may increase the risk of prolonged cytopenias compared to prior bb2121 studies, which generally did not administer bb2121 in the early post-transplant period. However, compared to the patient population on prior bb2121 studies, patients on this study will have received less prior MM therapy and are expected to have a lower overall disease burden; these factors may decrease risk of prolonged cytopenias. Guidelines for evaluation and management of prolonged cytopenias after bb2121 are described in Appendix I.
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2.5.4 lenalidomide related toxicities

Common toxicities described for lenalidomide include:
x Cardiac: hypotension  
x Constitutional: Weakness, insomnia, rigors, chills, sweating, weight loss and fever
x Dermatologic: rash, dry skin, itching x Endocrine: hypothyroidism  
x Gastrointestinal: Constipation, dehydration, dry mouth, diarrhea, dyspepsia, nausea, vomiting and stomatitis x Hematologic: anemia, neutropenia, leucopenia, lymphopenia and thrombocytopenia; thromboembolic events (deep vein thrombosis and pulmonary embolism)
x Infection x Metabolic: hypokalemia, liver damage x Musculoskeletal: arthralgia, back/neck pain, joint pain, muscle cramp and weakness x Neurologic: Somnolence, dizziness, headache, tremor, asthenia, paresthesia, and numbness x Pulmonary: cough, dyspnea, pneumonitis x Renal: increased creatinine, renal failure x Reproductive: teratogenicity and miscarriage x Subsequent neoplasms
Pregnancy reporting: See Section 4.5, Adverse Event Reporting. Other instructions related to lenalidomide: During maintenance, only one cycle (maximum 28-day supply) of therapy may be dispensed to the patient each month. If a dose of lenalidomide is missed, it should be taken as soon as possible on the same day. If it is missed for the entire day, it should not be made up. Patients taking more than the prescribed dose of lenalidomide should be instructed to seek emergency medical care if needed and contact study staff immediately. See Section 4.5 and Appendix C (Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods) and D (Lenalidomide REMS program).
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2.5.5 subsequent neoplasms and long

Autologous HCT and lenalidomide are standard of care interventions that have been known to increase the risk for subsequent neoplasms. The investigational intervention included in this trial may further increase risk of subsequent neoplasms. According to regulatory requirement related to genetically modified cellular products, recipients are required to be followed for 15 years to primarily monitor the development of subsequent neoplasm (Section 4.1.2) . Patients will co-enroll in the long term follow up protocol using the Center for International Blood and Marrow Transplant Research (CIBMTR) Cellular Therapy Registry (Chapter 4) similar to the mechanism proposed for commercial Ide-cel.
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2.6 supportive care and toxicity

2.6.1 LD Chemotherapy Supportive Care and Toxicity Management The following medications/supportive therapies are recommended during LD chemotherapy, as applicable:  
x Pre-hydration will be administered per institutional guidelines prior to initiating LD
chemotherapy. Hydration post LD chemotherapy may be administered if required per institutional guidelines.  
x The antiemetic regiment will be based on institutional guidelines. Dexamethasone or other systemic steroids are not permitted.  
x The use of ondansetron, oral or IV, or similar serotonin inhibitor, on days –5, -4, and -3 prior to chemotherapy is suggested.  
x Chemotherapy-induced cytopenias should be managed with myeloid growth factor, blood product transfusion support, and prophylactic anti-microbials according to local institutional guidelines. Myeloid growth factor may be administered per institutional guidelines. It is recommended that myeloid growth factor be administered per physician discretion no earlier than 7 days post bb2121 infusion.
2.6.2 CAR T-cell (bb2121) Infusion Supportive Care and Toxicity Management 2.6.2.1 Infusion Reaction Management Mild infusion reactions should be managed expectantly with antipyretics, antihistamines, and anti-emetics. Corticosteroids should be avoided because of the potential impact on efficacy of infused bb2121. Rigors may be treated with meperidine (Demerol®).
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2.6.2.2 prolonged or recurrent cytopenia

A high index of suspicion is warranted in the event of prolonged or recurrent cytopenias, especially in conjunction with hypogammaglobulinemia, CD4 lymphopenia (CD4 less than 200/μl) and/or recent use of corticosteroids. Viral reactivation and other serious opportunistic infections should be considered in these settings and prophylactic, preemptive or symptomatic treatment with anti-microbial, anti-fungal, anti-pneumocystic and/or antiviral therapies should be considered, per local institutional guidelines. Refer to Appendix I for Cytopenia Management Guidelines.
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2.6.2.3 cytokine release syndrome management

Supportive management for CRS includes anti-pyretic for fever control, intravenous fluids to vasopressor agents for hypotension and supplemental oxygen to positive pressure ventilatory support for hypoxia. In some cases, tocilizumab, an anti-IL-6R antibody, will be required for treatment of moderate to severe CRS. Tocilizumab must be available at the site prior to infusion of the subject. Tocilizumab is administered at a dose of 8 mg/kg (maximum dose 800 mg). Other anti-IL-6 agents could be considered in the event of severe CRS not responding to tocilizumab and discussion with the protocol chairs is recommended. Dosing of any other anti-IL-6 agent should be per prescribing information. Refer to Appendix H for detailed CRS management guidelines. 2.6.2.4 Neurologic Symptom Management Neurologic symptoms may begin 3 to 23 days (median 10 days) after CAR T cell infusion and in severe cases may require admission to the ICU for frequent monitoring, respiratory support, or intubation for airway protection. Any signs or symptoms of neurotoxicity (other than headache) should prompt hospitalization. Patients with neurotoxicity can be treated with corticosteroids, anti-convulsive agents and in rare cases cyclophosphamide. Refer to Appendix H for neurotoxicity management guidelines.
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2.6.2.5 tumor lysis syndrome management

Subjects at high risk for Tumor Lysis Syndrome (TLS) should receive prophylactic treatment per standard clinical practice. Treatment of TLS should be administered per institutional standards. In severe cases hemodialysis may be required. 2.6.2.6 Intravenous Immunoglobulin (IVIG) Therapy Intravenous immunoglobulin (IVIG) therapy may be used per institutional guidelines.  
2.6.2.7 Antiviral Therapy Antiviral therapy with appropriate antiviral agent for HBV is recommended for subjects with known history of hepatitis B exposure (i.e., HBcAb-positive) to prevent HBV reactivation. Prophylactic anti-viral therapy may be stopped 12 months after CAR T-cell infusion. After stopping prophylaxis, it is recommended that HBV DNA should be tested every three months indefinitely due to uncertain risk of HBV reactivation after CAR T-cell therapy targeting plasma cells. Subjects with known history of hepatitis B exposure who cannot tolerate or have contraindications to antiviral therapy should be monitored every three months with HBV DNA testing. Appropriate first-line agents for prophylaxis include entecavir, tenofovir, and lamivudine (note that lamivudine has higher resistance rates). Any subject who develops a positive HBV DNA test or positive HBsAg test on-study should be evaluated by a gastroenterologist or infectious disease specialist. 2.6.2.8 Pneumocytis Jiroveci Prophylaxis It is recommended that Pneumocystis jiroveci prophylaxis continue for 6 months following administration of fludarabine.
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2.6.2.9 vaccination

Avoid administration of vaccines during and for 6 months following bb2121 infusion. Administration of vaccines should begin 6 months post bb2121 infusion per institutional guidelines. Live vaccines should be avoided for 2 years following bb2121 infusion.  
2.6.3 Lenalidomide Supportive Care Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) Prophylaxis for DVT/PE will be done according to institutional guidelines.
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2.7 concomitant medications

Subjects should be discouraged from use of illicit drugs, herbal remedies, self-prescribed drugs, tobacco products, or excessive alcohol at any time during the clinical study. 2.7.1 Permitted Concomitant Medication and Procedures Subjects with myeloma-associated bone disease may receive bisphosphonate therapy prior to study entry, unless such therapy is contraindicated. The use of bisphosphonates is permitted throughout the study. Platelet/red blood cell transfusions and hematopoietic growth factors are also permitted during the study unless specifically noted. Leukocyte filters are encouraged for all platelet and packed RBC transfusions. Concurrent use of hormones for non-cancer related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable.  
2.7.2 Prohibited Concomitant Medications and Procedures The following medications are prohibited during the study. A protocol deviation must be reported via the BMT CTN DCC PD process if a subject receives any of the following during the study:  
x Systemic steroids: dexamethasone, prednisone or other corticosteroids are not allowed unless used for the treatment of CRS or neurotoxicity, or as described below. If steroids are to be administered, it should be discussed with the protocol team unless in the setting of acute clinical requirements (e.g., Grade 3 or 4 CRS). Generally, the only setting for administration of systemic corticosteroids will be CRS management or severe neurotoxicity, following the guidelines in Section 2.6.2.2 and Appendix H.  
x Therapeutic doses of steroids may be used in life-threatening situations and for other medical conditions when indicated, or after loss of detectable bb2121 cells. Pretreatment containing steroids may be given for necessary medications (e.g., IVIG or in the setting of radiologic contrast allergy) after discussion with the sponsor. Premedication with steroids for bb2121 infusion is not allowed. Physiologic replacement, dosing of steroids (less than or equal to 12 mg/m2/day hydrocortisone or equivalent [less than or equal to 3 mg/m2/day prednisone or less than or equal to 0.45 mg/m2/day dexamethasone]) is allowed. Use of inhaled, topical, intranasal corticosteroids or local steroid injections (e.g., intra-articular injection) is permitted unless otherwise specified.  
x Any systemic anti-myeloma therapy within 14 days prior to leukapheresis.  
x Bridging myeloma therapies between leukapheresis and LD chemotherapy x Any systemic anti-myeloma therapy within 14 days of LD chemotherapy until the patient completes follow up x Any concurrent chemotherapy, immunotherapy, biologic, experimental or hormonal therapy until the patient completes follow up. Palliative radiotherapy for treatment of symptomatic bone or soft tissue lesions is allowed.  
x Avoid administration of vaccines during and for 6 months following bb2121 infusion. Administration of vaccines should begin 6 months post bb2121 infusion per institutional guidelines. Live vaccines should be avoided for 2 years following bb2121 infusion.
The following medications should be used with caution during the study. The protocol team must be notified if a subject receives any of these during the study.  
x Any concurrent chemotherapy, radiation therapy, immunotherapy, biologic or hormonal therapy for cancer treatment (including treatment of myeloma after documented progression).  
x Herbal and natural remedies are to be avoided. x Immunosuppressive medications including, but not limited to systemic corticosteroids at doses not exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and tumor necrosis factor alpha (TNF-α) blockers unless used for the management of severe CRS or neurotoxicity.
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2.8 study drug supply 2.8.1

Lenalidomide (Revlimid®) will be provided to research subjects for the duration of the maintenance phase of this trial at no charge to them or their insurance providers. Lenalidomide will be provided in accordance with BMS/Celgene Corporation's Lenalidomide REMS program. Per standard Lenalidomide REMS program requirements, all physicians who prescribe lenalidomide for research subjects enrolled into this trial, and all research subjects enrolled into this trial, must be registered in, and must comply with, all requirements of the Lenalidomide REMS program. Further information about the Lenalidomide REMS program is available at www.celgeneriskmanagement.com. Drug will be shipped on a per patient basis by the contract pharmacy to the clinic site for IND studies. Lenalidomide will be provided by BMS/Celgene and distributed by Biologics, Incorporated. Patients must be registered in the Lenalidomide REMS program in order to receive lenalidomide through the program (please see Appendix D). Lenalidomide (NSC 703813)
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note

Before lenalidomide is dispensed, patients must 1) have a negative pregnancy test (if applicable) and 2) study patients must be counseled through the Lenalidomide REMS program. A maximum 28-day supply may be dispensed to a patient at one time. For more information, please refer to www.lenalidomiderems.com. Only use the study specific drug request form per patient for ordering through Biologics. Chemical Name: 3-(4'-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione Other Names: CC-5013, Revlimid™, CDC-501 Classification: Immunomodulatory Agent CAS Registry Number: 191732-72-6 Molecular Formula: C13H13N303 **M.W.:** 259.25
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mechanism of action

Lenalidomide, a thalidomide analog, is an immunomodulatory agent with a spectrum of activity that is still under investigation. Some of its effects include inhibition of inflammation, inhibition of angiogenesis, inhibition of hematopoietic tumor cell proliferation, modulation of stem cell differentiation and up regulating responses of T cells and NK cells.
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drug supply and storage

Lenalidomide (Revlimid®) will be provided to research subjects through the treatment center for the duration of their participation in this trial at no charge to them or their insurance providers. Lenalidomide will be provided in accordance with BMS/Celgene Corporation's Lenalidomide REMS program. Per standard Lenalidomide REMS program requirements, all physicians who prescribe lenalidomide for research subjects enrolled into this trial, and all research subjects enrolled into this trial, must be registered in, and must comply with, all requirements of the Lenalidomide REMS Further information about the Lenalidomide REMS program is available at www.celgeneriskmanagement.com.
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administration

Take lenalidomide by mouth with or without food. Do not crush, chew or open capsules.
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dispensing

Only enough lenalidomide for one cycle may be dispensed at one time.
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patient care implications and counseling

Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. An embryofetal development study in animals indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy. The teratogenic effect of lenalidomide in humans cannot be ruled out. Therefore, a risk minimization plan to prevent pregnancy must be observed.
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potential drug interactions

Periodic monitoring of digoxin levels is recommended during co-administration with lenalidomide. Monitor patients receiving concomitant warfarin per standard practice guidelines. Lenalidomide is not a substrate of human CYP enzymes, nor is it an inhibitor or inducer.
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drug ordering and accountability

The REMs program provides education and counseling on the risks of fetal exposure, blood clots and reduced blood counts. Counseling will be provided by Biologics, Inc. prior to drug distribution. Please refer to Appendix D (Lenalidomide REMs program). The patient will be required to receive counseling every 28 days during treatment with lenalidomide, follow the pregnancy testing and birth control requirements of the program that are appropriate in order to take the telephone surveys regarding compliance with the program. All physicians must be registered prescribers of Revlimid® in the REMs program. Physician registration allows access to the REMs software to enroll patients in the REMs program. The prescriber should submit the Registration Form via fax number 919-256-0794 or REMs Online *(RAO)*for Revlimid®) to BMS/Celgene Customer Care. Please reference Appendix D (REMs program) and follow the directions for submitting the registration. Biologics, the distributor of the lenalidomide, will not dispense or ship Revlimid® prior to BMS/Celgene's receipt of registration. Prescription information MUST BE entered using the REMs study specific electronic prescription form referenced in Appendix D (REMs program). An authorization **number** must be on the prescription form at the time of faxing. Prescriptions for Revlimid® must be sent to Biologics Clinical Trial Division at the following FAX number: 919-256-0794. A maximum of a 28-day supply of Revlimid® may be dispensed per cycle sent to the actual address noted on the REMs electronic prescription form. Biologics will verify the authorization number and complete the patient counseling. Refer to Appendix D (REMs program).
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2.9 patient withdrawal from study

Patients on the BMT CTN 1902 study have voluntarily agreed to the study and may withdraw at any time. Additionally, the treating physician may discontinue therapy with reasonable justification. The following criteria would result in discontinuation of study therapy:
x Disease progression  
x Unacceptable adverse event(s)
x Participant decides to withdraw from the study x General or specific changes in the participant's condition render the participant unacceptable for further treatment in the opinion of the treating investigator.
After enrollment, patients who withdraw from the study for any reason prior to 12 months from infusion will continue to be followed per protocol for 12 months post infusion unless the patient withdraws consent for study follow up. In the event of patient withdrawal, written documentation of the withdrawal must be provided to the BMT CTN.
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2.10 study conduct

This study will be conducted in accordance with the protocol, protocol-specific Manual of Procedures (located on the BMT CTN SharePoint Website), and the following:  
a. Consensus ethical principles derived from international guidelines including the Declaration of Helsinki b. Applicable ICH Good Clinical Practice (GCP) Guidelines c. Applicable laws and regulations
The National Marrow Donor Program (NMDP) single Institutional Review Board (IRB) of Record will oversee this study and conduct the study-specific reviews as required by federal regulations and per the NMDP IRB Standard Operating Procedures (SOPs). Site personnel will enter data in the electronic case report form (eCRF) in Advantage eClinical as described in the BMT CTN 1902 Forms Guide. Source documentation should be made available for monitoring visits, audits and regulatory inspections as described in the protocol-specific MOP. Participating Principal Investigators (PIs) bear ultimate responsibility for training of site staff as well as the scientific, technical, and administrative aspects of conduct of the protocol, even when certain tasks have been delegated to coinvestigators, subinvestigators, or staff. The PIs have a responsibility to protect the rights and welfare of patients and comply with all requirements regarding the clinical obligations and all other pertinent requirements in 21 CFR part 312. In addition to following applicable federal, state, and local regulations, investigators are expected to follow ethical principles and standards and receive training in GCP every three years and human subjects training within the past 3 years and thereafter as per institutional requirements.
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chapter 3 3 study endpoints

Until disease progression, all disease classifications are relative to the patient's disease status prior to initial systemic anti-myeloma therapy. The response categories described below are in congruence with the International Myeloma Working Group consensus criteria for myeloma response [23].  
3.1.1 Response Categories
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stringent complete response (scr)

sCR requires, in addition to CR (defined below), all of the following:  
x Complete response as defined below plus normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry (κ/λ ratio ≤ 4:1 or ≥ 1:2 for κ and λ patients, respectively, after counting ≥100 plasma cells.
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complete response (cr)

CR requires all of the following:  
x Absence of the original monoclonal paraprotein in serum and urine by routine electrophoresis and by immunofixation. The presence of new monoclonal bands consistent with oligoclonal immune reconstitution does not exclude CR.  
x Less than 5% plasma cells in a bone marrow aspirate and also on trephine bone biopsy, if biopsy is performed.  
x No increase in size or number of lytic bone lesions on radiological investigations (development of a compression fracture does not exclude CR)1.  
x Disappearance of soft tissue plasmacytomas.
Patients in whom some, but not all, the criteria for CR are fulfilled are classified as partial responses (see below), providing the remaining criteria satisfy the requirements for partial response. This includes patients in whom routine electrophoresis is negative but in whom immunofixation has not been performed.
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very good partial remission (vgpr)

VGPR requires, in addition to PR (defined below), all of the following:  
x Serum or urine paraprotein detectable by immunofixation but not on electrophoresis.
OR  
x Greater than or equal to 90% reduction in serum paraprotein plus urine paraprotein less than 100 mg/24hrs.  
x For free light chain only disease, VGPR requires a 90% reduction of involved light chain
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partial response (pr)

PR requires one of the following:  
x Greater than or equal to 50% reduction in the level of the serum monoclonal paraprotein and reduction in 24-hour urinary monoclonal paraprotein either by greater than or equal to 90% or to less than 200 mg/24 hours.  
x If the serum and urine M-protein are unmeasurable, greater than or equal to 50% reduction in the difference between involved and uninvolved FLC levels or a 50% decrease in level of involved FLC with 50% decrease in ratio, x If the bone marrow is the only measurable parameter, greater than or equal to 50% reduction in bone marrow plasma cells given that the baseline count was greater or equal to 30%,
x Greater than or equal to 50% reduction in the size of soft tissue plasmacytomas if present at baseline (by radiography or clinical examination)1.
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minimal response (mr)

x Greater than or equal to 25% and less than 50% reduction in the level of serum monoclonal paraprotein and reduction in 24-hour urinary monoclonal protein by 50-89%.  
x Greater than or equal to 50% reduction in the size of soft tissue plasmacytomas if present at baseline (by radiography or clinical examination).
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stable disease (sd)

x Patients who do not meet criteria for sCR, CR, VGPR, partial response or progressive disease (section 3.1.1) are considered to have stable disease (SD).
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3.1.2 disease progression definitions progressive

Progression from CR or sCR requires one or more of the following:
x A reappearance of serum monoclonal paraprotein, with a level of at least 0.5 g/dL.  
x 24-hour urine protein electrophoresis with at least 200 mg paraprotein/24 hours.  
x Abnormal FLC levels of greater than 10 mg/dl, only in patients without measurable paraprotein in the serum and urine.  
x At least 10% plasma cells in a bone marrow aspirate or on trephine biopsy. x Definite increase in the size of existing bone lesions or soft tissue plasmacytomas.  
x Development of new bone lesions or soft tissue plasmacytomas. x Development of hypercalcemia (corrected serum Ca greater than 11.5 mg/dL or greater than 2.8 mmol/L) not attributable to any other cause.
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progressive disease (pd) for patients

For patients not in CR or sCR, progressive disease requires one or more of the following:  
x Greater than 25% increase in the level of the serum monoclonal paraprotein, which must also be an absolute increase of at least 0.5 g/dL.  
x Greater than 25% increase in 24-hour urine protein electrophoresis, which must also be an absolute increase of at least 200 mg paraprotein /24 hours.  
x Absolute increase in the difference between involved and uninvolved FLC levels
(absolute increase must be greater than 10 mg/dl), only in patients without measurable paraprotein in the serum and urine.  
x Greater than 25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, which must also be an absolute increase of at least 10%.  
x Definite increase in the size of existing bone lesions or soft tissue plasmacytomas.  
x Development of new bone lesions or soft tissue plasmacytomas.  
x Development of a compression fracture does not exclude continued response and may not indicate progression.  
x Development of hypercalcemia (corrected serum Ca greater than 11.5 mg/dL or greater than 2.8 mmol/L) not attributable to any other cause.
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3.2 primary endpoint

The primary endpoint is 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.
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3.3 clinical secondary endpoints 3.3.1

Disease progression defined according to Section 3.1.2 or initiation of off protocol antimyeloma therapy is the event for this endpoint. Death without documentation of disease progression is the competing event. Patients alive without disease progression at last contact are considered censored for this event. 3.3.2 Disease Response Disease response will be assessed according to Section 3.1.1. The following will be reported in all patients as defined below:  
x 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)
x Conversion to MRD negativity. MRD will be assessed by multi-color flow at 10-5 level.  
3.3.3 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. Patients alive without disease progression at last contact are considered censored for this event. 3.3.4 Incidence of Cytokine Release Syndrome (CRS) Overall incidence of CRS of any grade and grade 3 or 4 CRS post CAR T-cell infusion will be reported on all patients. 3.3.5 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 infusion.  
3.3.6 Incidence of Neurotoxicity Overall incidence of CAR T-cell related neurotoxicity per the ASBMT immune effector cell associated neurotoxicity syndrome (ICANS) Consensus Grading (Appendix H). 3.3.7 Progression Free Survival Progression free survival (PFS) is defined as progression of disease or death from any cause. Surviving patients without disease progression will be censored at the date of last contact. 3.3.8 Feasibility of Re-Initiation of Lenalidomide Maintenance Time to re-initiation of lenalidomide maintenance therapy following CAR T cell infusion will be summarized using the cumulative incidence estimator, treating death as a competing risk. Cumulative incidence at 180 days post infusion will be summarized along with a 90% confidence interval.
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3.4 exploratory endpoints 3.4.1 incidence

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 outlined in Appendix H. 3.4.2 Incidence of Infections per Protocol-Specific MOP The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each patient. 3.4.3 Maintenance Feasibility The feasibility of resuming maintenance following enrollment by 180 days after CAR Tcell infusion will be described. The proportion of patients initiating maintenance at 180 days following bb2121 infusion will be reported.
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3.4.4 overall survival

The event is death from any cause. The time to this event is the time from initial enrollment to death, loss to follow-up, or the end of the study, whichever comes first. Patients alive at the time of last observation are considered censored.
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3.4.5 car t-cell 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.
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3.4.6 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 progressionfree at 12 months.
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3.4.7 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.
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3.4.8 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.
chapter 4
4 patient registration enrollment and

Patients will be enrolled in a two-step process for eligibility assessment and to schedule apheresis as the first step of CAR T-cell manufacturing. Patients will be enrolled after receiving their first autologous transplant and at least 3 months of maintenance therapy with lenalidomide. Once a potentially eligible patient is identified, the BMT CTN study team will review and confirm a manufacturing spot with BMS/Celgene for that patient. The clinical center will then proceed to register the patient with BMS/Celgene to schedule leukapheresis and to initiate the chain of custody process. Once the clinical center completes the patient registration with BMS/Celgene they can enroll the patient into the first segment in Advantage eClinical, the electronic data capture system, and complete enrollment procedures. At the time of enrollment, an authorized user at the clinical center completes the demographics and primary eligibility, which includes questions confirming that the patient signed consent, meets the eligibility criteria for study entry and tentative date for leukapheresis will be recorded. Advantage eClinical will utilize a multi-segment approach to assess eligibility criteria and allow for enrollment into the various stages of the trial. A set of eCRF Guidelines will provide clinical site users the necessary details to properly navigate and interpret data capture across these segments.
chapter 4
4.1.1 product manufacturing release and

Product manufacturing timeline initiates with the scheduling of leukapheresis, which will be managed through the standard BMS manufacturing process. Pheresis procedures will follow standard procedures and the product will be shipped to BMS/Celgene for manufacturing. BMS will maintain the chain of custody of the product and communicate with the clinical center on the status of product manufacturing. Upon completion of manufacturing, BMS will determine whether the product falls within specification to be released according to standard criteria applied to all bb-2121 products. If a manufactured product is determined to be out of specification, this will be escalated as included in sections 2.4.3 and 4.5.5. This will be reviewed by the non-conforming product medical monitor and escalated to the FDA. The product must not be infused until FDA approval is received. This decision will be made on a case-by-case basis and the patient and center will be informed by the BMT CTN For products that fall within specification, the shipment and additional coordination will be done between BMS chain of custody personnel and the center. Initiation of LD chemotherapy, product thawing and infusion will proceed considering patient eligibility and following standard operating procedures.
chapter 4
4.1.2 long term follow-up

All patients will be followed for 15 years using the CIBMTR Cellular Therapy Registry. For patients who were not previously reported to the CIBMTR, they must be consented to the CIBMTR Research Database Protocol, which covers data sharing of transplants and cellular therapies. Participating centers will then generate a CIBMTR Research Identification Number (CRID) and report using the cellular therapy essential data (CTED) forms. For patients who previously consented to share data with the CIBMTR prior to the autologous HCT and have a CRID number, no additional consent is required. If the patient received the autologous transplant at a different institution, patients should be reconsented to the CIBMTR Research Database protocol which includes transplant and cellular therapies. Patients will also sign consent for collection of biospecimen if indicated to work up for clinical manifestations of recombinant competent lentivirus (RCL), including but not limited to subsequent neoplasm. The CIBMTR long term follow up for patients enrolled in the BMT CTN 1902 clinical trial will collect annual clinic visits starting in year 2 to year 15 to monitor the need to collect samples for RCL testing.
chapter 4
4.2 study monitoring 4.2.1 follow-up

The follow up schedule for study visits after enrollment in Advantage eClinical and subsequently after CAR T-cell infusion are outlined below in tables 4.2.1A and 4.2.1B, respectively. The follow up schedule is the intended schedule; however, the date of the follow up evaluations may vary due to delays in treatment or treatment interruption related to Adverse Events and toxicities. The visit window for the scheduled evaluations is included in each table. Patients will be followed for 12 months post bb2121 infusion.  
| Study Visit                    | Target Day                                                |
|--------------------------------|-----------------------------------------------------------|
| Pre-Enrollment Screening       | < 30 days prior to enrollment unless otherwise  specified |
| Leukapheresis                  | approximately 14 days post-enrollment                     |
| Screening to Initiate LD Chemo | < 7 days prior to Initiating LD Chemo                     |
| Initiation of LD Chemo         | 5 days prior to planned bb2121 infusion                   |
| Screening for bb2121 Infusion  | Day of bb2121 infusion                                    |
| bb2121 Infusion                | < 7 days after the planned date of bb2121 infusion        |
| Pre-Maintenance Screening      | < 14 days prior to maintenance initiation                 |
| Maintenance Start              | Day 30-180 post bb2121 infusion                           |
chapter 4
4.2.1a follow-up schedule after enrollment

| Study Visit         | Target Day Post Infusion   |
|---------------------|----------------------------|
| Day 4, 7,10, 14, 21 | +/- 2 days                 |
| Day 30, 60, 90,     | +/- 7 days                 |
| Day 180, 270, 365   | +/- 28 days                |
chapter 4
4.3 patient evaluations

4.3.1 Pre-Enrollment Evaluations and Requirements The following screening evaluations must be performed less than or equal to 30 days prior to initial enrollment after informed consent (or otherwise noted below) has been obtained, as specified in **Table 4.3A:**
1. History, physical examination, height, and weight  
2. Karnofsky Performance Score 3. Cardiac Assessment (performed less than or equal to 12 weeks from enrollment):
Left ventricular ejection fraction by echocardiogram (ECHO) or MUGA.  
4. Infectious Disease Markers: Hepatitis panel (Hepatitis B and C) and HIV Antibody 5. Laboratory Disease Evaluation (multiple myeloma restaging should be done after completion of at least3 months of lenalidomidebased maintenance)
a. Quantitative serum immunoglobulins b. Serum protein electrophoresis (SPEP) c. 24 hours urine to determine protein excretion, urine electrophoresis (UPEP) d. Immunofixation of urine and serum regardless of SPEP and UPEP results e. Serum free light chains ratios (FLC)
The following screening evaluations will be performed less than or equal to 14 days prior to enrollment after informed consent has been obtained, as specified in **Table 4.3A:**  
1. CBC with differential 2. Liver functions and blood chemistries: Serum creatinine, corrected serum calcium, total bilirubin, AST, ALT.  
3. Calculated or measured creatinine clearance 4. Pregnancy test, serum beta-HCG (sensitivity of at least 50 mIU/mL) for FCBP 5. Oxygen saturation by pulse oximetry 6. Coagulation Panel including partial thromboplastin time (PTT), international normalized ration (INR), fibrinogen 4.3.2 Evaluations Required Following Initial Study Enrollment:
1. CBC with differential (performed within 24 hours prior to leukapheresis) 2. Leukapheresis Product for bb2121 manufacturing