A Phase I Clinical Trial of T Cells Expressing a Novel Fully-human Anti-BCMA CAR for Treating Multiple Myeloma
Phase: PHASE1
Conditions: Myeloma-Multiple, Myeloma, Plasma-Cell
Sponsor: National Cancer Institute (NCI)

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Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
Version Date: October 28, 2025
Abbreviated Title: Fully-Human Anti-BCMA-CAR T Cells 
NIH Protocol #: 18-C-0125
OSP#: 1807-1780
IBC#:  RD-18-III-02
NCT#: NCT03602612
Version Date:  October 28, 2025
Title:  A Phase I Clinical Trial of T Cells Expressing a Novel Fully-Human Anti-BCMA 
CAR for Treating Multiple Myeloma
NCI Principal Investigator:  
James N. Kochenderfer, M.D. 
Surgery Branch
Center for Cancer Research
National Cancer Institute
National Institutes of Health
10 Center Drive, Rm. 6B17, MSC 1203
Telephone:  240-760-6062
Email:  kochendj@mail.nih.gov
Investigational Agents:    
Drug Name:
Anti-BCMA-CAR- 
transduced  autologous 
peripheral blood 
lymphocytes (PBL)
Cyclophosphamide
Fludarabine
IND Number:
18246
Sponsor:
Center for Cancer Research (CCR), NCI, NIH
Manufacturer:
Department of 
Transfusion Medicine 
(DTM)
Generic
Generic
Supplier:
Department of 
Transfusion Medicine 
(DTM)
CC Pharmacy
CC Pharmacy

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Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
Version Date: October 28, 2025
PRÉCIS 
Background:
•
Multiple myeloma (MM) is a malignancy of plasma cells. 
•
MM is nearly always incurable.
•
T cells can be genetically modified to express chimeric antigen receptors (CARs) that 
specifically target malignancy-associated antigens.
•
Autologous T cells genetically modified to express CARs targeting the B-cell antigen CD19 
have caused complete remissions in a small number of patients with leukemia or lymphoma.  
These results demonstrate that CAR-expressing T cells have anti-malignancy activity in 
humans.
•
B-cell maturation antigen (BCMA) is a protein expressed by normal plasma cells and the 
malignant plasma cells of multiple myeloma.
•
BCMA is not expressed by normal cells except for plasma cells and some mature B cells.
•
We have constructed a novel anti-BCMA CAR that can specifically recognize BCMA-
expressing target cells in vitro and eradicate BCMA-expressing tumors in mice.
•
This CAR has an antigen-recognition domain made up of a single fully-human heavy chain 
variable region.
•
We hypothesize that anti-BCMA-CAR-expressing T cells will specifically eliminate BCMA-
expressing MM cells in patients
•
Possible toxicities include cytokine-associated toxicities such as fever, hypotension, and 
neurological toxicities.  Elimination of normal plasma cells and unknown toxicities are also 
possible.
Objectives:
Primary
•
Determine the safety and feasibility of administering T cells expressing an anti-BCMA CAR 
to patients with MM.
Eligibility:
•
Greater than or equal to 18 years of age and less than or equal to age 73.
•
Patients must have measurable MM defined as a serum M-protein ≥1.0 g/dL or a urine M-
protein ≥200 mg/24 hours or an involved serum free light chain (FLC) level ≥10 mg/dL 
(provided FLC ratio is abnormal) or a biopsy-proven plasmacytoma of 2.0 cm or more in 
largest dimension, or greater than or equal to 30% bone marrow plasma cells. 
•
Patients must have previously received at least 3 different treatment regimens for MM.
•
Patients must have prior exposure to an IMiD such as lenalidomide, and a proteasome 
inhibitor
•
Patients must have a creatinine level of < 1.5 mg/dL

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Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
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•
Patients must have a cardiac ejection fraction >  50%.
•
An ECOG performance status of 0-2 is required.
•
Patients on any anticoagulant medications except aspirin are not eligible.
•
No active infections are allowed.
•
Absolute neutrophil count ≥ 1000/L, platelet count ≥ 55,000/L, hemoglobin ≥ 8g/dL 
•
ALT and AST ≤ 2.5-fold higher than the upper limit of normal.
•
At least 14 days must elapse between the time of any prior systemic treatment (including 
corticosteroids) and the required leukapheresis.
•
At least 14 days must elapse between the time of any prior systemic treatment (including 
corticosteroids) and initiation of protocol treatment.
•
The patient’s MM will need to be assessed for BCMA expression by flow cytometry or 
immunohistochemistry performed at the NIH.  The myeloma must express BCMA.  If 
unstained, paraffin-embedded bone marrow or plasmacytoma sections are available from 
prior biopsies, these can be used to determine BCMA expression by immunohistochemistry; 
otherwise patients will need to come to the NIH for a bone marrow biopsy or other biopsy of 
a plasmacytoma to determine BCMA expression.  The sample for BCMA expression can 
come from a biopsy obtained at any time before enrollment.
Design:
•
This is a phase I dose-escalation trial
•
Patients will undergo leukapheresis
•
T-cells obtained by leukapheresis will be genetically modified to express an anti-BCMA 
CAR
•
Patients will receive a lymphocyte-depleting chemotherapy conditioning regimen with the 
intent of enhancing the activity of the infused anti-BCMA-CAR-expressing T cells.
•
The chemotherapy conditioning regimen is cyclophosphamide 300 mg/m2 daily for 3 days 
and fludarabine 30 mg/m2 daily for 3 days.  Fludarabine will be given on the same days as 
the cyclophosphamide.
•
After the chemotherapy ends, the patients will have two days with no treatments and then 
receive an infusion of anti-BCMA-CAR-expressing T cells.
•
The initial dose level  will be 0.75x106 CAR+ T cells/kg of recipient bodyweight.
•
The cell dose administered will be escalated until a maximum tolerated dose is determined. 
•
Following the T-cell infusion, there will be a mandatory 9-day minimum inpatient 
hospitalization to monitor for toxicity. 
•
Outpatient follow-up is planned for 2 weeks, and 1, 2, 3, 4, 6, 9, and 12 months after the 
CAR T-cell infusion.  Afterwards, follow-up will be every six months up to at least 5 years.

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Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
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TABLE OF CONTENTS 
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE...........................................................................................10
1
INTRODUCTION .................................................................................................................10
1.1
Study Objectives .............................................................................................................10
1.1.1
Primary Objective....................................................................................................10
1.1.2
Exploratory Objectives ............................................................................................10
1.2
Background and Rationale..............................................................................................10
1.2.1
Introduction..............................................................................................................10
1.2.2
Multiple myeloma epidemiology and standard treatment .......................................11
1.2.3
Allogeneic transplantation for MM .........................................................................12
1.2.4
T-cell gene therapy ..................................................................................................12
1.2.5
Chimeric antigen receptors......................................................................................13
1.2.6
BCMA......................................................................................................................15
1.2.7
Previous clinical experience with anti-BCMA CAR T cells...................................18
1.2.8
Anti-BCMA CAR development and preclinical testing..........................................20
1.2.9
Rationale for immunosuppressive chemotherapy and selection of lymphocyte-
depleting chemotherapy regimen...........................................................................................26
1.2.10
Rationale for dose-escalation and starting dose.......................................................27
1.2.11
Summary of risks and potential benefits .................................................................28
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................29
2.1
Eligibility Criteria ...........................................................................................................29
2.1.1
Inclusion Criteria .....................................................................................................29
2.1.2
Exclusion criteria.....................................................................................................30
2.1.3
Recruitment Strategies.............................................................................................32
2.2
Screening Evaluation ......................................................................................................32
2.2.1
Screening activities performed after a consent for screening has been signed........32
2.3
Participant Registration and Status Update Procedures..................................................33
2.4
Treatment Assignment Procedures for the Registartion Purposes Only:........................33
3
STUDY IMPLEMENTATION .............................................................................................34
3.1
Study Design...................................................................................................................34

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3.1.1
General study plan ...................................................................................................34
3.1.2
Protocol schema.......................................................................................................36
3.1.3
Dose Limiting Toxicity-the dose limiting toxicity assessment period is 28 days. ..37
3.1.4
Dose Escalation .......................................................................................................37
3.2
Dose Modifications/Delay ..............................................................................................39
3.3
Drug Administration .......................................................................................................39
3.3.1
Leukapheresis ..........................................................................................................39
3.3.2
Anti-BCMA-CAR-expressing T-cell preparation ...................................................40
3.3.3
Conditioning chemotherapy and anti-BCMA CAR T-cell administration-
chemotherapy administration can be either inpatient or outpatient.......................................40
3.3.4
Potential repeat treatment ........................................................................................42
3.4
Protocol Evaluation.........................................................................................................42
3.4.1
Baseline evaluations and interventions....................................................................42
3.4.2
Studies to be performed on Day 0 and during the mandatory 9-day inpatient 
admission after cell infusion..................................................................................................44
3.4.3
Post-infusion outpatient evaluation .........................................................................45
3.5
Study Calendar................................................................................................................48
3.6
Gene-therapy-specific follow-up ....................................................................................53
3.7
Cost and Compensation ..................................................................................................53
3.7.1
Costs ........................................................................................................................53
3.7.2
Compensation ..........................................................................................................53
3.7.3
Reimbursement........................................................................................................53
3.8
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................54
3.8.1
Criteria for removal from protocol therapy .............................................................54
3.8.2
Off-Study Criteria....................................................................................................54
3.9
Stopping Criteria.............................................................................................................55
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................55
4.1
Antibiotic prophylaxis.....................................................................................................55
4.2
Blood product support.....................................................................................................56
4.3
Anti-emetics....................................................................................................................56
4.4
Granulocyte colony-stimulating factor ...........................................................................56
4.5
Avoidance of corticosteroids ..........................................................................................56
4.6
Toxicity management guidlines......................................................................................56

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5
BIOSPECIMEN COLLECTION...........................................................................................56
5.1
CORRELATIVE STUDIES FOR RESEARCH.............................................................56
5.1.1
Biospecimen collection before the start of the conditioning chemotherapy: ..........57
5.1.2
Biospecimen collection Day 0 and after anti-BCMA-CAR T-cell infusion during 
the required hospitalization....................................................................................................57
5.1.3
Biospecimen collection during outpatient follow-up ..............................................57
5.1.4
Immunological Testing............................................................................................58
5.1.5
Additional biopsies and additional blood draws......................................................59
5.1.6
Future studies...........................................................................................................59
5.2
Sample Storage, Tracking and Disposition.....................................................................59
5.2.1
Samples Sent to the BPC Lab ..................................Error! Bookmark not defined.
5.2.2
Sample Storage, Tracking and Disposition .............................................................59
5.2.3
Protocol Completion/Sample Destruction ...............................................................61
5.2.4
Samples for Genetic/Genomic Analysis..................................................................61
6
DATA COLLECTION AND EVALUATION .....................................................................62
6.1
Data Collection ...............................................................................................................62
6.1.1
Adverse event recording..........................................................................................63
6.2
DATA SHARING PLANS .............................................................................................63
6.2.1
Human Data Sharing Plan .......................................................................................63
6.3
Genomic Data Sharing Plan............................................................................................64
6.4
Response Criteria ............................................................................................................64
6.4.1
Important Considerations on response criteria ........................................................64
6.4.2
International Myeloma Working Group uniform response criteria:........................65
6.4.3
Minimal residual disease (MRD) criteria (requires complete response as defined 
above) 67
6.5
Toxicity Criteria..............................................................................................................67
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN.....67
7.1
Definitions.......................................................................................................................67
7.2
OHSRP Office of Compliance and Training / IRB Reporting........................................68
7.2.1
Expedited Reporting ................................................................................................68
7.2.2
IRB Requirements for PI Reporting at Continuing Review ....................................68
7.3
NCI Clinical Director Reporting.....................................................................................68
7.4
Institutional Biosafety Committee (IBC) Reporting Criteria..........................................68

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7.4.1
Serious Adverse Event Reports to IBC ...................................................................68
7.4.2
Additional Information to IBC ................................................................................68
7.5
Data and Safety Monitoring Plan....................................................................................68
7.5.1
Principal Investigator/Research Team.....................................................................68
7.5.2
Safety Monitoring Committee (SMC).....................................................................69
8
Sponsor Protocol/ Safety Reporting ......................................................................................69
8.1
Definitions.......................................................................................................................69
8.1.1
Adverse Event..........................................................................................................69
8.1.2
Serious Adverse Event (SAE) .................................................................................69
8.1.3
Life-threatening .......................................................................................................70
8.1.4
Severity....................................................................................................................70
8.1.5
Relationship to Study Product .................................................................................70
8.2
Assessment of Safety Events ..........................................................................................70
8.3
Reporting of Serious Adverse Events .............................................................................71
8.4
Reporting Pregnancy.......................................................................................................71
8.4.1
Maternal exposure ..................................................................................................71
8.4.2
Paternal exposure.....................................................................................................71
8.5
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND...................71
9
CLINICAL MONITORING..................................................................................................72
10
STATISTICAL CONSIDERATIONS ...............................................................................72
10.1
Statistical Hypothesis ..................................................................................................72
10.2
Sample Size Determination.........................................................................................72
10.3
Populations For Analyses............................................................................................74
10.4
Statistical Analyses......................................................................................................74
10.4.1
General Approach....................................................................................................74
10.4.2
Analysis of the Primary Endpoints..........................................................................74
10.4.3
Analysis of the Secondary Endpoint(s) ...................................................................74
10.4.4
Safety Analyses .......................................................................................................74
10.4.5
Baseline Descriptive Statistics.................................................................................74
10.4.6
Planned Interim Analyses........................................................................................74
10.4.7
Sub-Group Analyses................................................................................................74
10.4.8
Tabulation of individual Participant Data................................................................74

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10.4.9
Exploratory Analyses...............................................................................................74
11
HUMAN SUBJECTS PROTECTIONS.............................................................................75
11.1
Rationale For Subject Selection ..................................................................................75
11.2
Participation of Children .............................................................................................75
11.3
Participation of Subjects Unable to Give Consent ......................................................75
11.4
Evaluation of Benefits and Risks/Discomforts ...........................................................76
11.4.1
Risk to family or relatives........................................................................................76
11.4.2
Risks of exposure to Ionizing Radiation..................................................................77
11.4.3
Risks of Scans and Contrast ....................................................................................77
11.4.4
Risks of blood Sampling..........................................................................................77
11.4.5
Risks of Bone marrow aspiration and biopsy..........................................................77
11.4.6
Risks of Intravenous Catheter..................................................................................77
11.4.7
Risks of Apheresis ...................................................................................................77
11.5
Consent Process and Documentation ..........................................................................78
11.5.1
Consent Process for Adults Who Lack Capacity to Consent to Research 
Participation...........................................................................................................................78
12
REGULATORY AND OPERATIONAL CONSIDERATIONS..................................78
12.1
STUDY DISCONTINUATION AND CLOSURE .................................................................78
12.2
QUALITY ASSURANCE AND QUALITY CONTROL........................................................79
12.3
CONFLICT OF INTEREST POLICY................................................................................79
12.4
CONFIDENTIALITY AND PRIVACY...............................................................................79
13
PHARMACEUTICAL INFORMATION ..........................................................................80
13.1
Retroviral Vector Containing the anti-BCMA CAR Gene .........................................80
13.1.1
Cells manufacturing.................................................................................................80
13.1.2
Toxicities .................................................................................................................81
13.1.3
Administration procedures: .....................................................................................81
13.2
Commercial Agents:....................................................................................................81
13.2.1
Cyclophosphamide ..................................................................................................81
13.2.2
FLUDARABINE .....................................................................................................81
14
REFERENCES ...................................................................................................................82
15
APPENDICES ....................................................................................................................91
15.1
Appendix A:-Performance Status Criteria ..................................................................91

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15.2
Appendix B:Data Collection Elements Required By Protocol ...................................92
15.3
Appendix C:   Guidelines for management of common toxicities that occur after CAR 
T-cell infusions ..........................................................................................................................94
15.4
Appendix D:   Infusion Instructions............................................................................99

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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council  for Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective
Determine the safety and feasibility of administering T cells expressing a novel fully-human anti-
B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) with a heavy-chain-only 
antigen-recognition domain to patients with multiple myeloma (MM) and to determine a 
recommended phase 2 dose of these anti-BCMA CAR T cells
1.1.2
Exploratory Objectives
•
Evaluate the in vivo persistence and phenotype of T cells expressing the anti-BCMA CAR.
•
Assess for associations between toxicity and immunologic parameters including blood 
CAR T-cell and cytokine levels.
•
Assess gene expression of infused CAR T cells and associations of CAR T-cell gene 
expression with CAR T-cell in vivo persistence and anti-myeloma activity.
•
Assess anti-BCMA-CAR-expressing T cells for anti-MM activity post infusion.
1.2
BACKGROUND AND RATIONALE
1.2.1
Introduction
Multiple myeloma (MM) is a malignancy of plasma cells that is almost always incurable.  New 
therapies are needed for MM.  Regressions of MM occurring in the setting of allogeneic stem cell 
transplantation (alloHSCT), and particularly after allogeneic donor lymphocyte infusions (DLIs), 
provide evidence that cellular immune responses can have a clinically significant anti-myeloma 
effect, but alloHSCT is associated with a significant transplant-related mortality and by chronic 
graft-versus-host disease.1,2 Many patients have obtained lengthy complete remissions of 

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lymphoma or chronic lymphocytic leukemia after infusions of autologous T cells that were 
genetically modified to express chimeric antigen receptors (CARs) targeting the B-cell antigen 
CD19.3,4  Anti-CD19 CARs are now FDA-approved treatments.  The lasting complete remissions 
of MM that sometimes occur in the setting of alloHSCT and the encouraging results obtained 
treating patients with anti-CD19-CAR-expressing T cells are rationales for attempting to develop 
CAR-T-cell therapies for MM.  B-cell maturation antigen (BCMA) is a protein that is expressed 
by MM cells.5  BCMA is also expressed by normal plasma cells and by some normal B cells, but 
BCMA is not expressed by other normal cells.5  The very limited expression of BCMA in normal 
tissues makes BCMA a very promising target for CAR-T-cell therapies.  We previously  developed 
the first anti-BCMA CAR, and we have demonstrated that T cells expressing this CAR have 
BCMA-specific activity in vitro and in vivo.5  Anti-BCMA-CAR-expressing T cells can eradicate 
MM tumors in mice.5  We then conducted a phase I clinical trial of T cells expressing this first 
anti-BCMA-CAR.  This is a protocol  to evaluate a new CAR that differs from our previously-
tested anti-BCMA CAR by having an antigen-recognition domain made up only of a fully-human 
heavy-chain variable domain.  The new CAR also differs from the old CAR by having a 4-1BB 
rather than a CD28 costimulatory domain.  The new anti-BCMA CAR trial will enroll patients 
with advanced MM persisting or progressing despite at least 3 prior therapies.  Patients enrolled 
on the trial will receive a single cycle of chemotherapy that is designed to decrease endogenous 
lymphocyte counts because extensive evidence exists that depleting endogenous lymphocytes, and 
possibly other cells, with chemotherapy or total body irradiation dramatically increased the anti-
tumor activity of adoptively transferred T cells.6-8  After the lymphocyte-depleting chemotherapy, 
patients will receive an infusion of autologous anti-BCMA-CAR T cells.  The amount of T 
cellswill escalate with sequential dose levels until a maximum tolerated dose (MTD) is determined. 
If at least 3 patients are treated on each dose level without an MTD being established, up to 12 
additional patients can be treated at the maximum feasible dose. The maximum feasible dose is 
defined as the dose of CAR T cells that can be feasibly produced. 
1.2.2
Multiple myeloma epidemiology and standard treatment
MM is a neoplasm of monoclonal plasma cells.9,10  For MM to be diagnosed, a patient must have 
a proliferation of monoclonal plasma cells plus other abnormalities such as anemia, renal 
insufficiency, hypercalcemia, and lytic bone lesions.10,11  MM is the second most frequently 
occurring hematologic cancer in the United States (U.S.).10  An estimated 22,350 new cases of 
MM were diagnosed in the U.S. in 2013, and an estimated 10,710 patients died from MM in the 
U.S. in 2013.12  Recent improvements in the therapy of MM have occurred.9,10,13  These improved 
treatments have increased the median survival of patients with newly-diagnosed MM from 3 years 
to slightly over 5 years, although the prognosis of newly-diagnosed MM patients varies widely.10,13  
Current standard non-transplant therapies for MM include various combinations of 
dexamethasone, bortezomib and its analogs, lenalidomide and its analogs, prednisone, melphalan, 
and cyclophosphamide.9,10,13,14  Myeloablative doses of chemotherapy followed by autologous 
stem cell transplantation is a standard therapy for MM patients with good performance status, and 
adequate bone marrow stem cells.10,13  Compared to standard doses of chemotherapy for first 
treatment of MM, administration of myeloablative doses of chemotherapy followed by autologous 
stem cell transplantation improved progression-free survival in most trials and overall survival in 
some trials.10,13 Myeloablative chemotherapy followed by autologous transplantation can also be 
used as a treatment for relapsed MM in some cases.10,13,15   Use of the International Uniform 

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Response Criteria for Multiple Myeloma is the most common approach for assessing clinical 
outcomes in MM.16  Despite the recent improvements in treatment, MM remains an almost always 
incurable disease.13,17,18  Patients obtaining remissions of MM almost always relapse.13  The 
median overall survival of patients with relapsed MM is 3 years or less.17   Survival is shorter for 
patients treated with lenalidomide plus dexamethasone who have received at least 2 prior lines of 
therapy compared to patients who received only one prior line of therapy.19  In patients with MM 
that was refractory to bortezomib, the median overall survival was only 9 months when the patient 
was also either ineligible for thalidomide or lenalidomide, or the patient had MM that was relapsed 
or refractory to thalidomide or lenalidomide.18  Utilizing the immune system to treat MM is one 
possible way to improve therapy of MM.  So far, the clearest evidence of activity of the immune 
system against MM comes from allogeneic transplantation studies.
1.2.3
Allogeneic transplantation for MM
Allogeneic stem cell transplantation (alloHSCT) can cure a fraction of patients with MM.20,21  
Myeloablative alloHSCT can induce long-term complete remissions of MM, but also has a 
transplant-related mortality rate (TRM) of 20% to 50%.20,21  The high TRM of myeloablative 
alloHSCT led investigators to test nonmyeloablative alloHSCT for MM.20-22 A commonly used 
transplantation strategy is to administer myeloablative chemotherapy plus an autologous stem cell 
transplant and then to conduct a nonmyeloablative alloHSCT a short time later.1,20,21  In some 
studies, this strategy has been shown to yield higher rates of progression-free and overall survival 
when compared to the strategy of 2 sequential autologous stem cell transplants.1,22 One recent trial 
showed an 8-year progression-free survival rate of 22% for patients receiving an autologous 
transplant followed by a nonablative alloHSCT compared to an 8-year progression-free survival 
of 12% for patients receiving sequential autologous transplants.1  These results showed a 
statistically significant advantage for the autologous followed by alloHSCT strategy, but also point 
out that the vast majority of patients are not cured by either approach.  
Because many nonmyeloablative transplant regimens that have been used to treat MM include 
very low doses of radiation or chemotherapy, nonmyeloablative alloHSCTs depend on an 
immunologic graft-versus-myeloma effect, and remissions of MM that occur after 
nonmyeloablative alloHSCT provide evidence that immune responses can be effective at 
eliminating MM.1,20,21  Direct evidence that lymphocytes can eliminate MM comes from donor 
lymphocyte infusions (DLIs).2,21  Twenty-two to twenty-eight percent of patients receiving DLIs 
to treat persisting MM after alloHSCT have achieved complete remissions (CRs).2,20,21  Of note, 
some of these patients obtaining CRs after DLIs did not receive any other therapies around the 
time of their DLI.2  These results demonstrate the ability of the immune system to eradicate MM.  
Unfortunately, both alloHSCT and DLIs utilize allogeneic lymphocytes; therefore, they are 
associated with the sometimes fatal complication of graft-versus-host disease2,20,21; in addition 
most patients receiving DLIs for MM do not obtain CRs, so developing of an effective autologous 
cellular immune therapy for MM would be a major advance.
1.2.4
T-cell gene therapy
T cells can be prepared for adoptive transfer by genetically modifying the T cells to express 
receptors that specifically recognize tumor-associated antigens.23-30  Genetic modification of T 
cells is a quick and reliable process, and clinical trials of genetically modified T cells targeting a 
variety of malignancies have been carried out.3,4,27,31,32  Genetically modified antigen-specific T 

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cells can be generated from peripheral blood mononuclear cells (PBMC) in sufficient numbers for 
clinical treatment within <10 days.3  Genetically modifying T cells with gammaretroviruses 
consistently causes high and sustained levels of expression of introduced genes without in vitro 
selection4,31,33,34, and genetic modification of mature T cells with gammaretroviruses has a long 
history of safety in humans.35-37  There are two general approaches for generating antigen-specific 
T cells by genetic modification:   introducing genes encoding natural  T cell receptors (TCRs) 
or introducing genes encoding CARs.24,26,27,29  CARs are fusion proteins incorporating antigen 
recognition moieties and T cell activation domains.28,38-40  The antigen-binding domains of most 
CARs currently undergoing clinical and preclinical development are antibody variable 
regions.24,28,38,40  TCRs recognize peptides presented by human leukocyte antigen (HLA) 
molecules; therefore, TCRs are HLA-restricted, and a particular TCR will only be useful in 
patients expressing certain HLA molecules24,26,27,38, which limits the number of patients who could 
be treated with T cells genetically modified to express a TCR.  In contrast, CARs recognize intact 
cell-surface proteins and glycolipids, so CARs are not HLA-restricted, and CARs can be used to 
treat patients regardless of their HLA types.24,27,41-43
1.2.5
Chimeric antigen receptors
Preclinical experiments evaluating CAR-expressing T cells as cancer therapy were initiated in 
1993.44,45  These experiments led to a clinical trial of CAR-transduced T cells targeting the -
folate receptor on ovarian cancer cells; no tumor regressions were observed during this clinical 
trial.46  CARs that were capable of recognizing a variety of tumor-associated antigens have been 
evaluated in many centers.24,38  Preclinical studies have assessed a wide variety of factors that 
could affect in vivo function of CAR-expressing T cells.  Multiple approaches for inserting CAR 
genes into T cells by using gammaretroviruses4,31,33-35,47-49, lentiviruses3,50-53, or transposon 
systems54,55 have been assessed.  Because all methods of T-cell genetic modification require a 
period of in vitro culture, various T-cell culture techniques have been evaluated.3,47,56  Different 
portions of CARs including antigen-recognition moieties, extracellular structural components, 
costimulatory domains such as the cytoplasmic portion of the CD28 protein, and T-cell-activation 
moieties such as the signaling domains of the CD3 protein can all be important to the in vivo 
function of CAR-expressing T cells, and all of these portions of CARs remain the subject of 
intensive investigation.38,47,51,57-59  Much of the preclinical work evaluating CARs has been 
performed with CARs targeting the B-cell antigen CD19.7,47-49,54,60,61 Data suggesting that T-cell 
costimulation played an important role in the activity of CAR-expressing T cells in vivo led 
investigators to add signaling moieties from the costimulatory molecule CD28 to CARs.49,58  These 
studies showed that adding CD28 moieties to CARs enhanced antigen-specific cytokine 
production and proliferation by anti-CD19 CAR T cells.58,62,63  T cells expressing CARs with 
CD28 signaling moieties and CD3 signaling domains were more effective than T cells expressing 
CARs without CD28 moieties at eradicating human leukemia cells from mice.62,63  Subsequently, 
CARs incorporating other signaling domains from costimulatory molecules such as 4-1BB 
(CD137) were developed.50  Anti-CD19 CARs containing the signaling domains of both 4-1BB 
and CD3 were superior to CARs containing the signaling domains of CD3 without any 
costimulatory domains at eradicating human malignant cells from mice.51,57   Similar to CD28, 
including 4-1BB signaling moieties in CARs led to increased CD19-specific proliferation and 
enhanced in vivo persistence.51  In contrast to T cells expressing a CAR with a CD28 moiety, the 
increased in vitro proliferation and prolonged in vivo persistence of T cells expressing a 4-1BB-

14
Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
Version Date: October 28, 2025
containing CAR occurred whether or not the T cells were exposed to the antigen that the CAR 
recognized.51,57  
Results from several clinical trials of anti-CD19 CAR T cells have been reported to date in peer-
reviewed papers.3,4,31,33,34,64-67  The first evidence of antigen-specific activity of anti-CD19 CAR T 
cells in humans was generated during a clinical trial at the National Cancer Institute (NCI) in a 
patient who experienced a dramatic regression of advanced follicular lymphoma.33  This clinical 
trial utilized a gammaretroviral vector to introduce an anti-CD19 CAR containing the signaling 
domains of the CD28 and CD3 molecules.33 The first patient treated on this protocol had a large 
disease burden of follicular lymphoma.  This first patient experienced no acute toxicities except 
for a low grade fever that lasted for 2 days, and he obtained a partial remission (PR) that lasted for 
32 weeks.33  Bone marrow biopsies revealed a complete elimination of extensive bone marrow 
lymphoma that was present before treatment; in addition, normal B-lineage cells were completely 
eradicated from the bone marrow.33  The bone marrow B-cell eradication was confirmed by flow 
cytometry, and it persisted for over 36 weeks.33  B cells were also completely absent from the 
blood during this time, while T cells and other blood cells recovered rapidly.33  Seven months after 
the anti-CD19 CAR T cell infusion, progressive lymphoma was detected in the patient’s cervical 
lymph nodes.  The lymphoma remained CD19+, so the patient was treated a second time with anti-
CD19 CAR T cells.  The first and second treatment regimens were the same except the patient 
received a higher dose of cells with the second treatment.  After the second treatment, the patient 
obtained a second ongoing partial remission.4   
Seven more patients were subsequently treated with the same regimen of chemotherapy, anti-
CD19 CAR T cells, and high-dose IL-2.4  In 4 of 7 evaluable patients on the trial, administration 
of anti-CD19 CAR T cells was associated with a profound and prolonged B-cell depletion.4,33  In 
all 4 patients with B-cell depletion, the depletion lasted for over 36 weeks. The B-cell depletion 
could not be attributed to the chemotherapy that was administered because blood B-cells recovered 
to normal levels in 8 to 19 weeks in patients receiving the same chemotherapy plus infusions of T 
cells targeting NY-ESO or gp100, which are antigens that are not expressed by B cells.33  Because 
normal B cells express CD19, prolonged normal B-cell depletion after anti-CD19 CAR T-cell 
infusions demonstrated that CAR-expressing T cells had a powerful ability to eradicate CD19+ 
cells in humans.  All of the patients with long-term B-cell depletion obtained either complete or 
partial remissions of their malignancies, and the 4 patients with long-term B cell depletion also 
developed hypogammaglobulinemia.  Hypogammaglobulinemia in these patients was routinely 
treated with infusions of intravenous immunoglobulins.  Of the eight patients treated, seven 
patients were evaluable for malignancy response; the one patient who was not evaluable died with 
pneumonia caused by influenza A.4  Six of the seven evaluable patients had remissions of their 
malignancies.  Two of the remissions were complete remissions (CRs) of CLL.4  Both of these 
CRs were confirmed by multicolor flow cytometry of bone marrow cells.4  One of these CRs lasted 
24 months, and the other is ongoing at 30 months.4  Most patients treated with this regimen of 
chemotherapy, anti-CD19 CAR T cells, and IL-2 experienced significant acute toxicities including 
fever, hypotension, and neurological toxicities such as delirium and obtundation.4  All of these 
toxicities peaked within 10 days after the cell infusion and resolved less than 3 weeks after the cell 
infusion.4  These acute toxicities correlated with serum levels of the inflammatory cytokines tumor 
necrosis factor and interferon-, and T cells producing these inflammatory cytokines in a CD19-
specific manner were detected in the blood of patients after the anti-CD19 CAR T cell infusions.4  
Subsequent studies with this same CAR demonstrated the effectiveness of anti-CD19 CAR T cells 

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Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
Version Date: October 28, 2025
against diffuse large B-cell lymphoma and led to multicenter phase II trials and an application for 
FDA approval.66
1.2.6
BCMA
One candidate antigen for immunotherapies for MM is BCMA (CD269) 68,69.  BCMA RNA was 
detected universally in MM cells, and BCMA protein was detected on the surface of plasma cells 
from MM patients by several investigators 70-73.  BCMA is a member of the tumor necrosis factor 
receptor (TNF) superfamily 74,75.  BCMA binds B-cell activating factor (BAFF) and a proliferation 
inducing ligand (APRIL) 75-77.  Among nonmalignant cells, BCMA has been reported to be 
expressed mostly by plasma cells and a small subset of mature B cells 68,69,76,78,79.  Mice deficient 
in BCMA were healthy and had a normal physical appearance 80,81.  BCMA-deficient mice had 
normal numbers of B cells, but survival of long-lived plasma cells was impaired 78,80.  
A critical factor for any antigen being considered as a target for immunotherapies is the antigen’s 
expression pattern in normal tissues.  BCMA has been reported to be expressed in plasma cells 
and in some B cells but to otherwise have limited expression 68-70,79.  To more completely assess 
the expression pattern of BCMA, we performed quantitative polymerase chain reaction (qPCR) on 
a panel of cDNA samples from a wide range of normal tissues (Figure 1).5  As a positive control, 
we performed qPCR on cDNA from cells of a plasmacytoma that was resected from a patient with 
advanced MM.5  Ninety-three percent of the cells from the plasmacytoma sample were plasma 
cells as determined by flow cytometry.  The BCMA expression of the plasmacytoma sample was 
dramatically higher than the BCMA expression of any other tissue (Figure 1).  Not surprisingly, 
BCMA cDNA copies were detected in several hematologic tissues such as blood leukocytes, bone 
marrow, spleen, lymph node, and tonsil.  Low levels of BCMA cDNA copies were detected in the 
samples of testis and trachea.  In addition, low levels of BCMA cDNA copies were detected in 
most gastrointestinal organs such as duodenum, rectum, and stomach (Figure 1).  One possible 
explanation for BCMA expression in gastrointestinal organs and the trachea was the known 
presence of plasma cells and B cells in tissues such as lamina propria and Peyer’s Patches 82,83.  
In Figure 1, actin cDNA copies and BCMA cDNA copies were measured by qPCR in all of the 
samples, and the results were expressed as the number of BCMA cDNA copies per 105 actin cDNA 
copies.5 

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Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
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Figure 1
Figure 1
After demonstrating a very restricted expression pattern of BCMA RNA by qPCR, we carried out 
an assessment of BCMA protein expression by immunohistochemistry (IHC).  As expected, our 
anti-BCMA IHC staining procedure yielded strong staining of BCMA-K562 cells, which 
expressed high levels of BCMA after being transduced with the gene encoding BCMA.  We found 
a lack of BCMA staining with NGFR-K562 negative control cells.5  We went on to evaluate 
BCMA protein expression in normal human organs.  Except for plasma cells, we did not detect 
BCMA protein expression by the cells of any of the organs that we stained.  We detected plasma 
cells expressing cell-surface BCMA in gastrointestinal organs.  BCMA expression by normal 
plasma cells probably accounts for the low levels of BCMA RNA detected in these organs because 
we did not detect BCMA expression by any of the other cells in these organs.  We detected BCMA-
expressing plasma cells in the tonsil.  The organs assessed by IHC and found to lack BCMA 
expression except for plasma cells are shown in Table 15  We concluded that BCMA expression 
detected at low levels in some organs by qPCR (Figure 1) was due to plasma cells in these organs.

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Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
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Table 1
For a protein to be an appropriate target for CAR-expressing T cells aimed at MM, the protein 
must be expressed on the surface of MM cells.  By flow cytometry of bone marrow samples from 
patients with MM, we found that 6/10 tested samples uniformly expressed high levels of BCMA 
by flow cytometry.  An example of this flow cytometry staining is shown in Figure 2.
Figure 2
As shown in Figure 2  flow cytometry for BCMA (solid line) and isotype-matched control staining 
(dashed line) revealed BCMA expression on the surface of MM cells from a plasmacytoma of a 
patient with MM.5  The plot is gated on plasma cells, which made up 93% of the total 
plasmacytoma cells.  In addition to the flow cytometry studies, we stained tissue sections from 
plasmacytomas of 3 patients with MM.  In all 3 of the samples, the neoplastic plasma cells 
expressed cell-surface BCMA.5
adrenal 
bladder 
bone  
breast 
cerebellum 
cerebral cortex
duodenum
eye 
fallopian tube 
esophagus 
stomach 
small intestine 
colon 
rectum 
heart 
kidney
liver
lung
ovary 
pancreas 
parathyroid 
pituitary 
placenta 
prostate 
skin 
spinal cord 
spleen 
skeletal muscle
testis 
thymus 
thyroid 
trachea 
cervix 
uterine endometrium
Organs stained for BCMA by immunohistochemistry and   
found to lack of BCMA expression except on plasma cells
Events
BCMA

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Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
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1.2.7
Previous clinical experience with anti-BCMA CAR T cells
This pre-clinical work led to the first in-humans clinical trial of CAR-Ts targeting BCMA at the 
NCI.84 An anti-BCMA CAR containing a murine scFv, a CD8 hinge and transmembrane region, a 
CD28 costimulatory domain, and a CD3 T-cell activation domain was created by synthesizing the 
appropriate DNA and ligating it into a gamma-retroviral backbone.84 Patients who had MM with 
uniform BCMA expression by either IHC or flow cytometry were enrolled.84 All participants 
received conditioning chemotherapy prior to infusion of CAR T cells with goals of depleting 
endogenous leukocytes, including depletion of regulatory T cells, and increasing serum cytokine 
levels of IL-15 and IL-7 to increase CAR-T activity.84-87  The chemotherapy regimen used was 
cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 given daily on days -5 to -3 followed by 
an infusion of CAR-BCMA T cells on day 0.84  Twenty-six patients have received CAR-BCMA 
T cells treated with either 0.3x106, 1x106, 3x106, or 9x106 CAR+ T cells/kg of bodyweight; 16 
patients were treated on the highest dose level. Five patients had a history of poor-prognosis 
chromosome 17p-deletion prior to protocol enrollment; results of 10 of these patients have been 
published.84 Toxicities were mild in patients receiving lower doses of CAR-Ts (0.3-3.0x106 CAR-
T/kg).84 As the dose of CAR-T escalated, patients began to have more symptoms of cytokine 
release syndrome.84 Patients treated at the highest dose level (9x106 CAR+T-cells/kg) experienced 
cytokine-release syndrome and a variety of grade 3 and 4 toxicities including neutropenia, 
thrombocytopenia, hypotension, and acute kidney injury that were managed without long-lasting 
complications.84 While CAR-BCMA T-cell toxicity was severe in some patients treated at the 
highest dose level, toxicities were mainly limited to the first two weeks after CAR-BCMA T-cell 
infusion.  Because of Grade 3 and 4 CRS experienced by some patients with high bone marrow 
myeloma burdens, the clinical protocol was modified to only allow enrollment of patients with 
lower myeloma burdens defined as MM making up 30% or less of bone marrow cells. Two patients 
experienced delayed neutropenia and thrombocytopenia that started approximately one month 
after CAR T-cell infusion when blood counts had recovered from the chemotherapy administered 
before CAR-BCMA T-cell infusions.  These patients were treated with filgrastim, eltrombopag, 
and prednisone based on the hypothesis that the cytopenias were caused by CAR T cells in the 
patient’s bone marrow.  At the time of delayed cytopenias, 15 percent of the first patient’s bone 
marrow T cells were CAR+, and 16.5 percent of the second patient’s bone marrow T cells were 
CAR+.  In both cases, cytopenias resolved after approximately 1 month.  A third patient had milder 
delayed thrombocytopenia and neutropenia that were treated with eltrombopag and G-CSF without 
corticosteroids. 
Of the 10 patients treated with lower doses of anti-BCMA CAR-Ts, one patient experienced a 
VGPR that lasted eight weeks, eight patients had SD that lasted from two to 12 weeks and one 
patient had a transient PR.84 Partial loss of BCMA expression on MM cells was demonstrated in 
one patient.84  13 of 16 evaluable patients treated at the highest dose level obtained objective anti-
myeloma responses with 2 stringent complete responses, 8 very good partial responses, and 3 
partial responses; the duration of responses varied.  The longest response to date is 75 weeks.  Eight 
of 10 evaluable patients treated with the highest dose of CAR-BCMA T cells obtained minimal 
residual disease negative status by bone marrow flow cytometry.  Consistent with BCMA-specific 
T-cell activity, plasma cells were reduced on bone marrow core biopsies in all 8 evaluated patients 
and absent in 4 of these patients 2-3 months after CAR-BCMA T-cell infusion. Of the five patients 
who had a history of the poor-prognosis chromosome 17p-deletion prior to protocol enrollment, 

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Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
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four obtained a PR or better. These results demonstrate that CAR-BCMA T cells can induce 
responses in poor-prognosis MM. 
A common concern raised with CAR-T therapy is whether soluble antigen may hinder efficacy. In 
the NCI trial, serum BCMA protein did not eliminate CAR-T cell activity against MM; moreover, 
serum BCMA levels were observed to drop significantly in patients who obtained responses to 
anti-BCMA CAR T cells.84 In agreement with pre-clinical work, the phase I clinical trial with anti-
BCMA CART cells did not demonstrate undue damage to nonhematopoietic organs after infusions 
of T-cells.84,88
Cohen et. al at the University of Pennsylvania have published their initial findings from a phase I 
trial of anti-BCMA CAR-T without conditioning chemotherapy in patients with relapsed or 
refractory MM.89 One patient was treated with 1.8x108 CAR T cells, two with 2x108 CAR T cells 
and three patients at the highest dose level of 5x108 CAR T cells.89  Toxicities were similar to 
those published by Ali et. al from the NCI experience, except for an episode of grade 4 posterior 
reversible encephalopathy syndrome (PRES) that manifested as severe delirium, seizures, 
obtundation and cerebral edema.89 This was treated with steroids, anti-epileptics, and 
cyclophosphamide; there was no long-term neurological dysfunction.89 Reported results show one 
patient has an ongoing stringent CR at seven months with an MRD-negative bone marrow by flow 
cytometry.89 One patient who had pleural and dural MM involvement was found to have CAR-Ts 
cells in pleural fluid and CSF and achieved VGPR with resolution of extramedullary disease; this 
patient’s VGPR lasted 5 months, and progression was associated with loss of BCMA expression 
on MM cells.89 Four patients had modest to minimal in vivo CAR T-cell proliferation and minimal 
to no anti-myeloma response.89 Of note, the trial reported by Cohen et al. utilized an anti-BCMA 
CAR with fully-human antibody variable regions. Full trial methods and results have yet to be 
published.
A third anti-BCMA CAR-T clinical trial is a multicenter trial being conducted by bluebird bio 
Inc.90 Twenty-one patients with relapsed/refractory MM have been infused with bb2121, an anti-
BCMA CAR-T that expresses a CAR with the same scFv as the anti-BCMA CAR used at the 
NCI.84  In contrast to the NCI anti-BCMA CAR, bb2121 has a 4-1BB costimulatory motif, and it 
is encoded by a lentivirus.90  Bb2121 is administered after cyclophosphamide plus fludarabine 
lymphocyte-depleting chemotherapy.90 To date, the authors report that the safety profile of bb2121 
has been favorable through doses as high as 800x106 CAR-Ts with no DLT observed.90 Seventy-
one percent of patients have had CRS that was generally mild.90 Efficacy of bb2121 in this study 
has been promising.  Of 3 patients receiving a CAR T-cell dose of 50x106 CAR T cells, one patient 
obtained a PR, but no patients obtained responses of VGPR or CR.90  Among 18 patients receiving 
CAR T-cell doses greater than 50 x106 CAR-Ts, 15 patients have reached at least 60 days of 
follow-up, and 11 of 15 patients with at least 60 days of follow-up have obtained best responses 
of VGPR or CR.90  All patients with at least 60 days of follow-up receiving a cell dose of greater 
than 50 x106 CAR-Ts have obtained at least a PR.90 
Fan et al. have reported early results from an on-going phase I anti-BCMA CAR trial that is 
enrolling patients with relapsed or refractory MM.91 The CAR used in this study is called LCAR-
B38M.  Among 19 patients reported, there was a 100% overall response rate.91 Eighteen patients 
obtained a stringent CR or a VGPR after receiving anti-BCMA CAR-T.91 CRS occurred in 74% 
of patients but was noted to be mild in most patients.91 

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Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
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1.2.8
Anti-BCMA CAR development and preclinical testing
The anti-BCMA CAR to be assessed in this protocol contains an antigen recognition domain made 
up only of a single fully-human variable heavy chain (FHVH) domain rather than the traditional 
CAR antigen-recognition domain of a single-chain variable fragment (scFv).  The FHVH33 heavy-
chain variable region sequence was obtained as part of a research agreement with TeneoBio Inc.  
TeneoBio derived this heavy chain variable region by immunizing a proprietory rat that is 
transgenic for human heavy chain variable region domains.  TeneoBio then selected heavy chain 
variable domains that bound with high affinity to human BCMA.  Investigators in the laboratory 
of James Kochenderfer then generated 9 different CARs that each incorporated one of 4 different 
heavy-chain-only anti-BCMA CARs with different costimulatory domains.  These CARs were 
assessed for specificity of antigen recognition and a wide variety of in vitro and in vivo functions.  
From these experiments the FHVH33 heavy-chain domain was found to be the one with the most 
sensitive and specific functional recognition of BCMA. After selecting FHVH33, the optimal 
overall CAR design was determined for evaluation in a clinical trial.  The selected anti-BCMA 
CAR  contains the hinge and transmembrane regions of the human CD8 molecule, the signaling 
moiety of the 4-1BB costimulatory molecule, and the signaling domains of the CD3 molecule.  
The CAR is designated FHVH33-CD8BBZ (Figure 3).  Some of the experiments demonstrating 
the function of FHVH33-CD8BBZ are described in this section of this protocol.  The clinical gene 
therapy vector encoding FHVH33-CD8BBZ is MSGV, which has been used in many prior clinical 
trials at the NCI.66,92
Figure 3
After transductions, we found high levels of cell surface expression of the FHVH33-CD8BBZ 
anti-BCMA CAR on the transduced T cells as shown in the representative example in Figure 4.
Figure 4
FHVH33-CD8BBZ
CD3
BCMA-Fc-PE
Untransduced
CD3
BCMA-Fc-PE

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Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
Version Date: October 28, 2025
Figure 4 shows anti-BCMA CAR expression on T cells from a multiple myeloma patient 7 days 
after transduction with gammaretroviruses encoding the anti-BCMA CAR.  Transductions were 
carried out 2 days after the cultures were started, so the T cells had been in culture for a total of 7 
days at the time of this analysis.  The plots are gated on live, CD3+ lymphocytes.
We also performed a series of in vitro assays to assess the function of anti-BCMA-CAR-expressing 
T cells, and we found that FHVH33-CD8BBZ-CAR-expressing T cells exhibited BCMA-specific 
activities including CD107a upregulation and cytokine production in vitro.  These experiments 
showed that anti-BCMA-CAR-expressing T cells are activated in a BCMA-specific manner.
Figure 5
Figure 5 shows upregulation of CD107a, which indicates degranulation and correlates with 
cytotoxicity93 when anti-BCMA CAR-expressing T cells  were cultured with the BCMA-
expressing cell line BCMA-K562.  CD107a was not upregulated when anti-BCMA-CAR-
expressing T cells  were cultured for 4 hours with the BCMA-negative control cell line NGFR-
K562.  Untransduced T cells did not upregulate CD107a when cultured with either BCMA-K562 
or NGFR-K562 (not shown).  The plots are gated on live CD3+ lymphocytes.  T cells transduced 
with the FHVH33-CD828Z anti-BCMA CAR produced large amounts of IFN when they were 
cultured overnight with the BCMA-expressing cell lines BCMA-K562 and RPMI8226 (Figure 6).  
In contrast, the anti-BCMA CARs produced only background levels of IFN when they were 
cultured with the BCMA-negative target cell lines NGFR-K562, CCRF-CEM, and 293-GP.  The 
anti-BCMA-CAR-transduced T cells also made minimal IFN when cultured without any target 
cell.  The experiment depicted in Figure 6 consisted of culturing the anti-BCMA-CAR-transduced 
T cells with the indicated target cell lines overnight and then performing a standard IFN enzyme-
linked immunosorbant assay (ELISA) to detect IFN in the culture supernatant.
FHVH33-CD8BBZ
BCMA-K562                                                        NGFR-K562

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Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
Version Date: October 28, 2025
Figure 6
                
 
A second ELISA experiment performed in a similar manner utilizing FHVH33-CD8BBZ anti-
BCMA CAR T cells from a different patient is shown in Table 2.  In the experimental results 
shown in Table 2, three different types of effector T cells from the same multiple myeloma patient 
were evaluated, untransduced T cells, T cells expressing the FHVH33-CD828Z CAR, and T cells 
expressing the FHVH33-CD8BBZ CAR.  FHVH33-CD828Z is identical to FHVH33-CD8BBZ 
except that FHVH33-CD828Z has a CD28 costimulatory domain while FHVH33-CD8BBZ has a 
4-1BB costimulatory domain.  The untransduced T cells expressed only background levels of IFN 
against all target cells.  T cells expressing either FHVH33-CD828Z or FHVH33-CD8BBZ 
specifically recognized BCMA as shown by the high levels of IFNg released when the CAR-
expressing T cells were cultured with the BCMA+ target cells BCMA-K562 an RPMI8226; in 
contrast, the CAR-expressing T cells produced much lower levels of IFNg when cultured with the 
BCMA-negative target cell lines Panc10.05, U251, 293GP, and the primary cells normal human 
bronchial epitheial cells (NHBE), human microvascular endotherlial cells (HMVEC), and primary 
human intestinal epithelial cells (InEpC).  T cells alone made low levels of IFN for all T cell types 
evaluated.  Compared to T cells expressing FHVH33-CD828Z, T cells expressing FHH33-
CD8BBZ produced higher levels of IFN when cultured with the RPMI8226 cell line.  The 
RPMI8226 cell line expresses low levels of BCMA.  In many IFN ELISA experiments and other 
functional assays, T cells expressing FHVH33-CD8BBZ have shown a greater ability than T cells 
expressing FHVH33-CD828Z to be activated by RPMI8226 cells.  These results suggest that 
compared to FHVH33-CD828Z, T cells expressing FHVH33-CD8BBZ have a greater ability to 
be activated by target cells expressing low levels of BCMA.  Another point made by the data in 
Table 2 is that CARs containing a 4-1BB moiety produce low levels of IFN when cultured alone 
or with BCMA-negative target cells.  This production of IFNg with CAR T cells cultured in the 
absence of the CAR target antigen is a very consistent finding with 4-1BB CARs that target a 
variety of antigens including anti-CD19 CARs in clinical use and other anti-BCMA CARs.51 
BCMA-K562
RPMI8226
NGFR-K562
CCRF-CEM
293-GP
T-cells only
0
2000
4000
6000
40000
60000
80000
Target cells
IFN (pg/mL)

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Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
Version Date: October 28, 2025
Table 2
Table 3 shows ELISA results from an experiment in which effector T cells were cultured in the 
presence of BCMA protein at concentrations ranging from 150 ng/mL to 0 ng/mL.  Effector T 
cells used in this experient were T cells from the same patient transduced with the SP6-CD828Z 
negative-control CAR, FHVH33-CD828Z, or FHVH33-CD8BBZ.  Target cells used in this 
experiment were either BCMA-K562 cells or RPMI8226 cells or the BCMA-negative NGFR-
K562 cells.  The T cells and target cells were cultured together overnight, and IFN was measured 
in the culture supernatant by a standard ELISA assay.  The presence of soluble BCMA protein did 
not block recognition of the BCMA+ target cells, and BCMA protein also did not cause 
nonspecific activation of the FHVH33-CD8BBZ T cells.  All numbers are pg/mL IFN.
Effector T cell
BCMA-
K562
RPMI-
8226
Panc10.
05
U251
293GP
NHBE
HMVEC
InEpC
T-cells 
Only
Untransduced
179
406
76
41
92
54
54
33
25
FHVH33-828Z 38548
13855
37
24
40
43
25
18
14
FHVH33-8BBZ 70216
33465
306
360
238
423
610
500
367
FHVH33-CD828Z-transduced T cells:  71% CAR expression
FHVH33-CD8BBZ-transduced T cells:  80% CAR expression
All values are pg/mL of IFN
BCMA+              BCMA-negative

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Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
Version Date: October 28, 2025
Table 3
Figure 7 presents the results of a 4 hour cytotoxicity assay in which RPMI8226 cells were used as 
target cells for either untransduced T cells or T cells transduced with FHVH33-CD8BBZ.  The 
graph gives specific cytotoxicity of BCMA+ RPMI8226 cells relative to the negative-control 
BCMA-negative CCRF-CEM cell line.  T cells expressing FHVH33-CD8BBZ were able to cause 
specific cytotoxity of the BCMA+ cell line.
Figure 7
Anti-BCMA-CAR-transduced T cells also proliferated in a BCMA-specific manner.  
Figure 8shows a carboxyfluorescein diacetate,succinimidyl ester (CFSE) proliferation assay in 
which anti-BCMA-CAR-transduced T cells were cultured for 4 days with either BCMA-K562 
BCMA-K562
Effector T cells 150ng/mL 50ng/mL
25ng/mL 0ng/mL
SP6-CD828Z
169
178
219
207
FHVH33-CD828Z
34821
38582
37225
35576
FHVH33-CD8BBZ
70008
63175
61903
60361
T-cells Only
150ng/mL 50ng/mL 25ng/mL 0ng/mL
115
116
136
121
24
18
21
22
117
114
125
122
Effector T cells
SP6-CD828Z
FHVH33-CD828Z
FHVH33-CD8BBZ
150ng/mL 50ng/mL 25ng/mL 0ng/mL
247
259
210
253
14870
17680
16949
17583
30838
34304
30650
31937
RPMI-8226
Effector T cells
SP6-CD828Z
FHVH33-CD828Z
FHVH33-CD8BBZ
20:1
6.7:1
2.2:1
0.7:1
0
25
50
75
FHVH33-CD8BBZ
Untransduced
T-cell to Target cell Ratio
% Cytotoxicity

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Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
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cells or BCMA-negative NGFR-K562 cells.  CFSE was diluted to a greater degree, indicating 
more proliferation, when the T cells were cultured with BCMA-K562 target cells (open histogram 
in Figure 8) compared to when anti-BCMA-CAR T cells were cultured with BCMA-negative 
NGFR-K562 target cells (solid histogram in Figure 8).  Note that the solid histogram representing 
culture of FHVH33-CD8BBZ T cells with NGFR-K562 cells is smaller than the open histogram 
representing culture of FHVH33-CD8BBZ T cells with BCMA-K562 cells because fewer T cells 
that were cultured with NGFR-K562 were left alive at the end of the assay.   The assay was 
conducted as described previously.5  
Figure 8 also includes a graph of CAR T-cell number at the beginning and at the end of the CFSE 
proliferation assay.  The number of T cells transduced with FHVH33-CD8BBZ was compared to 
the number of T cells expressing FHVH33-CD828Z.  In multiple experiments, we consistently 
found superior in vitro proliferation of T cells expressing FHVH33-CD8BBZ compared with T 
cells expressing FHVH33-CD828Z.
Figure 8
We established RPMI8226 human multiple myeloma cell line tumors in immunodeficient mice.  
We allowed sizable tumors to develop over 17  days then we treated the mice with a single 
intravenous infusion of anti-BCMA-CAR-transduced human T cells.  After infusion of anti-
BCMA-CAR T cells, dramatic regressions of all tumors occurred between day 6 and day 15 after 
the T cell infusion, and 100% of mice receiving anti-BCMA-CAR T cells were cured (Figure 9 
and Figure 10)  The CARs used in this experiment included FHVH33-CD8BBZ, FHVH33-
CD828Z, and the CAR used in our previous NCI anti-BCMA CAR trial, 11D5-3-CD828Z.  In 
contrast, tumors continued to increase in size in all untreated mice.  The mice receiving infusions 
of anti-BCMA-CAR-transduced T cells had no signs of toxicity during this experiment.
Day 0
Day 4
0
1
2
3
4
5
CAR+ T cells x106
FHVH33-CD828Z
FHVH33-CD8BBZ
Day after stimulation

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Figure 9
In the experiments depicted in Figure 9 and Figure 10, anti-BCMA-CAR T cells were infused on 
Day 0, and no other treatments were administered.  In the experiments reported in Figure 9 and 
Figure 10, there were 5 mice in all groups.  
Figure 10
1.2.9
Rationale for immunosuppressive chemotherapy and selection of lymphocyte-depleting 
chemotherapy regimen
We plan to administer a conditioning chemotherapy regimen of cyclophosphamide and fludarabine 
before infusions of anti-BCMA-expressing T cells because substantial evidence demonstrates an 
enhancement of the anti-malignancy activity of adoptively-transferred T cells when chemotherapy 
or radiotherapy are administered before the T cell infusions.6,8,94  In mice, administering 
chemotherapy or radiotherapy prior to infusions of tumor-antigen-specific T cells dramatically 
enhanced the anti-tumor efficacy of the transferred T cells.6,8,26,27,94,95  Administering 
chemotherapy or radiotherapy enhances adoptive T-cell therapy by multiple mechanisms including 
depletion of regulatory T cells and elevation of T-cell stimulating serum cytokines including 
interleukin-15 (IL-15) and interleukin-7 (IL-7), and possibly depletion of myeloid suppressor cells 
Day after T-cell infusion
Tumor volume in mm3
Day 0
Day 6
Day 12
Day 18
Day 24
Day 30
0
100
200
300
400
MSGV-FHVH33-CD8BBZ
Untreated
MSGV-11D5-3-CD828Z
MSGV-FHVH33-CD828Z
Day after T cell infusion
Percent Survival
0
10
20
30
40
0
20
40
60
80
100
Untreated
MSGV-FHVH33-CD8BBZ
MSGV-11D5-3-CD828Z
MSGV-FHVH33-CD828Z

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and other mechanisms.6,8,95,96  Removal of endogenous “cytokine sinks” by depleting endogenous 
T cells and natural killer cells caused serum levels of important T-cell stimulating cytokines such 
as IL-15 and IL-7 to increase, and increases in T-cell function and anti-tumor activity were 
dependent on IL-15 and IL-7.6  Experiments in a murine xenograft model showed that regulatory 
T cells could impair the anti-tumor efficacy of anti-CD19 CAR T cells.97  Myeloid suppressor cells 
have been shown to inhibit anti-tumor responses.96  Experiments with a syngeneic murine model 
showed that lymphocyte-depleting total body irradiation (TBI) administered prior to infusions of 
anti-CD19-CAR-transduced T cells was required for the T cells to cure lymphoma.7   In these 
experiments, some mice received TBI, and other mice did not receive TBI.  All mice were then 
challenged with lymphoma and treated with syngeneic anti-CD19-CAR T cells.  Mice receiving 
TBI had a 100% cure rate and mice not receiving TBI had a 0% cure rate.7 
Strong suggestive evidence of enhancement of the activity of adoptively-transferred T cells has 
been generated in humans.31,98,99  Very few clinical responses have occurred and very little 
evidence of in vivo activity has been generated in clinical trials of anti-CD19-CAR T cells 
administered without lymphocyte-depleting chemotherapy.31,34  In contrast, many regressions and 
evidence of long-term B-cell depletion have occurred in clinical trials in which patients received 
anti-CD19-CAR T cells after lymphocyte-depleting chemotherapy.3,4,33,52   The chemotherapy 
regimen that best increases the anti-malignancy efficacy of CAR-expressing T cells is not known, 
but the most commonly used chemotherapy regimens that have been used in clinical trials and that 
convincingly demonstrate persistence and in vivo activity of adoptively transferred T cells have 
included cyclophosphamide and fludarabine.3,4,32,33,98,99  Both cyclophosphamide and fludarabine 
are highly effective at depleting lymphocytes.98,99  One well-characterized and commonly used 
regimen is the combination of 300 mg/m2 of cyclophosphamide administered daily for 3 days and 
fludarabine 30 mg/m2 administered daily for three days on the same days as the 
cyclophosphamide.100  Multiple cycles of this regimen can be tolerated by heavily pretreated 
leukemia patients.66,100   
1.2.10  Rationale for dose-escalation and starting dose
The clinical trial described in this protocol is planned as a dose escalation in which the number of 
anti-BCMA-CAR T cells administered to patients will be increased with sequential dose levels.  
The rationale for conducting a dose-escalation trial of a cellular therapy is based on two main 
sources of evidence.  First, the anti-tumor efficacy of adoptively-transferred T cell treatments 
increases as the dose of T cells administered to mice increases.101-103  Second, in the setting of 
allogeneic transplantation, relapsed malignancy is often treated with infusions of allogeneic donor 
lymphocytes (DLIs).104,105  The incidence of graft-versus-host disease, which is caused by T cells 
attacking allogeneic antigens on host tissues, increases as the dose of T cells administered in DLIs 
increases’.104,105 
The starting CAR T-cell dose of 0.75x106 CAR+ T cells/kg is based on experience in past CAR 
clinical trials.  The 0.75x106 CAR+ T cells/kg dose is considered a dose lower than that at which 
substantial toxicity has been observed.  We believe starting at a lower dose is prudent given that 
this is the first trial of a heavy-chain-only CAR. The following clinical trials were used to guide 
the starting dose of this trial.  Note that it was our goal to use a dose lower than the MTD of prior 
trials.  NCI protocol 09-C-0082 (Kochenderfer et al Journal of Clinical Oncology, 2017), a trial of 
anti-CD19 CAR T cells had an MTD of 2x106 CAR+ T cells/kg.66  NCI protocol 14-C-0168, a trial 

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of anti-BCMA CAR T cells had an MTD of 9x106 CAR+ T cells/kg.106  A multicenter trial of anti-
BCMA CAR T cells conducted by bluebird bio, Inc. determined that a flat dose of 450 x106 CAR+ 
T cells was the optimal dose for the expansion phase of the study (unpublished results).  The 450 
x 106 flat dose of CAR T cells would be 4.5x106 CAR+ T cells/kg for a 100 kg patient.  Because 
the CAR to be tested in the current trial and the CAR tested in the bluebird bio trial both contain a 
4-1BB domain, we predict the activity of the CAR to be tested in the current trial, FHVH33-
CD8BBZ will be most like the CAR in the bluebird trial.
1.2.11 Summary of risks and potential benefits
This clinical trial is being performed to evaluate a genetically-modified T-cell therapy for multiple 
myeloma, which is an almost always incurable disease.13  Only patients with multiple myeloma 
who have persisting or relapsed myeloma despite at least 3 prior lines of therapy will be enrolled. 
The risks of the study fall into 4 general categories.  First, chemotherapy that could cause 
cytopenias is part of the protocol.  As with any chemotherapy that causes neutropenia and 
thrombocytopenia, this chemotherapy could cause toxicities such as infections and bleeding. The 
second category of toxicity is cytokine-release-type toxicities such as high fevers, hypotension and 
neurological toxicities such as delirium, obtundation, myoclonus, seizures, headache, and transient 
focal neurological toxicities including aphasia and focal paresis.  These cytokine-release-type 
toxicities have been detected in other clinical trials of CAR T cells during the first 2 weeks after 
anti-CD19 CAR T cells or anti-BCMA T cells were infused.4,106,107   In most cases, these toxicities 
have been transient with toxicities generally resolving within 2 days to 2 weeks.  The third main 
category of toxicity is direct damage to normal tissues by the CAR T cells.  This could happen 
because of unexpected cross-reactivity of the anti-BCMA CAR with proteins other than BCMA in 
vivo. We have not observed organ damage in our completed study of anti-BCMA CAR T cells.106  
A potential toxicity caused by anti-BCMA CAR T cells damaging normal cells is 
hypogammaglobulinemia due to depletion of plasma cells and a subset of mature B cells.  
Hypogammaglobulinemia has been a complication for many patients on clinical trials of anti-
CD19 CAR-expressing T cells and anti-BCMA T cells.4,33  .  Hypogammaglobulinemia in these 
patients was routinely treated with infusions of intravenous immunoglobulins.4  Finally, 
genotoxicity is a theoretical risk of any type of integrating gene therapy. To our knowledge, 
genotoxicity, such as occurrence of a replication-competent retroviruses or transformation of T 
cells caused by insertional mutagenesis has never occurred in a clinical trials of T-cell gene 
therapies.35,36  The specific gene therapy vector backbone, MSGV1, proposed for use in this 
clinical trial has been used in hundreds of patients over the past 13+ years by our group and 
others.4,25,108,109
The potential benefits to subjects enrolling on this trial include the possibility that the anti-BCMA-
CAR T cells can cause a significant anti-myeloma effect.  Many patients enrolled on early trials 
of anti-CD19 CAR T cells and anti-BCMA CAR T cells obtained prolonged complete remissions 
of advanced malignancies3,4,106,110, so there is a chance that recipients of anti-BCMA CAR T cells 
on this clinical trial of fully-human heavy-chain-only CARs could also derive a direct benefit from 
participation in this trial.  Patients might also derive a benefit from knowing that they are 
contributing to the development of new cellular therapies for cancer.  Aiding in the development 
of new therapies might help future patients.

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2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
Note: if a patient meets an eligibility requirement as outlined below, and is enrolled on the protocol 
but then is found to no longer meet the eligibility requirement after enrollment but before the start 
of protocol treatment, the treatment will be aborted or delayed until eligibility criteria are met.
2.1.1
Inclusion Criteria
2.1.1.1
Multiple Myeloma criteria
•
BCMA expression must be detected on malignant plasma cells from either bone marrow 
or a plasmacytoma by flow cytometry or immunohistochemistry.  If patient has 
plasmacytomas, one plasmacytoma must be biopsied to demonstrate BCMA expression. A 
specific quantitative level of BCMA expression for eligibility is not specified, but patients 
with multiple myeloma cells that are  negative for BCMA by flow cytometry and 
immunohistochemistry on either bone marrow biopsy or plasmacytoma biopsy will not be 
enrolled.  These assays must be performed at the National Institutes of Health (NIH).  It is 
not required that the specimen used for BCMA determination comes from a sample that 
was obtained after the patient’s most recent treatment.  If paraffin embedded unstained 
samples of bone marrow involved with MM or a plasmacytoma are available, these can be 
shipped to the NIH for BCMA staining, otherwise new biopsies will need to be performed 
for determination of BCMA expression.
•
BCMA expression will need to be documented on the majority of malignant plasma cells 
by flow cytometry at the NIH at some time after the original anti-BCMA CAR T-cell 
infusion in all patients undergoing a second anti-BCMA CAR T-cell infusion.  
•
Patients must have received at least 3 different prior treatment regimens for multiple 
myeloma
•
Must have prior exposure to an “IMiD” such as lenolidamide and a proteasome inhibitor
•
Patients must have measurable MM as defined by at least one of the criteria below.
➢One or more of these abnormalities defines measurable multiple myeloma:
➢Serum M-protein greater or equal to 1.0 g/dL. 
➢Urine M-protein greater or equal to 200 mg/24 h.
➢Serum free light chain (FLC) assay: involved FLC level greater or equal to 10 mg/dL 
(100 mg/L) provided serum FLC ratio is abnormal.
➢A biopsy-proven plasmacytoma at least 2.0 cm in largest dimension
➢Bone marrow core biopsy with 30% or more plasma cells
2.1.1.2
Other inclusion criteria
•
Greater than or equal to 18 years of age and less than or equal to age 73. 
•
Able to understand and sign the Informed Consent Document.
•
Clinical performance status of ECOG  0-2

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•
Patients of both sexes must be willing to practice birth control from the time of enrollment 
on this study and for four months after last day of receiving protocol treatment.
•
Seronegative for HIV antibody.  (The experimental treatment being evaluated in this 
protocol depends on an intact immune system.  Patients who are HIV seropositive can have 
decreased immune-competence and thus are less responsive to the experimental treatment 
and more susceptible to its toxicities.) 
•
A patient with a negative blood PCR test for hepatitis B DNA test can be enrolled. If 
hepatitis B DNA (PCR) testing is not available, patients with a negative hepatitis B surface 
antigen and negative hepatitis B core antibody can be enrolled.
•
Patients must be tested for the presence of Hepatitis C antigen by PCR and be HCV RNA 
negative in order to be eligible.  Only if Hepatitis C PCR testing is not available in a timely 
manner, patients who are Hepatitis C antibody-negative can be enrolled.
•
Absolute neutrophil count greater than or equal to 1000/mm3 without the support of 
filgrastim or other growth factors within the previous 10 days.  
•
Platelet count greater than or equal to 55,000/mm3 without transfusion support within the 
past 10 days. 
•
Hemoglobin greater than 8.0 g/dL.
•
Less than 5% plasma cells in the peripheral blood leukocytes 
•
Serum ALT and AST less or equal to 2.5 times the upper limit of the institutional normal.
•
Serum creatinine less than or equal to 1.5 mg/dL.
•
Total bilirubin less than or equal to 2.0 mg/dL, except in patients with Gilbert’s Syndrome 
who must have a total bilirubin less than 3.0 mg/dL.
•
At least 14 days must have elapsed since any prior systemic therapy at the time the patient 
starts the cyclophosphamide and fludarabine conditioning regimen, and patients’ toxicities 
must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo). 
•
Because this protocol requires collection of autologous blood cells by leukapheresis in 
order to prepare anti-BCMA-CAR T cells, systemic anti-myeloma therapy including 
systemic corticosteroid steroid therapy of greater than 5 mg/day of prednisone or 
equivalent dose of another corticosteroid are not allowed within 2 weeks prior to the 
required leukapheresis.
•
Normal cardiac ejection fraction (greater than or equal to 50% by echocardiography) and 
no evidence of hemodynamically significant pericardial effusion as determined by an 
echocardiogram.
•
For patients with past participation in gene-therapy, cryopreserved PBMC that have not 
been genetically-engineered must be available.
2.1.2
Exclusion criteria 
•
Patients on any anticoagulants except aspirin.
•
Patients that require urgent therapy due to tumor mass effects or spinal cord compression.

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•
Patients that have active hemolytic anemia.
•
Patients with second malignancies in addition to multiple myeloma are not eligible if the 
second malignancy has required treatment within the past 3 years or is not in complete 
remission. There are two exceptions to this criterion:  successfully treated non-metastatic 
basal cell or squamous cell skin carcinoma.   
•
Women of child-bearing potential who are pregnant or breastfeeding because of the 
potentially dangerous effects of the preparative chemotherapy on the fetus or infant.  
Women of child bearing potential cannot have a positive pregnancy test.  Women of child-
bearing potential are defined as all women except women who are post-menopausal or who 
have had a hysterectomy. Postmenopausal will be defined as women over the age of 55 
who have not had a menstrual period in at least 1 year.
•
Active systemic infections (defined as infections causing fevers or requiring anti-microbial 
treatment), active coagulation disorders or other major uncontrolled medical illnesses of 
the cardiovascular, respiratory, endocrine, renal, gastrointestinal, genitourinary, 
neurologic, or immune system, history of myocardial infarction, active cardiac arrhythmias 
including active atrial fibrillation, history of any arrhythmias other than sinus tachycardia 
or atrial fibrillation, currently taking any anti-arrythmic or congestive heart failure 
medications, active obstructive or restrictive pulmonary disease.
•
Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency 
Disease). 
•
Systemic corticosteroid steroid therapy of greater than 5 mg/day of prednisone or 
equivalent dose of another corticosteroid (prednisone, dexamethasone, etc) is not allowed 
within 2 weeks prior to either the required leukapheresis or within 2 weeks prior to CAR 
T-cell infusion (and at any time after the CAR T cell infusion).
•
History of severe immediate hypersensitivity reaction to any of the agents used in this 
study.
•
Patient unwilling to undergo intensive care unit treatment including mechanical 
ventilation, cardiopulmonary resuscitation, vasoactive drugs, and hemodialysis.
•
History of allogeneic stem cell transplantation
•
Patients with current spinal cord compression (without intradural myeloma involvement).
•
Patients who have a history (or current evidence) of cerebrospinal fluid multiple myeloma, 
or intra-dural central nervous system masses.
•
Patients with active autoimmune skin diseases such as psoriasis or other active autoimmune 
diseases such as rheumatoid arthritis.
•
Patients must not have required supplemental oxygen within the past month unless it was 
for a resolved infection.
•
Patient must not have received genetically modified cells except on prior NCI gene therapy 
protocols.

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2.1.3
Recruitment Strategies
This protocol may be abstracted into a plain language announcement posted on the NIH websites 
and on NIH social media platforms. Participants will be recruited from the current patient 
population at NIH, and local community physicians.
2.2
SCREENING EVALUATION
2.2.1
Screening activities performed after a consent for screening has been signed
Note: Screening evaluation testing/procedures are conducted under the separate screening 
protocol, 01C0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural Research 
Program Clinical Protocols).
The following assessments must be completed within 30 days prior to starting the chemotherapy 
conditioning regimen unless otherwise noted (if not, then the evaluation must be repeated): 
•
Complete history and physical examination, including: weight, vital signs, ECOG
•
Confirmation of diagnosis of MM by the NCI Laboratory of Pathology and confirmation 
of BCMA expression on malignant plasma cells from either bone marrow or a 
plasmacytoma by flow cytometry or immunohistochemistry.  The sample used for this 
BCMA expression analysis can come from any time prior to enrollment on the protocol.
•
Bone marrow aspirate and biopsy specifically ask for BCMA immunohistochemistry 
staining of the bone marrow biopsy.  Order cytogenetics with interphase FISH 
(pretreatment aspirate only) and flow cytometry on the bone marrow aspirate. Specifically 
request 2 separate bone holes for bone marrow aspiration.  The aspirate for hemepath (0.5 
mL) and flow (2-2.5 mL) should be done from 1 bone hole and the aspirate for research (2-
2.5 mL) should be done from a second bone hole followed by an aspirate for cytogenetics 
(1-2 mL) from the second bone hole. Note: Only bone marrow aspirates done before CAR 
T-cell treatment and 2 weeks after CAR T-cell infusion require aspirates through 2 bone 
holes.  All other aspirates only need to be done through 1 bone hole.    
The bone marrow biopsy must take place at some time after the patient’s most recent 
myeloma treatment.  If the patient agrees to future use of specimens when screening bone 
marrow is obtained, reserve one tube of bone marrow aspirate to be sent to the Surgery 
Branch Cell Production Facility SB-CPF. Bldg. 10 3W-3808.  Phone: 240-858-3755.  Bone 
marrow aspirate cells and supernatant will be cryopreserved. As many vials as possible 
with 10 million cells or less will be cryopreserved, and 2 vials of supernatant with 0.5 to 1 
mL each will be cryopreserved. A bone marrow biopsy must be performed within 24 days 
of the start of the protocol-required conditioning chemotherapy.  If this screening bone 
marrow aspirate and biopsy is performed within 24 days of the start of the conditioning 
chemotherapy, a second baseline bone marrow biopsy does not need to be performed. 
•
All patients must have flow cytometry staining of bone marrow or plasmacytoma cells for 
BCMA by Dr. Stetler-Stevenson’s lab (NCI Laboratory of Pathology).
•
EKG
•
MRI of spine and pelvis (only if clinically indicated in patients with back pain or pelvic 
pain or a history of plasmacytomas of spine or pelvic) 

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•
MRI of the brain
•
If necessary to assess disease, obtain a skeletal X-ray survey
•
PET scan of torso and/or extremities (only if needed to evaluate disease)
•
CT scans of areas with possible lesions/plasmacytomas  This may include areas such as the 
head, neck, chest, abdomen and pelvis. (only if needed to evaluate disease)
•
Donor venous assessment
•
 DNA (PCR) for Hepatitis B and C; antibody testing for HIV, HTLV-I/II, T. cruzi (Chagas 
agent), West Nile, and syphilis (RPR), only if DNA testing is not available, order Hepatitis 
C antibody, Hepatitis B core antibody, and hepatitis B surface antigen.
•
Echocardiogram
•
(Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, 
Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total (Mg), 
Phosphorus, Alkaline Phosphatase, ALT, AST, Total Bilirubin, Direct Bilirubin, LDH, 
Total Protein, Total CK, Uric Acid)
•
CBC with differential and platelet count
•
Serum immunofixation electrophoresis
•
Serum immunoglobulin free light chains 
•
Glucose-6-phosphate dehydrogenase (G6PD) deficiency screening
•
TSH (T4 and T3)
•
Serum Cortisol
•
β-HCG pregnancy test (serum or urine) on all women of child-bearing potential 
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found at https://nih.sharepoint.com/sites/NCI-CCR-OCD-
Communications/SitePages/OEC-Administrative---Clinical-Research-(ADCR).aspx?Mode=Edit.  
2.4
TREATMENT ASSIGNMENT PROCEDURES FOR THE REGISTARTION PURPOSES ONLY:
Cohorts 
Number
Name
Description
1
Cohort 1
Subjects enrolled to determine the MTD or maximum feasible dose  
2
Cohort 2
Subjects enrolled after the MTD or maximum feasible dose has been 
identified

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Arms
Number
Name
Description
1
Conditioning 
chemotherapy plus CAR 
T-cells dose escalation 
Patients will receive escalating doses (up to 5 planned) of CAR+ 
T cells infused on day 0 + Cyclophosphamide: 300 mg/m2 IV 
infusion over 30 minutes on days -5, -4 and -3 + Fludarabine: 30 
mg/m2 IV infusion over 30 minutes administered immediately 
following the cyclophosphamide on days -5, -4,and -3
2
Conditioning 
chemotherapy plus CAR 
T-cells expansion phase
6.0x106 cells/kg  dose (maximum feasible dose) of CAR T Cells 
+ Cyclophosphamide: 300 mg/m2 IV infusion over 30 minutes 
on days -5, -4 and -3 + Fludarabine: 30 mg/m2 IV infusion over 
30 minutes administered immediately following the 
cyclophosphamide on days -5, -4,and -3
Arm Assignment
Patients in Cohort 1 will be directly assigned to Arm 1.
Patients in Cohort 2 will be directly assigned to Arm 2.
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
3.1.1
General Study Plan  
This protocol is a phase I dose-escalation study of autologous T cells that are genetically modified 
to express an anti-BCMA CAR.
The protocol will enroll patients with multiple myeloma previously treated with at least 3 prior 
lines of therapy.  Patients will be evaluated for general health, and multiple myeloma staging will 
be carried out.  An assessment of BCMA expression will be an important part of the eligibility 
screening.  Patients enrolled on the study will undergo leukapheresis, and anti-BCMA-CAR-
expressing T cells will be generated by transducing the patient’s T cells with a gammaretrovirus 
encoding the anti-BCMA CAR.  Patients will receive a conditioning chemotherapy regimen of 
cyclophosphamide 300 mg/m2 daily for 3 days and fludarabine 30 mg/m2 IV daily for 3 days on 
the same days.  This is an extensively-used chemotherapy regimen that can be easily administered 
on an outpatient basis.  Two days after the end of the conditioning chemotherapy, patients will 
receive a single infusion of anti-BCMA-CAR-expressing T cells.  A minimum 9-day 
hospitalization will be required after the cell infusion to monitor closely for acute toxicities.  It is 
expected that some patients will need to be hospitalized for up to 30 days to allow all toxicities to 
resolve to the point that discharge from the hospital is prudent.  Patients are required to stay within 
60 minutes driving time from the Clinical Center until day 14 after the CAR T-cell infusion.   
Patients will then be evaluated for toxicity and multiple myeloma will be staged 2 weeks and 1, 2, 
3, 4, 6, 9, and 12 months after the infusion.  They will be followed every 6 months afterwards for 
at least 5 years.

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A small number of subjects may be eligible for re-enrollment if a patient is removed from the 
protocol before completing protocol treatment; or the patient is going to receive a second 
treatment.  These patients would be required to meet all eligibility criteria at the time of re-
enrollment.  Patients will be assigned a new sequential study number for the reenrollment study 
period. Any cryopreserved anti-BCMA CAR T cells produced from a patient who was removed 
from the study can be used to treat that patient after re-enrollment.  We do not anticipate changes 
in the risk profile for the initial versus re-enrollment

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3.1.2
Protocol Schema
Leukapheresis
In vitro generation of 
Anti-BCMA-expressing
T cells (7-9 days); cryopreservation
Pretreatment staging
Infusion of recipient with
Anti-BCMA-CAR-expressing T-Cells
(Inpatient for 9-days minimum post 
infusion)
Potential repeat treatments for patients with 
persistent myeloma
Follow-up 2 weeks and 1, 2, 3, 4, 6, 9, and 12 
months post-infusion. Then every 6 months 
up to 5 years post-infusion.
Outpatient or inpatient 
cyclophosphamide plus fludarabine 
conditioning chemotherapy
Patient Baseline evaluation

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3.1.3
Dose Limiting Toxicity-the dose limiting toxicity assessment period is 28 days.
DLTs are defined as follows (Note that DLTs will not occur in patients who do not receive CAR 
T-cell infusions but do receive the conditioning chemotherapy):
•
Grade 3 toxicities possibly or probably or definitely related to the anti-BCMA CAR T cells 
and lasting more than 9 days
•
Grade 4 toxicities possibly or probably or definitely related to the anti-BCMA CAR T cells.
The following specific toxicities will not be DLTs:
•
Neutropenia (ANC<500/L) lasting 10 days or less is not a DLT
•
Neutropenia with an ANC>500/mL is not a DLT
•
Anemia (Hgb<8 g/dL) lasting 10 days or less is not a DLT
•
Anemia with Hgb greater than or equal to 8 g/dL is not a DLT
•
Transfusion-dependent thrombocytopenia lasting 28 days or less is not a DLT
•
Thrombocytopenia that is not transfusion-dependent is not a DLT
•
Hypotension requiring continuous treatment with vasopressors for 72 hours or less is not a 
DLT.  
•
Fever is not a DLT.
•
All cytopenias except neutropenia, anemia, and thrombocytopenia are not DLTs
•
Asymtomatic electrolyte disturbances regardless of grade are not DLTs
•
Prolonged QT interval as long as ventricular arrhythmias do not occur is not a DLT
•
Grade 1, 2, or 3 creatine kinase elevation is not a DLT
•
Infections controlled by antibiotics are not DLTs
3.1.4
Dose Escalation
The trial will be a dose-escalation with 5 dose levels based on the patient’s actual bodyweight.  
Dose Escalation Schedule
Dose Level
Dose of IND Agent 
Level -1
0.4x106 CAR+ T cells per kg of recipient bodyweight
Level 1
0.75x106 CAR+ T cells per kg of recipient bodyweight
Level 2
1.5x106 CAR+ T cells per kg of recipient bodyweight 
Level 3
3.0x106 CAR+ T cells per kg of recipient bodyweight 

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Dose Escalation Schedule
Dose Level
Dose of IND Agent 
Level 4
6.0x106 CAR+ T cells per kg of recipient bodyweight
Level 5
12.0x106 CAR+ T cells per kg of recipient bodyweight
A minimum of 3 patients will be enrolled at each dose level.  There will be a minimum of 9 days 
between the CAR T-cell infusion of a patient and the start of the conditioning chemotherapy 
regimen for the next patient.  This will cause a 14 day delay between sequential CAR T-cell 
infusions.
If sufficient cells cannot be grown to meet the criteria for the assigned dose level but sufficient 
cells can be grown to meet the requirements of one dose level lower than the assigned dose level, 
the patient will be enrolled in the appropriate dose level for the number of cells infused. If a DLT 
occurs in an additional patient entered at a lower dose due to cell growth limitations, accrual will 
continue at this level as described in the dose-escalation scheme below.  Accrual will be halted at 
the higher level until the dose level at the lower level is complete as described below.  If sufficient 
cells cannot be produced to infuse the number of cells called for by one dose level lower than the 
called for dose level, the treatment will be aborted.  A second attempt will be made to prepare cells 
for the patient if the patient agrees and if the patient still meets all eligibility criteria. 
Should none of the first 3 patients treated on a dose level experience a DLT, the first patient can 
be infused on the next higher dose level after a 28-day delay following CAR T-cell infusion of the 
third patient.  Should 1 of 3 patients experience a dose limiting toxicity at a particular dose level,  
three more patients would be treated at that dose level. If 1/6 patients have a DLT at a particular 
dose level, the first patient can be infused on the next higher dose level after a 28-day delay 
following CAR T-cell infusion of the 6th patient. If a level with 2 or more DLTs in 3-6 patients has 
been identified, 3 additional patients will be accrued at the next-lowest dose for a total of 6, in 
order to further characterize the safety of the MTD.  
If 2 of 3 patients on Dose level 1 experience DLTs, accrual will proceed on dose level -1.
The MTD is the dose at which a maximum of 1 of 6 patients has a DLT.  After a MTD is defined, 
additional patients can be treated at the MTD.  Up to 12 total additional recipients can be treated 
after an MTD is established to more completely characterize toxicity of the MTD.  If cell growth 
limitations preclude administration of the MTD, the patient will receive as many cells as possible 
up to the MTD.  If it proves to be technically impossible or impractical to achieve the higher dose 
levels due to cell production constraints and a MTD has not been reached, the highest achievable 
dose level will be declared the maximum feasible dose, and up to 12 additional recipients will be 
treated with the maximum feasible cell dose. 
The maximum feasible dose has been determined to be 6x106 CAR+ cells/kg based on technical 
difficulty preparing larger numbers of CAR+ T cells and lack of establishment of a MTD after 
treating at least 3 patients on all dose levels.
Dose escalation will follow the rules outlined in the Table below:

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Version Date: October 28, 2025
Number of Patients with 
DLTat a Given Dose Level
Escalation Decision Rule
0 out of 3
Enter up to 3 patients at the next dose level
> 2
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Up to three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose.
1 out of 3
Enter up to 3 more patients at this dose level.
•
If 0 of these 3 patients experience DLT, proceed 
to the next dose level.
•
If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Up to three (3) 
additional patients will be entered at the next 
lowest dose level if only 3 patients were treated 
previously at that dose.
<1 out of 6 at the highest 
dose or 1 level below the 
maximally administered dose
This is the MTD and is generally the recommended phase 
2 dose.  At least 6 patients must be entered at the 
recommended phase 2 dose.
3.2
DOSE MODIFICATIONS/DELAY
Other Toxicity:
•
Patients may be removed from further treatment if they have active infections defined as 
infections causing fevers or infections requiring anti-microbial therapy that arise while 
patients are on-study but before the CAR T-cell infusion; however such patients are eligible 
for treatment if they meet all eligibility criteria after the infection resolves.  
•
If a patient experiences a grade 3 or greater toxicity (with the exception of cytopenias 
including neutropenia, lymphopenia, anemia, or thrombocytopenia) while on-study before 
the CAR T-cell infusion, the CAR T-cell infusion must be delayed until the toxicity 
improves to a grade 2 or less. Exceptions to this would be if the grade 3 toxicity was present 
at baseline or related to progressing disease.
3.3
DRUG ADMINISTRATION
3.3.1
Leukapheresis
The patient will undergo a 10-20 liter leukapheresis (generally, 15 liters will be processed to 
target a yield of 6-10 x109 lymphocytes) in the Department of Transfusion Medicine (DTM) 
Dowling Apheresis Clinic according to DTM standard operating procedures.  The procedure 
requires dual venous access, and takes approximately 3-4 hours to complete.  A central line will 
be placed if peripheral venous access is not sufficient. 

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3.3.2
Anti-BCMA-CAR-expressing T-cell preparation
After cells are obtained by apheresis, further cell processing to generate anti-BCMA CAR-
expressing T cells will occur in the DTM according to standard operating procedures (SOPs).  
Either freshly-collected cells or cryopreserved cells can be used to initiate the cell-preparation 
process.  In addition as stated in eligibility criteria, cryopreserved cells stored continuously in the 
Center for Cellular Engineering can be used to prepare autologous clinical cell products on other 
NCI cell therapy protocols, if the future cell therapy is conducted under a different NCI protocol. 
Peripheral blood mononuclear cells will be isolated. Sufficient cells for 2 complete cell 
productions will be retained in the Department of Transfusion Medicine; the excess cells will be 
sent to the Surgery Branch Cell Production Facility SB-CPF. Bldg. 10 3W-3808.  Phone: 240-858-
3755for cryopreservation at 100 to 200 million PBMC per vial.  These cells will be used in 
research. The anti-CD3 monoclonal antibody OKT3 will be used to stimulate T-cell proliferation. 
Two days after the start of the T-cell cultures, the cells will be transduced by exposing them to a 
supernatant containing replication-incompetent gammaretroviruses encoding the anti-BCMA 
CAR.  The cells will continue to proliferate in culture.  The total cell production process will take 
7 to 9 days before cells are cryopreserved.  Ten vials of the infused cells will be cryopreserved and 
stored in the Surgery Branch Cell Production Facility SB-CPF.  Each vial will contain 10-20 
million cells.
Before infusion, the percentage of T cells expressing the anti-BCMA CAR will be determined by 
flow cytometry, and this percentage of BCMA+ T cells will be used in calculating the total number 
of cells to be infused to meet the dose requirements of the dose-escalation plan described in 3.1.4  
In addition to flow cytometry, further testing of the cells will take place prior to infusion to evaluate 
for microbial contamination, replication-competent retroviruses, and viability.  Details of this 
testing can be found in the appropriate DTM SOPs. When a patient is no longer eligible for 
retreatment on this protocol due to meeting any of the off-study criteria listed in section 3.8.2, any 
remaining cryopreserved pretreatment PBMC collected on this protocol will be transferred from 
the Department of Transfusion Medicine to the Principal Investigator of this protocol for storage 
in the Surgery Branch Cell Production Facility SB-CPF. Bldg. 10 3W-3808.  Phone: 240-858-3755 
and possible use in research.  
Note: All cells sent to the Surgery Branch Cell Production facility will be transferred to NCI 
Frederick Biorepository.
3.3.3
Conditioning chemotherapy and anti-BCMA CAR T-cell administration-chemotherapy 
administration can be either inpatient or outpatient
3.3.3.1
Overall summary of the treatment plan
Drug
Dose 
Days
Cyclophosphamide 
300 mg/m2 IV infusion 
over 30 minutes 
Daily x 3 doses on days -5, 
-4, -3
Fludarabine
30 mg/m2 IV infusion over 
30 minutes administered 
immediately following the 
Daily x 3 doses on days -5, 
-4, -3

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Drug
Dose 
Days
cyclophosphamide on day -
5, -4, -3
Anti-BCMA CAR T cells
Variable. 
One time dose on day 0
3.3.3.2
Detailed treatment plan
Day -5, -4, and -3:  Patients will receive pre-hydration with 1000 mL 0.9% sodium chloride I.V. 
over 1 to 3 hours. 
Patients will receive anti-emetics following NIH Clinical Center guidelines, but dexamethasone 
will not be administered.  One suggested regimen is ondansetron 16 to 24 mg orally on days -5, 
-4, and -3 before chemotherapy (I.V. ondansetron can be substituted).    Patients should be provided 
with anti-emetics such as lorazepam and prochlorperazine to use at home.  
On days -5, -4, and -3, cyclophosphamide at a dose of 300 mg/m2 I.V. will be diluted in 100 mL 
5% dextrose solution and infused over 30 minutes.  After the cyclophosphamide on days -5, -4, 
and -3, patients will receive 30 mg/m2 I.V. fludarabine in 100 mL 0.9% sodium chloride over 30 
minutes.  Note: in patients with an estimated creatinine clearance of 30 - 70 
mL/minute/1.73m2, the daily dose of fludarabine will be reduced by 20%.  Creatinine 
clearance will be estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-
EPI) formula.
Following the fludarabine infusion, patients will receive 1000 mL 0.9% sodium chloride I.V. over 
1-2 hours.  Furosemide will be given if needed.  
Days -2 and -1:  No interventions except as needed for general supportive care such as anti-emetics.  
To minimize bladder toxicity, patients should increase normal oral fluid intake to at least 2 L/day.
Day 0:  Anti-BCMA CAR T cells will be administered.  Premedication for the cell infusion will 
be given approximately 30 minutes prior to the infusion.  The premedications are acetaminophen 
650 mg orally and diphenhydramine 12.5 mg IV.  Cells are delivered to the patient care unit from 
the Department of Transfusion Medicine.  Prior to infusion, the cell product identity label is 
double-checked by two authorized staff (MD or RN), and identification of the product and 
documentation of administration are entered in the patient’s chart as is done for blood banking 
protocols.  The cells are to be infused intravenously over 20 to 30 minutes via a central line with 
non-filtered tubing through an INFUSION PUMP, gently agitating the bag during infusion to 
prevent cell clumping.  Cells may arrive on the unit in a syringe instead of a bag.  In this case, the 
cells can be administered to the patient by pushing the cells through a free flowing normal saline 
line per nursing SOP, but still must be infused over 20-30 minutes.  Details of the infusion 
procedure are included in Appendix D (Note: The cell infusion may be delayed up to a day per 
the PI’s discretion)
Days 0 to 9: Mandatory hospitalization for observation and treatment as necessary.  Note:  
hospitalization for CAR T-cell patients is routinely extended; extension of hospitalization beyond 
the required 9 days is anticipated for CAR T cell toxicity management.  In addition, patients are 

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required to stay within 60 minutes driving time from the Clinical Center until day 14 after the CAR 
T-cell infusion.  
Guidelines for dealing with toxicities that often occur after CAR T cell infusions including 
hypotension, fever and tachycardia are given in 15.3.
A CBC with differential will be obtained daily.  If the absolute neutrophil count becomes less than 
500/microliter, filgrastim will be initiated at a dose of 300 micrograms daily subcutaneously for 
patients under 70 kg in weight and at a dose of 480 micrograms daily for patients over 70 kg in 
weight.  Filgrastim will be given daily and then discontinued as soon as the absolute neutrophil 
count recovers to 2000/microliter.
3.3.4
Potential repeat treatment
Patients obtaining any response except progressive disease are potentially eligible for a repeat 
treatment consisting of conditioning chemotherapy followed by an infusion of anti-BCMA CAR 
T cells.  Retreatment will be at least 2 months after the original treatment.  The dose of anti-BCMA 
CAR T cells administered during repeat treatments will be the dose level currently enrolling 
patients receiving initial CAR T-cell infusions.  The repeat treatment will include the same 
conditioning chemotherapy as the initial treatment. 
To be eligible for a repeat treatment, patients must have not experienced a DLT with their first 
treatment.  Patients must also meet the same eligibility requirements listed in Section 2.1.  BCMA 
expression must be documented after the first anti-BCMA CAR infusion and before the second 
BCMA CAR T-cell infusion.  The patients must undergo screening evaluation as listed in Section 
2.2 except infectious disease serology screening is not required to be repeated unless clinically 
indicated.  Follow-up testing for retreatment will be the same as for the first treatment. The patient 
may be re-enrolled on the the study as a new patient to allow this re-treatment and these patients 
will be considered in the total sample size for this study. All patients receiving a second treatment 
will be identified as patients receiving repeat treatments in any reports of results of this trial.  A 
maximum of 2 total treatments can be administered to any one patient, and at least 2 months must 
elapse between the first treatment and the second treatment.  
Second treatments including DLTs will not affect the dose escalation plan described in section 
3.1.4.  DLTs that occur in patients receiving a repeat treatment will not affect the dose escalation 
of patients receiving an initial treatment. However, excessive DLTs among re-treatments will 
result in a discontinuation of this practice. Specifically, if 2 of the first 3 patients re-treated,  3 or 
more of the first 6 re-treated patients, 4 or more out of the first 9 re-treated patients,  or greater 
than 1/3 of the total patients receiving a repeat treatment experiences a DLT during repeat 
treatment, then repeat treatments will be discontinued altogether.
3.4
PROTOCOL EVALUATION
3.4.1
Baseline evaluations and interventions
Bone marrow aspirate and biopsy must be performed within 24 days of the start of the conditioning 
chemotherapy.  If the screening bone marrow aspirate and biopsy were done within 24 days of the 
start of conditioning chemotherapy, the baseline bone marrow aspirate and biopsy should not be 
done unless clinically indicated.  Specifically ask for BCMA, CD3, CD8, and CD4 
immunohistochemistry staining of the bone marrow biopsy.  Order cytogenetics with interphase 
FISH (pretreatment only) and flow cytometry on the bone marrow aspirate. Specifically request 2 

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separate bone holes for bone marrow aspiration.  The aspirate for hemepath (0.5 mL) and flow (2-
2.5 mL) should be done from 1 bone hole and the aspirate for research (2-2.5 mL) should be done 
from a second bone hole followed by an aspirate for cytogenetics (1-2 mL) from the second bone 
hole. Note:  Only bone marrow aspirates done before CAR T-cell treatment and 2 weeks after 
infusion require aspirates throught 2 bone holes.  All other bone marrow aspirates only need to be 
done through 1 bone hole. For all bone marrow aspirates, bone marrow supernatant must be 
collected and frozen in the same manner as serum is collected and frozen.
BCMA immunohistochemical staining was performed using Ventana Ultra automated staining 
system (Ventana, Tucson, AZ) according to manufacturer’s directions.  Incubation in mouseanti-
BCMA primary antibody (Santa Cruz Biotechnology clone D6) was followed by anti-mouse 
secondary antibody incubation.  Flow cytometry on bone marrow aspirates was performed by 
using standard methods and the Santa Cruz Biotechnology clone D6 antibody that is specific for 
BCMA.
The following tests must be completed within 14 days prior to the start of the conditioning 
chemotherapy regimen:
•
Patients must have a central venous access before the time of cell infusion.  This might 
require placement of a non-valved P.I.C.C line or other device.
•
Physical exam with vital signs and oxygen saturation
•
PET-CT scan in all patients
•
CT scans of areas with possible lesions/plasmacytomas.  This may include areas such as 
the head, neck, chest, abdomen and pelvis. (If needed to stage MM) Spine MRI if needed 
to stage MM
•
Skeletal survey.  Additional scans and x-rays may be performed if clinically indicated 
based on patients’ signs and symptoms.
•
Serum immunofixation electrophoresis 
•
250 microgram cosyntropin stimulation test if suspicious for adrenal insufficiency based 
on low serum sodium or high serum potassium or hypotension or a history of adrenal 
insufficiency or low serum cortisol or other clinical indications (This may be performed 
after start of chemotherapy as long it is performed before the cell infusion)
•
24-hour urine collection with immunofixation electrophoresis timed urine
•
24-hour urine collection for urine protein
•
Serum immunoglobulin free light chains 
•
Anti CMV antibody titer, HSV serology, and EBV panel, T cruzi serology, toxoplasmosis 
serology (Note: patients who are known to be positive for any of the above do not need to 
be retested; may be performed within 3 months of chemotherapy start date)
•
Blood will be collected for research purposes.  Draw 12 CPT tubes (8 mL each of blood 
will be collected prior to initiation of the conditioning chemotherapy regimen. This is a 
total of 96 mL of blood. Some of this blood will be used for immunology assays and some 
will be used for RCR assays. This blood can be collected on different days as long as a 

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total of 12 CPT tubes are collected prior to cell initiation of the chemotherapy.  Send to the 
Surgery Branch Cell Production Facility SB-CPF. Bldg. 10 3W-3808.  Phone: 240-858-
3755.
•
In addition to the CPT tubes, draw 16 mL of blood to obtain serum for research purposes 
(2 SST tubes, 8 mL per tube) within 3 days prior to the start of the chemotherapy.  Send to 
the Biospecimen Processing Core (BPC) lab; For sample pick-up, page 102-11964.
The following tests must be completed within 7 days of the start of the conditioning chemotherapy 
regimen:
•
TBNK 
•
Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, Glucose, 
Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total (Mg), Phosphorus, 
Alkaline Phosphatase, ALT, AST, Total Bilirubin, Direct Bilirubin, LDH, Total Protein, 
Total CK (creatine kinase), Uric Acid (to be repeated on  the first day of the chemotherapy 
at the discretion of the PI) 
•
2-microglobulin 
•
ABO typing
•
Ionized calcium
•
CBC with differential and platelet count 
•
PT/PTT
•
Fibrinogen
•
Urinalysis; if results are abnormal, send for urine culture
•
β-HCG pregnancy test (serum or urine) on all women of child-bearing potential
•
C-reactive protein (CRP)
3.4.2
Studies to be performed on Day 0 and during the mandatory 9-day inpatient admission 
after cell infusion
•
Vital signs including pulse oximetry will be monitored q1h x 4  hours (+/- 15 minutes) 
after completion of the CAR T cell infusion and approximately every 4 hours (+/-15 
minutes) otherwise unless otherwise clinically indicated.
•
Daily physical exam
•
CBC twice a day from day 0 until day 9 with differential daily. After day 9 do a CBC with 
differential daily until discharge. (In the case of a later day infusion or early discharge, this 
may be only once a day.)
•
TBNK on the day of CAR T-cell infusion (day 0), day 7 and day 14 after infusion
•
Chemistries twice a day starting from day 0 to day 9.  After day 9 do chemistries once a 
day until discharge: (Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), 
Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total 

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(Mg), Phosphorus, Alkaline Phosphatase, ALT, AST, Total Bilirubin, Direct Bilirubin, 
LDH, Total Protein, Uric Acid, creatine kinase. (In the case of a later day infusion or early 
discharge, this may be only once a day.)
•
PT/PTT  and fibrinogen daily while hospitalized
•
Day 0 Research Blood: 1 SST tube will be drawn on the morning of CAR cell infusion 
prior to infusion of CAR T cells. Send to the BPC lab; for sample pick-up, page 102-11964.
•
Post-infusion Research blood:  Every Monday, Wednesday, and Friday during 
hospitalization, starting on the first Monday, Wednesday, or Friday after the day of CAR 
T-cell infusion and lasting up to 20 days after infusion of anti-BCMA-CAR-transduced T 
cells, 56 mL of patient peripheral blood will be obtained (6 CPT tubes 8 mL each and 1 
SST tube 8 mL). Send CPT tubes to the Surgery Branch Cell Production Facility SB-CPF. 
Bldg. 10 3W-3808.  Phone: 240-858-3755. Send SST tubes to the BPC lab; for sample 
pick-up, page 102-11964. 
•
Additional Post-infusion research blood: 1 SST tube will be drawn on the first Sunday 
after CAR T-cell infusion.  This tube will be stored refrigerated on the nursing unit and 
processed first thing Monday morning at the latest. Send to the BPC lab; For sample pick-
up, page 102-11964. 
Note regarding research blood collection: If any of the above time points fall on federal holiday 
then, we may collect research blood on the  next day.
3.4.3
Post-infusion outpatient evaluation
After completion of therapy the patient will be followed for potential complications related to anti-
BCMA–CAR T-cell infusion. The patient will be seen at the NIH in follow-up to evaluate disease 
status and late problems related to anti-BCMA –CAR T-cell infusion at days +14 (+/- 1 day), +30 
(+/- 5 days), +60(+/- 7 days), +90(+/- 7 days), and +120(+/- 7 days); and at 180(+/- 14 days), 270 
(+/- 14 days), and 365 (+/- 30 days) months  after anti-BCMA –CAR T-cell infusion. After 12 
months, the patient will be seen every 6 months (+/- 30 days) up to five years. All of these time 
points have allowable ranges (see Table in section 3.5). At these times patients will have the 
following tests performed to determine clinical response:
•
6 CPT tubes of Research Blood (48 mL) will be collected to obtain blood for 
immunological testing. Send to the Surgery Branch Cell Production Facility SB-CPF. Bldg. 
10 3W-3808.  Phone: 240-858-3755. 
•
1 SST tube (8 mL) of Research Blood will be obtained for serum collection. Send to the 
BPC lab; For sample pick-up, page 102-11964. 
Note: after the first year of follow-up, research blood will be reduced to 4 CPT tubes 
(32 mL total) during required protocol visits.
•
PET scans will be performed if needed to stage disease as described in section 3.5.
•
CT scans of areas with lesions/plasmacytomas starting 1 month after infusion.  This may 
include areas such as the head, neck, chest, abdomen and pelvis. (Only if a 
plasmacytoma/lesion was detected before treatment)

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•
MRI of spine (Only if a plasmacytoma/lesion was detected before treatment)
•
Physical exam with vital signs and oxygen saturation
•
(Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, 
Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total (Mg), 
Phosphorus, Alkaline Phosphatase, ALT, AST, Total Bilirubin, Direct Bilirubin, LDH, 
Total Protein, Total CK, Uric Acid
•
PT/PTT, fibrinogen
•
TBNK
•
Ionized calcium
•
CBC with differential
•
C-reactive protein (CRP)
•
Blood for serum 2-microglobulin
•
Blood for immunoglobulin free light chains
•
Blood for serum immunofixation electrophoresis 
•
24-hour urine collection with immunofixation electrophoresis timed urine (can be omitted 
if not needed for staging after day 30). 
•
24-hour urine collection with protein timed urine (can be omitted if not needed for staging 
after day 30).
•
Urinalysis: if results are abnormal, send for urine culture 
•
At the 2 week follow-up, bone marrow aspirate and biopsy must be performed.  Aspirate 
must be sent for flow cytometry to the lab of Dr. Maryalice Stetler-Stevenson. BCMA 
staining must be requested for the flow cytometry.  BCMA immunohistochemistry should 
also be requested on the bone marrow biopsy.Specifically ask for BCMA, CD3, CD8, and 
CD4 immunohistochemistry staining of the bone marrow biopsy.  Specifically request 2 
separate bone holes for bone marrow aspiration.  The aspirate for hemepath (0.5 mL) and 
flow (2-2.5 mL) should be done from 1 bone hole and the aspirate for research (2-2.5 mL) 
should be done from a second bone hole. 
•
At 2 week follow-up, a peripheral blood sample will be collected. Peripheral blood must 
be  sent for flow cytometry analysis to the lab of Dr. Maryalice Stetler-Stevenson to 
evaluate for malignant plasma cells, the BCMA expression on any malignant plasma cells 
present and CAR positive T cells. 
•
At the 2 month follow-up, a bone marrow aspirate and biopsy will be collected.  Aspirate 
must be sent for flow cytometry to the lab of Dr. Maryalice Stetler-Stevenson.  BCMA 
staining must be requested for the flow cytometry.  BCMA immunohistochemistry should 
also be requested on the bone marrow biopsy.  This may also be performed at day +30 if 
clinically indicated.  Specifically ask for BCMA, CD3, CD8, and CD4 
immunohistochemistry staining of the bone marrow biopsy.  The aspirate for hemepath 
(0.5 mL), flow (2-2.5 mL) and research (2-2.5 mL) can be done from 1 bone hole.

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•
At the 6-month, 18-month, 30 -month, and 42-month follow-up appointments, a bone 
marrow aspirate and biopsy will be performed.  Aspirate must be sent for flow cytometry 
to the lab of Dr. Maryalice   Stetler-Stevenson.  BCMA staining must be requested for the 
flow cytometry.  BCMA immunohistochemistry should also be requested on the bone 
marrow biopsy.  Specifically ask for BCMA, CD3, CD8, and CD4 immunohistochemistry 
staining of the bone marrow biopsy.  The aspirate for hemepath (0.5 mL), flow (2-2.5 mL) 
and research (2-2.5 mL) can be done from 1 bone hole.
•
For each bone marrow aspirate performed, send one tube of bone marrow aspirate to 
Surgery Branch Cell Production Facility SB-CPF. Bldg. 10 3W-3808.  Phone: 240-858-
3755.  Bone marrow cells should be cryopreserved and the liquid bone marrow supernatant 
should also be saved at -80 degrees. As many vials as possible with 10 million cells or less 
will be cryopreserved, and 2 vials of supernatant with 0.5 to 1 mL each will be 
cryopreserved.
•
Gene-therapy-specific follow-up must be carried out as described in section 3.6

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3.5
STUDY CALENDAR
Follow up
Procedures a
Screening/
Baseline
Pre-cell infusion/ 
Day 0
Day 
+7b
Day+14 
(+- 1 
day) and  
Day+30 
(+/- 5 
days)
Day 
+60 
(+/- 7 
days)
Day 
+90 
(+/- 7 
days)
Day 
+120 
(+/- 7 
days)
Day 
+180 
(+/- 14 
days)
Day 
+270 
(+/- 14 
days)
Day 
+365 
(+/- 30 
days)
Every 6 months 
after day 365(+/- 
30 days) up to 5 
years
Clinical Assessments
History and PE
X
X
X
X
X
X
X
X
X
X
X
Vital signs, O2 saturationo
X
X
X
X
X
X
X
X
X
X
X
Height, weight
Xs
Xs
Performance Score
X
X
Laboratory Assessments
CBC with differential 
X
X
X
X
X
X
X
X
X
X
X
Sodium, Potassium 
Chloride, CO2, 
Creatinine, Glucose, BUN, 
Albumin, Calcium, 
Magnesium, Phosphorus, 
Alkaline Phosphatase, 
ALT, AST, T. Bilirubin, D. 
Bilirubin, LDH, Total 
Protein, CK, Uric Acid
X
X
X
X
X
X
X
X
X
X
X
Serum C-reactive peptide
Xh
Xm
Xm
X
X
X
X
X
X
X
X
PT/PTT, Fibrinogen
Xh
X
X
X
X
X
X
X
X
X
Ionized calcium
Xh
X
X
X
X
X
X
X
X
Thyroid Stimulating 
Hormone, T3
XK

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Follow up
Procedures a
Screening/
Baseline
Pre-cell infusion/ 
Day 0
Day 
+7b
Day+14 
(+- 1 
day) and  
Day+30 
(+/- 5 
days)
Day 
+60 
(+/- 7 
days)
Day 
+90 
(+/- 7 
days)
Day 
+120 
(+/- 7 
days)
Day 
+180 
(+/- 14 
days)
Day 
+270 
(+/- 14 
days)
Day 
+365 
(+/- 30 
days)
Every 6 months 
after day 365(+/- 
30 days) up to 5 
years
2-HCG (serum or urine 
in women of childbearing 
potential)
X
2-microglobulin
Xh
X
X
X
X
X
X
X
X
Anti-CMV, HSV, EBV, 
T.cruzi,toxoplasma
Xh,j
Antibody screen for 
Hepatitis B and C; HIV, 
HTLV-I/II, West Nile, and 
syphilis (RPR)
X
TBNK 
Xh
X
X
X
X
X
X
X
X
X
X
G6PD
XK
Urinalysis (culture prn)
Xh
X
X
X
X
X
X
X
X
24 hr urine with 
immunofixation 
electrophoresis timed 
urine and urine 24 hour 
protein
Xh
X
Xf
Xf
Xf
Xf
Xf
Xf
Xf
ABO typing
Xh
Serum immunoglobulin 
free light chains 
X
X
X
X
X
X
X
X
X
Serum immunofixation 
electrophoresis
X
X
X
X
X
X
X
X
X

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Follow up
Procedures a
Screening/
Baseline
Pre-cell infusion/ 
Day 0
Day 
+7b
Day+14 
(+- 1 
day) and  
Day+30 
(+/- 5 
days)
Day 
+60 
(+/- 7 
days)
Day 
+90 
(+/- 7 
days)
Day 
+120 
(+/- 7 
days)
Day 
+180 
(+/- 14 
days)
Day 
+270 
(+/- 14 
days)
Day 
+365 
(+/- 30 
days)
Every 6 months 
after day 365(+/- 
30 days) up to 5 
years
Peripheral blood flow 
cytometry
Xt
Radiological Assessments
Skeletal Survey  
X
CT scan of disease 
affected areas 
Xu
Xi,e
Xe
Xe
Xe
Xe
Xe
Xe
Xe
PET 
Xh
Xf
Xf
Xf
Xf
Xf
Brain MRI
X
Spine MRI e
X
X e
X e
X e
X e
X e
X e
X e
X e
Other Specific Assessments
Serum Cortisol
Xk
250 microgram 
cosyntropin test c
Xh
EKG, echocardiogram
X
RCR
X
X
X
X
Xg
Central Venous catheter 
placement
X
Venous Assessment
X
Response Evaluation
Bone marrow 
aspirate/biopsy d, q 
X
Xl
X
X
Xv
Research Blood n. p. r
X h
Xn
X
X
X
X
X
X
X
X
X

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Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
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Follow up
Procedures a
Screening/
Baseline
Pre-cell infusion/ 
Day 0
Day 
+7b
Day+14 
(+- 1 
day) and  
Day+30 
(+/- 5 
days)
Day 
+60 
(+/- 7 
days)
Day 
+90 
(+/- 7 
days)
Day 
+120 
(+/- 7 
days)
Day 
+180 
(+/- 14 
days)
Day 
+270 
(+/- 14 
days)
Day 
+365 
(+/- 30 
days)
Every 6 months 
after day 365(+/- 
30 days) up to 5 
years
Adverse Events
     X
X
X
X
X
X
X
X
X
X
Concomitant Medications 
X
     X
X
X
X
X
X
X
X
X
X
a see section 2.2 and section 3.3.1 for details
b see section 3.4.2 for details of testing during hospitalization
c only if cortisol<18 mg/dL or clinical suspicion of adrenal insufficiency
d bone marrow biopsy will include flow cytometry, BCMA expression, cytogenetics (pretreatment bone marrow aspirate only), amyloid staining 
(pretreatment bone marrow biopsy only), and molecular studies of each sample.
e Only if a plasmacytoma/lesion was detected before treatment
f  if useful for response assessment
g RCR blood collection will only continue after the 1 year time-point if a previous RCR test has been positive, see section 3.6 for details
h     required at baseline, only needed at screening if needed to evaluate disease..
i only D+30, no CTs or PETs indicated at D+14
j Patients who are known to be positive for any of these tests do not need to be retested; may be performed within 3 months of chemotherapy start 
date
k only at Screening
l Always do a bone marrow aspirate and biopsy on day 14; only do a bone marrow aspirate and biopsy on Day  30 if clinically indicated. 
Additional bone marrow biopsies and aspirates might be needed if clinically indicated due to low blood counts or for myeloma response 
assessment.
m Done Daily during hositalization
nIn addition to  baseline research blood, 1 SST tube must be drawn on the morning of CAR T-cell infusion prior to  CAR T-cell infusion
o +/- 15 minutes
 pDraw 1 SST tube on the first Sunday after CAR T-cell infusion.  This SST tube should be stored refrigerated on the nursing unit until Monday 
morning when it should be processed first thing Monday morning at the latest.

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qA bone marrow aspirate and biopsy with flow cytometry will also be performed to confirm suspected complete remission. Note that 2 separate 
bone holes will be required for the pretreatment and 2-week follow-up bone marrow aspirates. All other bone marrow aspirates will only require 1 
bone hole.
r In addition to the day 0 and 1st Sunday research blood mentioned above, research blood is drawn every Mon-Wed-Fri while the patient is 
inpatient.
sWeight at admission is adequate even if not D0.  Height is only required to be performed sometime before starting chemotherapy.
t only D+14
u only if needed to stage MM
v Bone marrow aspirate and biopsy with flow cytometry will be perfomed at the 6-month, 18-month, 30-month, and 42- month time-
points

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3.6
GENE-THERAPY-SPECIFIC FOLLOW-UP 
•
Long-term follow up of patients receiving gene transfer is required by the FDA and must 
continue even after the patient comes off the treatment study.  Physical examinations will 
be performed and documented annually for 5 years following cell infusion to evaluate long-
term safety.  After 5 years, health status data will be obtained from surviving patients via 
telephone contact or mailed questionnaires for 10 additional years for a total of 15 years 
after cell infusion.  Blood will need to be collected at least annually for long-term follow-
up of gene therapy. After 5 years, patients who are still on this study will be transferred to 
the long-term gene therapy protocol NCI protocol 15-C-0141 to complete long-term gene-
therapy follow-up.
•
Persistence of CAR transduced cells will be assessed by quantitative PCR and/or flow 
cytometry at 1, 2, 3, 4, 6 and 12 months after cell infusion, or until CAR-expressing cells 
are no longer detectable.  If any patient shows a high level of persistence of CAR gene 
transduced cells or an increasing population of CAR gene transduced T cells at month 6 or 
later (by FACS staining or qPCR), the previously archived samples will be subjected to 
techniques that would allow the identification of predominant clonal populations of  
transduced cells.
•
Patients’ blood samples will be obtained and undergo analysis for detection of replication 
competent retroviruses (RCR) by PCR prior to cell infusion and at 3, 6, and 12 months post 
cell administration.  If all of these samples are negative for RCR, blood collection for RCR 
will be discontinued after the 12 month time-point..
•
S+L- culture-based replication-competent retrovirus testing will be conducted on the 
infusion CAR T cells of all patients
3.7
COST AND COMPENSATION 
3.7.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not covered 
by insurance company.  Medicines that are not part of the study treatment will not be provided or 
paid for by the NIH Clinical Center.    
3.7.2
Compensation
Participants will not be compensated on this study.
3.7.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the participant as 
appropriate.  The amount and form of these payments are determined by the NCI Travel and 
Lodging Reimbursement Policy.

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3.8
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to documenting removal from study, effort must be made to have all subjects complete a 
safety visit approximately 30 days after the last dose of study therapy.
3.8.1
Criteria for removal from protocol therapy
Note that the treatment consists of a conditioning chemotherapy regimen followed by a T-cell 
infusion. 
Patients will be taken off treatment for the following:
•
Any DLT makes patients ineligible for repeat treatments.
•
The patient no longer meets the eligibility criteria for the protocol after enrolling but before 
start of the chemotherapy conditioning regimen.  If the reason that the patient is not eligible 
can be rapidly resolved within 2 weeks, the patient can proceed on treatment for up to two 
weeks, otherwise the patient must come off treatment and then off study as appropriate. An 
exception to this is that a platelet count of 50,000 or more is considered adequate to start 
chemotherapy.
•
The patient started chemotherapy but cannot complete the entire treatment (ending with 
completed cell infusion) for any reason specified in the protocol or PI discretion.  If the 
reason that the patient is no longer eligible can be rapidly resolved, the patient can proceed 
on treatment, otherwise the patient must come off treatment and then off study as 
appropriate.  
•
The patient receives any other treatment for multiple myeloma except bisphosphonates and 
repeat treatment on this protocol.  Bisphosphonates are allowed when administered to 
prevent osteopenia more than 2 months after the anti-BCMA-CAR T-cell infusion.  
•
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment on this study in the judgment of the investigator.
•
Participant requests to be withdrawn from active therapy
•
Investigator discretion
•
Positive pregnancy test
3.8.2
Off-Study Criteria
Patients will be taken off study for the following: (all patients coming off study will enroll on the 
long-term gene therapy follow-up protocol 15-c-0141)
•
The patient completes the study upon reaching 5 years after CAR T-cell infusion.
•
The patient completes off treatment follow-up
•
The patient voluntarily withdraws
•
There is significant patient noncompliance
•
PI discretion
•
Death

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Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
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•
PI decision to end this study 
•
The patient no longer meets the eligibility criteria for the protocol after enrolling but before 
start of the chemotherapy conditioning regimen.
•
Development of progressive or relapsed multiple myeloma after anti-BCMA CAR T cell 
infusion in patients not desiring or not eligible for re-treatment on this protocol.
•
The patient receives any anti-myeloma therapy except bisphosphonates.  Bisphosphonates 
are allowed 2 months or more after the CAR T-cell infusion.
3.9
STOPPING CRITERIA
•
If no responses of PR or CR occur after 2 patients are treated on the highest dose level, the 
protocol will be stopped.
•
Instructions for how to proceed when toxicity occurs will be as instructed by the dose 
escalation section of the protocol.
•
A death on study not attributible to progressive malignancy within 30 days of a cell 
infusion for the initial 5 subjects will be a cause for a pause to accrual pending discussion 
with the FDA and IRB.
•
If 3 or more of the first 9 treated patients experience grade 4 toxicity possibly or probably 
attributable to CAR T cells within 30 days of cell infusion, this will be a cause for a pause 
to accrual to reassess the safety of the product pending amendment of the protocol 
approved/reviewed by the FDA and IRB.
4
CONCOMITANT MEDICATIONS/MEASURES
4.1
ANTIBIOTIC PROPHYLAXIS
•
Patients with a CD4 T-cell count less than 200 will be maintained on pneumocystis 
prophylaxis with atovaquone or inhaled pentamidine.  Patients with a CD4 T-cell count 
less than 200 will also be maintained on acyclovir or valacyclovir.   
Patients with serum IgG level less than 600 mg/dL will receive intravenous 
immunoglobulin replacement as needed to maintain an IgG level above 600 mg/dL after at 
least 1 month post-CAR T-cell infusion.  An example of an intravenous immunoglobulin 
infusion to be used for this purpose would be Gammunex 500 mg/kg given as a single dose.  
Intravenous immunoglobulin infusions should be preceded by premedication with 
diphenhydramine and acetaminophen, and rate of infusion should be started at low rates 
and escalated in a step-wise manner
•
Neutropenic patients will start on broad spectrum antibiotics with a first fever of 38.30C 
or greater or two fevers of 38.0 separated by at least 1 hour and concomitant ANC < 
500/mL. 
•
Aminoglycosides will be avoided unless clear evidence of sepsis.

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4.2
BLOOD PRODUCT SUPPORT
•
Leukocyte filters will be utilized for all blood and platelet transfusions with the exception 
of the CAR-transduced T cell infusions to decrease sensitization to transfused WBC and 
decrease the risk of CMV infection.
•
Patients who are seronegative for CMV should receive CMV-negative blood products 
whenever possible.
•
Using daily CBC’s as a guide, the patient will receive platelets and packed red blood cells 
(PRBC’s) as needed.  Attempts will be made to keep Hgb >8.0 gm/dL, and platelets 
>10,000/mm3.  All blood products with the exception of the CAR-transduced T cells will 
be irradiated.  Leukocyte filters will be utilized for all PRBC and platelet transfusions to 
decrease sensitization to transfused WBC’s and decrease the risk of CMV infection.
4.3
ANTI-EMETICS
Anti-emetics will follow NIH Clinical Center Guidelines (except that corticosteroids will be 
avoided). 
4.4
GRANULOCYTE COLONY-STIMULATING FACTOR
A CBC will be obtained daily while the patient is inpatient.  If the absolute neutrophil count 
becomes less than 500/microliter, Filgrastim will be initiated at a dose of 300 micrograms daily 
for patients under 70 kg in weight and a dose of 480 micrograms daily for patients over 70 kg in 
weight only in patients with absolute neutrophil counts less than 500/microliter.  Filgrastim will 
be discontinued as soon as the absolute neutrophil count recovers to 2000/microliter.
4.5
AVOIDANCE OF CORTICOSTEROIDS
Patients should not take corticosteroids including prednisone, dexamethasone or any other 
corticosteroid at a dose equivalent to 5 mg/day or more of prednisone for any purpose without 
approval of the Principal Investigator.
4.6
TOXICITY MANAGEMENT GUIDLINES
Guidelines for management of common CAR toxicities including cytokine release syndrome 
(CRS) and neurologic toxicity are in section 15.3.
5
BIOSPECIMEN COLLECTION
Biospecimen collection on this protocol will consist of blood draws and acquisition of bone 
marrow aspirates and possible biopsies of plasmacytomas for research purposes.  Blood and bone 
marrow collection is described above in Sections 2.2, 3.4, and 3.5.
5.1
CORRELATIVE STUDIES FOR RESEARCH
Note regarding research Biospecimen collection: If any of the below time points fall on a federal 
holiday then, we may collect research blood on the  next day.
Note: Platforms and procedures for analysis may be adjusted based upon current technology and/or 
collaborations in place at the time of actual analyses.

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5.1.1
Biospecimen collection before the start of the conditioning chemotherapy:
•
One heparinized syringe containing 2-2.5 mL of bone marrow aspirate to be sent to the 
Surgery Branch Cell Production Facility SB-CPF, Bldg. 10 3W-3808, Phone: 240-858-
3755. It will be used in functional assays to see if anti-BCMA-CAR T cells can recognize 
the patient’s multiple myeloma cells. 
•
Blood will be collected for research purposes.  A total of 12 CPT tubes (8 mL each of blood 
will be collected prior to initiation of the conditioning chemotherapy regimen. This is a 
total of 96 mL of blood. Some of this blood will be used for immunology assays and some 
will be used for RCR assays. This blood can be collected on different days as long as a 
total of 12 CPT tubes are collected prior to the start of the chemotherapy and within 14 
days of the start of the chemotherapy.  Send to the Surgery Branch Cell Production Facility 
SB-CPF, Bldg. 10 3W-3808, Phone: 240-858-3755
•
16 mL of blood will be drawn to obtain serum for research purposes (2 SST tubes, 8 mL 
per tube) within 14 days prior to the start of the chemotherapy.  Send to the BPC lab.
•
An apheresis is required to obtain cells used to prepare the anti-BCMA CAR T cells that 
are administered on this protocol.  After sufficient cells are processed for all possible 
clinical needs, the left over apheresis cells can be cryopreserved for research use.  Note 
that these cells would simply be discarded if not used for research. 
•
Specimens will be cryopreserved and assays will be performed retrospectively.
5.1.2
Biospecimen collection Day 0 and after anti-BCMA-CAR T-cell infusion during the 
required hospitalization
Every Monday, Wednesday, and Friday during hospitalization, starting on the first Monday, 
Wednesday, or Friday after the CAR T-cell infusion and lasting up until 14 days after infusion of 
anti-BCMA-CAR-transduced T cells, 56 mL of patient peripheral blood will be obtained (6 CPT 
tubes 8 mL each and 1 SST tube 8 mL). Also, 1 SST tube (8 mL) will be drawn on the morning of 
CAR cell infusion prior to infusion of CAR T cells. 1 SST tube (8 mL) will be drawn on the first 
Sunday after CAR T-cell infusion. The 1 SST tube will be sent to BPC  The 6 CPT tubes sent to 
Surgery Branch Cell Production Facility SB-CPF, Bldg. 10 3W-3808, Phone: 240-858-3755. 
•
Additional research blood may be collected at any time during the clinical course at the 
discretion of the PI (within the volume restriction limits) allowing for the research studies 
already outlined in this protocol to be performed at the time of an unanticipated clinical 
event, if necessary to address the objectives of the study.
5.1.3
Biospecimen collection during outpatient follow-up
•
Patients will return for outpatient follow-up clinic visits 2 weeks, 1 month, 2  months, 3 
months, 4 months, 6 months, 9 months and 12 months after the anti-BCMA- CAR T-cell 
infusion. After the 12-month follow-up appointment patients will return for follow-up 
every 6 months.  The specimens listed below will be performed at each outpatient clinic 
visit during the first year of follow up.
➢6 CPT tubes of Research Blood (48 mL) will be collected to obtain blood for 
immunological testing. Send CPT tubes to Surgery Branch Cell Production Facility 
SB-CPF, Bldg. 10 3W-3808, Phone: 240-858-3755. 

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➢1 SST tube (8 mL) of Research Blood will be obtained for serum collection.  The 
SST tubes will be sent to BPC.
NOTE: After 1 year research blood collected will be reduced to 4 CPT tubes at each visit.
•
At the 2 week, 2 month and 6 month, 18 month, 30 month and 42 month follow-ups, bone 
marrow aspirate and biopsy will be performed and the aspirate will be cryopreserved.  
5.1.4
Immunological Testing
•
T-cell assays: Direct immunological monitoring will consist of quantifying CD3+ T cells 
that express the anti-BCMA CAR by quantitative PCR, and/or by flow cytometry.  These 
assays will be performed to measure the persistence and estimate the proliferation of the 
infused CAR+ T cells.  A quantitative PCR assay or a flow cytometry assay will be used 
to quantitate CAR+ T cells at all post-infusion time-points up to at least 3 to 6 months after 
infusion, and CAR+ T cell analysis will continue until the CAR+ T cell level drops to 
undetectable levels unless a stable low level of CAR+ T cells is present at more than a year 
after infusion.  The absolute number of CAR+ PBMC will be estimated by multiplying the 
percentage of CAR+ PBMC by the absolute number of lymphocytes plus monoctyes per 
microliter of blood.  Ex vivo immunological assays will be used to measure the BCMA-
specific functional activity of the CAR+ T cells and will consist of assays such as 
intracellular cytokine staining and anti-CD107a degranulation assays. Immunological 
assays will be standardized by the inclusion of pre-infusion recipient PBMC and in some 
cases an aliquot of the engineered T cells cryopreserved at the time of infusion. 
•
Studies of patient T-cell and antibody immune responses against the CAR will be carried 
out.
•
Serum cytokine levels will also be measured by enzyme-linked immune sorbent assays. 
•
Gene expression studies might be performed on patient multiple myeloma cells and on the 
infusion CAR T cells of each patient.  Methods used will be either Nanostring and/or 
RNAseq (RNA sequencing).
•
Patients’ blood samples will be obtained and undergo analysis for detection of replication 
competent retroviruses (RCR) by PCR prior to cell infusion and at 3 and 6 months, and 
at one year post cell administration. Monitoring for RCR will be discontinued if all 
patient samples have been negative for RCR at the 12 month time-point .. If any post-
treatment samples are positive, further analysis of the RCR and more extensive patient 
follow-up will be undertaken, in consultation with the FDA.   RCR PCR assays detect the 
Gibbon Ape Leukemia Virus (GALV) envelop gene and are performed under contract by 
the National Gene Vector Laboratory at Indiana University  The results of these tests are 
maintained by the contractor performing the RCR tests and by the Surgery Branch (SB) 
research team.
•
Due to nature of these studies, it is expected that expansion of specific T-cell clones will 
be observed as T-cell proliferate in response to the targeted antigen.  Therefore, care will 
be taken to track T-cell persistence, but presence of an oligoclonal T cell population does 
not indicate an insertional mutagenesis event.    If any patient shows a high level of 
persistence of CAR gene transduced cells or an increasing population of CAR gene 

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transduced T cells at month 6 or later (by FACS staining or qPCR), the previously archived 
samples will be subjected to techniques that would allow the identification of predominant 
clonal populations of  transduced cells.  Such techniques may include T cell cloning or 
LAM-PCR.  If a predominant or monoclonal T cell clone derived from CAR gene 
transduced cells is identified during the follow-up, the integration site and sequence will 
be identified and subsequently analyzed against human genome database to determine 
whether the sequences are associated with any known human cancers.  If a predominant 
integration site is observed, the T cell cloning or LAM-PCR test will be used at an interval 
of no more than three months after the first observation to see if the clone persists or is 
transient.  In all instances where monoclonality is persistent and particularly in instances 
where there is expansion of the clone, regardless of whether or not the sequence is known 
to be associated with a known human cancer, the subject should be monitored closely for 
signs of malignancy, so that treatment, if available, may be initiated early.
5.1.5
Additional biopsies and additional blood draws
Patients might be asked to undergo biopsies or additional blood draws as clinically indicated. 
Additional blood draws might be necessary to investigate T cell responses and serum cytokine 
levels in cases of clinical events such as rapid regressions of malignancy or toxicity.  .  These 
biopsies will only be performed if minimal morbidity is expected based on the procedure 
performed and the granulocyte and platelet count.  Biopsy tissue will be processed in the NCI 
Laboratory of Pathology. Remainder material from such biopsies studies will be performed to 
evaluate the antigen expression by the tumor and to evaluate the reactivity of lymphocyte from 
these biopsies. In addition the presence of transduced cells may be quantitated.
5.1.6
Future studies 
Blood and tissue specimens collected in the course of this research project may be banked and 
used in the future to investigate new scientific questions related to this study the patient provides 
consent for this. However, this research may only be done if the risks of the new questions were 
covered in the consent document. If new risks are associated with the research (e.g. analysis of 
germ line genetic mutations) a protocol amendment will be required and informed consent will be 
obtained from all research subjects to whom these new studies and risks pertain. 
5.2
SAMPLE STORAGE, TRACKING AND DISPOSITION
5.2.1
Sample Tracking and Processing
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. All 
samples will be sent to Biospecimen Processing Core (BPC) and/or SB-CPF for processing and/or 
and storage until they are distributed to the designated place of analysis as described in the 
protocol. Samples will not be sent outside NIH without appropriate approvals and/or agreements, 
if required. 
5.2.1.1
Biospecimen Processing Core (BPC) 
5.2.1.1.1 Samples Sent to the BPC Lab
•
Venous blood samples will be collected in either a 4-mL or an 8-mL SST tube to be 
processed for serum and stored for future research. 

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o
Record the date and exact time of draw on the tube. Blood tubes may be kept in the 
refrigerator until pick-up. 
After delivery to the SB-CPF, peripheral blood mononuclear cell samples will be sent to the Head, 
Clinical Support Laboratory Clinical Services Program, Applied/Developmental Directorate 
Frederick National Laboratory for Cancer Research for processing and cryopreservation. They will 
be stored long-term at the NCI Frederick Repository.
5.2.1.1.2 BPC Contact Information 
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main BPC number) or, if no answer, 240-760-6190 (main 
clinical pharmacology lab number).
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.
5.2.2
Sample Storage and Disposition
All samples sent to the Biospecimen Processing Core (BPC) will be barcoded, with data entered 
and stored in the Labmatrix utilized by the BPC. This is a secure program, with access to Labmatrix 
limited to defined BPC lab personnel, who are issued individual user accounts. Installation of 
Labmatrix is limited to specified computers . These computers all have a password restricted login 
screen. 
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without Labmatrix access. Data will be  recorded for each sample as applicable 
(e.g.  the patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, 
material type, as well as box and freezer location). Patient demographics associated with the 
clinical center patient number are provided in the system. For each sample, there are notes 
associated with the processing method (delay in sample processing, storage conditions on the ward, 
etc.). 
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
Labmatrix. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables.
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80°C according 
to stability requirements. These freezers are located onsite in the BPC and offsite at NCI Frederick 
Central Repository Services in Frederick, MD. Visitors to the laboratory are required to be 
accompanied by laboratory staff at all times. 
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked inLabmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB-approved protocol) and that any unused samples 

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must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to ensure that 
the samples requested are being used in a manner consistent with IRB approval. 
5.2.2.1
Sample Storage, Tracking, and Disposition for Surgery Branch
Samples received by the Surgery Branch research lab will be tracked using password protected 
web-based NCI database Labmatrix. All specimens will be tracked for date of receipt in the 
Surgery Branch lab, date analyzed, date returned to the originating hospital and/or date destroyed. 
Specimens will be stored in a locked laboratory cabinet or refrigerators in a locked research lab. 
All specimens will be entered into Labmatrix with identification and storage location. Access to 
the stored specimens will be restricted. Access to Labmatrix will be granted upon PI approval only. 
It is the responsibility of the NCI PI to ensure that the specimens are being used and stored in a 
manner consistent with IRB approval. All samples are stored in monitored freezers/refrigerators 
in 3NW NCI-SB laboratories at specified temperatures with alarm systems in place.
5.2.3
Protocol Completion/Sample Destruction
Any specimens remaining at the completion of the protocol will be stored indefinitely in the 
conditions described above. The study will remain open so long as sample or data analysis 
continues. All samples and data from consenting participants will be stored in identifiable format 
until they are no longer of scientific value or if a participant withdraws consent for their continued 
use, at which time they will be destroyed. 
If, at any time, a participant withdraws from the study and does not wish for their existing samples 
to be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed or returned to the participant if so requested. The participant’s samples 
and data will be excluded from future distributions, but those which have already been distributed 
for approved research use will not be able to be retrieved. 
The PI will record any loss or unanticipated destruction of samples as a deviation. Reports will be 
made per the requirements of section 7.2.
5.3
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
Samples for gene expression analysis will use RNAseq and/or NanostringTM.  These studies will 
be used to determine gene expression in multiple myeloma cells and infusion CAR T cells.  The 
purpose of these studies is to assess gene expression at the RNA level not to study germline 
mutations.
5.3.1
Description of the scope of genetic/genomic analysis
RNAseq and/or NanostringTM will be used to determine gene expression in multiple myeloma cells 
and infusion CAR T cells.  The purpose of these studies is to assess gene expression at the RNA 
level not to study germline mutations.  One purpose of these studies is to determine if different 
levels of gene expression in malignant cells are associated with response to CAR T-cell therapy.  
Another purpose of these studies is to determine if different levels of gene expression in infusion 
CAR T cells are associated with anti-malignancy responses caused by CAR T cells or persistence 
of CAR T cells.

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5.3.2
Certificate of Confidentiality 
As part of study efforts to provide confidentiality of subject information, this study has obtained a 
Certificate of Confidentiality, which helps to protect personally identifiable research information. 
The Certificate of Confidentiality allows investigators on this trial to refuse to disclose identifying 
information related to the research participants, should such disclosure have adverse consequences 
for subjects or damage their financial standing, employability, insurability or reputation. The 
informed consent includes the appropriate coverage and restrictions of the Certificate of 
Confidentiality.
5.3.3
Management of Results
The analysis that we perform in our laboratory are for research purposes only; they are not nearly 
as sensitive as the tests that are performed in a laboratory that is certified to perform genetic testing. 
Changes that we observe unrelated to our research may or may not be valid. Therefore, we do not 
plan to inform participants of the results of testing on the tissue and blood that is performed in our 
research lab. However, subjects will be contacted if a clinically actionable gene variant is 
discovered. Clinically actionable findings for the purpose of this study are defined as disorders 
appearing in the American College of Medical Genetics and Genomics recommendations for the 
return of incidental findings that is current at the time of primary analysis. (A list of current 
guidelines 
is 
maintained 
on 
the 
CCR 
intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists) Subjects will 
be contacted at this time with a request to provide a blood sample to be sent to a CLIA certified 
laboratory. The CLIA testing may be funded by the PI or the CCR. If the research findings are 
verified in the CLIA certified lab, the subject will be referred to the NCI Genetics Branch for 
genetic counseling on the implications of the results. Subjects that do not wish to return to the NCI 
will be referred to a local genetics health care provider (at their expense). 
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis. 
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
Data will be prospectively collected and entered into a 21 CFR Part 11-compliant data capture 
system provided by the NCI CCR and ensuring data accuracy, consistency and timeliness. The 
NCI PI, research nurse, and designated members of the research team will have access to these 
data via web access. The principal investigator, associate investigators/research nurses and/or a 
contracted data manager will assist with the data management efforts. Primary and final analyzed 
data will have identifiers so that research data can be attributed to an individual human subject 
participant. 
The medical record will maintain complete records on each patient including any pertinent 
supplementary information obtained from outside laboratories, outside hospitals, radiology 
reports, laboratory reports, or other patient records. The NCI study database will serve as the 
primary source from which all research analyses will be performed.  

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Data collection will include the patient history, specialty forms for pathology, radiology, toxicity 
monitoring, and relapse data and an off-study summary sheet, including a final assessment by the 
treating physician. 
All AEs, will be followed until return to baseline or stabilization of event. 
Document AEs from the first study intervention, Study Day 1, through 30 days after the study 
treatment was last administered. Beyond 30 days after the last intervention, only adverse events 
which are serious and related to the study intervention need to be recorded, unless otherwise noted 
in Section 6.1.1.
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred this will be reported expeditiously per 
requirements in section 7.2.1. 
6.1.1
Adverse event recording
•
Grade 1 adverse events will not be recorded.
•
All Grade 2 events will be recorded regardless of attribution up to at least 30 days after 
CAR T-cell infusion
•
After 30 days after CAR T-cell infusion Grade 2 adverse events that will be recorded:
a.
Unexpected events that are possibly, probably, or definitely related to the research.
b. Expected events that are probably or definitely related to the study interventions 
will be recorded only for the first year after the infusion.
c.
All Infections proven by culture, PCR, antigen detection or other laboratory 
methods will be recorded for the first year after infusion regardless of attribution.
d. Any serious events that are deemed clinically significant by the PI
•
All grade 3, 4, and 5 adverse events will be recorded regardless of attribution.
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
I will share human data generated in this research for future research as follows:
  x__ Coded, linked data in an NIH-funded or approved public repository.  
_x__ Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
_x__ Coded, linked or identified data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 
Data will be shared through:
  x__ An NIH-funded or approved public repository.  Insert name or names: ClinicalTrials.gov.
_x__ BTRIS (automatic for activities in the Clinical Center)

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_x__ Approved outside collaborators under appropriate individual agreements.
_x__ Publication and/or public presentations.
When will the data be shared
_x__ Before publication.
_x__ At the time of publication or shortly thereafter.
6.3
GENOMIC DATA SHARING PLAN
Unlinked genomic data will be deposited in the database of genotypes and phenotypes (dbGaP) in 
compliance with the NIH Genomic Data Sharing Policy.
6.4
 RESPONSE CRITERIA
Responses will be categorized by using the International Uniform Response Criteria for Multiple 
myeloma 2016 updated version.111  Multiple myeloma staging will be conducted at the 2 week 
follow-up appointment and at each subsequent follow-up appointment.  The appropriate staging 
studies will need to be determined for each patient because of the variability in multiple myeloma.   
6.4.1
Important Considerations on response criteria
•
Response criteria for all categories and subcategories of response except CR and sCR are 
applicable only to patients who have ‘measurable’ disease by at least one of the three 
measurements as defined below
•
All responses must be confirmed to be stable in two evaluations made at any time.
6.4.1.1
Definition of measurable disease16
Any one or combination of these abnormalities defines measurable disease:
•
Serum M-protein greater or equal to  1.0 g/dL (10 g/L). 
•
Urine M-protein is greater or equal to 200 mg/24 h.
•
Serum FLC assay: Involving FLC level greater or equal to10 mg/dL (100 mg/L) 
provided serum FLC ratio is abnormal.
•
Presence of a biopsy-proven plasmacytoma
•
Bone marrow plasma cells >30% of total bone marrow cells
6.4.1.2
Laboratory tests for measurement of M-protein
•
Serum M-protein level is quantitated using densitometry on SPEP except in cases where 
the SPEP is felt to be unreliable such as in patients with IgA monoclonal proteins migrating 
in the beta region.  If SPEP is not available or felt to be unreliable (e.g., in some cases of 
IgA myeloma) for routine M-protein quantitation during therapy, then quantitative 
immunoglobulin levels on nephelometry or urbidometry can be accepted.  However, this 
must be explicitly reported, and only nephelometry can be used for that patient to assess 
response and SPEP and nephelometric values cannot be used interchangeably.

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•
Urine M-protein measurement is estimated using 24-h UPEP only.  (Random or 24 h urine 
tests measuring kappa and lambda light chain levels are not reliable and are not 
recommended)
6.4.1.3
Suggested follow-up to meet response criteria 
•
Patients with measurable disease by both SPEP and UPEP need to be followed by both 
SPEP and UPEP for response assessment and categorization;
•
Except for assessment of sCR, CR, and VGPR, patients with “measurable disease” 
restricted to the SPEP will need to be followed routinely only by SPEP; 
•
Patients with “measurable disease” restricted to the UPEP will need to be followed 
routinely only by UPEP;
•
Patients with “measurable disease” in either SPEP or UPEP or both will be assessed for 
response only based on these two tests and not by the FLC assay; 
•
FLC response criteria are only applicable to patients without measurable disease in the 
serum or urine, and to fulfill the requirements of the category of sCR; 
•
Bone marrow is required only for categorization of CR  
•
 For good clinical practice patients should be periodically screened for light chain escape 
with UPEP or serum FLC assay.
•
Plasmacytomas can be staged at baseline and followed for response with CT scans by 
measuring target lesions with the sums of the products of the diameters method. For 
purposes of defining CR, masses greater than 2.0 cm will be considered abnormal.
6.4.2
International Myeloma Working Group uniform response criteria: 
6.4.2.1
Stringent Complete Remission (sCR)
•
CR as defined below plus
o
Normal FLC ratio and
o
Absence of clonal cells in bone marrow by immunohistochemistry or 
immunofluorescence or flow cytometry (only1 bone marrow evaluation is needed).
6.4.2.2
Complete Remission (CR) 
•
Negative immunofixation on the serum and urine and 
•
Disappearance of any soft tissue plasmacytomas and
•
5% or less plasma cells in bone marrow  (only 1 bone marrow evaluation is needed)
•
No evidence of progressive or new bone lesions if radiographic studies were performed
(X-Rays not required in absence of clinical indication)
Comments: To be considered a CR, 
•
Both serum and urine immunofixation must be carried out and be negative regardless of 
the size of baseline M-protein in the serum or urine; 

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•
Patients with negative UPEP values pretreatment still require UPEP testing to confirm CR 
and exclude light chain or Bence–Jones escape 
6.4.2.3
Very Good Partial Remission (VGPR) 
•
Serum and urine M-protein detectable by immunofixation but not on electrophoresis or
•
90% or greater reduction in serum M-protein plus urine M-protein level <100mg per 24 h
•
No evidence of progressive or new bone lesions if radiographic studies were performed 
(X-Rays not required in absence of clinical indication)
•
90% decrease in the sum of the products of the the diameters of soft tissue plasmacytomas 
is required.
6.4.2.4
Partial Remission (PR)
•
50% or greater reduction of serum M-protein and 
•
90% or greater reduction in 24-h urinary M-protein (or to less than 200mg per 24 h) and
•
50% or greater reduction in the size of soft tissue plasmacytomas, if present at baseline
•
 No evidence of progressive or new bone lesions if radiographic studies were performed 
(X-Rays not required in absence of clinical indication)
Only if the serum and urine M-protein are not measurable (as per definition in section 6.4.1.1),
•
 50% or greater decrease in the difference between involved and uninvolved FLC levels 
is required (in lieu of the serum and urine M-protein criteria).
6.4.2.5
Stable Disease (SD) 
•
Not meeting criteria for CR, VGPR, PR or progressive disease 
(Not recommended for use as an indicator of response; stability of disease is best described by 
providing the time to progression estimates)
•
All response categories require two consecutive assessments made at any time before the 
institution of any new therapy; 
•
Confirmation with repeat bone marrow biopsy not needed.
•
Presence/absence of clonal cells is based upon the κ/λ ratio.  An abnormal κ/λ ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma 
cells for analysis.  An abnormal ratio reflecting presence of an abnormal clone is κ/λ ration 
of greater than 4:1 or less than 1:2.
6.4.2.6
Progressive Disease (PD)a
Requires one or more of the following:
•
Increases of greater or equal to 25% from the lowest post-treatment (nadir) value in
o
Serum M-component (minimum absolute increase of 0.5g/dL) or
o
Urine  M-component (minimum absolute increase of 200mg/24h) or

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o
Percentage of bone marrow plasma cells (minimum absolute percentage of 10%)
o
Only in patients without measurable serum and urine M-protein levels:  The difference 
between involved and uninvolved FLC levels.  The absolute increase must be >10 
mg/dL.   The FLC ratio must be abnormal.
•
Definite development of new bone lesions or clear increase in size of on or more bone 
lesion(s) (must be 50% or greater increase of a lesion at least 1 cm in longest length at 
nadir) on CT scan or new plasmacytoma 2.0 cm or larger on CT scan.
•
50% or more increase in the sum of the products of the diameters of multiple soft tissue 
plasmacytomas or 50% or more increase in the size of a single soft tissue plasmacytoma.
•
Development of hypercalcemia solely attributable to the disease (corrected serum calcium 
>11.5 mg/dL) 
aAll relapse categories require 2 consecutive assessments made at any time before 
classification as relapse or progression or institution of a new therapy.
6.4.3
Minimal residual disease (MRD) criteria (requires complete response as defined above)
•
Sustained MRD-negative MRD negativity in the marrow (next generation flow (NGF) or 
next generation sequencing (NGS) or both) and by imaging  as confirmed at least with 
assessments at least 1 year apart.
•
Flow MRD-negative-Absence of aberrant clonal plasma cells in the bone marrow by NGF 
using Euro Flow standard operating procedures or equivalent; must have sensitivity of one 
in 105 nucleated cells.
•
Sequencing MRD-negative-absence of clonal plasma cells by NGS on bone marrow 
aspirate with a method with sensitivity of 1 in 105 nucleated cells.
•
Imaging plus MRD-negative-MRD negativity as defined by NGF or NGS plus 
disappearance of every area of increased tracer uptake found at baseline or a preceding 
PET/CT or decrease to less than mediastinal blood pool SUV or decrease to less than that 
of surrounding normal tissue.
6.5
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/hrpp-policy-guidelines/

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7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at: https://irbo.nih.gov/hrpp-policy-
guidelines/   Note: Only IND Safety Reports that meet the definition of an unanticipated problem 
will need to be reported per these policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/hrpp-policy-guidelines/. 
7.3
NCI CLINICAL DIRECTOR REPORTING
Problems expeditiously reported to the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee.  A separate submission is not necessary. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.  
To report these deaths, please send an email describing the circumstances of the death at 
NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA
7.4.1
Serious Adverse Event Reports to IBC
The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life-threatening 
experience associated with the use of  anti-BCMA CAR T cells as soon as possible but in no event 
later than 7 calendar days of initial receipt of the information.  Serious adverse  events that are 
unexpected and associated with the use of the anti-BCMA CAR-expressing T cells, but are not 
fatal or life-threatening, must be reported to the NIH IBC as soon as possible, but not later than 15 
calendar days after the investigator’s initial receipt of the information.  Adverse events may be 
reported by using the FDA Form 3500a.
7.4.2
Additional Information to IBC
Refer to the current IBC reporting requirements to provide additional information to the IBC, 
including any related to annual/progress reports, as applicable.
7.5
DATA AND SAFETY MONITORING PLAN
7.5.1
Principal Investigator/Research Team 
The clinical research team will meet on a weekly basis when patients are being actively treated on 
the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the principal investigator. 
Events meeting requirements for expedited reporting as described in section 7.2.1 will be 
submitted within the appropriate timelines. The principal investigator will review adverse event 
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will personally conduct or supervise the investigation and provide appropriate delegation of 
responsibilities to other members of the research staff. 
7.5.2
Safety Monitoring Committee (SMC)
This protocol will require oversight from the Safety Monitoring Committee (SMC).  Initial review 
will occur as soon as possible after the annual IRB continuing review date.   Subsequently, each 
protocol will be reviewed as close to annually as the quarterly meeting schedule permits or more 
frequently as may be required by the SMC.   For initial and subsequent reviews, protocols will not 
be reviewed if there is no accrual within the review period. Written outcome letters will be 
generated in response to the monitoring activities and submitted to the Principal investigator and 
Clinical Director or Deputy Clinical Director, CCR, NCI.
8
SPONSOR PROTOCOL/ SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6 (R2))
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:
•
Death,
•
A life-threatening adverse event (see 8.1.3)
•
Inpatient hospitalization or prolongation of existing hospitalization 
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.
•
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions
•
A congenital anomaly/birth defect.

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•
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32)
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  
•
Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.
•
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity and 
relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution.
SAEs will be:
•
Assessed for severity and relationship to study product and alternate etiology (if not related 
to study product) by a licensed study physician listed on the Form FDA 1572 as the site 
principal investigator or sub-investigator.
•
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.
•
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All  serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
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8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets a protocol-defined serious criterion or meets the definition of Adverse Event 
of Special Interest that require expedited reporting must be submitted immediately (within 24 
hours of awareness) to OSRO Safety using the CCR SAE report form.
All SAE reporting must include the elements described in section 8.2.
SAE reports will be submitted via an electronic SAE reporting system (e.g., HiLIT). In the event 
of system downtime or issues , SAE reports will be submitted using the CCR SAE Report form to 
the sponsor at: OSROSafety@mail.nih.gov. CCR SAE report form and instructions can be found 
at: https://nih.sharepoint.com/:u:/r/sites/NCI-CCR-OCD-Communications/SitePages/Forms-and-
Instructions.aspx?csf=1&web=1&e=uWBXtI [add if multicenter: at NIH or request from your 
study coordinator for non-NIH 
Following the assessment of the SAE by OSRO, other supporting documentation of the event may 
be requested by the OSRO Safety and should be provided as soon as possible.
8.4
REPORTING PREGNANCY
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and instructions 
can be found here: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions.
8.4.1
Maternal exposure
If a patient becomes pregnant during the study, the study treatment should be discontinued 
immediately, and the pregnancy reported to the Sponsor no later than 24 hours of when the 
Investigator becomes aware of it. The Investigator should notify the Sponsor no later than 24 hours 
of when the outcome of the Pregnancy become known,
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as SAEs. 
The outcome of all pregnancies should be followed up and documented.
8.4.2
Paternal exposure
Male patients should refrain from fathering a child or donating sperm during the study and for 4 
months after the last dose of receiving protocol treatment.
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies occurring from the date of the first dose until (120 days) after the last dose should, if 
possible, be followed up and documented. Pregnant partners may be offered the opportunity to 
participate in an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry 
study) to provide data about the outcome of the pregnancy for safety reporting purposes.
8.5
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected .  CCR will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study product 
and the adverse event.  CCR will notify FDA and all participating investigators (i.e., all 

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investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32. 
All serious events will be reported to the FDA at least annually in a summary format.
9
CLINICAL MONITORING 
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6, and SOPs; and human subjects protection. This is done through independent 
verification of study data with source documentation focusing on:
•
Informed consent process
•
Eligibility confirmation
•
Drug administration and accountability
•
Adverse events monitoring
•
Response assessment.
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center.
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct.
10 STATISTICAL CONSIDERATIONS  
10.1 STATISTICAL HYPOTHESIS
The primary endpoint of this trial is to determine the safety of administering anti-BCMA-CAR-
expressing T cells to patients with multiple myeloma.  The primary approach for assessing this 
endpoint will be through a dose escalation.  
Exploratory objectives of this trial are to measure any anti-malignancy effect that might occur, to 
assess the feasibility of administering anti-BCMA-CAR-expressing T cells, and to measure 
persistence, function, and gene expression of anti-BCMA-CAR-expressing T cells. 
10.2 SAMPLE SIZE DETERMINATION
The sample size of this clinical trial will be determined by the requirements of the dose-
escalation scheme.  A maximum of 30 treated patients will be needed to complete the dose 
escalation scheme, and an additional 12-patient expansion group will be treated at the MTD.  
The 12-patient expansion group to better characterize the MTD is needed because of the 
substantial variability between patients receiving infusions of CAR T cells.  The total number of 
treated patients will be a maximum of 42 including patients who may be re-enrolled.  We 
estimate that 120 patients will need to be screened at the NIH to recruit up to 42 treated patients.  

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The trial uses a dose-escalation design, with 5 dose levels and a -1 dose level if needed.  The 
number of anti-BCMA-CAR-expressing T cells transferred for each dose level is as follows: 
Dose level -1
0.4x106 CAR+ T cells per kg of recipient bodyweight
Dose level 1
0.75x106 CAR+ T cells per kg of recipient bodyweight
Dose level 2
1.5x106 CAR+ T cells per kg of recipient bodyweight 
Dose level 3
3.0x106 CAR+ T cells per kg of recipient bodyweight 
Dose level 4
6.0x106 CAR+ T cells per kg of recipient bodyweight
Dose level 5
12.0x106 CAR+ T cells per kg of recipient bodyweight
Patients will be enrolled sequentially; therefore, enrollment will not proceed to a higher dose 
level until all patients have been treated on the prior dose level.  If sufficient cells cannot be 
grown to meet the criteria for the assigned dose level, the patient will receive the dose of cells 
called for by one dose level lower than the assigned dose level.  If sufficient cells cannot be 
grown to meet the dose requirement called for one dose level lower than the assigned dose level, 
the treatment will be aborted.  If a DLT occurs in an additional patient entered at a lower dose 
due to cell growth limitations, accrual will continue at this level as described in the dose-
escalation scheme in section 3.1.4.  Accrual will be halted at the higher level until accrual at the 
lower level is complete as described above.
Should none of the first 3 patients treated on a dose level experience a DLT, the first patient can 
be infused on the next higher dose level after a 28-day delay following CAR T-cell infusion of 
the third patient.  Should 1 of 3 patients experience a DLT at a particular dose level,  three more 
patients would be treated at that dose level. If 1/6 patients have a DLT at a particular dose level, 
the first patient can be infused on the next higher dose level after a 28-day delay following CAR 
T-cell infusion of the 6th patient.If a level with 2 or more DLTs in 3-6 patients has been 
identified, 3 additional patients will be accrued at the next-lowest dose for a total of 6, in order to 
further characterize the safety of the MTD.  The MTD is the dose at which a maximum of 1 of 6 
patients has a DLT.  After a MTD is defined, additional patients can be treated on this trial: up to 
12 total additional recipients can be treated after a MTD is established in order to better define 
safety and toxicity at that dose level. If treatment of at least 3 patients on each dose level is 
completed without establishing a MTD, a maximum feasible dose can be declared, and up to 12 
additional patients can be treated at the maximum feasible dose level. If cell growth limitations 
preclude administration of the maximum tolerated dose to a patient in the expansion group, the 
patient will receive as many cells as possible up to the MTD. 
DLTs that occur in patients receiving a repeat treatment will not affect the dose escalation of 
patients receiving an initial treatment. However, excessive DLTs among re-treatments will result 
in a discontinuation of this practice. Specifically, if 2 of the first 3 patients re-treated,  3 or more 
of the first 6 re-treated patients, 4 or more out of the first 9 re-treated patients,  or greater than 1/3 
of the total patients receiving a repeat treatment experiences a DLT during repeat treatment, then 
repeat treatments will be discontinued altogether.

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10.3
 POPULATIONS FOR ANALYSES
All treated patients will be included in the safety analysis dataset.
10.4
 STATISTICAL ANALYSES
10.4.1 General Approach
This is a standard 3+3 dose escalation study. Toxicity data will be obtained and used to 
determine the MTD of the treatment.
10.4.2 Analysis of the Primary Endpoints 
The toxicity obtained on each patient will be determined and used to report the number of 
patients at each dose level who experience a DLT, following standard phase I procedures.
10.4.3 Analysis of the Secondary Endpoint(s)
There are no secondary endpoints.
10.4.4 Safety Analyses
The study will determine the toxicity experienced on each patient enrolled on the trial and report 
this by dose level.
10.4.5 Baseline Descriptive Statistics
None will be provided in a formal manner; brief descriptions may be incorporated in a final 
report.
10.4.6 Planned Interim Analyses
Toxicity will be evaluated at each dose level as the patients accrue to the trial. Stopping criteria 
are described in section 3.9.
10.4.7 Sub-Group Analyses
None
10.4.8 Tabulation of individual Participant Data
None
10.4.9 Exploratory Analyses
The degree of persistence of anti-BCMA-CAR-transduced T cells will be evaluated by a 
quantitative measure (flow cytometry and/or quantitative PCR) in all patients.  Serum cytokine 
levels and T-cell gene expression levels are other important exploratory assessments.  Anti-
malignancy effects will be measured by clinical response and categorized according to the 
International Uniform Response Criteria for Multiple Myeloma (Section 6.4). The clinical 
multiple myeloma responses will be interpreted cautiously in the context of a pilot study which 
may be used to guide parameters for study in future protocols if warranted.
All other evaluations of exploratory objectives will be performed using exploratory techniques. 
No formal adjustment for multiple comparisons will be used since the evaluations are being done 
to generate hypotheses.  Exploratory assessments will include analysis for associations between 

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clinical outcomes such as severity of toxicity and serum cytokine levels or severity of toxicity 
and blood CAR T-cell levels.  Parametric and nonparametric tests will be used as appropriate.  
11 HUMAN SUBJECTS PROTECTIONS 
11.1 RATIONALE FOR SUBJECT SELECTION
•
The patients to be entered in this protocol have multiple myeloma which is an almost 
always incurable disease; moreover, patients will have progressive or relapsed myeloma 
despite at least 3 prior therapies.  These patients have limited life expectancies.  Subjects 
from both sexes and all racial/ethnic groups are eligible for this study if they meet the 
eligibility criteria.  To date, there is no information that suggests that differences in disease 
response would be expected in one group compared to another.  Efforts will be made to 
extend accrual to a representative population, but in this preliminary study, a balance must 
be struck between patient safety considerations and limitations on the number of 
individuals exposed to potentially toxic and/or ineffective treatments on the one hand and 
the need to explore sex and ethnic aspects of clinical research on the other hand.  If 
differences in outcome that correlate to sex or to ethnic identity are noted, accrual may be 
expanded or a follow-up study may be written to investigate those differences more fully.
•
MM remains an incurable disease despite recent advances in therapy.
•
Over the last 40 years and throughout the most recent era of improved therapy with novel 
agents, the depth of the disease response to therapy (including T- cells targeting B-cell 
maturation antigen) has remained the single most predictive factor for event free and 
overall survival in MM
•
Therefore, improving the rate and depth of responses remains a high priority for clinical 
research in MM.
•
This justifies the enrollment of all subjects with MM eligible for T- cells targeting B-cell 
maturation antigen in this phase I/II study in an attempt to improve the clinical outcome 
while feasibility and safety are being evaluated.
•
Because patients on previous trials of CAR T cells have experienced hypotension, 
tachycardia, prolonged fevers, neurological toxicities, and depressed myocardial function.  
In many cases these toxicities were severe enough to require intensive care unit admission. 
We will limit enrollment to patients 70 years of age or less because based on our admittedly 
limited experience with prior CAR-T cell clinical trials, younger patients tolerate and 
recover from these toxicities better than elderly patients.
11.2 PARTICIPATION OF CHILDREN
Children will not be enrolled on this study.  Multiple myeloma is extremely uncommon in children; 
moreover, since the efficacy of this experimental procedure is unknown, it does not seem 
reasonable to expose children to this risk without further evidence of benefit.  
11.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol.  However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 

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research participation (section 11.4 ), all subjects will be offered the opportunity to fill in their 
wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or cognitively 
impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent 
Assessment Team (ACAT) for evaluation to assess ongoing capacity of the subjects and to identify 
an LAR, as needed. Please see section 11.5.1 for consent procedure. 
11.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
The experimental treatment has a chance to provide clinical benefit though this is unknown.  A 
goal of this study is to improve upon the number of patients who may benefit from adoptive cell 
therapy by using genetically-modified T-cells.  This specific protocol is being performed to 
evaluate a genetically modified T-cell therapy for multiple myeloma, which is an almost always 
incurable disease. 
 Only patients with multiple myeloma who have progressive or relapsed myeloma despite at least 
3 prior lines of therapy will be enrolled. 
The risks of the study fall into 3 general categories (see section 12 for details).  First, chemotherapy 
that could cause cytopenias is part of the protocol.  As with any chemotherapy that causes 
neutropenia and thrombocytopenia, this chemotherapy could cause toxicities such as infections 
and bleeding. The second category of toxicity is cytokine-release type toxicities such as high 
fevers, tachycardia, hypotension and neurological toxicities such as delirium, obtundation, 
myoclonus, seizures, headache, and transient focal neurological toxicities including aphasia and 
focal paresis.  These cytokine-release-type toxicities have been detected in other clinical trials of 
CAR T cells during the first 2 weeks after anti-BCMA CAR T cells were infused.4,107  The third 
main category of toxicity is direct damage to normal tissues by the CAR T cells.  This could happen 
because of unexpected expression of BCMA on normal cells or because of unexpected cross-
reactivity of the anti-BCMA CAR with proteins other than BCMA in vivo.  Another potential 
toxicity of anti-BCMA CAR T cells is hypogammaglobulinemia due to depletion of plasma cells 
and mature B cells.  Hypogammaglobulinemia has been a complication of many patients on 
clinical trials of anti-BCMA CAR-expressing T cells.4,33  Hypogammaglobulinemia in these 
patients was routinely treated with infusions of intravenous immunoglobulins.4  
The gammaretroviral vector used in this trial inserts into the T-cell DNA of patients, so in theory, 
insertional mutagenesis could occur, but insertional mutagenesis has not occurred in any of the 
hundreds of patients treated with mature T cells that were genetically modified by gammaretroviral 
vectors.35-37
The success of this clinical trial cannot be predicted at this time.  Because all patients in this 
protocol have advanced multiple myeloma and limited life expectancies the potential benefit is 
thought to outweigh the potential risks.  It is also anticipated that this study will provide scientific 
information relevant to tumor immunotherapy.  
11.4.1 Risk to family or relatives
Family members or relatives may or may not want to be aware of familial tendencies or genetic 
risks of disease which may cause anxiety about possible future health problems.  Patients will be 

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notified of any medically significant and actionable incidental findings. Study results will not be 
shared with patients.
11.4.2 Risks of exposure to Ionizing Radiation
The procedures for performing the CT scans will follow clinical policies, no special procedures 
apply to these additional assessments for research purposes.  In summary, subjects may receive 
additional radiation exposure from up to eight (8) CT head+ Neck +CAP and five (5)18FDG-
PET/CT scans in the first year of the study.
The total additional radiation dose for research purposes will be approximately 16.9 rem in the 
first year of the study. This amount is more than would be expected from everyday background 
radiation. Being exposed to too much radiation can cause harmful side effects such as an increase 
in the risk of cancer. The risk of getting cancer from the radiation exposure in this study is 1.7 out 
of 100 (1.7%) and of getting a fatal cancer is 0.8 out of 100 (0.8%).
11.4.3 Risks of Scans and Contrast
If contrast dye is used, there is a small chance of developing an allergic reaction from the contrast 
material including gadolinium, which may cause symptoms ranging from mild itching or a rash to 
severe difficulty breathing, shock or rarely, death.  The contrast material may also cause kidney 
problems. Gadolinium for research MRI scans will not be given to patients who have impaired 
kidney function or who received gadolinium within the previous month.Common reactions include 
pain in the vein where the contrast was given, a metallic or bitter taste in the mouth , headache, 
nausea and a warm or flushing feeling that lasts from 1-3 minutes. 
An IV line may need to be inserted for administration of the contrast agent or anesthetic, which 
may cause pain at the site where the IV is placed and there is a small risk of bruising or infection
11.4.4 Risks of blood Sampling
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting.
11.4.5 Risks of Bone marrow aspiration and biopsy
Side effect of  bone marrow aspiration and biopsy may feel a pressure sensation when the needle 
is being inserted and a pulling sensation and brief pain as the marrow is withdrawn. Potential 
complications of this procedure are local bleeding, pain at the site, and infection. Both of these are 
very rare. Bleeding can be stopped by applying local pressure and an infection can be treated with 
antibiotics.
11.4.6 Risks of Intravenous Catheter
Side effect of placing some catheters include pain, bleeding, infection and rarely, collapsed lung.  
The long- term risks of the catheter rarely include infection and clotting of veins.  
11.4.7 Risks of Apheresis
The risks of apheresis are similar to whole blood donation and include pain and bruising at the 
needle insertion site in the arms, lightheadedness, dizziness, nausea, and rarely fainting due to a 
rare reflex reaction to needle placement and to the temporary decrease in blood volume during 
apheresis.  It may also feel tingling around your mouth or in your fingers caused by a blood thinner 

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given during the procedure.  The tingling may reduce by giving calcium containing chewable 
antacid.  All the symptoms usually go away within a few minutes of stopping the procedure.   
11.5 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided to the participant or consent designee(s) (e.g., 
legally authorized representative [LAR] if participant is an adult unable to consent) for review 
prior to consenting.  A designated study investigator will carefully explain the procedures and tests 
involved in this study, and the associated risks, discomforts and benefits. In order to minimize 
potential coercion, as much time as is needed to review the document will be given, including an 
opportunity to discuss it with friends, family members and/or other advisors, and to ask questions 
of any designated study investigator. A signed informed consent document will be obtained prior 
to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
local policy, including HRPP policy 303) per discretion of the designated study investigator and 
with the agreement of the participant/consent designee(s).  Whether in person or remote, the 
privacy of the subject will be maintained. Consenting investigators (and participant/consent 
designee, when in person) will be located in a private area (e.g., clinic consult room). When 
consent is conducted remotely, the participant/consent designee will be informed of the private 
nature of the discussion and will be encouraged to relocate to a more private setting if needed.
11.5.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation
For participants addressed in section 11.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 11.5.
12 REGULATORY AND OPERATIONAL CONSIDERATIONS 
12.1
STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigators, funding agency, the Investigational New Drug (IND) sponsor and regulatory 
authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and 
will provide the reason(s) for the termination or suspension.  Study participants will be contacted, 
as applicable, and be informed of changes to study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to participants
•
Demonstration of efficacy that would warrant stopping   
•
Insufficient compliance to protocol requirements
•
Data that are not sufficiently complete and/or evaluable
•
Determination that the primary endpoint has been met
•
Determination of futility

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Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
12.2
QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Council for Harmonisation 
Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory 
Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities.
12.3
CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial.  The study leadership in conjunction with the NIH has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest.
12.4
CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, 
the study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records.

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The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be stored at the National Cancer Institute Center for Cancer Research (NCI CCR). This will 
not include the participant’s contact or identifying information. Rather, individual participants and 
their research data will be identified by a unique study identification number. The study data entry 
and study management systems used by the clinical site(s) and by NCI CCR research staff will be 
secured and password protected. At the end of the study, all study databases will be archived at 
the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants.
13 PHARMACEUTICAL INFORMATION  
Note: The commercial drugs used in this study will not alter labelling of the FDA approved drugs 
and nor does the investigation involve a route of administration or dosage level in use in a patient 
population or other factor that significantly increases the risks (or decreases the acceptability of 
the risks) associated with the use of the drug product.
13.1 RETROVIRAL VECTOR CONTAINING THE ANTI-BCMA CAR GENE 
13.1.1 Cells manufacturing
The retroviral vector supernatant (MSGV-FHVH33-CD8BBZ) encoding a CAR directed against 
BCMA was prepared and preserved following cGMP conditions in the University of Cincinnati 
Medical Center Vector Production Facility. The retroviral vector utilizes the MSGV retroviral 
vector backbone and consists of 7007 bps including the 5' LTR from the murine stem cell virus 
(promoter), packaging signal including the splicing donor (SD) and splicing acceptor sites,  the 
anti-BCMA  CAR protein containing a signal peptide from human CD8-alpha signal sequence, the 
fully-human heavy chain variable region 316833 (FHVH33), CD8 (hinge and transmembrane), 
CD28 (cytoplasmic region), and TCR zeta (cytoplasmic region), followed by the murine stem cell 
virus 3'LTR.   
The supernatant will be stored at –80oC or shipped on dry ice and stored in the Dept. of Transfusion 
Medicine, NIH or at FisherBiosciences, Rockville, MD. Both storage facilities are equipped with 
around-the-clock temperature monitoring. Upon request, supernatant will be delivered on dry ice 
to be used in in vitro transductions of T cells. There will be no re-use of the same unit of supernatant 
for different patients. Retroviral titer has been shown to be stable after immediate thawing and 

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immediate use. Handling of the vector should follow the guidelines of Biosafety Level-2 (BSL-
2).   The specific guidelines for Biosafety Level-2 (BSL-2) can be viewed at 
http://bmbl.od.nih.gov/sect3bsl2.htm 
13.1.2 Toxicities
Please refer to section 1.2.11
13.1.3 Administration procedures: 
Please see section Error! Reference source not found..
13.2 COMMERCIAL AGENTS
Please refer to the US approved package insert for the full prescribing information here: 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails
13.2.1 Cyclophosphamide
13.2.1.1 Source
Cyclophosphamide will be purchased by the NIH Clinical Center Pharmacy Department from 
commercial sources and is supplied as a lyophilized powder in various vial sizes.
13.2.1.2 Administration procedures
The cyclophosphamide used in this regimen will be given as Intravenous infusion over 30 minutes. 
13.2.2 Fludarabine
13.2.2.1 Source 
Fludarabine monophosphate will be purchased by the NIH Clinical Center Pharmacy Department 
from commercial sources and is supplied as a white, lyophilized powder. Each vial contains 50 mg 
of fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH.  Fludarabine is 
stored at room temperature.
13.2.2.2 Administration procedures
Parenteral drug products should be inspected visually for particulate matter and discoloration prior 
to administration. Fludarabine is administered as an IV infusion in 100 mL 0.9% sodium chloride, 
USP over 15 to 30 minutes.  

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14  REFERENCES
1.
Gahrton G, Iacobelli S, Björkstrand B, et al. Autologous/reduced-intensity allogeneic 
stem cell transplantation vs autologous transplantation in multiple myeloma: long-term 
results of the EBMT-NMAM2000 study. Blood. 2013;121(25):5055-5063.
2.
Salama M, Nevill T, Marcellus D, et al. Donor leukocyte infusions for multiple myeloma. 
Bone Marrow Transplantation. 2000;26(11):1179-1184.
3.
Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent 
antitumor effects and can establish memory in patients with advanced leukemia. Science 
Translational Medicine. 2011;3(95).
4.
Kochenderfer JN, Dudley ME, Feldman SA, et al. B-cell depletion and remissions of 
malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 
chimeric-antigen-receptor-transduced T cells. Blood. 2012;119(12):2709-2720.
5.
Carpenter RO, Evbuomwan MO, Pittaluga S, et al. B-cell maturation antigen is a 
promising target for adoptive T-cell therapy of multiple myeloma. Clinical Cancer 
Research. 2013;19(8):2048-2060.
6.
Gattinoni L, Finkelstein SE, Klebanoff CA, et al. Removal of homeostatic cytokine sinks 
by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ 
T cells. Journal of Experimental Medicine. 2005;202(7):907-912.
7.
Kochenderfer JN, Yu Z, Frasheri D, Restifo NP, Rosenberg SA. Adoptive transfer of 
syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine 
CD19 can eradicate lymphoma and normal B cells. Blood. 2010;116(19):3875-3886.
8.
North RJ. Cyclophosphamide-facilitated adoptive immunotherapy of an established 
tumor depends on elimination of tumor-induced suppressor T cells. Journal of 
Experimental Medicine. 1982;155(4):1063-1074.
9.
Palumbo A, Anderson K. Multiple myeloma. New England Journal of Medicine. 
2011;364(11):1046-1060.
10.
Munshi NC, Anderson KC. Plasma Cell Neoplasms. In: DeVita VT, Lawrence TS, 
Rosenberg SA, eds. Cancer:  Principles and Practice of Oncology 9th ed 2011.
11.
Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working 
Group updated criteria for the diagnosis of multiple myeloma. The Lancet Oncology. 
2014;15(12):e538-e548.
12.
Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following 
non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with 
refractory metastatic melanoma. Journal of Clinical Oncology. 2005;23(10):2346-2357.
13.
Rajkumar SV. Treatment of multiple myeloma. Nature Reviews Clinical Oncology. 
2011;8(8):479-491.
14.
Cherry BM, Korde N, Kwok M, Roschewski M, Landgren O. Evolving therapeutic 
paradigms for multiple myeloma: Back to the future. Leukemia and Lymphoma. 
2013;54(3):451-463.

83
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Version Date: October 28, 2025
15.
Gonsalves WI, Gertz MA, Lacy MQ, et al. Second auto-SCT for treatment of relapsed 
multiple myeloma. Bone Marrow Transplantation. 2013;48(4):568-573.
16.
Durie BGM, Harousseau JL, Miguel JS, et al. International uniform response criteria for 
multiple myeloma. Leukemia. 2006;20(9):1467-1473.
17.
Jakubowiak A. Management Strategies for Relapsed/Refractory Multiple Myeloma: 
Current Clinical Perspectives. Seminars in Hematology. 2012;49(SUPPL. 1):S16-S32.
18.
Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple 
myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter international 
myeloma working group study. Leukemia. 2012;26(1):149-157.
19.
Stadtmauer EA, Weber DM, Niesvizky R, et al. Lenalidomide in combination with 
dexamethasone at first relapse in comparison with its use as later salvage therapy in 
relapsed or refractory multiple myeloma. European Journal of Haematology. 
2009;82(6):426-432.
20.
Bensinger WI. The current status of reduced-intensity allogeneic hematopoietic stem cell 
transplantation for multiple myeloma. [Review] [48 refs]. Leukemia. 2006;20(10):1683-
1689.
21.
Zeiser R, Finke J. Allogeneic haematopoietic cell transplantation for multiple myeloma: 
reducing transplant-related mortality while harnessing the graft-versus-myeloma effect. 
[Review] [70 refs]. European Journal of Cancer. 2006;42(11):1601-1611.
22.
Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting with autografting for 
newly diagnosed myeloma. New England Journal of Medicine. 2007;356(11):1110-1120.
23.
Brenner MK, Heslop HE. Adoptive T cell therapy of cancer. Current Opinion in 
Immunology. 2010;22(2):251-257.
24.
Park TS, Rosenberg SA, Morgan RA. Treating cancer with genetically engineered T 
cells. Trends in Biotechnology. 2011;29(11):550-557.
25.
Morgan RA, Dudley ME, Wunderlich JR, et al. Cancer regression in patients after 
transfer of genetically engineered lymphocytes.[see comment]. Science. 
2006;314(5796):126-129.
26.
Rosenberg SA. Cell transfer immunotherapy for metastatic solid cancer-what clinicians 
need to know. Nature Reviews Clinical Oncology. 2011;8(10):577-585.
27.
Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy for cancer: 
Harnessing the T cell response. Nature Reviews Immunology. 2012;12(4):269-281.
28.
Kershaw MH, Teng MWL, Smyth MJ, Darcy PK. Supernatural T cells: Genetic 
modification of T cells for cancer therapy. Nature Reviews Immunology. 2005;5(12):928-
940.
29.
Hoyos V, Savoldo B, Dotti G. Genetic modification of human T lymphocytes for the 
treatment of hematologic malignancies. Haematologica. 2012;97(11):1622-1631.
30.
Turtle CJ, Hudecek M, Jensen MC, Riddell SR. Engineered T cells for anti-cancer 
therapy. Current Opinion in Immunology. 2012;24(5):633-639.

84
Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
Version Date: October 28, 2025
31.
Brentjens RJ, Rivière I, Park JH, et al. Safety and persistence of adoptively transferred 
autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-
cell leukemias. Blood. 2011;118(18):4817-4828.
32.
Robbins PF, Morgan RA, Feldman SA, et al. Tumor regression in patients with 
metastatic synovial cell sarcoma and melanoma using genetically engineered 
lymphocytes reactive with NY-ESO-1. Journal of Clinical Oncology. 2011;29(7):917-
924.
33.
Kochenderfer JN, Wilson WH, Janik JE, et al. Eradication of B-lineage cells and 
regression of lymphoma in a patient treated with autologous T cells genetically 
engineered to recognize CD19. Blood. 2010;116(20):4099-4102.
34.
Savoldo B, Ramos CA, Liu E, et al. CD28 costimulation improves expansion and 
persistence of chimeric antigen receptor-modified T cells in lymphoma patients. Journal 
of Clinical Investigation. 2011;121(5):1822-1826.
35.
Scholler J, Brady TL, Binder-Scholl G, et al. Decade-long safety and function of 
retroviral-modified chimeric antigen receptor T cells. Science Translational Medicine. 
2012;4(132).
36.
Recchia A, Bonini C, Magnani Z, et al. Retroviral vector integration deregulates gene 
expression but has no consequence on the biology and function of transplanted T cells. 
Proceedings of the National Academy of Sciences of the United States of America. 
2006;103(5):1457-1462.
37.
Heslop HE, Slobod KS, Pule MA, et al. Long-term outcome of EBV-specific T-cell 
infusions to prevent or treat EBV-related lymphoproliferative disease in transplant 
recipients. Blood. 2010;115(5):925-935.
38.
Zhao Y, Wang QJ, Yang S, et al. A herceptin-based chimeric antigen receptor with 
modified signaling domains leads to enhanced survival of transduced T lymphocytes and 
antitumor activity. Journal of Immunology. 2009;183(9):5563-5574.
39.
Irving BA, Weiss A. The cytoplasmic domain of the T cell receptor zeta chain is 
sufficient to couple to receptor-associated signal transduction pathways. Cell. 
1991;64(5):891-901.
40.
Eshhar Z, Waks T, Gross G, Schindler DG. Specific activation and targeting of cytotoxic 
lymphocytes through chimeric single chains consisting of antibody-binding domains and 
the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proceedings of 
the National Academy of Sciences of the United States of America. 1993;90(2):720-724.
41.
Louis CU, Savoldo B, Dotti G, et al. Antitumor activity and long-term fate of chimeric 
antigen receptor-positive T cells in patients with neuroblastoma. Blood. 
2011;118(23):6050-6056.
42.
Curran KJ, Pegram HJ, Brentjens RJ. Chimeric antigen receptors for T cell 
immunotherapy: Current understanding and future directions. Journal of Gene Medicine. 
2012;14(6):405-415.

85
Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
Version Date: October 28, 2025
43.
Pule MA, Savoldo B, Myers GD, et al. Virus-specific T cells engineered to coexpress 
tumor-specific receptors: persistence and antitumor activity in individuals with 
neuroblastoma.[see comment]. Nature Medicine. 2008;14(11):1264-1270.
44.
Hwu P, Shafer GE, Treisman J, et al. Lysis of ovarian cancer cells by human 
lymphocytes redirected with a chimeric gene composed of an antibody variable region 
and the Fc receptor gamma chain. Journal of Experimental Medicine. 1993;178(1):361-
366.
45.
Hwu P, Yang JC, Cowherd R, et al. In vivo antitumor activity of T cells redirected with 
chimeric antibody/T-cell receptor genes. Cancer Research. 1995;55(15):3369-3373.
46.
Kershaw MH, Westwood JA, Parker LL, et al. A phase I study on adoptive 
immunotherapy using gene-modified T cells for ovarian cancer. Clinical Cancer 
Research. 2006;12(20 Pt 1):6106-6115.
47.
Kochenderfer JN, Feldman SA, Zhao Y, et al. Construction and preclinical evaluation of 
an anti-CD19 chimeric antigen receptor. Journal of Immunotherapy. 2009;32(7):689-702.
48.
Cheadle EJ, Gilham DE, Thistlethwaite FC, Radford JA, Hawkins RE. Killing of non-
Hodgkin lymphoma cells by autologous CD19 engineered T cells. British Journal of 
Haematology. 2005;129(3):322-332.
49.
Brentjens RJ, Latouche JB, Santos E, et al. Eradication of systemic B-cell tumors by 
genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-
15.[see comment]. Nature Medicine. 2003;9(3):279-286.
50.
Imai C, Mihara K, Andreansky M, et al. Chimeric receptors with 4-1BB signaling 
capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia. 
2004;18(4):676-684.
51.
Milone MC, Fish JD, Carpenito C, et al. Chimeric receptors containing CD137 signal 
transduction domains mediate enhanced survival of T cells and increased antileukemic 
efficacy in vivo. Molecular Therapy: the Journal of the American Society of Gene 
Therapy. 2009;17(8):1453-1464.
52.
Porter DL, BL; Kalos, M et al. Chimeric Antigen Receptor-Modified T Cells in Chronic 
Lymphoid Leukemia. The New England Journal of Medicine. 2011;365(8):725-733.
53.
Wang X, Naranjo A, Brown CE, et al. Phenotypic and functional attributes of lentivirus-
modified CD19-specific Human CD8 + central memory T cells manufactured at clinical 
scale. Journal of Immunotherapy. 2012;35(9):689-701.
54.
Cooper LJ, Topp MS, Serrano LM, et al. T-cell clones can be rendered specific for 
CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect. 
Blood. 2003;101(4):1637-1644.
55.
Kebriaei P, Huls H, Jena B, et al. Infusing CD19-directed T cells to augment disease 
control in patients undergoing autologous hematopoietic stem-cell transplantation for 
advanced B-lymphoid malignancies. Human Gene Therapy. 2012;23(5):444-450.

86
Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
Version Date: October 28, 2025
56.
Hollyman D, Stefanski J, Przybylowski M, et al. Manufacturing validation of biologically 
functional T cells targeted to CD19 antigen for autologous adoptive cell therapy. Journal 
of Immunotherapy. 2009;32(2):169-180.
57.
Song DG, Ye Q, Carpenito C, et al. In vivo persistence, tumor localization, and antitumor 
activity of CAR-engineered T cells is enhanced by costimulatory signaling through 
CD137 (4-1BB). Cancer Research. 2011;71(13):4617-4627.
58.
Maher J, Brentjens RJ, Gunset G, Rivière I, Sadelain M. Human T-lymphocyte 
cytotoxicity and proliferation directed by a single chimeric TCRζ/CD28 receptor. Nature 
Biotechnology. 2002;20(1):70-75.
59.
Guest RD, Hawkins RE, Kirillova N, et al. The role of extracellular spacer regions in the 
optimal design of chimeric immune receptors: Evaluation of four different scFvs and 
antigens. Journal of Immunotherapy. 2005;28(3):203-211.
60.
Rossig C, Bar A, Pscherer S, et al. Target antigen expression on a professional antigen-
presenting cell induces superior proliferative antitumor T-cell responses via chimeric T-
cell receptors. Journal of Immunotherapy. 2006;29(1):21-31.
61.
Cheadle EJ, Hawkins RE, Batha H, O'Neill AL, Dovedi SJ, Gilham DE. Natural 
expression of the CD19 antigen impacts the long-term engraftment but not antitumor 
activity of CD19-specific engineered T cells. Journal of Immunology. 2010;184(4):1885-
1896.
62.
Brentjens RJ, Santos E, Nikhamin Y, et al. Genetically targeted T cells eradicate systemic 
acute lymphoblastic leukemia xenografts. Clinical Cancer Research. 2007;13(18 Pt 
1):5426-5435.
63.
Kowolik CM, Topp MS, Gonzalez S, et al. CD28 costimulation provided through a 
CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor 
efficacy of adoptively transferred T cells. Cancer Research. 2006;66(22):10995-11004.
64.
Porter CD, Collins MK, Tailor CS, et al. Comparison of efficiency of infection of human 
gene therapy target cells via four different retroviral receptors. Human Gene Therapy. 
1996;7(8):913-919.
65.
Jensen MC, Popplewell L, Cooper LJ, et al. Antitransgene rejection responses contribute 
to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen 
receptor redirected T cells in humans. Biology of Blood and Marrow Transplantation. 
2010;16(9):1245-1256.
66.
Kochenderfer JN, Somerville RPT, Lu T, et al. Lymphoma Remissions Caused by Anti-
CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-
15 Levels. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 2017;35(16):1803-1813.
67.
Turtle CJ, Hanafi LA, Berger C, et al. Immunotherapy of non-Hodgkin's lymphoma with 
a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T 
cells. Science Translational Medicine. 2016;8(355).

87
Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
Version Date: October 28, 2025
68.
Laabi Y, Gras MP, Carbonnel F, et al. A new gene, BCM, on chromosome 16 is fused to 
the interleukin 2 gene by a t(4;16)(q26;p13) translocation in a malignant T cell 
lymphoma. EMBO Journal. 1992;11(11):3897-3904.
69.
Laabi Y, Gras MP, Brouet JC, Berger R, Larsen CJ, Tsapis A. The BCMA gene, 
preferentially expressed during B lymphoid maturation, is bidirectionally transcribed. 
Nucleic Acids Research. 1994;22(7):1147-1154.
70.
Novak AJ, Darce JR, Arendt BK, et al. Expression of BCMA, TACI, and BAFF-R in 
multiple myeloma: A mechanism for growth and survival. Blood. 2004;103(2):689-694.
71.
Neri P, Kumar S, Fulciniti MT, et al. Neutralizing B-cell-activating factor antibody 
improves survival and inhibits osteoclastogenesis in a severe combined immunodeficient 
human multiple myeloma model. Clinical Cancer Research. 2007;13(19):5903-5909.
72.
Bellucci R, Alyea EP, Chiaretti S, et al. Graft-versus-tumor response in patients with 
multiple myeloma is associated with antibody response to BCMA, a plasma-cell 
membrane receptor. Blood. 2005;105(10):3945-3950.
73.
Moreaux J, Legouffe E, Jourdan E, et al. BAFF and APRIL protect myeloma cells from 
apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood. 
2004;103(8):3148-3157.
74.
Thompson JS, Schneider P, Kalled SL, et al. BAFF binds to the tumor necrosis factor 
receptor-like molecule B cell maturation antigen and is important for maintaining the 
peripheral B cell population. Journal of Experimental Medicine. 2000;192(1):129-135.
75.
Mackay F, Schneider P, Rennert P, Browning J. BAFF and APRIL: A tutorial on B cell 
survival. Vol 21. Annual Review of Immunology2003:231-264.
76.
Kalled SL. The role of BAFF in immune function and implications for autoimmunity. 
Immunological Reviews. 2005;204:43-54.
77.
Tai YT, Li XF, Breitkreutz I, et al. Role of B-cell-activating factor in adhesion and 
growth of human multiple myeloma cells in the bone marrow microenvironment. Cancer 
Research. 2006;66(13):6675-6682.
78.
O'Connor BP, Raman VS, Erickson LD, et al. BCMA Is Essential for the Survival of 
Long-lived Bone Marrow Plasma Cells. Journal of Experimental Medicine. 
2004;199(1):91-97.
79.
Ng LG, Sutherland APR, Newton R, et al. B cell-activating factor belonging to the TNF 
family (BAFF)-R is the principal BAFF receptor facilitating BAFF costimulation of 
circulating T and B cells. Journal of Immunology. 2004;173(2):807-817.
80.
Xu S, Lam KP. B-cell maturation protein, which binds the tumor necrosis factor family 
members BAFF and APRIL, is dispensable for humoral immune responses. Molecular 
and Cellular Biology. 2001;21(12):4067-4074.
81.
Schiemann B, Gommerman JL, Vora K, et al. An essential role for BAFF in the normal 
development of B cells through a BCMA-independent pathway. Science. 
2001;293(5537):2111-2114.

88
Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
Version Date: October 28, 2025
82.
Brandtzaeg P. Function of mucosa-associated lymphoid tissue in antibody formation. 
Immunological Investigations. 2010;39(4-5):303-355.
83.
Soutar CA. Distribution of plasma cells and other cells containing immunoglobulin in the 
respiratory tract of normal man and class of immunoglobulin contained therein. Thorax. 
1976;31(2):158-166.
84.
Ali SA, Shi V, Maric I, et al. T cells expressing an anti–B-cell maturation antigen 
chimeric antigen receptor cause remissions of multiple myeloma. Blood. 
2016;128(13):1688-1700.
85.
Kochenderfer JN, Rosenberg SA. Treating B-cell cancer with T cells expressing anti-
CD19 chimeric antigen receptors. Nat Rev Clin Oncol. 2013;10(5):267-276.
86.
Kochenderfer JN, Somerville RPT, Lu T, et al. Lymphoma Remissions Caused by Anti-
CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-
15 Levels. Journal of Clinical Oncology. 2017;35(16):1803-1813.
87.
Lee JC, Hayman E, Pegram HJ, et al. In vivo inhibition of human CD19-targeted effector 
T cells by natural T regulatory cells in a xenotransplant murine model of B cell 
malignancy. Cancer Res. 2011;71(8):2871-2881.
88.
Carpenter RO, Evbuomwan MO, Pittaluga S, et al. B-cell maturation antigen is a 
promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res. 
2013;19(8):2048-2060.
89.
Cohen AD, Garfall AL, Stadtmauer EA, et al. B-Cell Maturation Antigen (BCMA)-
Specific Chimeric Antigen Receptor T Cells (CART-BCMA) for Multiple Myeloma 
(MM): Initial Safety and Efficacy from a Phase I Study ABSTRACT. Blood. 
2016;128(22):1147-1147.
90.
Berdeja JG, Lin Y, Raje NS, et al. First-in-human multicenter study of bb2121 anti-
BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: POSTER Updated 
results. Journal of Clinical Oncology. 2017;35(15_suppl):3010-3010.
91.
Fan F, Zhao W, Liu J, et al. Durable remissions with BCMA-specific chimeric antigen 
receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma 
ABSTRACT. Journal of Clinical Oncology. 2017;35(15_suppl):LBA3001-LBA3001.
92.
Hughes MS, Yu YY, Dudley ME, et al. Transfer of a TCR gene derived from a patient 
with a marked antitumor response conveys highly active T-cell effector functions. Human 
Gene Therapy. 2005;16(4):457-472.
93.
Rubio V, Stuge TB, Singh N, et al. Ex vivo identification, isolation and analysis of 
tumor-cytolytic T cells. Nature Medicine. 2003;9(11):1377-1382.
94.
Muranski P, Boni A, Wrzesinski C, et al. Increased intensity lymphodepletion and 
adoptive immunotherapy - How far can we go? Nature Clinical Practice Oncology. 
2006;3(12):668-681.
95.
Klebanoff CA, Khong HT, Antony PA, Palmer DC, Restifo NP. Sinks, suppressors and 
antigen presenters: How lymphodepletion enhances T cell-mediated tumor 
immunotherapy. Trends in Immunology. 2005;26(2):111-117.

89
Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
Version Date: October 28, 2025
96.
Dumitru CA, Moses K, Trellakis S, Lang S, Brandau S. Neutrophils and granulocytic 
myeloid-derived suppressor cells: Immunophenotyping, cell biology and clinical 
relevance in human oncology. Cancer Immunology, Immunotherapy. 2012;61(8):1155-
1167.
97.
Lee JC, Hayman E, Pegram HJ, et al. In vivo inhibition of human CD19-targeted effector 
T cells by natural T regulatory cells in a xenotransplant murine model of B cell 
malignancy. Cancer Research. 2011;71(8):2871-2881.
98.
Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in 
patients after clonal repopulation with antitumor lymphocytes. Science. 
2002;298(5594):850-854.
99.
Dudley ME, Yang JC, Sherry R, et al. Adoptive cell therapy for patients with metastatic 
melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. 
Journal of Clinical Oncology. 2008;26(32):5233-5239.
100.
O'Brien SM, Kantarjian HM, Cortes J, et al. Results of the fludarabine and 
cyclophosphamide combination regimen in chronic lymphocytic leukemia. Journal of 
Clinical Oncology. 2001;19(5):1414-1420.
101.
Klebanoff CA, Gattinoni L, Palmer DC, et al. Determinants of successful CD8 + T-cell 
adoptive immunotherapy for large established tumors in mice. Clinical Cancer Research. 
2011;17(16):5343-5352.
102.
Overwijk WW, Theoret MR, Finkelstein SE, et al. Tumor regression and autoimmunity 
after reversal of a functionally tolerant state of self-reactive CD8+ T cells. Journal of 
Experimental Medicine. 2003;198(4):569-580.
103.
Li S, Yang J, Urban FA, et al. Genetically engineered T cells expressing a HER2-specific 
chimeric receptor mediate antigen-specific tumor regression. Cancer Gene Therapy. 
2008;15(6):382-392.
104.
Deol A, Lum LG. Role of donor lymphocyte infusions in relapsed hematological 
malignancies after stem cell transplantation revisited. Cancer Treatment Reviews. 
2010;36(7):528-538.
105.
Tomblyn M, Lazarus HM. Donor lymphocyte infusions: The long and winding road: how 
should it be traveled? Bone Marrow Transplantation. 2008;42(9):569-579.
106.
Ali SA, Shi V, Maric I, et al. T cells expressing an anti-B-cell maturation antigen 
chimeric antigen receptor cause remissions of multiple myeloma. Blood. 
2016;128(13):1688-1700.
107.
Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular 
remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Science 
Translational Medicine. 2013;5(177).
108.
Johnson LA, Morgan RA, Dudley ME, et al. Gene therapy with human and mouse T-cell 
receptors mediates cancer regression and targets normal tissues expressing cognate 
antigen. Blood. 2009;114(3):535-546.

90
Abbreviated Title: Fully-human Anti-BCMA-CAR T cells 
Version Date: October 28, 2025
109.
Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric 
antigen receptors for acute lymphoblastic leukaemia in children and young adults: A 
phase 1 dose-escalation trial. The Lancet. 2015;385(9967):517-528.
110.
Kochenderfer JN, Rosenberg SA. Treating B-cell cancer with T cells expressing anti-
CD19 chimeric antigen receptors. Nature Reviews Clinical Oncology. 2013;10(5):267-
276.
111.
Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group 
consensus criteria for response and minimal residual disease assessment in multiple 
myeloma. The Lancet Oncology. 2016;17(8):e328-e346.

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15 APPENDICES
15.1 APPENDIX A: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale*
Grade
Descriptions
0
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory.  Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work).
2
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours.
3
In bed >50% of the time.  Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours.
4
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982.

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15.2 APPENDIX B: DATA COLLECTION ELEMENTS REQUIRED BY PROTOCOL 
All of the following elements will be recorded in the study database:
A. Patient Enrollment
•
Date of birth, age, sex, race, ethnicity
•
Height
•
Weight
•
ECOG
•
Date of original diagnosis
•
Stage at diagnosis
•
Plasmacytoma present: Yes or No
•
Tumor Histology and date of confirmation
•
BCMA expression by tumor type of tissue studied and date of confirmation
•
Date of Informed Consent signature, consent version and date of registration
•
Baseline History/Physical
•
Baseline Symptoms 
•
Prior therapy
•
Prior radiation
•
Prior Bone Marrow Biopsy that includes the percent of plasma cells and BCMA results
•
Findings of consultations done at screening
B. Study Drug administration and response for each course of therapy given
•
Dates anti-BCMA-CAR-transduced T cells given
•
Dose level, actual dose in CAR+ T cells/kg, schedule and route given
•
Height, weight, and body surface area at start of each course
•
Response assessment for each restaging performed
•
Concomitant medications will not be collected in the study database
        
C. Laboratory and Diagnostic Test Data
1.  All Clinical laboratory and diagnostic test results done at screening and until day 
30 post infusion with the following exceptions:
Diagnostic tests which are not specified in the protocol, and if the results are not 
needed to document the start or end of an adverse event that requires reporting.
Serologies such as CMV, HSV, EBV, toxoplasmosis, adenovirus,, TTV data that 
were not need for eligibility will not be collected.
2. All staging studies including serum protein electrophoresis, urine protein 
electrophoresis, serum free light chains, bone marrow biopsy reports, flow 
cytometry reports, serum immunoglobulin reports including beta-2 microglobulin, 
complete blood count and differential reports, serum creatinine reports, TBNK 
results, serum protein, urine albumin, serum calcium (including ionized), ESR and 

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CRP results. MRI, X-ray (including skeletal survey), and CT scan results will only 
be reported if they were used for staging.
D. Adverse Events
Please see section 6.1.1Adverse Event Recording
E.  Tumor response and measurements
•
Restaging studies performed at protocol specified time points and as clinically 
indicated.
•
Any physical exam findings will be collected as Adverse Events and labs results.
•
Years 5-15 follow-up is only for survival.
F.   Off study
•
Date and reason for off study
•
Date and cause of death
•
Autopsy findings if available

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15.3 APPENDIX C:  GUIDELINES FOR MANAGEMENT OF COMMON TOXICITIES THAT OCCUR 
AFTER CAR T-CELL INFUSIONS
Infusions of CAR T cells are often complicated by significant acute toxicities in the first 2 to 3 
weeks after the infusion.  In many cases the toxicities correlate with serum inflammatory cytokine 
levels. 
The toxicities most often experienced by patients receiving infusions of CAR T cells include, but 
are not limited to, tumor lysis syndrome, fever, fatigue, hypotension, tachycardia, acute renal 
failure, and neurological toxicities such as aphasia, ataxia, headache, somnolence, and coma.  
Fever is usually the first toxicity to occur.  
Note these are guidelines that might require modification based on clinical circumstances of each 
patient, and failure to exactly follow these guidelines is not a protocol deviation or violation.
Administration of corticosteroids should be avoided if possible to avoid killing or impairing the 
function of the CAR T cells.
General supportive care guidelines
1. All patients with significant malignancy burdens and without a contradiction such as allergy 
should be started on allopurinol at the time of the start of the chemotherapy conditioning 
regimen or 1 day before the CAR T cell infusion.  The suggested allopurinol dose is 200 to 
300 mg/day with a possible loading dose of 300 to 400 mg. 
2. Vital signs should be checked a minimum of every 4 hours during hospitalization.  Increasing 
the time interval between vital sign checks for patient convenience or other reasons should be 
avoided.
3. Strict ins and outs should be recorded on all patients.
4. As a minimum, keep hemoglobin greater than 8.0 g/dL and platelets greater than 
20K/microliter.
5. Administer fresh frozen plasma (FFP) for a PTT 1.5-fold or more above the upper limit of 
normal.
6. For patients with an increased PTT, check the fibrinogen level and keep the fibrinogen level 
above 100 mg/dL with cryoprecipitate.
7. Fevers should be treated with acetaminophen and comfort measures. NSAIDs and 
corticosteroids should be avoided.
8. Patients with a heart rate persistently higher than 115/minute and fever should have vital signs 
checked every 2 hours.
9. Patients who are neutropenic and febrile should be receiving broad-spectrum antibiotics.
10.  Avoid meperidine due to seizure risk.
11. Minimize benzodiazepine use to avoid aggravating delirium.  

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12. Patients on this protocol will be placed on strict fall precautions including instructions to get 
out of bed only with assistance under the following conditions:
1. Any history of syncope or near-syncope within 1 month before CAR T-cell infusion or 
any time after CAR T-cell infusion.
2. Any blood pressure reading of less than 100 mm Hg systolic blood pressure after anti-
CD19 CAR T-cell infusion if 100 mm Hg is lower than the patients baseline systolic 
blood pressure.
3. Heart rate greater than 100 beats per minute.
13. Any patient with syncope, near-syncope, or light-headedness will have orthostatic blood 
pressure and heart rate checked and receive intravenous fluids as appropriate.  These 
patients will also receive an ECG.
14. A CBC will be obtained twice daily while the patient is inpatient.  If the absolute neutrophil 
count becomes less than 500/microliter, Filgrastim will be initiated at a dose of 300 
micrograms daily for patients under 70 kg in weight and a dose of 480 micrograms daily for 
patients over 70 kg in weight only in patients with absolute neutrophil counts less than 
500/microliter.  Filgrastim will be discontinued as soon as the absolute neutrophil count 
recovers to 2000/microliter.
15. Hypotension is a common toxicity requiring intensive care unit (ICU) admission.  In general 
patients should be kept well-hydrated.  Maintenance I.V. fluids (normal saline (NS) should 
be started on most patients with high fevers especially if oral intake is poor or the patient has 
tachycardia.  I.V. fluids are not necessary for patients with good oral intake and mild fevers.  
For patients who are not having hypotension or tumor lysis syndrome, a generally even fluid 
balance should be strived for after allowing for insensible fluid losses in patients with high 
fevers.  The baseline systolic blood pressure is defined for this protocol as the average of all 
systolic blood pressure readings obtained during the 24 hours prior to the CAR T-cell infusion.  
The first treatment for hypotension is administration of IV NS boluses.  
•
Patients with a systolic blood pressure that is less than 80% of their baseline blood 
pressure and less than 100 mm Hg should receive a 1 L NS bolus. 
•
 Patients with a systolic blood pressure less than 90 mm Hg should receive a 1 L 
NS bolus if this is lower than their baseline blood pressure. 
These I.V. fluid management suggestions may need to be modified based on the clinical 
characteristics of individual patients such as pulmonary status, cardiac function, edema and 
other factors.
16. Patients receiving more than 1 fluid bolus for hypotension should have a stat EKG and 
troponin, and a cardiac echocardiogram as soon as possible.
ICU transfer 
Patients should be transferred to the ICU after consultation with the ICU physicians under 
these circumstances.  Patients not meeting these criteria could also require ICU admission at 
the discretion of the clinical team caring for the patient. 

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•
Systolic blood pressure less than 70% the patient’s baseline blood pressure and less 
than 100 mm Hg after administration of a 1L NS bolus.
•
Anytime the systolic blood pressure is less than 90 mm Hg after a 1L NS bolus.
•
Continuous tachycardia with a heart rate higher than 125 beats per minute on at least 
2 occasions separated by 2 hours.
•
Oxygen requirement of more than a 4L standard nasal cannula
1.  All patients transferred to the ICU for hypotension or tachycardia should have a stat EKG 
and a cardiac echocardiogram within 6 hours of the time of transfer.
2. Patients with hypotension not responding to IV fluid resuscitation should be started on 
norepinephrine at doses called for by standard ICU guidelines.
3. Patients should have a cardiac echocardiogram and an EKG within 6 hours of starting 
norepinephrine.
4. Patients in the ICU should get twice-daily labs (CBC with differential, acute care panel, 
mineral panel, hepatic panel, uric acid, LDH.  Patients in the ICU should also get a daily 
troponin level). 
5. Patients receiving vasopressors should have a cardiac echocardiogram at least every other 
day.
Immunosuppressive drug administration
In general, immunosuppressive drugs are administered in a stepwise escalation based on 
toxicity severity.  The first immunosuppressive drug administered is usually tocilizumab.  If 
toxicity does not improve after tocilizumab,  treatment progresses to  intermediate-dose or 
high-dose methylprednisolone.  For certain severe toxicities listed below, high-dose 
methylprednisolone must be given immediately. 
Tocilizumab administration
Tocilizumab should be administered under the following circumstances if the listed 
disorders are thought to be due to cytokine release from CAR T cells.  Tocilizumab is 
administered at a dose of 8 mg/kg infused IV over 1 hour (dose should not exceed 800 mg).
•
Left ventricular ejection fraction less than 45% by echocardiogram
•
Creatinine greater than 2-fold higher than the most recent level prior to CAR T-cell 
infusion
•
Norepinephrine requirement at a dose greater than 3 g/minute for 36 hours since 
the first administration of norepinephrine.
•
Requirement of  5 mcg/minute or more of norepinephrine to maintain systolic blood 
pressure greater than 90 mm Hg.
•
Oxygen requirement of 40% or greater fraction of inspired oxygen (FIO2) to 
maintain oxygen saturation of >92%.

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•
Subjective significant dyspnea and respiratory rate greater than 25 for 2 hours or 
more.
•
PTT or INR>2x upper limit of normal
•
Bleeding possibly related to cytokine-release syndrome
•
Creatine kinase greater than 5x upper limit of normal 
Intermediate-dose methylprednisolone for toxicities not responsive to 
tocilizumab
1. Give methylprednisolone 50 mg every 6 hours for any of the toxicities under #19 above that 
don’t improve after tocilizumab administration. 
High-dose methylprednisolone should be given immediately under these 
circumstances: 
1. Give methylprednisolone 200 mg every 6 hours for systolic blood pressure that is less than 
90 mm Hg while the patient is on 15 mcg/minute or higher doses of norepinephrine. If the 
patient has not had tocilizumab, give 8 mg/kg of tocilizumab along with the 
methylprednisolone.  
2. Give methylprednisolone 200 mg every 6 hours for hypotension requiring 15 mcg/minute or 
more of norepinephrine continuously for 8 hours or more.  If the patient has not already had 
tocilizumab, administer 8 mg/kg tocilizumab in addition to methylprednisolone.
3. Give methylprednisolone 200 mg every 6 hours for any left ventricular ejection fraction 30% 
or less.  If the patient has not already had tocilizumab, administer 8 mg/kg tocilizumab in 
addition to methylprednisolone.
4.  Give methylprednisolone 200 mg every 6 hours for any situation in which pulmonary toxicity   
makes mechanical ventilation likely to be required within 4 hours.  If the patient has not had 
tocilizumab, administer 8 mg/kg tocilizumab in addition to methylprednisolone.
5. In life-threating toxicity not improving after 200 mg of methylprednisolone, 1000 mg of 
methylprednisolone can be administered.
In general, stop corticosteroid use when toxicity improves to a tolerable level.  For example, 
in patients with hypotension, stop methylprednisolone  6 to 12 hours after vasopressors are 
no longer needed.
Neurological toxicity
1. All patients with neurological toxicities other than somnolence and delirium should get a 
neurology consult.

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2. All patients with significant neurological toxicity should get an MRI of the brain.
3. All patients with significant neurological toxicity should get a lumbar puncture after MRI if 
it is safe to perform a lumbar puncture.
4. The following patients should receive dexamethasone 10 mg intravenously every 6 hours 
until the toxicities improve.  Note:  for seizures administer standard seizure therapies in 
addition to dexamethasone.  For patients already getting higher doses of corticosteroids for 
CAR-related toxicity, it is not necessary to add dexamethasone 10 mg every 6 hours. Stop 
dexamethasone as soon as toxicity improves to a tolerable level; the duration of 
dexamethasone use will need to be determined on a patient to patient basis. Tocilizumab is 
possibly not effective for neurological toxicity, so it should not be given when patients have 
isolated neurological toxicity.
1.     Inability of patient to follow simple commands such as “squeeze my 
fingers”.
2.  Any generalized seizure
3. Somnolence that is different than normal sleep such as constant sleep or 
difficult to arouse or any difficulty with airway protection
4. Ataxia severe enough to preclude ambulation
5. Disorientation to person or place that persists continuously longer than 24 
hours
6. Neurologic toxicity lasting more than 2 hours that is severe enough to 
interfere with self-care activities of daily living (ADLs)
7. Severe agitation or confusion that limit the ability to care for the patient 
without restraints
    

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15.4 APPENDIX D: INFUSION INSTRUCTIONS   
Equipment:  
Primary IV tubing (2)
Secondary IV tubing (1)
NS (sodium chloride 0.9%) 250cc bags (2)
IV infusion pump
Gloves
Steps:
Key Points:
1.     The RN will be informed of the 
approximate time of cell arrival at 
the bedside.
2.  Verify the physician orders:
- to administer the cells
- for the date of administration
- for premedication orders 
- protocol number
•
Premeds are acetaminophen 650 mg PO 
and diphenhydramine 12.5 mg IV.
3.  Verify that the protocol consent 
4.  Ensure that emergency and monitoring  
equipment are available in the patient’s 
room:
-  oxygen
-  suction
-  vital sign monitor with pulse oximeter
   and thermometer   
5.  Provide patient education covering 
infusion procedure, potential complications 
and associated symptoms to report. 
7.  Measure and record baseline vital signs, 
respiratory and circulatory assessments.

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8.  Verify the patency of the patient’s IV 
access.
A central venous access device such as a 
non-valved PICC line should be used.
9.  Hang a primary line of 250cc NS at a kvo 
rate - NEW bag and NEW tubing. 
This MUST be ready and infusing prior to 
the cells being delivered to the unit.
The patient’s primary IV hydration can 
infuse via a separate lumen while the cells 
are infusing, but NO MEDs should be 
administered during this time. 
Have a second bag of 250cc NS and tubing 
ready as an emergency line.
This will be the dedicated NS line for 
infusing the cells.  Under no circumstances 
are any other substances to be infused into 
the line.  
Cell death occurs quickly – the infusion 
must be initiated immediately. 
Do not infuse medication during the cell 
infusion.  If emergency meds must be 
administered, 
use 
the 
hydration 
or 
emergency NS IV line. 
 This will be the emergency IV solution and 
can be used for medication administration.
Do not use an inline filter for cells. 
10.  The primary RN will be notified 
approximately 10 minutes before the cells 
arrive on the unit.  The cells will be hand 
delivered to the bedside.
It is critical to be at the bedside awaiting the 
arrival of the cells for infusion.  
It is critical to be at the bedside awaiting the 
arrival of the cells for infusion; have 
baseline VS, assessment, and IV lines 
hooked up when the cells arrive.  Cell death 
occurs as soon as the cells are removed 
from the laboratory.  Initiate the infusion 
as quickly as possible.
12.  Prior to spiking the cell bag, two RNs 
will perform the identification procedure.  
Both RNs must have their names charted in 
the CRIS cellular therapy flow sheet
13.   Infuse the cells by INFUSION PUMP 
or syringe over 20-30 minutes.
a. Piggyback the cells into the dedicated 
NS line; use the backflush technique 
to prime the line.
b.   While the cells are infusing, gently 
agitate the bag of cells every few 
minutes. When the cell bag is 
empty, backflush NS to rinse the bag 
This prevents the cells from clumping in the 
bag.

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and infuse this at the same rate as the 
cells; rinse bag until NS runs clear. 
        c.  Note: in some cases cells will arrive 
from DTM in a syringe.  In this case 
infuse the cells via syringe over 20-30 
minutes in the dedicated NS line 
proximal port, see nursing cellular 
infusion SOP for further details.
14.  Measure and record VS before and after 
the cell infusion, q1h x 4, and then q4h after 
completion of the infusion.  
a.Assess and document the    patient’s 
respiratory and circulatory status 
post cell infusion.  
15.  Documentation:
a.
After the cells have infused, remove 
the adhesive backed “cell therapy 
product” tag from the cell bag and 
place it on a progress note in the 
patient’s chart. 
b.    Document the cell infusion in  
CRIS using the appropriate screens.