Phase II Multicenter Trial of Anti-BCMA CAR T-Cell Therapy for MM Patients With Sub-Optimal Response After Auto HCT and Maintenance Len. BMTCTN1902
Phase: PHASE2
Conditions: Multiple Myeloma
Sponsor: Medical College of Wisconsin

 
CONFIDENTIAL 
 
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 
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 
___________________________________  
___________________________________ 
          Approval Signature (Protocol Chair)  
 
            Approval Signature (Protocol Chair) 
___________________________________ 
                  Approval Signature (Protocol Sponsor) 
 
Alfred  Garfall, MD
I am approving this document.
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
Marcelo  Pasquini, MD, MS
25/Apr/2022 08:42 AM EDT
I am approving this document.
Marcelo Pasquini, MD, MS

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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 
Affiliate Study Participants: 
Beth Israel Deaconess Medical Center 
University of Wisconsin Carbone Cancer 
Center  
 
 
 
 
 
 

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PROTOCOL SYNOPSIS - BMT CTN 1902 
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 

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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 
Study Duration:  
Patients will be followed for 12 months after bb2121 infusion 
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.  
 
 
 
 
 

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BMT CTN 1902 STUDY SCHEMA 
 
  
 

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Table of Contents 
 
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 

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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 

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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 

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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 

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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 Background 
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] 
1.1.1 Autologous Stem Cell Transplantation in MM 
Autologous HCT remains a cornerstone of MM therapy. Autologous HCT is safe with non-
relapse 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] 
1.1.2 The Role of Maintenance Therapy after Autologous HCT 
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 

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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 meta-
analysis 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 to PFS and OS 
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 
Figure 1.1.4: PFS by Response to Lenalidomide 
Maintenance from Shah, Gunjan L. et al. 

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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]  
Table 1.1.4: Kinetics of Response During Maintenance Therapy on BMT CTN 0702 
 
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 

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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.  
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.  
Table 1.1.5: Results in Phase 1 studies of anti-CD19 CAR T-Cells in pediatric/young-
adult B cell acute lymphoblastic leukemia (ALL) and non-Hodgkin 
lymphoma (NHL) 
Product 
Study 
Population 
N 
ORR 
Durability 
Ref 
Tisa-cel 
ELIANA 
Rel/ref ALL, age 3-23 
75 
81% 
59% of responders in 
rem @ M9-M12 
[29] Maude et 
al. NEJM 
2018 
Tisa-cel 
JULIET 
rel/ref DLBCL 
93 
40% 
CR 
79% of CRs in 
remission @12m 
[30] Schuster 
NEJM 2019 
Axi-cel 
ZUMA-1 
rel/ref 
DLBCL/PMBCL/tFL 
101 
40% 
CR 
~70% of CRs in 
remission @ 12m 
[31] Neelapu 
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 

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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.  
1.1.6 Anti-B Cell Maturation Antigen CAR T-Cell Therapy for MM 
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.  
Table 1.1.6: Results of Phase I Studies of Anti-BCMA CAR T-Cells for  
Relapsed/Refractory MM Patients. 
Trial 
N 
Median 
prior lines 
of therapy 
ORR at 
optimal 
dose 
VGPR/CR 
at optimal 
dose 
Durability (at 
optimal doses) 
Ref 
NCI 
26 
7.5 
81% 
(13/16) 
63% 
(10/16) 
Median PFS 7.1 
months 
[37, 38] Ali, S.A., et 
al.; Brudno, J.N., et 
al. 
Penn/ 
Novartis 
25 
7 
64% 
(7/11) 
36% 
(4/11) 
Median PFS 4.1 
months 
[39] Cohen, A.D., et 
al. 
Bluebird/
BMS/Cel
gene 
43 
7.5 
96% 
(21/22) 
86% 
(19/22) 
Median PFS 11.8 
months 
[40] Raje, N.S., et al. 
 

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1.1.7 Rationale for CAR T-Cells as a Component of First-Line MM Therapy 
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 anti-
CD19 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.  
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-

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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 dose-
limiting 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 3-
4 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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Figure 1.1.8: Rate of Recovery of Post-bb2121 Cytopenias as Reported by Raje et 
al. [40] 
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. 
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 
2.1 Study Overview 
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 pre-
induction 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.  
2.2 Hypothesis and Study Objectives 
2.2.1 Hypothesis 
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.  
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. 
 
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.  
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 T-
cell 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) 
 
1 Anti-myeloma therapy is defined as systemic treatment intended to treat the underlying myeloma disease. Treatments 
intended to alleviate pain and other symptoms of disease are not considered anti-myeloma therapy. 

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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.  
 
1 A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not 
undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea 
following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had 
menses at any time in the preceding 24 consecutive months). 

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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 
 
1 Anti-myeloma therapy is defined as systemic treatment intended to treat the underlying myeloma disease. Treatments 
intended to alleviate pain and other symptoms of disease are not considered anti-myeloma therapy. 

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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. 

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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 

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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 CAR-
T related toxicities, with the exception of Grade 2 neuropathy) 
 
1 If CAR T-Cell infusion is delayed greater than 7 days, refer to section 2.4.5.1.  

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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.  
2.4 Treatment Plan  
2.4.1  Treatment Prior to Enrollment 
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 post-
transplant 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 re-
initiated 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. 
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. 
 
1 Anti-myeloma therapy is defined as systemic treatment intended to treat the underlying myeloma disease. Treatments 
intended to alleviate pain and other symptoms of disease and/or administration of ≤160mg of dexamethasone or 
equivalent alternative steroid dose within a 30-day period are not considered anti-myeloma therapy. 

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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. 
2.4.4.1 Renal Insufficiency Dose Adjustment for Fludarabine 
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).  
Table 2.4.4: Lymphodepletion and CAR T Infusion Treatment Plan 
Drug 
Dose 
Day -
5 
Day -
4 
Day -
3 
Day 
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  
 
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.  
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 

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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 re-
administered. Final decision on such delayed bb2121 infusion will rest with the BMT CTN 
1902 protocol chairs and/or protocol officer. 
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 post-
transplant lenalidomide maintenance/consolidation in combination with other agents prior 
to enrollment will not resume the prior combination regimen after CAR T cell infusion.  

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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.  
Table 2.4.6A: Eligibility and Dosing Requirements for Initiation of Maintenance 
Therapy Post CAR T Infusion 
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 
Starting Lenalidomide Dose 
10mg daily for 21 
of 28-day cycles 
(first cycle at 5 
mg)5 
5mg daily for 21 of 
28-day cycles6 
Cannot initiate 
maintenance7 
1 Stem cell re-infusion may be performed per the cytopenia management guidelines in Appendix I prior to day 180 to 
meet the required hematologic eligibility requirements. The BMT CTN 1902 Protocol Chairs and/or Officer must be 
consulted prior to stem cell re-infusion. 
2 Refer to section 2.3.5 and 2.3.6 for full set of eligibility requirements for Initiation of Maintenance Therapy 
3 Platelet count requirements must be achieved without platelet transfusion within 7 days or thrombopoietin mimetics 
within 28 days 
4 Filgrastim allowed to achieve required ANC 
5Maintenance dose after CAR T-cell in cycle two should be similar to the dose prior to enrollment. For example: if the 
patient was tolerating 10mg daily for 21 days out of 28-day cycle, the dose of 10mg should be the goal beyond cycle 2 
post CAR T-cell. Patients should meet count requirements in table or dose must be reduced. 56-day delay is the 
maximum window in starting next cycle. 
6If the 5mg dose is tolerated, the dose may be escalated per section 2.4.6.2 after completion of 3 cycles.  
7 Although the hematologic requirements need to meet the parameters above, maintenance therapy cannot be initiated 
beyond 180 days post CAR-T Cell Infusion without prior approval. See sections 2.3.6 and 2.4.6 for additional 
information.  
 
 

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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.  
Table 2.4.6B: Required Treatment Modification Guidelines for Lenalidomide 
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 
 (platelet count < 30,000/mm³) 
Hold lenalidomide. Follow CBC weekly.  
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 
Grade 4 
Discontinue lenalidomide permanently. Continue to follow the 
patient per-protocol 
Desquamating (blistering) rash  
any Grade 
Discontinue lenalidomide permanently. Continue to follow the 
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 Lenalidomide-
related 
≥ Grade 3 
Hold lenalidomide.  
If the toxicity resolves to ≤ grade 2 restart lenalidomide at next lower 
dose level.  
Hyperthyroidism or 
Hypothyroidism 
Hold lenalidomide.  
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 
2If a subject, or the partner of a male study subject, misses her period or if her pregnancy test or her menstrual bleeding 
is abnormal, pregnancy testing, and counseling must be performed (Section 4.5.2.3).  

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Table 2.4.6C: Lenalidomide Dose Reduction Steps During Lenalidomide 
Maintenance Therapy 
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.  
Table 2.4.6D:     Lenalidomide Dose Re-Escalation Steps During Lenalidomide 
Maintenance Therapy 
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 
 
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. 
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), 

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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. 
2.5.3.2 Neurologic Toxicities  
CAR T-cell therapy is associated with potentially serious neurologic toxicities and life-
threatening 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 seizure-
like activity, and can accompany CRS (precede or follow other CRS symptoms) or can 
occur in isolation. Refer to Appendix H for neurotoxicity management guidelines.  
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. 
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.  
2.5.3.5 Plasma Cell Aplasia and Hypogammaglobulinemia 
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.  

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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 retrovirus-
mediated 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.  
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.  
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. 

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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). 
2.5.5 Subsequent Neoplasms and Long Term Follow up  
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.  
2.6 Supportive Care and Toxicity Management  
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.  
 

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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®). 
 
2.6.2.2 Prolonged or Recurrent Cytopenia Management  
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. 
 
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.  
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. 
 

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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.  
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. 
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. 

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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). 

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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. 
2.8 Study Drug Supply  
2.8.1 Lenalidomide  
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) 
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.  
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. 
Administration: 
Take lenalidomide by mouth with or without food. Do not crush, chew or open capsules. 
Dispensing:  
Only enough lenalidomide for one cycle may be dispensed at one time.  
Patient Care Implications and Counseling: 
Risks Associated with Pregnancy 
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. 
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. 
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 

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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).  
2.9 Patient Withdrawal from Study and Off Study Criteria 
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. 
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). 

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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, sub-
investigators, 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 AND DEFINITIONS 
3.1 Definition of Disease Status 
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  
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.  
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. 
 
1 If not clinically indicated, radiographs are not required to document CR. 
 

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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 
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. 
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). 
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). 
 
1 Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI scans, or 
dedicated CT scans where applicable. For patients with only skin involvement, skin lesions should be 
measured with a ruler. Measurement of tumor size will be determined by the SPD 

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3.1.2 Disease Progression Definitions 
Progressive Disease (PD) from CR or sCR 
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.  
Progressive Disease (PD) for Patients not in CR or sCR 
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. 
 
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 
Disease progression defined according to Section 3.1.2 or initiation of off protocol anti-
myeloma 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.  

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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.  
3.4 Exploratory Endpoints  
3.4.1  Incidence of Toxicities Grade > 3 per CTCAE Version 5.0 
All Grade 3 or higher toxicities will be tabulated. The proportion of patients experiencing 
cytokine release syndrome CRS will be reported including overall and grades 3-4 based 
on the ASTCT grading 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 T-
cell infusion will be described. The proportion of patients initiating maintenance at 180 
days following bb2121 infusion will be reported. 
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.  
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.  
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 progression-
free 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. 
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.  
 

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CHAPTER 4 
4 
PATIENT REGISTRATION, ENROLLMENT AND EVALUATION 
4.1 Enrollment Procedures 
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.  
4.1.1 Product Manufacturing, Release and Infusion 
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.  

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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.  
4.2 Study Monitoring  
4.2.1 Follow-Up Schedule  
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.  
4.2.1A: FOLLOW-UP SCHEDULE AFTER ENROLLMENT  
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 
1 bb2121Infusion must occur ≤ 7 days after the planned date of infusion. If bb2121 infusion is delayed 
beyond Day 7, the Protocol Chairs must be notified. Protocol Chair approval for infusion is required for any 
delay > 14 days.  

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4.2.1B: FOLLOW UP SCHEDULE POST-CAR T-CELL INFUSION 
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 
 
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  

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4.3.3 Evaluations Required Prior to Initiating LD Chemotherapy 
The following baseline evaluations to determine eligibility for LD chemotherapy must be 
performed less than or equal to 7 days prior to initiating LD chemotherapy unless 
otherwise noted, as specified in Table 4.3A 
1. History, physical examination, height, and weight  
2. CBC with differential 
3. Liver functions and blood chemistries: Serum creatinine, total bilirubin, AST, ALT.  
4. Calculated or measured creatinine clearance  
5. Pregnancy test, serum beta-HCG (sensitivity of at least 50 mIU/mL) for FCBP  
6. Assessment for toxicities and adverse events  
7. Laboratory Disease Evaluation (may be performed ≤ 14 days prior to initiating LD 
chemotherapy)  
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 (FLC) ratio 
8. Bone Marrow Evaluation: local assessment of unilateral bone marrow biopsy and 
aspirate are required only to confirm CR in patients (may be performed less than 
14 days prior to initiating LD chemotherapy). 
9. Coagulation Panel including partial thromboplastin time (PTT), international 
normalized ration (INR), and fibrinogen  
10. Baseline evaluation for Neurotoxicity including Immune-effector Cell 
Encephalopathy (ICE) and Immune Effector Cell Associated Neurotoxicity (ICAN) 
(see Appendix H) 
11. Protocol-required Samples for Correlative Studies and Future Research1 (Table 
4.3B) 
a. Bone marrow aspiration (16 mL) 
b. Peripheral blood (71 mL) 
4.3.4 Evaluations and Requirements Prior to CAR T-Cell Infusion 
The following evaluations will be performed locally on the day of and prior to bb2121 
infusion (all results are required prior to infusion except CRS panel):  
1. History, physical examination, height, and weight  
2. CBC with differential 
 
1 See appendix B for details 

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3. Liver functions and blood chemistries: Serum creatinine, total bilirubin, AST, ALT.  
4. CRS panel: ferritin C-reactive protein  
4.3.5 Evaluations and Requirements Following CAR T-Cell Infusion 
Assessments will be performed on Days 4, 7, 10, 14, and 21 post bb2121infusion (unless 
otherwise indicated). More frequent evaluations may occur as clinically indicated. Refer 
to Table 4.3A for details on assessments to be performed:  
1. History, physical examination including height, and weight  
2. CBC with differential  
3. Evaluation for Neurotoxicity including Immune-effector Cell Encephalopathy (ICE) 
and Immune Effector Cell Associated Neurotoxicity (ICAN) (see Appendix H) 
4. Evaluation for CRS (see Appendix H) 
5. CRS panel: ferritin and C-reactive protein 
6. Assessment for toxicities and adverse events  
7. Protocol-required Samples for Correlative Studies and Optional Future Research 
(Table 4.3B):  
a. Peripheral blood (16 mL) on Day 4, 7, 14, and 21 post-bb2121 infusion 
The following assessments are required monthly for the first 3 months following bb2121 
infusion then every 3 months thereafter until 12 months following bb2121 infusion (unless 
otherwise indicated). Refer to Table 4.3A for details on assessments to be performed:  
1. History, physical examination height, and weight  
2. CBC with differential  
3. Liver functions and blood chemistries: Serum creatinine, total bilirubin, AST, ALT  
4. Pregnancy test, serum beta HCG (sensitivity of at least 50 mIU/mL) for FCBP 
monthly until at least 1 year following lymphodepleting chemotherapy or 4 weeks 
following discontinuation of lenalidomide whichever is later. There are insufficient 
exposure data to provide any recommendation concerning the duration of 
contraception following treatment with bb2121. Any decision regarding 
contraception after bb2121 infusion should be discussed with the treating 
physician.  
c. For FCBP that initiate lenalidomide:  
i. FCBP with regular or no menstruation must have a pregnancy test 
weekly for the first 28 days and then every 28 days while on therapy 
(including breaks in therapy); at discontinuation of lenalidomide and 
at Day 28 post the last dose of lenalidomide. Females with irregular 
menstruation must have a pregnancy test weekly for the first 28 
days and then every 14 days while on therapy (including breaks in 
therapy), at discontinuation of lenalidomide and at Day 14 and Day 
28 post the last dose of lenalidomide (Appendix C). 

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ii. The subject must follow the requirements of the Lenalidomide 
REMS program of the BMS/Celgene Corporation. This program 
provides education and counseling on the risks of fetal exposure, 
blood clots and reduced blood counts. 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. 
5. Assessment for toxicities and adverse events 
6. Evaluation for Neurotoxicity including Immune-effector Cell Encephalopathy (ICE) 
and Immune Effector Cell Associated Neurotoxicity (ICAN) 
7. Laboratory Disease Evaluation  
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)  
8 Bone Marrow Evaluation: local assessment of unilateral bone marrow biopsy and 
aspirate are required only to confirm CR in patients  
9. Protocol-required Samples for Correlative Studies and Optional Future Research1 
(Table 4.3B):  
a. Peripheral blood (16 mL) on Day 60, 180, and 270 post-bb2121 infusion 
b. Peripheral blood (71mL) on Day 30, 90, 365 post-bb2121 infusion  
c. Bone Marrow Aspirate on Day 30 (14mL), 90 (16mL), 180 (8mL), 365 
(16mL) post-bb2121 infusion  
4.3.6 Pre-Maintenance Evaluations and Requirements 
The following evaluations to determine eligibility for maintenance initiation must be 
performed less than or equal to 14 days prior to the initiation of lenalidomide maintenance 
therapy unless otherwise noted below.  
1. History, physical examination including routine neurologic examination, height, 
and weight  
2. Assessment for toxicities and adverse events  
3. CBC with differential 
4. Liver functions and blood chemistries: Serum creatinine, total bilirubin, AST, ALT.  
 
1 See appendix B for details 

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5. Pregnancy test, serum beta-HCG (sensitivity of at least 50 mIU/mL) for FCBP 
Women are required to have 2 pregnancy tests prior to the initiation of lenalidomide 
as follows (Appendix C) 
a. The first is required within 10 to 14 days prior to prescribing lenalidomide,  
b. The second is required within 24 hours of prescribing lenalidomide.  
4.3.7 Evaluations at the Time of Disease Progression  
1. Protocol-required Samples for Correlative Studies and Optional Future Research1 
(Table 4.3B):  
a. Peripheral blood (71mL)  
b. Bone Marrow Aspirate (16mL)  
 
 
 
1 See appendix B for details 

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TABLE 4.3A: PATIENT CLINICAL ASSESSMENTS 
 
Study 
Assessments 
Pre-
Enrollment 
Screening  
(< 30 days 
prior to 
enrollment) 
Leukapheresis  
(< approximately 
14 days post-
initial enrollment) 
Pre-LD 
Chemo 
Screening  
(< 7 days prior 
to initiating LD 
Chemo) 
Pre-bb2121 
Infusion 
Screening / 
bb2121 
Infusion  
(< 7 days after 
planned date of 
bb2121 
infusion) 
Pre-
Maintenance 
Screening 
(< 14 days 
prior to 
maintenance 
initiation) 
Days Post bb2121 Infusion 
Disease 
Progression7 
4, 7, 10, 
14, 21 
(+/- 2 
days) 
30 (+/- 7 
days) 
60 (+/- 
7 days) 
90 (+/- 
7 
days) 
180 (+/- 
28 
days) 
270  
(+/- 28 
days) 
365 (+/- 
28 days)  
Demographics and 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Assessment8 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
History, physical 
exam, weight and 
height 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Karnofsky 
performance score  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac 
Assessment: ECHO 
or MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious Disease 
Markers: Hepatitis 
and HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CRS Panel: ferritin 
C-reactive protein 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
CBC, differential, 
platelet count, liver 
functions, and blood 
chemistries1 
X12 
X11 
X 6 
X 
X 
X13 
X 6 
X 
X 6 
X 
X 
X 6 
 
X6 
 
Evaluation of 
Creatinine 
Clearance 
X12 
 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test2 
X12 
 
X 
 
X9 
 
X 
X 
X 
X 
X 
X 
 
Oxygen saturation 
by pulse oximetry  
X12 
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative serum 
immunoglobulins 
X 
 
X10 
 
 
 
X 
X 
X 
X 
X 
X 
 
SPEP and 
immunofixation 
X 
 
X10 
 
 
 
X 
X 
X 
X 
X 
X 
 
24 Hour Urine for 
UPEP, protein 
excretion and 
immunofixation 
X 
 
X10 
 
 
 
X 
X 
X 
X 
X 
X 
 

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Study 
Assessments 
Pre-
Enrollment 
Screening  
(< 30 days 
prior to 
enrollment) 
Leukapheresis  
(< approximately 
14 days post-
initial enrollment) 
Pre-LD 
Chemo 
Screening  
(< 7 days prior 
to initiating LD 
Chemo) 
Pre-bb2121 
Infusion 
Screening / 
bb2121 
Infusion  
(< 7 days after 
planned date of 
bb2121 
infusion) 
Pre-
Maintenance 
Screening 
(< 14 days 
prior to 
maintenance 
initiation) 
Days Post bb2121 Infusion 
Disease 
Progression7 
4, 7, 10, 
14, 21 
(+/- 2 
days) 
30 (+/- 7 
days) 
60 (+/- 
7 days) 
90 (+/- 
7 
days) 
180 (+/- 
28 
days) 
270  
(+/- 28 
days) 
365 (+/- 
28 days)  
Serum free light 
chain ratio 
X 
 
X10 
 
 
 
X 
X 
X 
X 
X 
X 
 
Local assessment of 
unilateral 
bone 
marrow aspirate and 
biopsy 
 
 
X10 
 
 
 
X 
 
X 
X 
X3 
X 
 
Coagulation 
Panel 
including PTT, INR, 
and fibrinogen 
X12 
 
X 
 
 
 
 
 
 
 
 
 
 
Evaluation 
for 
CRS/ICANS 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Toxicity assessment4 
 
 
X5 
 
X 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
 
 
1Blood chemistries include: serum creatinine, corrected serum calcium (if applicable), AST and ALT as required per protocol. 
2 For female of childbearing potential: A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; 
or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
3Bone Marrow aspirate and biopsy required only to confirm CR in patients if suspected due to other assessments, e.g. serology. 
4The toxicity assessment will include a review of all toxicities including ICANS (immune-effector cell associated neurotoxicity syndrome), myelotoxicity and appropriate lab evaluations experienced during the entire 
assessment period and the highest grade for each 
toxicity during the assessment period will be recorded on the Toxicity or Myelotoxicity form in EDC using CTCAE version 5. 
5 Toxicity Assessment will include Neurotoxicity Assessments (ICE and ICAN) and Myelotoxicity Assessments (see Appendix H) 6 CBC needs to be collected and results reported in CRF at the same time as optional 
research samples are collected. 7 Only needed for patients that progress while in study follow up and optional research samples are being collected. 
8Eligibility to proceed to next stage of trial will be assessed at each timepoint as indicated. 
9Two pregnancy tests required prior to the initiation of lenalidomide: The first required within 10 to 14 days prior to prescribing lenalidomide and the second required within 24 hours of prescribing lenalidomide (see 
Appendix C). 
10To be performed ≤ 14 days prior to initiating LD chemotherapy. 
11CBC with differential required within 24 hours prior to leukapheresis to determine ALC. 
12To be performed ≤ 14 days prior to enrollment and after ICF has been obtained. 
13Only CBC with differential required. 
 
 

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TABLE 4.3B: SAMPLE COLLECTION TIME POINTS 
 
Sample Collection 
Leuka-
pheresis 
Pre-LD 
Chemo 
Days Post CAR-T Cell Infusion 
Disease 
Progression
1 
4 
7 
14 
21 
30 
60 
90 
180 
270 
365 
Bone Marrow Aspirate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 MRD, BCMA expression and Immune 
Profiling Assessment (6mL) 
 
X 
 
 
 
 
X2 
 
X 
X 
 
X 
X 
 MRD Assessment by NGS (2 mL) 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
X 
CAR-T Cell expansion and persistence 
(2 mL) 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
X 
 Optional Repository Sample for Future 
Research (6 mL) 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
X 
Total Maximum Marrow Volume (mL) 
 
16 
 
 
 
 
14 
 
16 
8 
 
16 
16 
Peripheral Blood 
 
 
 
 
 
 
 
 
 
 
 
 
 
CAR-T Cell expansion and persistence 
(8mL) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immune Reconstitution (10mL) 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
X 
Optional Repository Sample for Future 
Research - PBMC (45mL) 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
X 
 Optional Repository Sample for Future 
Research – Serum (8mL) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Total Maximum Blood Volume (mL) 
 
71 
16 
16 
16 
16 
71 
16 
71 
16 
16 
71 
71 
Leukapheresis 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukapheresis product for bb2121 
manufacturing  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Only required for patients that progress while in study follow up  
2 Only Immune Profiling Assessment done from Day 30 sample 

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4.4 Data Reporting  
4.4.1 Criteria for Forms Submission 
Forms that are not entered into the EDC system, Advantage eClinical® within the specified 
time will be considered delinquent. A missing form will continue to be requested either 
until the form is entered into the EDC and integrated into the Data and Coordinating 
Center’s (DCC) master database, or until an exception is granted and entered into the 
Missing Form Exception File. 
Internal Data Monitoring 
It is the responsibility of the site PI to ensure the validity of all patient data as well as the 
safety 
of all patients. 
Data Monitoring and Auditing 
The Data Safety and Monitoring Board (DSMB) for the BMT CTN will convene as per 
standard procedure to review serious toxicities and adverse events for the purpose of 
determining whether the trial should be modified or stopped. Triggers for referral to the 
DSMB are described in the Interim Analysis and Stopping Guidelines of Section 5.3. If 
the monitoring of the safety endpoints described in Section 5.3 results in a trigger for 
consultation with the DSMB, the DSMB may make recommendations about whether to 
continue accrual. 
Records 
Any publication or presentation will refer to patients by a unique patient number and not 
by name to assure patient confidentiality. 
4.4.2 Reporting Patient Deaths  
Recipient death information must be entered into the EDC within 24 hours of knowledge 
of the patient’s death via a Death Form. If the cause of death is unknown at that time, it 
need not be recorded at that time. However, once the cause of death is determined, the 
form must be updated in EDC. In addition, any death occurring from the infusion of 
bb2121 through 60 days following the infusion (or longer to include 21 days of 
lenalidomide maintenance) must also be reported via the Adverse Event Reporting 
process described in section 4.5 below.  
4.4.3 Center for International Blood and Marrow Transplant Research (CIBMTR) Data 
Reporting  
Centers participating in BMT CTN trials must register pre- and post-transplant outcomes 
on all consecutive hematopoietic stem cell transplants done at their institution during their 
time of participation to the Center for International Blood and Marrow Transplant 
Research (CIBMTR). Registration is done using procedures and forms of the Stem Cell 

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Transplant Outcomes Database (SCTOD). Enrollment in BMT CTN 1902 must be 
indicated on the SCTOD pre-transplant registration form. Additionally, CIBMTR pre- and 
post- transplant Comprehensive Report Forms must also be submitted for all patients 
enrolled on this trial. CIBMTR forms will be submitted directly to the CIBMTR at the times 
specified on the Form Submission Schedule. Patients will be followed by the CIBMTR 
from time of autologous transplant through 15 years post-transplant.  
4.5 Adverse Event Reporting  
AE reporting requirements are summarized below and in table 4.5. Any unanticipated 
serious adverse events (SAEs) from time of enrollment through the study defined follow 
up are required to be reported. All SAEs must be reported from the infusion of 
bb2121CAR-T therapy through 60 days after the infusion completes or through 21 days 
of lenalidomide maintenance, whichever is longer. All grades of non-serious AEs must 
also be reported from the infusion of bb2121 CAR-T therapy through the longer of either 
60 days after the infusion completes or through 21 days of lenalidomide maintenance 
either by 1) reporting of all grades of toxicities anticipated for the participant population 
captured on the Toxicity or Myelotoxicity Form or 2) completion of the Adverse Event 
Form (single page only) for any event not captured on the Toxicity or Myelotoxicity Form. 
In addition, any SAEs occurring after that 60-day period/21 days of lenalidomide 
maintenance up to disease progression assessed as related to the investigational product 
bb2121 must be reported. Any occurrence of grade 4 myelotoxicity after initiating 
lenalidomide that persists for more than 4 weeks despite interruption/discontinuation of 
lenalidomide is also required to be reported as an SAE, as outlined in section 4.5.4.1. 
From the 61st day following the completion of the bb2121 infusion or the 22nd day of 
lenalidomide maintenance, only non-serious AEs captured through the Toxicity and 
Myelotoxicity Form are required to be reported. All reported SAEs are to be followed up 
until resolved, judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized.  
SAEs related to lenalidomide after 21 days of maintenance should be reported to 
BMS/Celgene under the voluntary reporting mechanism. 
Infections and deaths are collected separately in EDC as this is a study endpoint; 
however, should an infection or death meet the SAE criteria and be assessed by the 
investigator as related to bb2121, the infection or death must also be reported following 
the SAE reporting guidelines. 
Underlying disease relapse events are collected in the EDC separately because they are 
part of the endpoint analysis. Events of underlying disease relapse are not to be reported 
as AEs/SAEs for this study. 
 
 
 
 
 
 
 

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Table 4.5: AE Reporting Phases 
 
Enrollment – 60 days post 
completion of bb2121 infusion 
or 21 days of lenalidomide 
maintenance, 
whichever 
is 
longer 
61 days post completion of infusion or 
22nd 
day 
of 
lenalidomide 
maintenance, whichever is longer – 
completion of AE reporting* 
Unanticipated SAEs or grade 4 
anticipated event not collected 
elsewhere 
in 
the 
study 
database (following protocol-
specific MOP Guidelines) 
 
X 
All SAEs» 
X 
 
SAEs related to bb2121 
X 
X^ 
Infections that are SAEs and 
related to bb2121 
X 
X 
Grade 4 myelotoxicity after 
initiating lenalidomide 
persisting for more than 4 
weeks despite 
interruption/discontinuation of 
lenalidomide 
X 
X 
Deaths related to b2121 
X 
X 
All anticipated AEs for the 
patient population captured via 
the Toxicity Form 
X 
X 
All anticipated 
hematologic 
AEs for the patient population 
captured via the Myelotoxicity 
Form+ 
X 
X 
All AEs (not captured through 
the Toxicity Form) 
X 
 
*Completion (whichever is longer) of reporting will occur at 1) completion of study defined follow-up, death or a 
withdrawal criterion outlined in section 2.9; 2) progression of disease; OR 3) following diagnosis of a subsequent 
neoplasm meeting a criterion in section 4.5.  
» Any unanticipated SAE from time of enrollment through the study defined follow up are required to be reported and 
all SAEs are to be reported from bb2121 CAR-T therapy through 60 days post infusion.  
^Any SAE assessed by the investigator as related to bb2121 after the patient meets a criterion to stop reporting SAEs 
will still require reporting. 
+ The Myelotoxicity Form will capture data on grade 4 myelotoxicities including whether the study lenalidomide is 
interrupted/disrupted and the duration of the interruption/disruption, along with a brief summary of the clinical details 
for grade 4 myelotoxicities that cause lenalidomide to be held for > 4 weeks. 
4.5.1 Definitions 
Adverse Event: An AE is any untoward medical occurrence in a patient administered an 
investigational product or has undergone study procedures and which does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease that is temporally associated with the use of a medical (investigational) product, 
whether or not related to the investigational product.  

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Serious Adverse Event: An SAE, as defined per 21 CFR 312.32, is any adverse event 
that results in one of the following outcomes, regardless of causality and expectedness:  
x Results in death 
x Is life-threatening. Life-threatening means that the person was at immediate risk 
of death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
x Requires or prolongs inpatient hospitalization (i.e., the event required at least 
a 24-hour hospitalization or prolonged a hospitalization beyond the expected 
length of stay). Hospitalization admissions and/or surgical operations scheduled to 
occur during the study period but planned prior to study entry are not considered 
SAEs if the illness or disease existed before the person was enrolled in the trial, 
provided that it did not deteriorate in an unexpected manner during the trial (e.g., 
surgery performed earlier than planned). 
x Results in persistent or significant disability/incapacity. Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions. 
x Is a congenital anomaly or birth defect; or 
x Is an important medical event when, based upon appropriate medical judgment, 
it may jeopardize the patient and require medical or surgical intervention to prevent 
one of the outcomes listed above. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
Medical and scientific judgment should be exercised in deciding whether expected 
reporting is also appropriate in situations other than those listed above. For example, 
important medical events may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one 
of the outcomes listed in the definition above (e.g., suspected transmission of an 
infectious agent by a medicinal product is considered an SAE). Any event is considered 
a SAE if it is associated with clinical signs or symptoms judged by the investigator to have 
a significant clinical impact. 
x An adverse event can be Anticipated or Unanticipated in regard to the patient 
population for this study. Anticipated adverse events are those that have been 
previously identified as resulting from administration of the agent. For the purposes 
of this study, an adverse event is considered anticipated when it appears in the 
current adverse event list, the Investigator’s Brochure, the package insert or is 
included in the informed consent document as a potential risk. 
x Unanticipated adverse events are those that vary in nature, intensity or 
frequency from information in the current adverse event list, the Investigator’s 
Brochure, the package insert, or when it is not included in the informed consent 
document as a potential risk. 

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4.5.2 Classification of Adverse Events by Severity 
The severity refers to the intensity of the reported event. The Investigator must categorize 
the severity of each reportable SAE according to the NCI CTCAE version 5.0. CTCAE 
guidelines 
can 
be 
referenced 
at 
the 
following 
website: 
http://ctep.cancer.gov/reporting/ctc.html. For any term that is not specifically listed in the 
CTCAE scale, intensity will be assigned a grade of one through five using the following 
CTCAE guidelines: 
1. Grade 1: Mild; asymptomatic or mild symptoms, clinical or diagnostic observations 
only; intervention not indicated 
2. Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
3. Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living 
4. Grade 4: Life-threatening consequences; urgent intervention indicated 
5. Grade 5: Death related to AE 
4.5.3 Classification of Adverse Events by Relationship to Investigational Product 
The relationship of each reported event to the study treatment will be assessed by the 
Investigator; after careful consideration of all relevant factors such as (but not limited to) 
the underlying study indication, coexisting disease, concomitant medication, relevant 
history, pattern of the SAE, temporal relationship to any study treatment interventions and 
de-challenge or re-challenge according to the following guidelines: 
1. Possibly, Probably, or Definitely Related: there is a reasonable possibility that 
the study treatment caused the event. A relationship of possibly, probably or 
definitely related to the investigational product is considered related for the 
purposes of regulatory authority reporting. 
2. Unlikely, or Not Related: There is no reasonable possibility that the 
investigational product caused the event. An unlikely or not related relationship to 
the investigational product is not considered related for the purposes of regulatory 
authority reporting.  
4.5.4 Required Adverse Event Reporting  
Adverse event reporting will be consistent with BMT CTN procedures (protocol-specific 
Manual of Procedures), unless otherwise specified in section 4.5 above. The protocol-
specific MOP defines reporting based on the terms Unexpected and Expected; however, 
for this study, the reporting will be based on the terms Unanticipated and Anticipated in 
addition to the MOP definition of Unexpected and Expected.  

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SAEs that require reporting as specified in section 4.5 will be reported through an 
expedited AE reporting system via an EDC. Life-threatening and fatal SAEs must be 
reported within 24 hours of knowledge of the event. All other SAEs must be 
reported within one business day of knowledge of the event. Events entered in EDC 
will be reported using NCI’s CTCAE Version 5.0.  
Non-serious AEs will be reported using NCI’s CTCAE Version 5.0 as specified in section 
4.5. For anticipated AEs, this may include reporting at regular intervals as defined on the 
Form Submission Schedule, including calendar-driven eCRFs (e.g., Toxicity) or event-
driven eCRFs (e.g., Relapse/Progression, Infection, Secondary Graft Failure and Death).  
The Data and Safety Monitoring Board (DSMB) will receive reports of all 
unanticipated/unexpected SAEs deemed to be related to bb2121 or maintenance therapy 
upon review by the BMT CTN Medical Monitor. A summary of all reported SAEs will be 
reviewed by the DSMB annually. 
Since this study is under an FDA Investigational New Drug, all suspected and unexpected 
fatal or life-threatening adverse events are reported to the FDA within seven calendar 
days after receipt of the information from the site, following FDA guidelines. All suspected 
and unexpected other serious adverse events are reported to the FDA within fifteen days 
of receipt of the information (21 CFR 312.32). Unexpected for regulatory reporting will be 
assessed by the BMT CTN Medical Monitor and will include events that are not included 
in the bb2121 Investigator’s Brochure. If the Medical Monitor assesses the event to be 
unrelated to the study, then the event will not require expedited reporting but will be 
included in a summary report issued annually. In addition, any event of grade 4 
myelotoxicity after initiating lenalidomide and persisting for more than 4 weeks despite 
interruption/discontinuation of lenalidomide will be reported in an expedited fashion to the 
FDA. Safety reporting to the FDA will be done by the BMT CTN based upon date of initial 
entry on the Adverse Event Forms and requires no additional action from the participating 
site. 
4.5.4.1 Adverse Event Reporting of Myelotoxicity 
Patients who develop neutropenia and thrombocytopenia (myelotoxicity) after initiation of 
lenalidomide that persists for more than 4 weeks despite interruption/discontinuation of 
lenalidomide are required to be reported in an expedited fashion via the Adverse Event 
Form, along with completion of the calendar-driven Myelotoxicity Form. These events will 
be assessed by the BMT CTN Medical Monitor and will be reported to the FDA as an 
expedited safety report. 
4.5.4.2 Adverse Event Reporting Following Progression  
If a patient meets the protocol defined definition of progression (Section 3.1.2), SAEs and 
non-serious AEs are no longer required to be reported on the Adverse Event Form once 
the patient is more than 60 days from the completion of bb2121 or 21 days of lenalidomide 
maintenance, whichever is longer. Any bb2121-related SAEs would require reporting 
following the SAE reporting guidelines. 

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4.5.4.3 Adverse Event Reporting Following a Subsequent Neoplasm 
Participants on this study are at risk of developing subsequent neoplasms. While 
subsequent neoplasms do not require expedited reporting, unless meeting one of the 
other criteria for AE/SAE reporting, the diagnosis of a subsequent neoplasm may alter 
reporting required for other AEs/SAEs. Adverse Event reporting following a subsequent 
neoplasm is dependent on the treatment received.  
x If a patient experiences a subsequent neoplasm resulting in initiation of non-
protocol systemic therapy, SAEs are no longer required to be reported once 
the patient is more than 60 days from completion of bb2121 or 21 days of 
lenalidomide maintenance, whichever is longer.  
x If a patient experiences a subsequent neoplasm that does not result in initiation 
of non-protocol systemic therapy, Adverse Events will continue to be reported 
per section 4.5 of the protocol.  
x Any bb2121-related SAEs would be reported until end of study. 
x Requests to discontinue Adverse Event Reporting for events that do not meet 
the criteria above will be considered on a case-by-case basis.  
4.5.4.4 Pregnancy Reporting 
Pregnancies, suspected exposure of a pregnant woman (including female partner of a 
male patient and exposure to lenalidomide while dispensing) and suspected pregnancies 
(including a positive pregnancy test regardless of age or disease state) of a female subject 
occurring at any time after the subject received bb2121 infusion therapy or lenalidomide; 
or within 28 days of the last dose of lenalidomide, 1 year after the last dose of LD chemo, 
are considered immediately reportable events. Therapy with lenalidomide is to be 
discontinued immediately and any unused drug should be returned. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported through the expedited 
AE reporting system in EDC. The female subject should be referred to an obstetrician-
gynecologist, preferably one experienced in reproductive toxicity for further evaluation 
and counseling. The Investigator should ensure that the pregnant participant or pregnant 
partner of a male participant has consulted a general practitioner or gynecologist as soon 
as possible and that the contact details of the healthcare provider who is following the 
pregnancy are provided to the investigator.  
The Investigator will follow the female subject until completion of the pregnancy and must 
notify BMT CTN immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the expedited AE reporting system in EDC.  
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic 
abortion), the investigator should report the abnormal outcome as an AE. If the abnormal 
outcome meets any of the serious criteria, it must be reported as an SAE using the 
expedited AE reporting system in EDC, within 24 hours of the investigator’s knowledge 
of the event. 

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All neonatal deaths that occur in connection with in utero exposure to lenalidomide should 
be reported within 28 days of birth, without regard to causality through the expedited AE 
reporting system in EDC. In addition, any infant should be followed for 1 year after birth 
and report any SAE through the expedited AE reporting system within 24 hours of the 
Investigator’s knowledge of the event. After 1 year any suspected SAE event should be 
reported to BMS/Celgene.  
Male Subjects 
If a female partner of a male subject taking investigational product becomes pregnant, 
the male subject receiving bb2121 therapy or lenalidomide should notify the Investigator, 
and the pregnant female partner should be advised to call her healthcare provider 
immediately. Attempts should be made to obtain consent from the female partner so that 
the information in section 4.5.4.3 can be provided for female partners of male participants 
and pregnancy outcomes.  
4.5.5 Reporting of Special Situations 
There are other special situations that require reporting through the AE expedited 
reporting system in EDC. If any of the following events occur, they are required to be 
reported within one business days of the site’s knowledge of the event, if the event occurs 
from the start of LD chemo through 21 days of lenalidomide or 60 days following bb2121, 
whichever is later: 
x Mishandling or misuse of bb2121 upon receipt of the product at the treatment 
center 
x Overdose, abuse and misuse that meets one of the criteria of a serious adverse 
event 
o Overdose, as defined for this protocol, refers to lenalidomide and bb2121 
dosing only. 
o On a per dose basis, an overdose is defined as the following amount over 
the protocol-specified dose of lenalidomide or bb2121 assigned to a given 
patient, regardless of any associated adverse events or sequelae. 
 PO any amount over the protocol-specified dose 
 IV 10% over the protocol-specified dose 
o On a schedule or frequency basis, an overdose is defined as anything more 
frequent than the protocol required schedule or frequency. 
o On an infusion rate basis, an overdose is defined as any rate faster than the 
protocol-specified rate.  
o Complete data about drug administration, including any overdose, 
regardless of whether the overdose was accidental or intentional, should be 
reported in the case report form.  
x Medication errors that meet one of the criteria of a serious adverse event 
x Occupational exposure of any kind 

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x Public health emergency 
x Any lot release criteria that is out of specification 
x BMS/Celgene product technical complaint whether or not it leads to an adverse 
event 
o Technical complaints can include but not limited to delivery of bb2121 in a 
defective bag or other issues with the product itself.  
Each of the above listed other special situations are to be considered medically important, 
even if no other serious criteria apply. These are immediately reportable via the expedited 
AE reporting system in EDC and must be reported within one business day of the 
Investigator’s first knowledge of the event. 
Any product that is out of specification for any lot release criteria, the event will be reported 
to the FDA as part of the escalation pathway. 
 

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CHAPTER 5 
5 
STATISTICAL CONSIDERATIONS 
5.1 Study Design 
This study is designed as a single-arm Phase II multi-center trial to investigate the use of 
anti- BCMA CAR T-cells to upgrade post autologous HCT responses among patients with 
MM. The primary endpoint is complete response (CR) by 6 months following initiation of 
LD chemotherapy. We plan to enroll n=40 patients on this trial in order to get at least n=33 
evaluable patients receiving the final selected dose of bb2121 infusion. There will be a 
safety run-in with staggered enrollment (see below, section 5.1.3) to assess for excess 
early toxicity of CAR T cells in this new clinical setting or prolonged cytopenias that limit 
resumption of maintenance lenalidomide; this run-in will start with the standard CAR T 
cell dose of 450 x10 6 cells and may include up to 6 patients at this dose; if there are 
toxicity concerns, the dose will be reduced to 300 x 10 6 cells which will then be the 
selected dose for this study. Only patients who are assigned to receive the selected dose 
in the run in will be evaluable for the primary endpoint. Once the final dose is selected for 
further enrollment, we will enroll up to 40 total patients at that dose, including those in the 
run-in. Assuming the potential for dose de-escalation after the first 6 patients were 
enrolled in the run in phase and at least 1 patient dropping out from enrollment before 
initiation of LD chemotherapy, this will result in at least n=33 evaluable patients at the 
final selected dose. It is estimated that 13 months of accrual will be necessary to enroll 
the targeted sample size after completion of the safety run in. Accrual will be reported by 
race, ethnicity, gender, and age. 
5.1.1 Study Duration 
Participants will be followed on trial for 12 months after initiation of CAR T cell infusion for 
primary, secondary, and exploratory endpoints.  
5.1.2 Randomization and Blinding 
This is a single arm trial with no randomization and no blinding. 
5.1.3 Safety Run-In and Staggered Enrollment 
5.1.3.1 Toxicities that will Govern Safety Run-In and Stagger. 
The following toxicities will trigger expansion of the safety run-in to six subjects or study 
pause depending on their frequency: 
a) Failure to start maintenance lenalidomide within 60 days of bb2121 infusion and 
continue with dose ≥5 mg/day for 21 days continuously without development of 
sustained grade 4 (failure to resolve to grade ≤3 within 7 days with supportive care, 
which may include filgrastim) neutropenia or thrombocytopenia.  
b) Occurrence of grade 4 or higher cytokine release syndrome.  

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5.1.3.2 Progress through Safety Run-In  
During the safety run-in, subjects will be enrolled in groups of 3. The second subject in 
each group will not proceed with lymphodepleting chemotherapy or bb2121 infusion until 
the preceding subjects starts lenalidomide by 60 days after bb2121 infusion. The third 
subject in each group will not proceed with lymphodepleting chemotherapy or bb2121 
infusion until the first patient completes at least 21 days of lenalidomide maintenance and 
the second subject is able to start lenalidomide maintenance by 60 days after bb2121 
infusion. Of note, according to section 2.3.5, subjects must be ≥30d post-infusion and 
have achieved ANC >1000/mm3 and platelet count ≥75,000/mm3 before initiating 
maintenance therapy. At discretion of the sponsor, enrollment and bb2121 manufacturing 
for subsequent subjects may proceed during post-infusion waiting period of preceding 
subjects. The first 3 subjects will be followed until they have completed 21 days of 
maintenance therapy without interruption due to hematologic toxicity before additional 
subjects are enrolled. 
If none of the first 3 subjects experience toxicities in section 5.1.3.1, enrollment will 
proceed without further inter-patient stagger. If 1 of the first 3 subjects experience a 
toxicity in section 5.1.3.1, an additional 3 subjects will be enrolled with intra-patient 
stagger as detailed in the preceding paragraph. If 2 of the toxicities in section 5.1.3.1 
above occur during the safety run-in, the safety run-in will restart with the bb2121 dose 
reduced to 300 x 106 cells. If 2 of the toxicities in section 5.1.3.1 occur during the safety 
run-in after dose de-escalation, further bb2121 infusions and enrollment will be paused 
for further review.  
 
5.1.4 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 
1/3 exhibit toxicity
0/3 exhibit toxicity
0/3 exhibit toxicity
3 subjects
receive bb2121
Open enrollment with no further stagger
Enroll 3 additional 
subjects on stagger
1/6 exhibit toxicity
2/6 exhibit toxicity
De-escalate dose
Enroll 3 subjects on stagger
Open enrollment with no further stagger
Enroll 3 additional 
subjects on stagger
1/3 exhibit toxicity
1/6 exhibit toxicity
2/6 exhibit toxicity
Pause study
2 exhibit 
toxicity
2 exhibit 
toxicity

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suboptimal disease responses after an autologous HCT and lenalidomide maintenance. 
The primary objective of this clinical trial is to estimate the proportions of patients 
achieving CR by 6 months, along with 90% confidence intervals, and to determine 
whether the use of bb2121 to upgrade post autologous HCT responses is sufficiently 
promising to warrant further study. Data from BMT CTN 0702 suggests that less than 
10% of patients not in CR after autologous HCT and 6 months of maintenance therapy 
will get patients into CR within a subsequent 6 months of maintenance therapy (see Table 
1.1.4). We will use a hypothesis testing framework to assess the potential efficacy of the 
addition of bb2121 cells to upgrade post autologous transplant responses. Specifically, 
we will test the null hypothesis that the 6-month probability of CR is less than or equal to 
10% against the alternative that it is greater than 10%, using a one-sided 5% significance 
level.  
5.2 Sample Size Considerations 
Assuming a 5% one-sided significance level, a sample size of n=33 or more evaluable 
patients receiving BCMA CAR T-cell therapy at the final selected dose will have at least 
90% power to conclude that the 6-month CR rate is greater than 10% when the true 6-
month CR rate is 30% (a 20% absolute improvement over the unpromising rate), using 
an exact binomial test. Furthermore, the expected margin of error of the 90% confidence 
interval when the observed 6-month CR rate is 30% is approximately +/-13%, assuming 
an evaluable sample size of n=33. 
5.3 Interim Analysis and Stopping Guidelines 
There will be no interim analyses for efficacy or futility for this trial. 
Assuming the trial will enroll at least 33 patients, additional safety monitoring will include 
three safety endpoints, CRS, ICANS and non-relapse mortality. For CRS the occurrence 
of at least two cases of grade 4 CRS (ASTCT Grading) will trigger a DSMB review. For 
ICANS, the occurrence of at least one event of grade 4 ICANS will trigger a DSMB review. 
For non-relapse mortality within 28 days of bb2121 cell infusion, based on the expected 
infrequency (less than 1% based on rate in BMT CTN 0702 within 28 days following 
second autologous HCT) of the event, the occurrence of two or more non-relapse deaths 
within 28 days of infusion will trigger a DSMB review.  
In addition, the safety monitoring rule will also include bone marrow dysfunction/failure 
and prolonged cytopenias. For bone marrow dysfunction or failure, there are two rules 
that will trigger DSMB review: 1) the occurrence of one bone marrow failure requiring CT 
rescue; and 2) if 15% of patients are unable to start lenalidomide maintenance by Day 60 
after CAR-T infusion. A DSMB review will also be triggered if 15% of patients who are 
able to start lenalidomide maintenance are unable to sustain therapy due to cytopenia-
driven interruption. Interruption of maintenance is defined as stopping maintenance 
cycles due to cytopenias and inability to resume for more than 60 days. Thresholds for 
discontinuation of maintenance are based on table 2.4.6, and details of 15% stopping rule 
for being unable to start or sustain lenalidomide maintenance are given below in Table 
5.3.  

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Table 5.3: Stopping rule for patients unable to start or sustain lenalidomide 
maintenance or unable to sustain therapy due to cytopenia-driven 
interruption 
# of patients 
# of events 
1-6 
1 
7-13 
2 
14-20 
3 
21-26 
4 
27-33 
5 
 
At a point that any of these monitoring rules are triggered, the NHLBI will be notified in 
order that the DSMB can be advised to review the data. Policies and composition of the 
DSMB are described in the protocol’s Manual of Procedures. The stopping guidelines 
serve as a trigger for consultation with the DSMB for additional review. 
5.4 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized for all participants. 
Characteristics to be examined may include: age, gender, race/ethnicity, Karnofsky 
performance status, cytogenetics,/ LDH,/ Beta 2 microglobulin, lines/types of initial 
systemic anti-myeloma therapy, interval from diagnosis of symptomatic MM to enrollment, 
interval from initial systemic therapy to enrollment, Light chain disease, Chemo vs. non-
chemo mobilization, timing from transplant to enrollment and to CAR T-Cell infusion, 
duration of lenalidomide therapy, initial response at enrollment, myeloma risk status  
5.5 Analysis Populations and General Analysis Guidelines 
5.5.1 Primary Analysis Population  
All patients starting LD chemotherapy prior to receiving a bb2121 infusion on study will 
be included in the primary analysis population. Time to event analyses will be started at 
the time of LD chemotherapy. Analyses for the primary and secondary endpoints will use 
the primary analysis population, except as otherwise specified. The primary analysis will 
occur once all patients have been followed for 6 months and data is locked. The primary 
analysis population will also be used for all analyses of safety data at the selected dose. 
Note that if there is a dose de-escalation in the run-in phase before selecting the final 
dose, then outcomes of patients at the initial higher dose will be described separately.  
5.5.2 General Analysis Guidelines 
Primary analyses for the primary, secondary, and exploratory endpoints will use the 
primary analysis population. Analyses of each endpoint in each population will follow the 
analysis plans as described below in sections 5.6 - 5.8. We expect minimal missing data 
(less than 5%) for the primary endpoint and secondary endpoints based on past 
experience with transplant and cellular therapy trials. If more than 10% of a key primary 
or secondary outcome is missing, we will apply an appropriate imputation method and 
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stage, analyses as described below will apply to the final selected dose, while patients at 
the higher dose will be summarized separately in a descriptive manner due to the small 
numbers of patients at that dose.  
5.5.3 As Treated Analysis 
The analysis plan will include as treated analysis among patients who received CAR T 
cell infusion including patients who received OOS product. All outcomes will be analyzed 
in this cohort. 
5.6 Analysis of Primary Endpoint 
If there is no censoring prior to 6 months and prior to achieving a CR, then the probability 
of CR by 6 months will be estimated using proportions. 90% confidence intervals will be 
provided based on exact binomial distributions. A one-sided exact binomial test 
comparing the estimated proportion of patients in CR by 6 months against a null 
hypothesis or uninteresting value of 10% will be conducted using a 5% one-sided 
significance level. If there is censoring present prior to 6 months and prior to achieving a 
CR, then the probability of CR by 6 months will be estimated using the cumulative 
incidence technique, with death as a competing risk and patients alive without CR at last 
contact considered censored. 90% confidence intervals for the cumulative incidence will 
be computed using the complementary log-log transformation.  
5.7 Analysis of Secondary Endpoints 
Analysis of secondary endpoints will be primarily descriptive, using estimates along with 
90% confidence intervals, as detailed below. 
5.7.1 Response to Treatment 
The proportion of patients achieving an upgrade in their response at any timepoint, and 
the proportion of patients who achieve MRD negativity at any timepoint will be described. 
Duration of response upgrade will be summarized using the Kaplan-Meier estimate, 
where death or loss of response upgrade are considered events, and the time to event is 
measured as the time from documentation of response upgrade to death, loss of 
response upgrade, or last contact.  
5.7.2 Progression-Free Survival (PFS) 
PFS survival will be estimated using the Kaplan-Meier estimator. Progression of disease 
or death from any cause will be considered events and surviving patients without disease 
progression will be censored at the date of last contact. A point estimate and 90% 
confidence interval will be provided for the probability of PFS at 12 months. 

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5.7.3 Non-Relapse Mortality (NRM) 
NRM will be estimated using the cumulative incidence function, treating progression as a 
competing event. A point estimate and 90% confidence interval will be provided for the 
cumulative incidence at 100 days, 6 months and 12 months post-transplant.  
5.7.4 Progression of Disease 
Progression will be estimated using the cumulative incidence function, treating death prior 
to progression as a competing event. A point estimate and 90% confidence interval will 
be provided for the probability of progression at 12 months post-transplant. 
5.7.5 Incidence of Cytokine Release Syndrome (CRS) 
Proportions of patients who experience CRS will be tabulated by grade (according to 
ASTCT criteria) and time period after infusion of CAR T-cells.  
5.7.6 Incidence of Prolonged Cytopenias 
Proportions of patients who experience prolonged cytopenias will be tabulated.  
5.7.7 Incidence of Neurotoxicity (ICANS)  
Proportions of patients who experience neurotoxicity (according to ASTCT criteria) will be 
tabulated by grade.  
5.7.8 Feasibility of Reinitiation of Lenalidomide Maintenance 
Time to reinitiation 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.  
5.8 Analysis of Exploratory Endpoints 
5.8.1 CAR T-Cell Expansion 
Quantitative summaries of CAR T-cell expansion measurements (median, range, IQR) 
will be provided at specified timepoints. Peak CAR T-cell expansion will be compared 
between subjects who are and are not in CR at 1 year, and between subjects who are 
and are not progression-free at 1 year, using Mann-Whitney Wilcoxon tests.  
5.8.2 CAR T-Cell Persistence 
Persistence will be summarized on each patient using AUC over the first 6 months or 
using presence of detectable CAR T-cells at 6 months post bb2121infusion. AUC will be 
compared between subjects who are and are not in CR at 1 year, and between subjects 
who are and are not progression-free at 1 year, using Mann-Whitney Wilcoxon tests. 

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Presence of detectable CAR T cells at 6 months post infusion will be compared between 
subjects who are and are not in CR at 1 year, and between subjects who are and are not 
progression-free at 1 year, using chi-square test or Fisher’s exact test as appropriate.  
5.8.3 BCMA Expression 
BCMA expression will be compared between baseline and post-CAR-T infusion using 
Wilcoxon signed rank tests.  
5.8.4 Immune Reconstitution 
Quantitative summary measures (median, range, IQR) will be provided for lymphocyte 
subsets at baseline and various time points after CAR T cell infusion.  
5.8.5 Overall Survival 
Overall survival will be estimated using the Kaplan-Meier estimator. Death from any cause 
will be the event and surviving patients will be censored at the date of last contact. A point 
estimate and 90% confidence interval will be provided for the probability of OS at 12 
months.  
5.8.6 Overall Toxicity 
All greater than or equal to grade 3 toxicities according to CTCAE version 5.0 will be 
categorized by SOC and preferred term (PT) using the MedDRA dictionary, and the 
number of AEs will be summarized by SOC, PT, peak grade. The number and percentage 
of participants with at least 1 grade 3 or higher AE will be summarized by SOC and PT. 
Detailed listings of unexpected SAEs, including severity and relationship to treatment, will 
be presented. 
5.8.7 Infections 
The number of grade 2 or higher infections and the number of patients experiencing 
infections will be tabulated by type of infection, severity, and time period after infusion of 
BCMA CAR T-cells.  
 

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APPENDIX A  
CRITERIA FOR SYMPTOMATIC MULTIPLE MYELOMA 
 
All three required: 
1. Monoclonal plasma cells in the bone marrow greater than or equal to 10% and/or 
presence of a biopsy-proven plasmacytoma 
2. Monoclonal protein present in the serum and/or urinea 
3. Myeloma defining events (1 or more)  
a. Myeloma- related organ dysfunctionb: 
i. Calcium elevation in the blood (serum calcium greater than 10.5 mg/l 
or upper limit of normal) 
ii. Renal insufficiency (serum creatinine greater than 2mg/dl) 
iii. Anemia (hemoglobin less than 10 g/dL) 
iv. Lytic bone lesions or osteoporosisc 
b. Any one or more of the following biomarkers of malignancy:  
i. Clonal bone marrow plasma cell percentage greater than or equal to 
60% 
ii. Involved: uninvolved serum free light chain ratio greater than or equal 
to 100 
iii. Greater than1 focal lesion of MRI  
 
*Note: These criteria identify Stage IB and Stages II and III A/B myeloma by Durie/Salmon 
stage. Stage IA becomes smoldering or indolent myeloma.  
 
a If no monoclonal protein is detected (nonsecretory disease), then ≥30% monoclonal 
bone marrow plasma cells and/or a biopsy-proven plasmacytoma required. 
b A variety of other types of end organ dysfunctions can occasionally occur and lead 
to a need for therapy. Such dysfunction is sufficient to support classification as 
myeloma if proven to be myeloma related. 
c If a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) 
are the sole defining criteria, then greater than or equal to 30% plasma cells are 
required in the bone marrow. 
 
*Myeloma management guidelines: a consensus report from the Scientific Advisors of the International 
Myeloma Foundation. The Hematology Journal (2003) 4, 379–398 

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APPENDIX B 
 
LABORATORY PROCEDURES 
Collection of MANDATORY Samples bb2121 Production, Immunologic Endpoints, 
and Additional Future Correlative Laboratory Studies 
Bone marrow aspirate and peripheral blood will be collected for patients who consent to 
the BMT CTN 1902 study. Sample collection will be performed periodically throughout the 
study and will provide clinical samples required for correlative laboratory testing 
associated with critical immunologic study endpoints. 
¾ Leukapheresis Sample for bb2121 manufacturing and cell content 
evaluation: A required sample of a sufficient quantity of peripheral blood 
mononuclear cells (PBMCs) collected via leukapheresis is required for the 
production of the bb2121 investigational product. Leukapheresis sample should be 
collected per the BMT CTN 1902 SOPs. Once the sample is collected at the 
specified time point, it will be shipped on the day of collection directly to the 
BMS/Celgene manufacturing facility. Additionally, the study team will request from 
the BMS/Celgene manufacturing facility, three 1.8 mL cryopreserved aliquots of 
both the leukapheresis and the final CAR T-cell product to be sent to the BMT CTN 
Biorepository for a future study team correlative to perform an extensive cell 
composition analysis for each product.  
¾ Research Samples for Laboratory Correlatives Associated with Immunologic 
Endpoints: Required research samples for study-specific immunologic 
correlatives include the collection of blood and marrow aspirate samples as 
summarized in the table below (and in table 4.3B). The correlative studies include 
(1) MRD assessment & BCMA expression by flow cytometry, (2) MRD assessment 
by NGS, (3) Peripheral blood immune reconstitution and marrow immune profiling 
by flow cytometry, and (4) the evaluation of CAR T-Cell expansion and 
persistence. Once the samples are collected at specified time points, they will be 
shipped on the day of collection directly to either a specified ancillary study 
laboratory for processing and testing or BMT CTN Biorepository for processing and 
long-term research aliquot storage. These samples will be tracked through 
GlobalTrace. Detailed procedures regarding specimen collection schedules, 
procedures and shipping instructions will be found in the BMT CTN 1902 Research 
Sample Information Guide.  
  
Collection of OPTIONAL BMT CTN Biorepository Samples Supporting Additional 
Planned Correlative Studies and Future Research:  
Bone marrow aspirate, peripheral blood PBMC, and serum, will be collected and stored 
to support some planned correlative studies and future research. Once the samples are 
collected at the transplant center at specified time points, they will be shipped on the day 
of collection to the BMT CTN Central Processing Laboratory for final processing and 
storage at the BMT CTN Research Repository. The collection, processing, and shipping 
of these biospecimens are summarized in the table below (and in table 4.3B). These 
samples will be tracked through GlobalTrace. Detailed procedures regarding specimen 
collection schedules, procedures and shipping instructions will be found in the BMT CTN 
1902 Research Sample Information Guide.

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B-2  
Mandatory Research Samples Associated with bb2121 Manufacturing and Immunologic Study Endpoints 
Purpose 
 Sample 
Type 
Sample Collection Summary 
Dates Samples Obtained 
Shipping Specifications 
Shipping 
Location 
Leukapheresis 
Sample for 
bb2121 
manufacturing 
Peripheral 
Blood 
Per BMS/Celgene bb2121 
manufacturing guidance 
At the time of leukapheresis, ≤ 
approximately 14 days following 
enrollment 
Per BMS/Celgene bb2121 
manufacturing guidance 
BMS/ Celgene 
Manufacturing 
Facility 
 
MRD & BCMA 
Expression 
Assessment 
And 
Immune 
Profiling 
 
6 mL 
Bone 
Marrow 
Aspirate 
Collect bone marrow aspirate 
sample and place 6 mL into a 
green top plastic BD 
Vacutainer® tube, containing 
Sodium-Heparin anticoagulant. 
Gently mix sample by inversion 
8-10 times to mix sample well 
with heparin anticoagulant. 
Prior to initiation of LD 
chemotherapy; at days 30, 90, 
180 and 365 post-bb2121 
infusion; and at the time of 
disease progression (if 
applicable). 
 Note: Only Immune Profiling 
Assessment done from Day 30 
sample 
Bone marrow aspirate 
sample will be shipped at 
ambient temperature on the 
day of collection to RPCI by 
priority overnight FED EX 
delivery. 
RPCI 
Laboratory 
MRD 
Assessment by 
NGS 
2 mL 
Bone 
Marrow 
Aspirate 
Collect bone marrow aspirate 
sample and place 2 mL into a 
lavender top plastic BD 
Vacutainer® tubes containing 
EDTA anticoagulant. Gently 
mix sample by inversion 8-10 
times to mix sample well with 
the EDTA anticoagulant. 
Prior to initiation of LD 
chemotherapy; at days 90, 180 
and 365 post-bb2121 infusion; 
and at the time of disease 
progression (if applicable). 
Bone marrow aspirate 
sample will be shipped at 
ambient temperature on the 
day of collection to the BMT 
CTN Research Repository 
by priority overnight FED EX 
delivery. 
BMT CTN 
Research 
Repository 
Immune 
Reconstitution 
10 mL 
Peripheral 
Blood 
Collect blood sample and place 
10 mL into a green top plastic 
BD Vacutainer® tube, 
containing Sodium-Heparin 
anticoagulant. Gently mix 
sample by inversion 8-10 times 
to mix sample well with heparin 
anticoagulant. 
Prior to initiation of LD 
chemotherapy; at days 30, 90, 
and 365 post-bb2121 infusion; 
and at the time of disease 
progression (if applicable). 
Blood sample tube will be 
shipped at ambient 
temperature on the day of 
collection to the PRCI 
laboratory by priority 
overnight FED EX delivery. 
RPCI Lab 
oratory 

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Mandatory Research Samples Associated with bb2121 Manufacturing and Immunologic Study Endpoints 
Purpose 
 Sample 
Type 
Sample Collection Summary 
Dates Samples Obtained 
Shipping Specifications 
Shipping 
Location 
CAR T Cell 
Expansion and 
Persistence 
 
2 mL  
Bone 
Marrow 
Aspirate 
 Collect bone marrow aspirate 
sample and place 2 mL into a 
lavender top plastic BD 
Vacutainer® tube, containing 
EDTA anticoagulant. Gently 
mix sample by inversion 8-10 
times to mix sample well with 
EDTA anticoagulant 
Prior to initiation of LD 
chemotherapy; at days 30, 90 
and 365 post bb2121 infusion; 
and at the time of disease 
progression (if applicable). 
 Bone marrow aspirate 
sample tube will be shipped 
at ambient temperature on 
the day of collection to the 
BMT CTN Research 
Repository by priority 
overnight FED EX delivery. 
 BMT CTN 
Research 
Repository 
8 mL  
Peripheral 
Blood 
 Collect blood sample and 
place 8mL into a lavender top 
plastic BD Vacutainer® tube, 
containing EDTA 
anticoagulant. Gently mix 
sample by inversion 8-10 
times to mix sample well with 
EDTA anticoagulant. 
Prior to initiation of LD 
chemotherapy; at days 4, 7, 14, 
21, 30, 60, 90, 180, 270, and 
365 post bb2121 infusion; and at 
the time of disease progression 
(if applicable). 
 Blood sample tube will be 
shipped at ambient 
temperature on the day of 
collection to the BMT CTN 
Research Repository by 
priority overnight FED EX 
delivery. 
 BMT TCN 
Research 
Repository 

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B-4  
Mandatory Biorepository Samples Supporting Additional Planned Research Sample Collections Studies 
Purpose 
 Sample 
Type 
Sample Collection Summary 
Dates Samples Obtained 
Shipping Specifications 
Shipping 
/Storage 
Location 
Future Research 
6 mL 
Bone Marrow 
Aspirate 
Collect bone marrow aspirated 
sample and place 6 mL into a 
green top plastic BD 
Vacutainer® tube, containing 
Sodium-Heparin anticoagulant. 
Gently mix sample by 
inversion 8-10 times to mix 
sample well with heparin 
anticoagulant. 
Prior to initiation of 
lymphodepleting LD 
chemotherapy; at days 30, 90, 
and 365 post-bb2121CAR T Cell 
infusion; and at the time of 
disease progression (if 
applicable). 
Bone marrow aspirate tube 
will be shipped at ambient 
temperature on the day of 
collection, to the BMT CTN 
Research Repository by 
priority overnight FED EX 
delivery for processing and 
final frozen storage of 
marrow aliquots.  
BMT CTN 
Research 
Repository 
Future Research 
45 mL  
Peripheral 
Blood 
Collect blood sample in green 
top plastic BD Vacutainer® 
tubes, containing Sodium-
Heparin anticoagulant. Gently 
mix sample by inversion 8-10 
times to mix sample well with 
heparin anticoagulant.  
 Prior to initiation of LD 
chemotherapy; at days 30, 90, 
and 365 post-bb2121 infusion; 
and at the time of disease 
progression (if applicable). 
Peripheral blood tubes will 
be shipped at ambient 
temperature on the day of 
collection, to the BMT CTN 
Research Repository by 
priority overnight FED EX 
delivery for processing and 
final frozen storage of 
PBMC aliquots. 
BMT CTN 
Research 
Repository 
Future Research 
8mL 
 Peripheral 
Blood 
(serum) 
Collect blood sample in a 
Red/Gray Top BD SST™ Tube 
with Silica Clot Activator & 
Polymer Gel. Let sample sit 
upright in rack for 30-60 
minutes. Centrifuge for 10 
minutes. Gel barrier will form 
separating the serum 
specimen from clot. 
Prior to initiation of LD 
chemotherapy; at days 4, 7, 14, 
21, 30, 60, 90, 180, 270, and 
365 post-bb2121 infusion; and at 
the time of disease progression 
(if applicable). 
Serum blood tube will be 
shipped at ambient 
temperature on the day of 
collection, to the BMT CTN 
Research Repository by 
priority overnight FED EX 
delivery for processing and 
final frozen storage of serum 
aliquots. 
BMT CTN 
Research 
Repository 

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APPENDIX C 
 
RISKS OF FETAL EXPOSURE, PREGNANCY TESTING GUIDELINES 
AND ACCEPTABLE BIRTH CONTROL METHODS 
Risks Associated with Pregnancy 
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. 
The use of lenalidomide in pregnant females and nursing mothers has not been studied 
nor has the effect of the lenalidomide on human eggs and sperm. The risks to a fetus are 
not known. However, because lenalidomide is related to thalidomide, and thalidomide is 
known to cause severe birth defects, the following requirements must be observed. 
Females of childbearing potential (FCBP)† must agree to use two reliable forms of 
contraception simultaneously or to practice complete abstinence from heterosexual 
intercourse during the following time periods related to this study: 1) for at least 28 days 
before starting study drug; 2) while participating in the study; and 3) for at least 28 days 
after discontinuation from the study. The two methods of reliable contraception must 
include one highly effective method (i.e., intrauterine device (IUD), hormonal [birth control 
pills, injections, or implants], tubal ligation, partner’s vasectomy) and one additional 
effective (barrier) method (i.e., latex condom, diaphragm, cervical cap). FCBP must be 
referred to a qualified provider of contraceptive methods if needed.  
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature female who: 
1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been 
naturally postmenopausal (amenorrhea following cancer therapy does not rule out 
childbearing potential) for at least 24 consecutive months (i.e., has had menses at any 
time in the preceding 24 consecutive months). 
Counseling 
All counseling will be conducted through the Lenalidomide REMS program. 
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two 
reliable forms of contraception simultaneously or to practice complete abstinence from 
heterosexual contact during the following time periods related to this study: 1) for at least 
28 days before starting study drug; 2) while participating in the study; 3) during dose 
interruptions; and 4) for at least 28 days after study treatment discontinuation.  
 
† A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or, 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in 
the preceding 24 consecutive months). 

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The two methods of reliable contraception must include one highly effective method and 
one additional effective (barrier) method. FCBP must be referred to a qualified provider 
of contraceptive methods if needed. The following are examples of highly effective and 
additional effective methods of contraception:  
Highly effective methods: 
Intrauterine device (IUD) 
Hormonal (birth control pills, injections, implants) 
Tubal ligation 
Partner’s vasectomy 
Additional effective methods: 
Male condom 
Diaphragm 
Cervical Cap 
 
Because of the increased risk of venous thromboembolism in patients with multiple 
myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills are 
not recommended. If a patient is currently using combined oral contraception the patient 
should switch to one of the effective methods listed above. The risk of venous 
thromboembolism continues for 4 to 6 weeks after discontinuing combined oral 
contraception. The efficacy of contraceptive steroids may be reduced during co-treatment 
with dexamethasone. 
Implants and levonorgestrel-releasing intrauterine systems are associated with an 
increased risk of infection at the time of insertion and irregular vaginal bleeding. 
Prophylactic antibiotics should be considered particularly in patients with neutropenia.  
Pregnancy testing 
The following pregnancy testing guidelines will be used throughout the study. Medically 
supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be performed 
for females of childbearing potential, including females of childbearing potential who 
commit to complete abstinence, as outlined below. 
Female Subjects:  
x FCBP must have two negative pregnancy tests (minimum sensitivity of 50 mIU/mL) 
prior to prescribing study drug. The first pregnancy test must be performed within 
10-14 days prior to prescribing study drug and the second pregnancy test must be 
performed within 24 hours prior to prescribing study drug (prescriptions must be 
filled within 7 days as required by Lenalidomide REMS). The subject may not 
receive study drug until the Investigator has verified that the results of these 
pregnancy tests are negative. 
x FCBP must commit either to abstain continuously from heterosexual intercourse 
or to use TWO methods of reliable birth control AT THE SAME TIME—one highly 
effective form of contraception and one additional effective contraceptive method 

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as defined below. Contraception must begin 4 weeks prior to initiating treatment 
with lenalidomide, during therapy, during dose interruptions, and continuing for at 
least 1 year following bb2121 infusion and until CAR-T cells are no longer present 
by qPCR on two consecutive tests, or 4 weeks following discontinuation of 
lenalidomide, whichever comes later.  
 
Male Subjects:  
x 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 and until CAR-T cells are no longer present by 
qPCR on two consecutive tests; or 4 weeks following discontinuation of 
lenalidomide whichever is later. 
All Subjects: 
x Only enough lenalidomide for one cycle of therapy may be dispensed with each 
cycle of therapy.  
x If pregnancy or a positive pregnancy test does occur in a study subject or the 
partner of a male study subject during study participation, lenalidomide must be 
immediately discontinued.

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APPENDIX D  
REVLIMID® (LENALIDOMIDE) OVERVIEW 
Lenalidomide REMS for Study Participants 
 
Lenalidomide REMS description:  
A program that allows patients enrolled in authorized clinical trials access to free 
Revlimid® (Lenalidomide) through the Lenalidomide REMS program.  
Access to the Lenalidomide REMS Program:  
1. All physicians must be registered prescribers of REVLMID in the Lenalidomide 
REMS Program. All clinical sites must have access to the Lenalidomide REMS 
program  
1) Prescriber enrolls in the Lenalidomide REMS online or calls the Lenalidomide 
REMS.  
2) Prescriber is registered within 15 minutes.  
3) Registration confirmation is provided to prescriber’s office.  
4) Lenalidomide REMS Kit is sent to prescriber’s office (overnight). The starter kit will 
contain the following:  
x Prescriber Guide to Lenalidomide REMS  
x Patient Resource Pack  
 
2. All studies must have an FDA letter of IND exemption or an active IND, active 
IRB approval and BMS/Celgene required regulatory documents  
3. Patients must sign the research specific IRB-approved informed consent and 
be enrolled in a BMS/Celgene-approved Medical Affairs clinical trial using 
Revlimid® (lenalidomide)  
4. The Lenalidomide REMS must be contacted to confirm if a patient needs to be 
registered by calling 1-888-423-5436 
5. Patients must also sign the appropriate Patient-Physician Agreement Form 
(PPAF) and follow all the procedures of the Lenalidomide REMS Program  
1) Patient and Prescriber complete the PPAF together. 
2) The form is faxed to the Lenalidomide REMS or submitted electronically to the 
Lenalidomide REMS. 
3) Patient is registered within 15 minutes.  
4) Confirmation is sent to prescribing office notifying them that the patient is now 
enrolled.  
6. Patients and prescribers must take the phone surveys as required by the 
Lenalidomide REMS Program (The PPAF generated for the patient determines 

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which phone survey questions will be asked). An authorization number is 
provided at the completion of the phone survey, the authorization number along 
with the patient risk category must be noted on the prescription form.  
 
Patient Survey requirements: 
x For men: Do not need to call Lenalidomide REMS the first month but must call 
monthly starting the second month. 
x For females of non-reproductive potential: Must call for the first month and then 
call every 6 months after. 
x For females of reproductive potential: Must call for the first month and then 
every month after. 
Prescribing Revlimid® (lenalidomide) in the Lenalidomide REMS program  
x BMS/Celgene Medical Affairs Operations will activate the study with the 
designated Lenalidomide REMS Pharmacy upon receipt of all required regulatory 
documents.  
x The designated Lenalidomide REMS Pharmacy will not dispense or ship Revlimid® 
(lenalidomide) prior to BMS/Celgene’s notification of activation.  
x Prescription information MUST BE entered using the BMT CTN 1902 
Lenalidomide REMS study specific electronic prescription form. This form 
can be found on the BMT CTN SharePoint website (https://bmtctnsp.net) 
x An authorization number and the patient’s risk category must be on the 
prescription form at the time of faxing.  
x Prescriptions for Revlimid® (lenalidomide) must be sent to the designated 
Lenalidomide REMS Pharmacy  
x Only a 28-days’ supply of Revlimid® (lenalidomide) may be provided per cycle and 
sent to the actual address noted on the Lenalidomide REMS electronic study 
specific prescription form.  
x The Lenalidomide REMS Pharmacy will verify the authorization number and 
complete the patient counseling.  
Protocol compliance and drug return  
x Patients will be required to return unused drug to the study site for destruction per 
institutional guidelines.  
x Sites may request that patients maintain a diary and/or to bring their bottles in for 
a pill count at each visit in order to review “patient compliance.”  

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IMPORTANT INFORMATION ABOUT Lenalidomide REMS  
 
 
 
 
 
 
 
 
How to Fill a REVLIMID® (lenalidomide) Prescription  
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
To avoid fetal exposure REVLIMID®(lenalidomide) is only available under a special restricted distribution 
program called Lenalidomide REMS 
x 
Only prescribers registered with Lenalidomide REMS can prescribe REVLIMID® (lenalidomide) 
x 
Only Lenalidomide REMS contract pharmacies can dispense REVLIMID® (lenalidomide) 
x 
In order to receive REVLIMID® (lenalidomide), patients must enroll in Lenalidomide REMS and agree to 
comply with the requirements of the Lenalidomide REMS program 
x 
Information about REVLIMID® (lenalidomide) and the Lenalidomide REMS program can be obtained by 
calling the Lenalidomide REMS toll-free at 1-888-423-5436, or at www. LENALIDOMIDEREMS.com 
1. 
Healthcare provider (HCP) instructs patient to complete patient survey  
2. 
HCP completes survey  
3. 
HCP completes patient prescription form  
4. 
HCP obtains Lenalidomide REMS authorization number  
5. 
HCP provides authorization number on patient prescription form  
6. 
HCP faxes form, including prescription  
7. 
HCP advises patient that a representative from a Lenalidomide REMS contract pharmacy will contact them  
8. 
Lenalidomide REMS contract pharmacy conducts patient education  
9. 
Lenalidomide REMS contract pharmacy calls for confirmation number  
10. 
Lenalidomide REMS contract pharmacy ships LENALIDOMIDE with the FDA-approved MEDICATION GUIDE  

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APPENDIX E  
HUMAN SUBJECTS 
 
1. Subject Consent 
A conference will be held with the patient, and family to discuss this study and alternative 
treatments available for the treatment of multiple myeloma. The conference will be 
conducted by the Principal Investigator or other designated physician. Potential risks 
associated with the study interventions should be discussed as objectively as possible. 
Consent will be obtained using an IRB-approved consent. 
The BMT CTN will provide a template of the consent form to each center. Each center 
will customize the template according to their local requirements and submit it for review 
by the local Internal Review Board (IRB). The DCC will verify the adequacy of the consent 
forms prior to submission to the IRB. Each center must provide evidence of IRB approval. 
2. Confidentiality 
Confidentiality will be maintained by individual names being masked and assigned a 
patient identifier code. The code relaying the patient’s identity with the ID code will be 
kept separately at the center. The ID code will be transmitted to the network. 
3. Participation of Women and Minorities and Other Populations 
Women and ethnic minorities and other populations will be included in this study. Accrual 
of women and minorities at each center will be monitored to determine whether their rates 
of enrollment are reflective of the distribution of potentially eligible women and minorities 
expected from data reported to the CIBMTR and from published data on incidence of MM 
in these groups. Centers will be notified if their rates differ significantly from those 
expected and asked to develop appropriate recruitment strategies. 
 

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APPENDIX F 
 
KARNOFSKY PERFORMANCE STATUS SCALE 
 
Index 
Specific Criteria 
General 
100 
Normal, no complaints, no evidence 
of disease. 
Able to carry on normal activity; no special care 
needed. 
90 
Able to carry on normal activity, 
minor signs or symptoms of disease. 
80 
Normal activity with effort, some 
signs or symptoms of disease. 
70 
Care for self, unable to carry on 
normal activity or to do work. 
Unable to work, able to live at home and care for 
most personal needs, varying amount of 
assistance needed. 
60 
Requires occasional assistance from 
others but able to care for most 
needs. 
50 
Requires considerable assistance 
from others and frequent medical 
care 
40 
Disabled, requires special care and 
assistance. 
Unable to care for self, requires institutional or 
hospital care or equivalent, disease may be 
rapidly progressing. 
 
30 
Severely disabled, hospitalization 
indicated, but death not imminent. 
20 
Very sick, hospitalization necessary, 
active supportive treatment 
necessary. 
10 
Moribund 
0 
Dead 

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APPENDIX G 
 
BB2121 INFUSION PROCESS 
bb2121 Preparation and Cell Thawing 
bb2121 must be delivered to the pre-defined department responsible for receiving cell 
products, thawed at the infusion site in a ~37°C water bath or approved thawing 
instrument and infused immediately within 1 hour; alternately, bb2121 may be thawed in 
the appropriate cell manipulation facility and administered as soon as possible within a 
maximum of 1 hour after thawing. If multiple drug product bags are to be administered to 
meet the protocol assigned dose, each bag will be thawed and administered 1 bag at a 
time within a maximum of 1 hour for each bag until the appropriate volume and 
corresponding CAR T-cell dose has been administered. In the event of a delay in 
completing the planned bb2121 infusion within 1 hour of thaw, bb2121 should still be 
administered; the reason for the delay should be recorded in the eCRF and the Sponsor 
will be notified. 
All procedures involving bb2121 must be performed using aseptic techniques by trained 
personnel. See bb2121 Product Receipt, Preparation, and Administration Manual for 
more detail. 
bb2121 Premedication 
Premedication should occur approximately 30 minutes prior to the infusion and should 
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.  
bb2121 Infusion 
bb2121 will be given on Day 0 (+ 14-day window), after lymphodepletion on Days -5, -4 
and -3 at a target dose of 150 to 450 × 106 CAR T-cells/infusion with a minimum dose of 
150 × 106 CAR+ T cells/infusion.  
On Day 0, bb2121 will be administered IV through non-filtered tubing (IMPORTANT—AN 
IN-LINE LEUKOCYTE FILTER MUST NOT BE USED). A central venous access device, 
such as a Hickman line or peripherally inserted central catheter (PICC) line, may be 
utilized and is encouraged in subjects with poor peripheral access.  
Vital signs are to be monitored prior to bb2121 infusion, midway through the infusion, 
upon completion of the infusion, and then every 15 minutes thereafter for the first hour, 
and hourly for the next 4 hours. Infusion reactions, including anaphylaxis, will be managed 
according to the medical judgment of the physician overseeing the infusion.  
Dose for Subjects for Whom the Targeted Dose Cannot be Manufactured 
bb2121 is manufactured on a per-subject basis and there is expected to be heterogeneity 
in the number of CAR T-cells that are manufactured for each subject. Subjects who have 
product manufactured with a dose of less than 150 x 106 CAR T-cells may proceed to a 
2nd leukapheresis procedure for a second attempt at bb2121 manufacturing. The 
administered bb2121 dose may be composed of more than one manufactured product 
from the same subject. 

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APPENDIX H
MANAGEMENT GUIDELINES FOR CYTOKINE RELEASE SYNDROME 
(CRS) AND NEUROLOGIC TOXICITIES
(1) Cytokine release syndrome (CRS)
Administration of cellular products such as chimeric antigen receptor (CAR)-expressing 
T cells can be associated with cytokine-associated toxicity due to systemic production 
and release of various cytokines into the circulation. Cytokine-associated toxicity, also 
known as cytokine release syndrome (CRS), is a toxicity that occurs as a result of immune 
activation.[58, 59]
(1.1) Pathophysiology of CRS
The hallmark of CRS is immune activation resulting in elevated inflammatory cytokines. 
CRS clinically manifests when large numbers of lymphocytes (B cells, T cells, and/or 
natural killer cells) and/or myeloid cells (macrophages, dendritic cells, and monocytes) 
become activated with therapeutic monoclonal antibody (mAb) infusions, most notably 
anti-CD3 (OKT3), anti-CD52 (alemtuzumab), and anti-CD20 (rituximab), and the CD28 
super-agonist, TGN1412. CRS is also frequently observed following administration of bi-
specific T cell engaging antibodies for leukemia, and adoptive cellular immunotherapies 
for cancer, most notably CAR T cells. Incidence, time to onset and severity of CRS due 
to CAR T cells is at least partially dependent on the infused cell dose and tumor 
burden/antigen density, presumably due to more rapid and higher levels of CAR T cell 
activation. Onset of CRS symptoms typically occurs days to occasionally weeks after the 
CAR T cell infusion, usually preceding maximal in vivo T cell expansion. CRS is 
associated with elevated interferon gamma (IFN ), interleukin (IL)-6, and tumor necrosis 
alpha (TNF ) levels, and increases in IL-2, granulocyte macrophage colony-stimulating 
factor (GM-CSF), IL-10, IL-8, IL-5, and fractalkine although the patter of elevated 
cytokines varies among subjects.[60, 61] IL-6 has been identified as a central mediate of 
toxicity in CRS. IL-6 is a pleiotropic cytokine with anti-inflammatory and proinflammatory 
properties. High levels of IL-6, present in the context of CRS, likely initiates a 
proinflammatory IL-6-mediated signaling cascade. 
(1.2) Clinical presentation of CRS
CRS is characterized by high fever, fatigue, nausea, headache, dyspnea, tachycardia, 
rigors, hypotension, hypoxia, myalgia/arthralgia, and anorexia. Clinical symptoms and 
severity of CRS are highly variable (Table H1),[58] and management can be complicated 
by concurrent conditions. CRS usually occurs within two weeks after infusion.[64]
x
Fever, especially high fever (≥ 38.5 °C or ≥ 101.3 °F), is a commonly observed 
hallmark of CRS, and many features of CRS mimic infection. Hence, infection must 
be considered in all subjects presenting with CRS symptoms, and appropriate 
cultures must be obtained, and empiric antibiotic therapy initiated per institutional 
standard of care.

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x Less common symptoms associated with CRS include cardiac dysfunction, adult 
respiratory distress and/or hepatic failure, coagulopathies, disseminated 
intravascular coagulation, and capillary leak syndrome.  
x Neurologic toxicity has been observed concurrently with CRS. 
x With other CAR T cell products, CRS has been reported in a few cases to be 
associated 
with 
findings 
of 
macrophage 
activation 
syndrome 
(MAS)/hemophagocytic lymphohistiocytosis (HLH), and the physiology of the 
syndromes may overlap.  
  
Table H1: Clinical Signs and Symptoms Associated with CRS 
Organ System 
Symptoms 
Constitutional  
Fever ± rigors, malaise, fatigue, anorexia, 
myalgia, arthralgia, nausea, vomiting, headache 
Respiratory 
Tachypnea, hypoxemia 
Cardiovascular 
Tachycardia, widened pulse pressure, 
hypotension, increased cardiac output (early), 
potentially diminished cardiac output (late) 
Coagulation 
Elevated D-dimer, hypofibrinogenemia ± bleeding 
Renal  
Acute kidney injury, azotemia 
Gastrointestinal 
Nausea, vomiting, diarrhea 
Skin 
Rash 
Hepatic 
Transaminitis, hyperbilirubinemia 
Neurologic* 
Headache, mental status changes, confusion, 
delirium, word finding difficulty or frank aphasia, 
hallucinations, tremor, dysmetria, altered gait, 
seizures 
*Adapted from Lee 2014,[58] Neurologic symptoms are typically reversible and can occur independent of CRS. 
Neurologic symptoms should be graded and treated independently even if overlapping with CRS.  
(1.3) Clinical management of CRS 
Across various CAR T cell products, early manifestations of CRS can predict more severe 
toxicity for both CRS and neurotoxicity. 
Subjects with B-cell acute lymphoblastic leukemia (ALL) and high burden of disease are 
at high risk of developing CRS.[64] Subjects with non-Hodgkin lymphoma (NHL) who have 
high baseline tumor burden (measured by the sum of product of the perpendicular 
diameters [SPD] or high serum lactate dehydrogenase [LDH ≥ 500 U/L] prior to the start 
of lymphodepletion) also have a higher risk of developing CRS and/or neurotoxicity.[65] 
High baseline levels of other commonly measured inflammatory markers, such as ferritin 
and C-reactive protein (CRP), were also associated with CRS. 
It should be noted that, although useful for identifying subjects at higher risk for developing 
CRS, CPR, ferritin, and serum cytokine levels should not be used for CRS clinical 
management/treatment decisions in the absence of other clinical signs and symptoms of 
CRS; for example, a subject with an elevated CRP but no concomitant symptoms may 
not require intervention. Thus, close observation of these subjects is strongly 
recommended.  

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Table H2: American Society of Blood and Marrow Transplant (ASBMT) CRS 
Consensus Grading 
CRS parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fever1 
Temperature ≥ 38 
°C 
Temperature ≥ 38 
°C 
Temperature ≥ 38 
°C 
Temperature ≥ 38 
°C 
With Hypotension 
None 
Not requiring 
vasopressors 
Requiring a 
vasopressor with 
or without 
vasopressin 
Requiring multiple 
vasopressors 
(excluding 
vasopressin) 
And/or2 Hypoxia 
None 
Requiring low-flow 
nasal cannula3 or 
blow-by 
Requiring high-
flow nasal 
cannula3, 
facemask, 
nonrebreather 
mask, or Venturi 
mask 
Requiring positive 
pressure (eg., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
Adapted from Lee 2018[28]. Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do 
not influence CRS grading. 
1 Fever is defined as temperature ≥ 38 °C not attributable to any other cause. In patients who have CRS then receive 
antipyretics or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent 
CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
2 CRS grade is determined by more severe event: hypotension or hypoxia not attributable to any other cause. For 
example, a patient with temperature of 39.5 °C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow 
nasal cannula is classified as grade 3 CRS. 
3 Low-flow nasal cannula is defined as oxygen delivered at ≤ 6 L/min. Low flow also includes blow-by oxygen delivery, 
sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at > 6 L/min. 
 
Detailed CRS management guidelines are shown in Figure H1. Treatment should be 
individualized for each subject’s clinical needs. This guidance emphasizes the importance 
of early intervention for grade 2 CRS, or in the setting of a rapid onset or rapid progression 
of CRS symptoms, to prevent the development of severe (grade 3 or greater) CRS and 
neurotoxicity. 
In some cases, tocilizumab, an anti-IL-6R-antibody, may be required to treat toxicities 
such as severe CRS. Please refer to the currently approved tocilizumab (Actemra®) 
prescribing information. Tocilizumab (Actemra®) has been approved by the Food and 
Drug Administration (FDA) for the treatment of CAR T cell-induced severe or life-
threatening CRS in adults. The preferred dose to intervene in adult subjects with CRS is 
8 mg/kg (maximum 800 mg) IV. If no clinical improvement in the signs and symptoms of 
CRS occurs after the first dose, additional doses of tocilizumab may be administered. 
Other anti-IL-6 agents, if available, should be considered in the event of severe CRS not 
responding to tocilizumab and corticosteroids. Dosing of any other anti-IL-6 agent should 
be per prescribing information.  
 

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Figure H1: Cytokine Release Syndrome (CRS) Management Guidance  
 
 
 
CRS 
Grade1 
Tocilizumab* 
Corticosteroids† 
Grade 1 
 
Symptoms require symptomatic 
treatment only (e.g., fever, nausea, 
fatigue, headache, myalgia, 
malaise). 
If onset 72 hours or more after infusion, 
treat symptomatically. 
If onset less than 72 hours after infusion, consider 
tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 
mg). 
Consider 
dexamethasone 10 mg 
IV every 24 hours. 
Grade 2 
 
Symptoms require and 
respond to moderate 
intervention. 
Oxygen requirement less than 
40% FiO2 or hypotension 
responsive to fluids, or low dose 
of one vasopressor, or Grade 2 
organ toxicity. 
Administer tocilizumab 8 mg/kg IV over 1 
hour (not to exceed 800 mg). 
Repeat tocilizumab every 8 hours as needed if not 
responsive to intravenous fluids or increasing 
supplemental oxygen. 
Limit to a maximum of 3 doses in a 24-hour period; 
maximum total of 4 doses. 
Consider 
dexamethasone 10 mg 
IV every 12 to 24 
hours. 
 
If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate 
dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours). 
If no improvement within 24 hours or continued rapid progression, switch to 
methylprednisolone 2 mg/kg followed by 2 mg/kg divided 4 times per day. 
After 2 doses of tocilizumab, consider alternative anti-cytokine 
agents. Do not exceed 3 doses of tocilizumab in 24 hours, or 4 
doses in total. 
Grade 3 
 
Symptoms require and respond to 
aggressive intervention. 
Fever, oxygen requirement greater than 
or equal to 40% FiO2, or hypotension 
requiring high-dose or multiple 
vasopressors, or Grade 3 organ toxicity, 
or Grade 4 transaminitis. 
Per Grade 2. 
Administer dexamethasone 10 
mg IV every 12 hours. 
If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate 
dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours). 
If no improvement within 24 hours or continued rapid progression, switch to 
methylprednisolone 2 mg/kg followed by 2 mg/kg divided 4 times per day. 
After 2 doses of tocilizumab, consider alternative anti-cytokine agents. 
Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total. 
Grade 4 
 
 
Life-threatening symptoms. 
Requirements for ventilator support, 
continuous veno-venous hemodialysis 
(CVVHD), or Grade 4 organ toxicity 
(excluding transaminitis). 
Per Grade 2. 
Administer dexamethasone 20 
mg IV every 6 hours. 
After 2 doses of tocilizumab, consider alternative anti-cytokine agents. Do not exceed 3 
doses of tocilizumab in 24 hours, or 4 doses in total. 
If no improvement within 24 hours, consider methylprednisolone (1-2 g, repeat every 24 
hours if needed; taper as clinically indicated) or other anti-T cell therapies. 

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In the most unresponsive cases additional treatment with T cell depleting therapies such 
as cyclophosphamide should be considered.[66]
(2) Neurologic Toxicities
CAR T cell therapy is associated with unique neurologic toxicities. Neurologic symptoms 
may include altered mental status, aphasia, altered level of consciousness, and seizures 
or seizure-like activity. The start of neurologic symptoms has been noted between 3 to 23 
days (median 10 days) [62] after CAR T cell infusion and in severe cases may require 
admission to the intensive care unit (ICU) for frequent monitoring, respiratory support, or 
intubation for airway protection. The symptoms are variable and generally occur as CRS 
is resolving or after CRS resolution.
(2.1) Pathophysiology of Neurologic Toxicities
The pathogenesis of neurotoxicity is poorly defined. Subjects with NHL who have high 
baseline tumor burden (measured by SPD or high serum LDH (≥ 500 U/L) prior to the 
start of lymphodepletion) also have a higher risk of developing neurotoxicity.[65] In 
addition, severe neurotoxicity has also been reported in subjects with B-cell ALL and 
higher disease burden at the time of CD19 directed CAR T cell infusion.[67]
Peak levels of IL-6, IFN- , ferritin, and CRP are significantly higher in subjects who 
develop any grade or grade ≥3 neurotoxicity.[68, 69] In a study treating NHL subjects with 
a CD19-directed CAR using a CD28 costimulatory domain, development of grade ≥3 
neurologic events and CRS correlated with elevation of various cytokines, including IL-6, 
IL-15, and IL-2R . Subjects with CRS-independent grade ≥3 neurologic events had 
higher CAR T cell levels and specific cytokines, including IL-2, GM-CSF, and ferritin.[31]
Protein levels in the cerebrospinal fluid (CSF) are usually elevated in patients with 
neurotoxicity, compared to baseline measurements, suggesting disruption of the blood-
brain barrier. Other organ dysfunction (hepatic and renal), as well as hypoxemia, and 
infection, might also contribute to the encephalopathy.[70] In another study, it has been 
reported that evidence for cytokine-mediated endothelial activation causes coagulopathy, 
capillary leak, and blood-brain barrier disruption allowing transit of high concentrations of 
systemic cytokines into the CSF.[67]
Current American Society of Blood and Marrow Transplant (ASBMT) Consensus Grading 
refers neurotoxicity observed CAR T cell therapy as immune effector cell-associated 
neurotoxicity syndrome (ICANS).[28]
(2.1) Clinical Management of Neurologic Toxicities
The optimal management of CAR T cell-induced neurotoxicity is unknown at this time. 
These management guidelines represent the current state of knowledge. Management 
should also be guided as per institutional or standard clinical practice, and as determined 
by the investigator or treating physician and/or consulting neurologist. A thorough 
neurologic evaluation, including electroencephalogram (EEG), magnetic resonance 
imaging (MRI) or computed tomography (CT) scan of the brain and diagnostic lumbar 
puncture and frequent monitoring of cognitive function should be considered. Please refer 

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to Table H2 for encephalopathy assessment tool for grading of ICANS, and Table H3 for 
the ASBMT ICAN Consensus Grading for adults.  
Table H2: Encephalopathy Assessment Tools for Grading of ICANS 
CARTOX-10 [70] 
ICE 
Orientation: orientation to year, month, city, 
hospital, president/prime minister of country of 
residence: 5 points 
Orientation: orientation to year, month, city, 
hospital: 4 points 
Naming: ability to name 3 objects (e.g., point to 
clock, pen, button): 3 points 
Naming: ability to name 3 objects (e.g., point to 
clock, pen, button): 3 points 
Writing: ability to write a standard sentence (e.g., 
“Our national bird is the bald eagle”): 1 point 
Writing: ability to write a standard sentence (e.g., 
“Our national bird is the bald eagle”): 1 point 
Attention: ability to count backwards from 1000 by 
10: 1 point 
Attention: ability to count backwards from 1000 by 
10: 1 point 
 
Following commands: ability to follow simple 
commands (e.g., “Show me 2 fingers” or “Close 
your eyes and stick out your tongue”): 1 point 
Adapted from Lee 2018 [28]. CARTOX-10 (left column) has been updated to the ICE tool (right column). ICE adds a 
command-following assessment in place of 1 of the CARTOX-10 orientation questions. The scoring system remains 
the same. 
Scoring: 10, no impairment. 
7-9, grade 1 ICANS: 
3-6, grade 2 ICANS: 
0-2, grade 3 ICANS:  
0 due to patient unarousable or unable to perform ICE assessment, grade 4 ICANS. 
 
Table H3: ASBMT ICANS Consensus Grading for Adults 
Neurotoxicity 
Domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE score1 
7-9 
3-6 
0-2 
0 (patient is 
unarousable and 
unable to perform 
ICE) 
Depressed levels 
of consciousness2 
Awakens 
spontaneously 
Awakens to voice 
Awakens only to 
tactile stimulus 
Patient is 
unarousable or 
requires vigorous 
or repetitive tactile 
stimuli to arouse. 
Stupor or coma 
Seizure 
N/A 
N/A 
Any clinical 
seizure focal or 
generalized that 
resolves rapidly or 
nonconvulsive 
seizures on EEG 
that resolve with 
intervention 
Life-threatening 
prolonged seizure 
(> 5 min); or 
repetitive clinical 
or electrical 
seizures without 
return to baseline 
in between 
Motor findings3 
N/A 
N/A 
N/A 
Deep focal motor 
weakness such as 
hemiparesis or 
paraparesis 
 
 

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Neurotoxicity 
Domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Elevated 
intracranial 
pressure 
(ICP)/cerebral 
edema 
N/A 
N/A 
Focal/local edema 
on neuroimaging4 
Diffuse cerebral 
edema on 
neuroimaging; 
Decerebrate or 
decorticate 
posturing; or 
cranial nerve VI 
palsy; or 
papilledema; or 
Cushing’s triad 
Adapted from Lee 2018[28]ICANS grading is determined by the most severe event (ICE score, level of consciousness, 
seizure, motor findings, raised ICP/cerebral edema) not attributable to any other cause; for example, a patient with an 
ICE score of 3 who has a generalized seizure is classified as grade 3 ICANS.  
N/A indicates not applicable. 
1 A patient with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia, but a patient with 
an ICE score of 0 may be classified as grade 4 ICANS if unarousable. 
2 Depressed level of consciousness should be attributable to no other cause (e.g., no sedating medication). 
3 Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE v5.0, but 
they do not influence ICANS grading. 
4 Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded 
from ICANS grading. It may be graded according to CTCAE v5.0. 
 
Treatable causes of neurologic dysfunction, such as infection or hemorrhage should be 
ruled out. Common manifestations of neurotoxicity (e.g., confusion, seizure, aphasia), 
can also be seen with infection, electrolyte imbalances, metabolic acidosis, uremia, 
concomitant medication use (e.g., narcotics), and other medical conditions. Other causes 
for such symptoms should be considered. 
MRI and CT scans of the brain are usually negative for any anatomical pathology that 
would account for the neurotoxicity symptoms observed in subjects treated with CAR T 
cell therapy, although rare cases of reversible T2/fluid attenuation inversion recovery 
(FLAIR) MRI hyperintensity involving the thalami, dorsal pons, and medulla, and cerebral 
edema have been reported.[70] 
For subjects who have neurologic toxicity in the present of CRS, the CRS should be 
managed following the guidelines provided in Figure H1.  
Neurotoxicity should be evaluated following the guidelines in  
Figure H2. For concurrent CRS and neurotoxicity, the most aggressive intervention 
recommended by either guideline should be employed (if the recommendations for steroid 
doses differ, use the highest dose and/or frequency). For subjects with grade 4 
neurotoxicity with cerebral edema, high-dose corticosteroids, hyperventilation and 
hyposmolar therapy has been recommended.[70] 
Note: Tocilizumab is not recommended for the treatment of neurotoxicity related to CAR 
T cell therapy unless CRS or MAS/HLH is also present. Results from 2 studies, one of 
preemptive use of tocilizumab, shortly after anti-CD19 CAR T cell therapy in 
relapsed/refractory NHL subjects,[71] and the other mandatory use of tocilizumab at first 

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fever (≥ 38.5 °C) in pediatric ALL patients treated with anti-CD19 CAR T cells,[59] 
demonstrated that early tocilizumab use either increased overall neurotoxicity and grade 
≥ 3 neurotoxicity rates (85% vs 62% overall; 35% vs 26% grade ≥ 3) or provided no 
improvement in neurotoxicity rates, respectively. These findings support the hypothesis 
that tocilizumab does not improve any may worsen isolated neurotoxicity.[71] 
Neurotoxicity management guidelines are provided in Figure H2 
Figure H2: Neurotoxicity Grading and Management Guidance  
NT Grade2 
Corticosteroids and Antiseizure Medications 
Grade 1 
 
 
Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. If 72 hours 
or more after infusion, observe patient. 
If less than 72 hours after infusion, consider dexamethasone 10 mg IV every 12 to 24 hours 
for 2 to 3 days. 
Grade 2 
 
 
Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. 
Start dexamethasone 10 mg IV every 12 hours for 2 to 3 days, or longer for persistent symptoms. 
Consider taper for a total steroid exposure of greater than 3 days. Steroids are not recommended for 
isolated Grade 2 headaches. 
If no improvement after 24 hours or worsening of neurologic toxicity, increase the dose and/or frequency 
of dexamethasone up to a maximum of 20 mg IV every 6 hours. 
Grade 3 
 
 
Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. 
Start dexamethasone 10 to 20 mg IV every 6 to 12 hours. Steroids are not recommended for isolated 
Grade 3 headaches. 
If no improvement after 24 hours or worsening of neurologic toxicity, escalate to 
methylprednisolone (2 mg/kg loading dose, followed by 2 mg/kg divided into 4 times a day; taper 
within 7 days). 
If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose 
methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated) and 
cyclophosphamide 1.5 g/m2. 
 
 

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Grade 4 
Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure 
prophylaxis. Start dexamethasone 20 mg IV every 6 hours. 
If no improvement after 24 hours or worsening of neurologic toxicity, escalate to high-dose 
methylprednisolone (1-2 g, repeated every 24 hours if needed; taper as clinically indicated). 
If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose 
methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated), and  may 
consider cyclophosphamide . 

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APPENDIX I 
 
MANAGEMENT GUIDELINES FOR CYTOPENIAS 
Management guidelines for neutropenia: 
Guidelines below refer to filgrastim use, but filgrastim biosimilars or pegfilgrastim may 
also be used where filgrastim use is specified below according to investigator discretion 
and local institutional practice.  
Patients should not receive filgrastim within 2 weeks of CAR T cell infusion. Beginning 2 
weeks (day 15) after CAR T cell infusion, filgrastim may be administered according to 
local institutional practice to address neutropenia. Neutropenia is expected within 4 weeks 
of CAR T cell infusion and does not require filgrastim support, though filgrastim may be 
used between as early as day 15 after CAR T cell infusion at discretion of investigators. 
For persistent neutropenia at any individual post-infusion time point beyond 4 weeks, 
minimum support should include the following:  
x If ANC less than 500/mm3 (grade 4), administer filgrastim x 1, re-check within 
one week.  
x If ANC is less than 500/mm3 on re-check, administer daily filgrastim and re-check 
within one week.  
x If ANC is less than 500/mm3 after daily filgrastim x 1 week, bone marrow biopsy 
should be performed to assess etiology of persistent neutropenia.  
Filgrastim may be administered for chronic neutropenia between 500/mm3 and 1000/mm3 
(grade 3) but is not required by the protocol. If ANC is not consistently greater than 1000 
by week 6 after CAR T cell infusion, bone marrow biopsy should be performed to assess 
the etiology of chronic neutropenia.  
Management guidelines for thrombocytopenia: 
Bone marrow biopsy to assess the etiology of thrombocytopenia should be performed if 
platelets are consistently less than 25,000/mm3 (grade 4) at week 6 after CAR T cell 
infusion, less than 50,000/mm3 (grade 3) at week 12 after CAR T cell infusion.  
Guidelines for stem cell re-infusion: 
Prolonged cytopenias have been reported after CAR T cell therapy. Cryopreserved 
autologous stem cells can be used to restore normal hematopoiesis in the circumstances 
defined below. The efficacy of this approach has not been well established, and the 
impact of this approach on the efficacy of CAR T cell therapy has not been studied. 
The use of cryopreserved autologous stem cells in this protocol will be considered in the 
following circumstances: 
1. Grade 4 thrombocytopenia with bleeding complications occurring more than 6 
weeks after CAR T cell infusion 

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2. Grade 4 neutropenia lasting more than 6 weeks after CAR T cell infusion and not 
responding to or continuing to require growth factor support 
3. Grade 3 or 4 cytopenias lasting more than 12 weeks post infusion  
4. At ANY TIME in a patient with life threatening bleeding or infectious 
complications that in the view of the treating physician could only be reversed 
with rapid hematologic reconstitution.  
5. Protracted transfusion requirements beyond 12 weeks post infusion not 
attributable to other causes. 
6. Other indications as discussed with the protocol chairs and medical monitors. 
The BMT CTN 1902 Protocol Chairs and Officer must be consulted prior to stem cell 
infusion. Prior approval from the BMT CTN Protocol Chairs or Office is required prior to 
stem cell re-infusion. Prior to stem cell reinfusion all patients should have the following 
tests performed to assess for other potential factors contributing to the cytopenias: 
1. Viral PCR: HHV6, CMV, EBV, Adeno, Parvovirus 
2. Thyroid function tests 
3. Iron Studies 
4. CRP and ESR 
5. Bone marrow aspirate and biopsy to assess overall cellularity, adequacy of iron 
stores, myeloma burden, and to evaluate for myelodysplasia, hemophagocytosis, 
large granular lymphocyte (LGL) leukemia (by flow cytometry and morphology), 
and clonal cytogenetic abnormalities.  
6. Autoimmune panel: ANA, ANCA panel, Antiplatelet antibodies, Coombs 
7. Aspirate and biopsy samples should be sent to central biorepository  

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APPENDIX J  
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APPENDIX K
INVESTIGATOR’S SIGNATURE
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
BMT CTN PROTOCOL 1902
Version 3.0, March 10, 2022
I have read all pages of this clinical study protocol. I agree to conduct the study as outlined in 
the protocol and to comply with all the terms and conditions set out therein. I confirm that I will 
conduct the study in accordance with ICH GCP guidelines and applicable local regulations. I 
will also ensure that subinvestigator(s) and other relevant members of my staff have access 
to copies of this protocol and the ICH GCP guidelines to enable them to work in accordance 
with the provisions of these documents.
Principal Investigator:
Signature:
Printed Name:
Date (MMDDYYYY)
Address: