Conditions: Myeloma-Multiple Myeloma, Plasma-Cell
Keywords: Chimeric Antigen Receptors B-cell Maturation Antigen Immunotherapy Adoptive T Cell Therapy
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 13
Healthy volunteers: no

Brief summary:
Background:

Multiple myeloma is a blood cancer that is usually incurable. T cells are part of the immune system. Researchers think changing a person's T cells to recognize their cancer could help the person's body kill tumor cells. This is a new approach that uses a patient's own cells to target multiple myeloma.

Objective:

To see if giving anti-Signaling lymphocytic activation molecule F7 (SLAM7) chimeric antigen receptor (CAR) T cells with a stop switch to people with multiple myeloma is safe and to see if adding a gene to stop T-cell activity can limit toxicity of this therapy.

Eligibility:

People ages 18-73 with multiple myeloma for which prior standard treatment has not worked

Design:

Participants will be screened with:

* Medical history
* Physical exam
* Blood, urine, and heart tests
* Bone marrow samples: A needle inserted into the participant's bone will remove marrow.
* Imaging scans: Participants will lie in a machine that takes pictures of the body.

Participants will have apheresis. They will receive a catheter or central line: A plastic tube will be inserted into a chest or arm vein. Blood will be removed and the T cells separated. The rest of the blood will be returned to the participant. The T cells will be manipulated in the lab.

Participants will get chemotherapy through the central line for 3 days.

Participants will receive the manipulated T cells through the central line. They will stay in the hospital at least 9 days.

Participants will have follow-up visits 2 weeks then 1, 2, 3, 4, 6, 9, and 12 months after the infusion. They will then have visits every 6 months for 3 years. Then they will be contacted once per year for 15 years. All visits will include blood tests, and 3 visits will include bone marrow biopsies....

Detailed description:
Background:

* Multiple myeloma (MM) is a nearly always incurable malignancy of plasma cells.
* T cells can be genetically modified to express chimeric antigen receptors (CARs) that target malignancy-associated antigens.
* Signaling lymphocytic activation molecule F7 (SLAM7) is highly and uniformly expressed on MM cells but is absent on normal tissues except for some leukocytes, including a subset of cluster of differentiation 8 (CD8)+ T cells, natural killer (NK) cells, B cells, plasma cells and monocytes.
* We have constructed a novel anti-SLAMF7 CAR that can specifically recognize SLAMF7- expressing target cells and eradicate SLAMF7-expressing tumors in mice.
* This protocol will test genetic modification of autologous T cells with genes encoding an inducible caspase 9 (IC9) cell-suicide system plus the anti-SLAMF7 CAR.
* Administration of the dimerizer drug Rimiducid (AP1903) is necessary to activate the inducible caspase 9 (IC9) suicide gene and eliminate CAR T cells.
* In this protocol, the suicide gene system will be used to eliminate CAR-expressing T cells in case of severe toxicities caused by the CAR T cells.
* Possible toxicities include cytokine-associated toxicities such as hypotension, and neurological toxicities. Elimination of NK cells and normal plasma cells could make patients more susceptible to infections. Unknown toxicities are also possible.

Objectives:

Primary

\- Determine the safety, feasibility of administering T cells expressing an anti-SLAMF7 CAR plus IC9 cell-suicide system 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 \>=0.6 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 1.5 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 immunomodulatory drug (IMiD) such as lenalidomide, and a proteasome inhibitor
* Patients must have a creatinine level of less than or equal to 1.5 mg/dL
* Patients must have a cardiac ejection fraction \>= 50%.
* An Eastern Cooperative Oncology Group (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/microL, platelet count \>= 55,000/microL, hemoglobin \>= 8g/dL
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 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 and initiation of protocol treatment. Systemic therapy includes corticosteroids at a dose equivalent to more than 5 mg of prednisone.
* Bone marrow plasma cells must make up less than or equal to 50% of total bone marrow cells less than or equal to 24 days prior to the start of protocol treatment.
* The patient's MM will need to be assessed for SLAMF7 expression by flow cytometry or immunohistochemistry performed at the National Institutes of Health (NIH). The myeloma must express SLAMF7. If unstained, paraffin-embedded bone marrow or plasmacytoma sections are available from prior biopsies, these can be used to determine SLAMF7 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 SLAMF7 expression. The sample for SLAMF7 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, and T cells will be modified to express the IC9-anti-SLAMF7 CAR construct.
* The chemotherapy conditioning regimen is cyclophosphamide 300 mg/m\^2 daily for 3 days and fludarabine 30 mg/m\^2 daily for 3 days. The intent of chemotherapy is to enhance CAR T-cell activity.
* After the chemotherapy ends, the patients will have two days with no treatments and then receive an infusion of CAR T cells.
* The initial dose level will be 0.66x10\^6 Anti-SLAMF7-CAR + T cells/kg of recipient bodyweight.
* The cell dose administered will be escalated for up to 4 doses 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 3 years after infusion.

Arms:
arm 1: Patients will receive escalating doses (up to 4 planned) of Anti-Signaling lymphocytic activation molecule F7 (SLAMF7)-CAR+ T cells infused on day 0 + Cyclophosphamide: 300 mg/m\^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3 + Fludarabine: 30 mg/m\^22 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4, and -3 arm 2: Maximum tolerated dose (MTD) dose of Anti-Anti-Signaling lymphocytic activation molecule F7 (SLAMF7)- CAR T Cells + Cyclophosphamide: 300 mg/m\^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3 + Fludarabine: 30mg/m\^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4, and -3

Interventions: intervention 1: Cyclophosphamide intervention 2: Fludarabine intervention 3: Rimiducid intervention 4: Anti-Signaling lymphocytic activation molecule F7 (SLAMF7) chimeric antigen receptor (CAR) T cells
Intervention descriptions: intervention 1: 300 mg/m\^2 intravenous (IV) over 30 minutes on days -5, -4, and -3 intervention 2: 30 mg/m\^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3 intervention 3: 0.4 mg/kg of Rimiducid intravenous (IV) over 2 hours. (A maximum of 2 doses separated by at least 48 hours) Note: Rimiducid may be administered as needed based on the patient condition at the discretion of the Principal Investigator. intervention 4: 0.3x10\^6- 12.0x10\^6 CAR+ T cells per kg of recipient bodyweight one-time dose on day 0

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
1 
Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
CC Protocol #: 19-C-0102 C 
IBC#: RD-19-III-02  
NCT#: NCT03958656 
Version Date: April 14, 2020 
Title:  A Phase I Clinical Trial of T-cells Expressing an anti-SLAMF7 CAR for Treating 
Multiple Myeloma 
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 
 
 
  
Agent Name: Anti-SLAMF7 
CAR- 
transduced 
autologous T cells  
Rimiducid 
IND 
Number: 
18793 
18793 
Sponsor: 
Center for Cancer Research 
Center for Cancer Research 
Manufacturer NIH DTM 
Bellicum Inc. 
 
Commercial Agents: Cyclophosphamide, fludarabine 
 
 


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
2 
PRÉCIS  
Background: 
• Multiple myeloma (MM) is a nearly always incurable malignancy of plasma cells.  
• T cells can be genetically modified to express chimeric antigen receptors (CARs) that target 
malignancy-associated antigens. 
• SLAMF7 is highly and uniformly expressed on MM cells but is absent on normal tissues except 
for some leukocytes, including a subset of CD8+ T cells, natural killer (NK) cells, B cells, plasma 
cells and monocytes.  
• We have constructed a novel anti-SLAMF7 CAR that can specifically recognize SLAMF7-
expressing target cells and eradicate SLAMF7-expressing tumors in mice.  
• This protocol will test genetic modification of autologous T cells with genes encoding an 
inducible caspase 9 (IC9) cell-suicide system plus the anti-SLAMF7 CAR.  
• Administration of the dimerizer drug Rimiducid (AP1903) is necessary to activate the IC9 
suicide gene and eliminate CAR T cells.  
• In this protocol, the suicide gene system will be used to eliminate CAR-expressing T cells in 
case of severe toxicities caused by the CAR T cells. 
• Possible toxicities include cytokine-associated toxicities such as hypotension, and neurological 
toxicities.  Elimination of NK cells and normal plasma cells could make patients more 
susceptible to infections. Unknown toxicities are also possible.  
Objectives: 
Primary 
• Determine the safety, feasibility of administering T cells expressing an anti-SLAMF7 CAR plus 
IC9 cell-suicide system 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 ≥0.6 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 1.5 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 immunomodulatory drug (IMiD) such as lenalidomide, 
and a proteasome inhibitor 
• Patients must have a creatinine level of < 1.5 mg/dL 
• Patients must have a cardiac ejection fraction > 50%. 
• An ECOG performance status of 0-2 is required. 


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
3 
• Patients on any anticoagulant medications except aspirin are not eligible. 
• No active infections are allowed. 
• Absolute neutrophil count ≥ 1000/µL, platelet count ≥ 55,000/µL, 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 and initiation of 
protocol treatment. Systemic therapy includes corticosteroids at a dose equivalent to more than 
5 mg of prednisone.  
• Bone marrow plasma cells must make up less than or equal to 50% of total bone marrow cells < 
24 days prior to the start of protocol treatment. 
• The patient’s MM will need to be assessed for SLAMF7 expression by flow cytometry or 
immunohistochemistry performed at the NIH.  The myeloma must express SLAMF7.  If 
unstained, paraffin-embedded bone marrow or plasmacytoma sections are available from prior 
biopsies, these can be used to determine SLAMF7 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 SLAMF7 expression.  The sample for SLAMF7 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, and T cells will be modified to express the IC9-anti-
SLAMF7 CAR construct. 
• The chemotherapy conditioning regimen is cyclophosphamide 300 mg/m2 daily for 3 days and 
fludarabine 30 mg/m2 daily for 3 days.  The intent of chemotherapy is to enhance CAR T-cell 
activity. 
• After the chemotherapy ends, the patients will have two days with no treatments and then 
receive an infusion of CAR T cells. 
• The initial dose level will be 0.66x106 Anti-SLAMF7-CAR + T cells/kg of recipient bodyweight. 
• The cell dose administered will be escalated for up to 4 doses 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 3 years after 
infusion. 
 


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
4 
TABLE OF CONTENTS  
PRÉCIS ..................................................................................................................................... 2 
TABLE OF CONTENTS.......................................................................................................... 4 
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 
Chimeric antigen receptor therapy in Multiple Myeloma .................................... 14 
1.2.7 
SLAMF7 .......................................................................................................... 17 
1.2.8 
Suicide Gene .................................................................................................... 20 
1.2.9 
Anti-SLAMF7 CAR development and preclinical testing ................................... 21 
1.2.10 Anti-SLAMF7 Therapy in MM: ........................................................................ 27 
1.2.11 Pre-clinical studies utilizing anti-SLAMF7 CAR T cells .................................... 28 
1.2.12 Summary of risks and potential benefits ............................................................ 29 
1.2.13 Toxicity............................................................................................................ 31 
1.2.14 Rationale for immunosuppressive chemotherapy and selection of lymphocyte-
depleting chemotherapy regimen ....................................................................... 32 
1.2.15 Rationale for dose-escalation and starting dose .................................................. 33 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT............................................. 34 
2.1 
Eligibility Criteria.................................................................................................... 34 
2.1.1 
Inclusion Criteria .............................................................................................. 34 
2.1.2 
Exclusion criteria: ............................................................................................. 36 
2.1.3 
Recruitment Strategies ...................................................................................... 37 
2.2 
Screening Evaluation ............................................................................................... 37 
2.2.1 
Screening activities performed prior to obtaining informed consent .................... 37 
2.2.2 
Screening activities performed after a consent for screening has been signed ...... 37 


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2.3 
Participant Registration and Status Update Procedures .............................................. 39 
2.4 
Treatment Assignment Procedures for the Registration Purposes Only: ..................... 39 
3 
STUDY IMPLEMENTATION ................................................................................ 40 
3.1 
Study Design ........................................................................................................... 40 
3.1.1 
General study plan ............................................................................................ 40 
3.1.2 
Protocol schema ............................................................................................... 41 
3.1.3 
Dose Limiting Toxicity-the dose limiting toxicity assessment period is 28 days. . 42 
3.1.4 
Dose Escalation ................................................................................................ 43 
3.2 
Dose Modifications/Delay ....................................................................................... 45 
3.3 
Drug Administration ................................................................................................ 45 
3.3.1 
Leukapheresis................................................................................................... 45 
3.3.2 
Anti-SLAMF7-CAR-expressing T-cell preparation ............................................ 46 
3.3.3 
Conditioning chemotherapy and CAR-SLAMF7 T-cell administration-chemotherapy 
administration can be either inpatient or outpatient ............................................ 46 
3.3.4 
Rimiducid administration .................................................................................. 48 
3.3.5 
Potential repeat treatment .................................................................................. 48 
3.4 
Protocol Evaluation ................................................................................................. 49 
3.4.1 
Baseline evaluations and interventions............................................................... 49 
3.4.2 
Studies to be performed on Day 0 and during the mandatory 9-day inpatient 
admission after cell infusion.............................................................................. 51 
3.4.3 
Post-infusion outpatient evaluation .................................................................... 52 
3.5 
Study Calendar ........................................................................................................ 55 
3.6 
Gene-therapy-specific follow-up .............................................................................. 61 
3.7 
Criteria for Removal from Protocol Therapy and Off Study Criteria .......................... 61 
3.7.1 
Criteria for removal from protocol therapy......................................................... 61 
3.7.2 
Off-Study Criteria ............................................................................................. 62 
3.8 
Protocol Stopping Criteria........................................................................................ 62 
4 
CONCOMITANT MEDICATIONS/MEASURES.................................................... 63 
4.1 
Antibiotic prophylaxis ............................................................................................. 63 
4.2 
Blood product support ............................................................................................. 63 
4.3 
Anti-emetics ............................................................................................................ 63 
4.4 
Granulocyte colony-stimulating factor...................................................................... 63 
4.5 
Avoidance of corticosteroids .................................................................................... 64 


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4.6 
Toxicity management guidelines .............................................................................. 64 
5 
BIOSPECIMEN COLLECTION.............................................................................. 64 
5.1 
CORRELATIVE STUDIES FOR RESEARCH ........................................................ 64 
5.1.1 
Biospecimen collection before the start of the conditioning chemotherapy: ......... 64 
5.1.2 
Biospecimen collection Day 0 and after CAR T-cell infusion during the required 
hospitalization .................................................................................................. 64 
5.1.3 
Biospecimen collection during outpatient follow-up........................................... 65 
5.1.4 
Immunological Testing ..................................................................................... 65 
5.1.5 
Biospecimen collection with Rimiducid administration: ..................................... 66 
5.1.6 
Additional biopsies and additional blood draws ................................................. 66 
5.1.7 
Future studies ................................................................................................... 67 
5.2 
Sample Storage, Tracking and Disposition ............................................................... 67 
5.2.1 
Samples Sent to Figg Lab.................................................................................. 67 
5.2.2 
Sample Storage, Tracking and Disposition......................................................... 67 
5.2.3 
Sample Storage, Tracking, and Disposition for Surgery Branch .......................... 69 
5.2.4 
Protocol Completion/Sample Destruction .......................................................... 69 
5.2.5 
Samples for Genetic/Genomic Analysis ............................................................. 69 
6 
DATA COLLECTION AND EVALUATION .......................................................... 70 
6.1 
Data Collection ....................................................................................................... 70 
6.1.1 
Adverse event recording: .................................................................................. 70 
6.2 
Data Sharing Plans .................................................................................................. 71 
6.2.1 
Human Data Sharing Plan ................................................................................. 71 
6.3 
Genomic Data Sharing Plan ..................................................................................... 71 
6.4 
Response Criteria .................................................................................................... 71 
6.4.1 
Important Considerations on response criteria .................................................... 71 
6.4.2 
International Myeloma Working Group uniform response criteria: ..................... 72 
6.4.3 
Minimal residual disease (MRD) criteria (requires complete response as defined 
above) .............................................................................................................. 74 
6.5 
Toxicity Criteria ...................................................................................................... 75 
7 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
 
75 
7.1 
Definitions .............................................................................................................. 75 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting .................................... 75 


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
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7.2.1 
Expedited Reporting ......................................................................................... 75 
7.2.2 
IRB Requirements for PI Reporting at Continuing Review ................................. 75 
7.3 
NCI Clinical Director Reporting .............................................................................. 75 
7.4 
Institutional Biosafety Committee (IBC) Reporting Criteria ...................................... 75 
7.4.1 
Serious Adverse Event Reports to IBC .............................................................. 75 
7.4.2 
Annual Reports to IBC...................................................................................... 76 
7.5 
NIH Required Data and Safety Monitoring Plan ....................................................... 77 
7.5.1 
Principal Investigator/Research Team................................................................ 77 
7.5.2 
Safety Monitoring Committee (SMC) ................................................................ 77 
8 
Sponsor Safety Reporting ........................................................................................ 77 
8.1 
Definitions .............................................................................................................. 77 
8.1.1 
Adverse Event .................................................................................................. 77 
8.1.2 
Serious Adverse Event (SAE) ........................................................................... 77 
8.1.3 
Life-threatening ................................................................................................ 78 
8.1.4 
Severity ............................................................................................................ 78 
8.1.5 
Relationship to Study Product ........................................................................... 78 
8.2 
Assessment of Safety Events.................................................................................... 78 
8.3 
Reporting of Serious Adverse Events ....................................................................... 79 
8.4 
Safety Reporting Criteria to the Pharmaceutical Collaborators .................................. 79 
8.4.1 
Reporting by CCR to Bellicum Pharmaceuticals Inc........................................... 79 
8.4.2 
Reporting by Study Team to Bellicum Pharmaceuticals Inc. ............................... 80 
8.5 
Reporting Pregnancy ............................................................................................... 80 
8.5.1 
Maternal exposure ........................................................................................... 80 
8.5.2 
Paternal exposure.............................................................................................. 80 
8.6 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND................. 81 
9 
CLINICAL MONITORING..................................................................................... 81 
10 
STATISTICAL CONSIDERATIONS ...................................................................... 81 
10.1 
Statistical Hypothesis............................................................................................... 81 
10.2 
Sample Size Determination ...................................................................................... 82 
10.3 
Populations for Analyses ......................................................................................... 83 
10.4 
Statistical Analyses.................................................................................................. 83 
10.4.1 General Approach ............................................................................................. 83 


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
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8 
10.4.2 Analysis of the Primary Endpoints..................................................................... 83 
10.4.3 Analysis of the Secondary Endpoint(s) .............................................................. 83 
10.4.4 Safety Analyses ................................................................................................ 83 
10.4.5 Baseline Descriptive Statistics ........................................................................... 83 
10.4.6 Planned Interim Analyses.................................................................................. 83 
10.4.7 Sub-Group Analyses ......................................................................................... 83 
10.4.8 Tabulation of individual Participant Data........................................................... 83 
10.4.9 Exploratory Analyses ........................................................................................ 83 
11 
COLLABORATIVE AGREEMENTS...................................................................... 84 
11.1 
Clinical Trial Agreement ......................................................................................... 84 
12 
HUMAN SUBJECTS PROTECTIONS.................................................................... 84 
12.1 
Rationale For Subject Selection................................................................................ 84 
12.2 
Participation of Children .......................................................................................... 85 
12.3 
Participation of Subjects Unable to Give Consent ..................................................... 85 
12.4 
Evaluation of Benefits and Risks/Discomforts .......................................................... 85 
12.4.1 Risks of exposure to Ionizing Radiation............................................................. 87 
12.5 
Consent Process and Documentation ........................................................................ 87 
13 
PHARMACEUTICAL INFORMATION ................................................................. 88 
13.1 
Retroviral Vector Containing the CAR-SLAMF7 Gene............................................. 88 
13.1.1 Cells manufacturing .......................................................................................... 88 
13.1.2 Source .............................................................................................................. 88 
13.1.3 Toxicities ......................................................................................................... 88 
13.1.4 Administration procedures: ............................................................................... 88 
13.2 
Commercial Agents: ................................................................................................ 88 
13.2.1 Cyclophosphamide ........................................................................................... 89 
13.2.2 Fludarabine ...................................................................................................... 89 
13.3 
Rimiducid ............................................................................................................... 89 
13.3.1 Source .............................................................................................................. 89 
13.3.2 Toxicity............................................................................................................ 89 
13.3.3 Formulation and preparation ............................................................................. 89 
13.3.4 Administration procedures: ............................................................................... 91 
14 
REFERENCES........................................................................................................ 92 


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
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9 
15 
APPENDICES ...................................................................................................... 104 
15.1 
Appendix A: Performance Status Criteria ............................................................... 104 
15.2 
Appendix B: Data Collection Elements Required By Protocol................................. 105 
15.3 
Appendix C:  Guidelines for management of common toxicities that occur after CAR 
T-cell infusions ..................................................................................................... 107 
15.4 
Appendix D:   Infusion Instructions........................................................................ 112 
15.5 
Appendix E:   CARTOX (Adapted from Neelapu et al, 2018): ................................ 115 
15.6 
Appendix F:   Cytokine Release Syndrome Grading Assessment (Adapted from Lee et 
al, 2019). ............................................................................................................... 116 
 


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
10 
1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
• Determine the safety and feasibility of administering T cells genetically modified to express 
a novel chimeric antigen receptor (CAR) targeting signaling lymphocyte activation molecule 
family member 7 (SLAMF7) and an inactivated caspase 9 cell-suicide system to patients 
with multiple myeloma (MM).   
1.1.2 Exploratory Objectives 
• Evaluate the in vivo persistence and phenotype of the CAR T cells.  
• Assess for associations between toxicity and immunologic parameters including blood and 
bone marrow CAR T-cell and cytokine levels. 
• Assess CAR T cells for anti-MM activity post infusion by evaluating MM responses by 
standard methods. 
• Assess efficacy of Rimiducid to eliminate CAR T cells in patients with severe infections and 
other toxicities 
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 
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.  Recently, three  phase 1 trials 
have shown that CAR T cells targeting B-cell maturation antigen (BCMA) are effective and have a 
tolerable safety profile in relapsed multiple myeloma.(5-8) The lasting complete remissions of MM 
that sometimes occur in the setting of alloHSCT and the encouraging results obtained treating 
patients with anti-BCMA and anti-CD19-CAR-expressing T cells are rationales for attempting to 
develop CAR T-cell therapies for MM.  
Signaling lymphocyte activation molecule 7 (SLAMF7), also known as CRACC, CS1 or CD319, is 
a homophilic, glycosylated cell surface protein that is uniformly expressed at high levels in MM as 
shown by gene expression studies and immunohistochemical analysis of whole blood, 
plasmacytomas and bone marrow tissue.(6, 9-13) Although SLAMF7 is expressed on a proportion 
of various lymphocyte subsets including NK cells, NKT cells, some CD8+ T cells, some B cells, 
some monocytes/macrophages and some dendritic cells, it is not expressed on normal 
nonhematopoietic tissues.(9) The limited expression of SLAMF7 in normal tissues makes it a 


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
11 
promising target for CAR T-cell therapies. However, to mitigate potential toxicities that may occur 
with the depletion of endogenous NK, CD8+ T cells, and other SLAMF7-expressing leukocytes, we 
have engineered a DNA construct that includes CAR and a suicide gene that can be activated if 
prolonged or severe toxicities occur.  
This protocol describes a novel T-cell therapy for patients with relapsed/refractory MM. This new 
CAR differs from prior anti-myeloma CAR therapies by targeting an antigen that is uniformly and 
highly expressed on MM cells as well as incorporating a suicide gene to limit toxicity of therapy. 
The anti-SLAMF7 CAR will incorporate a CD28 costimulatory domain.  This 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 demonstrates that depleting endogenous 
lymphocytes, and possibly other leukocytes, with chemotherapy or total body irradiation 
dramatically increases the anti-tumor activity of adoptively transferred T cells.(14-16)  After the 
lymphocyte-depleting chemotherapy, patients will receive an infusion of autologous anti-SLAMF7-
CAR T cells.  The T cell dose will escalate with sequential cohorts of patients until a maximum 
tolerated dose is determined. 
 
1.2.2 Multiple myeloma epidemiology and standard treatment 
Multiple myeloma (MM) is a neoplasm of monoclonal plasma cells.(17, 18)  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.(18, 19)  MM is the second 
most frequently occurring hematologic cancer in the United States (U.S.).(18)  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.(20)  Recent improvements in the therapy of MM have occurred.(17, 18, 
21)  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.(18, 21)   
Current standard therapies for MM include various combinations of dexamethasone, bortezomib and 
its analogs, lenalidomide and its analogs, prednisone, melphalan, and cyclophosphamide.(17, 18, 21, 
22)  Myeloablative doses of chemotherapy followed by autologous stem cell transplantation (ASCT) 
is a standard therapy for MM patients with good performance status, and adequate bone marrow 
stem cells.(18, 21)  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.(18, 21) Myeloablative chemotherapy followed by autologous transplantation can also be used 
as a treatment for relapsed MM in some cases.(18, 21, 23)   Use of the International Uniform 
Response Criteria for Multiple Myeloma is the most common approach for assessing clinical 
outcomes in MM.(24)  Despite the recent improvements in treatment, MM remains an almost always 
incurable disease.(21, 25, 26)  Patients obtaining remissions of MM almost always relapse.(21)  The 
median overall survival of patients with relapsed MM is 3 years or less.(25)   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.(27)  In patients with MM 
that was refractory to bortezomib, the median overall survival was only 9 months when the patient 


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12 
was also either ineligible for thalidomide or lenalidomide, or the patient had MM that was relapsed 
or refractory to thalidomide or lenalidomide.(26)  Utilizing the immune system to treat MM is one 
possible way to improve therapy of MM. Recently published data from two phase 1 clinical trials 
utilizing anti-BCMA CAR T cells to treat relapsed/refractory MM have produced promising results. 
An NCI trial demonstrated an ORR of was 81% with 63% very good partial remissions or complete 
remission; a multi-center clinical trial of a different anti-BCMA CAR demonstrated ORR of 94% in 
18 patients at 40 weeks.(5, 6) 
 
1.2.3 Allogeneic transplantation for MM 
Allogeneic stem cell transplantation (alloHSCT) can cure a fraction of patients with MM.(28, 29)  
Myeloablative alloHSCT can induce long-term complete remissions of MM, but also has a 
transplant-related mortality rate (TRM) of 20% to 50%.(28, 29)  The high TRM of myeloablative 
alloHSCT led investigators to test nonmyeloablative alloHSCT for MM.(28-30) 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, 28, 29)  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, 30) 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, 28, 29)  Direct 
evidence that lymphocytes can eliminate MM comes from donor lymphocyte infusions (DLIs).(2, 
29)  Twenty-two to twenty-eight percent of patients receiving DLIs to treat persisting MM after 
alloHSCT have achieved complete remissions (CRs).(2, 28, 29)  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 disease(2, 28, 29) 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.(31-38)  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.(3-6, 35, 39, 40)  Genetically modified antigen-specific T cells 
can be generated from peripheral blood mononuclear cells (PBMC) in sufficient numbers for clinical 


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13 
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 selection(4, 39, 
41, 42), and genetic modification of mature T cells with gammaretroviruses has a long history of 
safety in humans.(43-45)  There are two general approaches for generating antigen-specific T cells 
by genetic modification: introducing genes encoding natural αβ T cell receptors (TCRs) or 
introducing genes encoding chimeric antigen receptors (CARs).(32, 34, 35, 37)  CARs are fusion 
proteins incorporating antigen recognition moieties and T cell activation domains.(36, 46-48)  The 
antigen-binding domains of most CARs currently undergoing clinical and preclinical development 
are antibody variable regions.(32, 36, 46, 48)  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 molecules(32, 34, 35, 46), 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.(32, 35, 49-51) 
 
1.2.5 Chimeric antigen receptors 
Preclinical experiments evaluating CAR-expressing T cells as cancer therapy were initiated in 
1993.(52, 53)  These experiments led to a clinical trial of CAR-transduced T cells targeting the α-
folate receptor on ovarian cancer cells; no tumor regressions were observed during this clinical 
trial.(54)  CARs that were capable of recognizing a variety of tumor-associated antigens have been 
evaluated in many centers.(32, 46)  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 gammaretroviruses(4, 39, 41-43, 55-57), lentiviruses(3, 58-61), or 
transposon systems(62, 63) 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, 55, 64)  
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 CD3ζ 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.(46, 55, 59, 65-67)  Much of the preclinical work evaluating CARs has 
been performed with CARs targeting the B-cell antigen CD19.(15, 55-57, 62, 68, 69) 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.(57, 66)  These studies showed that adding CD28 moieties to CARs enhanced antigen-specific 
cytokine production and proliferation by anti-CD19 CAR T cells.(66, 70, 71)  T cells expressing 
CARs with CD28 signaling moieties and CD3ζ signaling domains were more effective than T cells 
expressing CARs without CD28 moieties at eradicating human leukemia cells from mice.(70, 71)  
Subsequently, CARs incorporating other signaling domains from costimulatory molecules such as 
4-1BB (CD137) were developed.(58)  Anti-CD19 CARs containing the signaling domains of both 
4-1BB and CD3ζ were superior to CARs containing the signaling domains of CD3ζ without any 
costimulatory domains at eradicating human malignant cells from mice.(59, 65)   Similar to CD28, 
including 4-1BB signaling moieties in CARs led to increased CD19-specific proliferation and 
enhanced in vivo persistence.(59)  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-


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14 
containing CAR occurred whether or not the T cells were exposed to the antigen that the CAR 
recognized.(59, 65)   
Results from several clinical trials of anti-CD19 CAR T cells have been reported to date in peer-
reviewed papers.(3, 4, 39, 41, 42, 72-75)  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 in a 
patient who experienced a dramatic regression of advanced follicular lymphoma.(41)  This clinical 
trial utilized a gammaretroviral vector to introduce an anti-CD19 CAR containing the signaling 
domains of the CD28 and CD3ζ molecules.(41) Subsequent development of this CAR was carried 
out, and it was found that anti-CD19 CAR T cells were an effective therapy for a variety of B-cell 
malignancies.(74, 76) Subsequent studies with this same CAR demonstrated the effectiveness of 
anti-CD19 CAR T cells against diffuse large B-cell lymphoma and led to multicenter phase II trials 
and FDA approval.(74) 
 
1.2.6 Chimeric antigen receptor therapy in Multiple Myeloma 
Success of CAR T-cells against leukemia and lymphoma has encouraged development of CAR T-
cell therapies for MM. A critical factor in determining the success or failure of a CAR-T therapy is 
the choice of target antigen. It is important that a selected antigen is uniformly expressed on the 
malignancy targeted by CAR T cells.(77-80) MM is a clonal malignancy, but over time, multiple 
sub-clones of MM evolve.(81-85) This leads to genetic and phenotypic heterogeneity of the MM 
cells within the same patient.(83, 84, 86) This phenotypic heterogeneity includes differences in cell 
surface antigen expression.(85) To avoid toxicity, the targeted antigen should be absent on essential 
normal tissues because CAR T cells might destroy cells expressing the target antigen whether the 
antigen-expressing cells are normal or malignant. Many potential CAR targets in MM have been the 
subject of pre-clinical testing including CD44 variant 6, CD70 and CD56.(87-90) CARs with CD19, 
immunoglobin kappa light chain and BCMA moieties have been tested both in the preclinical and 
clinical trial setting:   
 
CD19:  
Several investigators have reported a population of cells that are distinct from the bulk population 
of malignant MM plasma cells; these cells phenotypically resemble B-cells and their role might be 
that of a cancer stem cell.(82, 86, 91-93)  Circulating B-cells that are clonally related to malignant 
plasma cells have been characterized in patients with MM; in-vitro studies suggest that CD138-
negative cells that express B-cell surface antigens including CD45, CD20 and CD19 can give rise to 
myeloma colonies.(82, 86, 91, 92, 94) Several studies suggest that the postulated myeloma stem cells 
have intrinsic drug-resistant properties that may promote relapse.(82, 92, 94) Garfall et al. 
hypothesized that CAR-Ts targeting CD19 would deplete myeloma cells with stem cell properties 
after myeloablative chemotherapy and standard ASCT.(95, 96) Ten myeloma patients who had a 
history of progressive MM after a prior ASCT received a second ASCT followed by an infusion of 
5x107 anti-CD19 CAR T cells 12-14 days after infusion of stem cells.(95, 96)  The ASCT 
chemotherapy conditioning regimen was 140-200 mg/m2 of melphalan.(96) CD19+ cells were 
detected at low levels among the MM plasma cells of seven of the nine patients evaluated by flow 
cytometry of pre-ASCT bone marrow; in these 7 patients 0.5-1.5% of MM cells were CD19+.(96)  
This finding emphasizes that anti-CD19 CAR-Ts are intended to target MM stem cells, not the bulk 


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15 
population of MM cells.  All 10 treated patients have progressed; the median PFS was 185 days 
(range 42-479).(96)  
 
Immunoglobulin Kappa Light Chain:  
Plasma cells do not generally express cell-surface immunoglobulin, but Ramos et al have employed 
a strategy to target a postulated multiple myeloma stem cell population that expresses surface 
immunoglobulins by generating a CAR targeting kappa light chain.(97) Targeting kappa-expressing 
cells spares lambda-expressing B-lymphocytes.(97) In a phase I study, seven patients with multiple 
myeloma were treated with kappa-targeted CAR-T cells.(97) All seven MM patients had active 
disease at the time of CAR-T infusion and had one or more lines of prior chemotherapy; six out of 
seven patients had an ASCT in the past.(97) Three patients received salvage chemotherapy within 
four weeks prior to infusion of CAR-T.(97) Those who did not have prior chemotherapy within four 
weeks of CAR-T infusion or who did not have an ALC <500 received 12.5 mg/kg cyclophosphamide 
prior to infusion of CAR-T cells.(97) Four patients had SD lasting six weeks to 24 months, and three 
patients had no response to kappa CAR-T infusion.(97)  
 
BCMA:  
B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells but not 
normal essential cells. BCMA is not expressed by hematopoietic stem cells or nonhematologic 
cells.(5, 98, 99) It is uniformly expressed on most cases of MM by IHC.(5)  By flow-cytometry, cell-
surface BCMA was expressed at varying levels by almost all cases of MM.(5) In pre-clinical work, 
T-cells expressing anti-BCMA CARs could specifically recognize BCMA, kill primary myeloma 
cells in vitro, and eradicate BCMA+ tumors in mice.(98)   
 
This pre-clinical work led to the first in-humans clinical trial of CAR T cells targeting BCMA at the 
National Cancer Institute (NCI).(5) An anti-BCMA CAR containing a murine scFv, a CD8 hinge 
and transmembrane region, a CD28 costimulatory domain, and a CD3ζ T-cell activation domain was 
created by synthesizing the appropriate DNA and ligating it into a gamma-retroviral backbone.(5) 
Patients who had MM with uniform BCMA expression by either immunohistochemistry (IHC) or 
flow cytometry were enrolled.(5) 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.(5, 74, 77, 100)  The chemotherapy regimen used was cyclophosphamide 300 mg/m2 and 
fludarabine 30 mg/m2 given daily on the same 3 days followed by CAR T-cell infusion 2 days after 
the end of the chemotherapy.(5)  Administration of chemotherapy or radiation therapy to deplete 
recipient leukocytes has been shown to enhance the activity of adoptively-transferred T cells.(15, 16, 
101)  
Twenty-six patients with MM were treated on this study at the NCI. Patients were treated at doses 
of 0.3-9x106 CAR+ T cells/kg. Of the patients treated on 0.3- 3x106 CAR+ T cells/kg, patients had a 
median of 7 prior lines of therapy; of the patients treated on the highest dose level of 9x106 CAR+ T 
cells/kg, patients had a median of 9.5 prior lines of therapy with 63% refractory to their last 
treatment.(8) At doses of 0.3-3x106 CAR+ T cells/kg, 2 of 10 patients experienced objective 
responses of PR or better.(8) Of the 16 patients who received BCMA CAR T cells at a dose of 9x106 
CAR+ T cells/kg, 13 patients had responses of PR or better.(5, 8) The overall response rate for these 
patients was 81%.(8) All but one patient on the highest dose level had a substantial decrease in their 


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16 
serum MM markers.(8) The median event-free survival for patients treated at a cell dose of 9x106/kg 
was 31 weeks with six patients having ongoing remissions.(8) To date, five responses have lasted 
more than 6 months.(8) In nine of nine patients that were evaluated with bone marrow biopsies and 
immunohistochemistry staining for CD138 before and 2 months after CAR-BCMA infusion, bone 
marrow plasma cells steeply decreased between these 2-time points.(8) Of the 16 patients receiving 
9x106 CAR+ T cells/kg, 11 patients were evaluable for minimal residual disease (MRD), and all 
achieved MRD negative status following CAR-BCMA T-cell infusion.(8) CAR-BCMA T-cell 
toxicity was mild at lower dose levels, with no CRS grades of 3 or 4 at cell doses of 0.3-3x106 CAR+ 
T cells/kg.(5) At a cell dose of 9x106 CAR+ T cells/kg, CRS related toxicities were substantial.(8, 
102) As the dose of CAR T cells escalated, patients began to have more symptoms of cytokine 
release syndrome, including fever and tachycardia.(5) The first two patients treated with 9x106 CAR+ 
T cells/kg experienced substantial cytokine release syndrome (CRS) toxicities. Because of the 
toxicities experienced by these two patients, the latter 14 patients treated with 9x106 CAR-BCMA 
T cells/kg were required to have lower MM burdens with BM involvement by myeloma of less than 
30% prior to cell infusion.(8) Six of sixteen patients receiving 9x106 CAR-BCMA T cells/kg (38%) 
required vasopressor support for hypotension for CRS following CAR T-cell infusion, and one 
patient required mechanical ventilation.(8) Five patients (31%) received tocilizumab and 3 patients 
(19%) received corticosteroids for CRS-related toxicities.(8) Two patients received stress-dose 
hydrocortisone for evidence of adrenal insufficiency before or during CRS.(8) Patients with CRS of 
Grade 3 or 4 had higher levels of bone marrow plasma cells compared with patients who had less 
than Grade 3 CRS, which indicates an increased chance of severe CRS in patients with high MM 
burdens(8).  
Neurologic toxicities were limited to confusion or delirium in the setting of high fevers during CRS 
except for one patient who experienced encephalopathy and grade 3 muscle weakness of all 
extremities that was thought due to critical illness polyneuropathy.(8)  
Most cytopenias occurred early after CAR-BCMA T-cell infusion and were attributable to 
chemotherapy, but two cases of cytopenias occurred after recovery of blood counts from 
chemotherapy-related cytopenias. Neutropenia rapidly resolved after filgrastim support in both of 
these cases.(8) Both patients received the thrombopoietin receptor agonist eltrombopag and 
prednisone. Platelets recovered to greater than 50,000/µL without platelet transfusions by 63 and 53 
days after CAR-BCMA T-cell infusion in the two patients. Toxicities were managed without long-
lasting complications.(5, 8)  
A second anti-BCMA CAR T-cell clinical trial was conducted by bluebird bio and Celgene Inc. and 
was a multicenter trial.(6) Twenty-one patients with relapsed/refractory MM were treated with 
bb2121, an anti-BCMA CAR-T that expresses a CAR with the same scFv as the anti-BCMA CAR 
used at the NCI.(5, 6)  In contrast to the NCI anti-BCMA CAR, bb2121 had a 4-1BB costimulatory 
motif, and was encoded by a lentivirus.(6)  Bb2121 was administered after cyclophosphamide plus 
fludarabine lymphocyte-depleting chemotherapy and at planned dose levels of 50, 150, 450, 800, 
and 1,200 x 106 CAR+ T cells.(6) As of May 2017, 21 heavily-pretreated patients were evaluable 
for clinical response.(6) Of these, three patients were treated on the lowest dose level. The lowest 
dose level had minimal anti-myeloma activity and minimal toxicity. Patients had a median of 7 prior 
lines of therapy and all patients had a history of an autologous transplant.(6) Median follow-up after 
bb2121 infusion was 15.4 weeks.(6) There were no reported grade 3 or higher neurotoxicity events 
on the dose-escalation phase of this trial, but one patient did experience Grade 4 neurologic toxicity 


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17 
on the expansion phase of this trial. CRS was primarily Grade 1 or 2 in 15 of 21 patients (71%); 2 
patients had Grade 3 CRS that resolved in 24 hours.(6) Four patients received tocilizumab and one 
patient received steroids to manage CRS.(6) The ORR was 89% and increased to 100% for patients 
treated with doses of 150 x 106 CAR+ T cells or higher.(6) No patients treated with doses of 150 x 
106 CAR+ T cells or higher had disease progression with time of follow up between 8 and 54 
weeks.(6) MRD negative results were obtained in all 4 patients evaluable for analysis.(6)  Of the 18 
patients treated at doses above the first dose level, the overall response rate (PR or better) was 94% 
and the CR rate was 56%. 
Cohen et. al 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.(7) One patient was treated 
with 1.8x108 CAR-Ts, two with 2x108 CAR-Ts and three patients at the highest dose level of 5x108 
CAR-Ts.(7)  Toxicities were similar to those published by Ali et. al, except for an episode of grade 
4 posterior reversible encephalopathy syndrome (PRES) that manifested as severe delirium, seizures, 
obtundation and cerebral edema.(7) This was treated with steroids, anti-epileptics, and interestingly, 
cyclophosphamide; there was no long-term neurological dysfunction.(7) Reported results show one 
patient has a stringent CR at seven months with an MRD-negative bone marrow by flow 
cytometry.(7) 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.(7)  
Currently, a new clinical trial has opened targeting CD38 (clinicaltrials.gov: NCT03464916).  CD38 
is a transmembrane glycoprotein involved in cell-adhesion, signal transduction and calcium 
regulation.(103, 104) It is normally expressed on precursor B-cells, plasma cells, T-cells, NK-cells, 
and myeloid precursors.(104-106) Among non-hematologic organs, CD38 is expressed on prostate 
cells, in the nervous system, gut, muscle cells, and on osteoclasts.(104, 105) Two monoclonal 
antibodies against CD38 have been tested clinically, Daratumumab and Isatuximab.(107, 108) 
Although at an early stage of development, CAR T cells have great promise to improve MM 
treatment. 
 
1.2.7 SLAMF7 
Signaling lymphocyte activation molecule 7 (SLAMF7), also known as CRACC, CS1 or CD319, is 
a homophilic, glycosylated cell surface protein and member of a larger signaling family of receptors 
involved in the effector functions of hematopoietic cells. (109-112) Receptors in this family 
modulate function through tyrosine switch motifs and intracellular adaptor proteins.(109, 112-114) 
The SLAMF7 structure is comprised of an extracellular region containing a single Ig variable-like 
domain and a single C2 domain, a transmembrane domain and a cytoplasmic domain with two 
tyrosine-based switch motifs.(111, 115) 
A critical factor for any antigen to be considered as a target for immunotherapy is the antigen’s 
expression pattern in normal tissues. Although SLAMF7 is highly expressed in almost all cases of 
MM it has very limited or absent expression on normal tissues aside from leukocytes such as CD8+ 
T cells, natural killer (NK) cells, B cells, plasma cells, some monocytes, NKT cells, and some 
dendritic cells. (9, 10, 110, 112, 113)  Notably, hematopoietic stem cells do not express 
SLAMF7.(111) SLAMF7 is not expressed on the surface of normal organ epithelial tissue such as 


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18 
lung, kidney, stomach, brain, breast, spleen, prostate, skeletal muscle, testis, liver, ovary, heart, 
thymus and small intestine epithelial tissue.(9, 10, 12) In one study by Hsi et al, organs staining 
positive for SLAMF7 were evaluated further by peri-cellular staining to detect infiltrating leukocytes 
and double staining with CD138 to detect plasma cells. Results showed that organs staining positive 
for SLAMF7 were due to the presence of infiltrating leukocytes and plasma cells, consistent with 
the published expression profile of SLAMF7.(9) Plasma cells and MM cells express higher levels 
of SLAMF7 mRNA and protein than on any other lymphocyte subset.(9)  
In Figure 1, actin cDNA copies and SLAMF7 cDNA copies were measured by qPCR in all of the 
samples, and the results were expressed as the number of SLAMF7 cDNA copies per 105 actin cDNA 
copies. 
Figure 1 
 
 
We went on to evaluate SLAMF7 protein expression in normal human organs.  Except for plasma 
cells and rare lymphocytes, we did not detect SLAMF7 protein expression by the cells of any of the 
organs that we stained.  We detected plasma cells expressing cell-surface SLAMF7 in 
gastrointestinal organs.  SLAMF7 expression by normal plasma cells probably accounts for the low 
levels of SLAMF7 RNA detected in these organs because we did not detect SLAMF7 expression by 
P la s m a c y to m a
A d re n a l
B o n e  m a rro w
B ra in
C e rv ix
C o lo n
D u o d e n u m
E p id id y m u s
E s o p h a g u s
F a t
H e a rt
S m a ll In te s tin e
In tra c ra n ia l A rte ry
K id n e y
L iv e r
L u n g
L y m p h  N o d e
B lo o d  le u c o c y te s
M a m m a ry  g la n d
M u s c le
N a s a l M u c o s a
O p tic  n e rv e
O v a ry
O v id u c t
P a n c re a s
0
1 0 0 0
2 0 0 0
3 0 0 0
S L A M F 7  c o p ie s /1 0
5  a c tin  c o p ie s
S L A M F 7  c o p ie s /1 0
5  a c tin  c o p ie s
P la s m a c y to m a
P e n is
P e ric a rd iu m
P itu ita ry
P la c e n ta
P ro s ta te
R e c tu m
R e tin a
S e m in a l v e s ic le s
S k in
S p in a l c o rd
S p le e n
S to m a c h
T e s tis
T h y m u s
T h y ro id
T o n g u e
T o n s il
T ra c h e a
U re th ra
B la d d e r
U te ru s
U v u la
V a g in a
V e n a  c a v a
0
1 0 0 0
2 0 0 0
3 0 0 0


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19 
any of the other cells except plasma cells and some lymphocytes and rare macrophages in these 
organs.   
Table 1 
 
 
SLAMF7 is highly and uniformly expressed on MM tumor cells in whole blood and in the bone 
marrow detected by both gene expression and IHC; according to studies, 80-95% of primary 
myeloma cells collected from MM patients express SLAMF7.(9-13) It is not as strongly or as 
uniformly expressed on NK cells, CD8+ T cells, B cells, monocytes or dendritic cells.(9, 10)  
 
SLAMF7 is expressed on normal leukocytes, including NK cells and CD8+ T cells. A small fraction 
of monocytes and CD4+ T cells also express SLAMF7 (Figure 2). Figure 2 shows the results of flow 
cytometry analysis on unmanipulated peripheral blood mononuclear cells (PBMC). The results show 
that CD3-negative, CD56+ NK cells almost all express SLAMF7. Also, a large fraction of 
CD3+CD8+ cells express SLAMF7. 
adrenal 
bladder 
bone  
breast 
cerebellum 
cerebral cortex
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 
tonsil
uterine cervix 
uterine endometrium
Organs stained for SLAMF7 by immunohistochemistry and found to lack SLAMF7 
expression except on plasma cells, some macrophages and some lymphocytes 


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20 
Figure 2 
 
 
 
SLAMF7 is expressed on MM cells independent of cytogenetic abnormalities.(116-118) 
Amplification of chromosome 1q23, the location of SLAMF7 gene family, is associated with more 
aggressive myeloma and unfavorable prognosis.(111) SLAMF7 is strongly and uniformly expressed 
in extramedullary plasmacytomas, lymphoplasmacytic lymphoma and bone marrow core samples of 
MM patients. Expression in MM persists after disease relapse and after proteasome inhibitor 
treatment.(111) Serum levels of soluble SLAMF7 correlate with stage and activity of MM in 
patients.(119) Downregulation of SLAMF7 in MM cells has been associated with reduced MM cell 
survival.(118) SLAMF7 may play a role in MM cell-bone marrow interactions.(111),(114)  
Under normal conditions, SLAMF7 receptors play a role in regulating immune cell functions, such 
as cell adhesion, growth and survival; however, the receptor’s full role is incompletely 
understood.(12, 112, 114) SLAMF7 receptor signaling may exert activating or inhibitory actions on 
cells depending on which lymphocyte subset is engaged and which adaptor protein is present. (9, 10, 
120) For example, SLAMF7 is thought to be important for NK cell-mediated anti-viral activities and 
general tumor surveillance when the EAT-2 adaptor protein is present; however, SLAMF7 signaling 
that occurs in the absence of EAT-2 signaling in CD4 T cells, CD8 T cells and NKT cells leads to 
decreased proliferation and cytokine secretion.(9, 10, 120)  In MM, SLAMF7 signaling lacks EAT-
2 downstream activation, thus MM cells do not proliferate with receptor engagement.(117) 
1.2.8 Suicide Gene  
The high expression of SLAMF7 on MM cells makes it an attractive target for CARs aimed at MM, 
but because of the expression of SLAMF7 on normal leukocytes, a mechanism for eliminating anti-
SLAMF7 CAR T cells after infusion into patients is necessary. In one pre-clinical study, cell line 
experiments from MM patients and healthy donors showed that on average 17.3% of NK cells, 
Gated on CD3-negative PBMC
Gated on CD3-negative PBMC
Gated on CD3-positive PBMC
Gated on CD3-positive PBMC
SLAMF7
SLAMF7
SLAMF7
SLAMF7
CD56
CD14
CD4
CD8


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
21 
35.4% of CD8+ T cells, 66.5% of B cells and 85% of CD4+ T cells were viable at the end of the 
fratricide assay with an anti-SLAMF7 CAR T cells.(10).  Thus, to mitigate potential toxicity caused 
by lymphocyte depletion, the inducible caspase 9 system iCasp9  (IC9) is the preferred safety switch 
for this project because of its proven clinical effectiveness.(121) The IC9 system has been found to 
be safe and well tolerated and is the most clinically-tested of the various suicide gene systems.(121, 
122) 
The IC9 suicide gene system requires that T cells are genetically modified to express the IC9 
gene.(121) The IC9 gene contains part of the apoptotic protein human caspase 9 protein fused to a 
drug binding domain derived from human FK-506 binding protein-12 (FKBP12).(123) Activation 
of the caspase 9 domain of the iCasp9 protein is dependent on dimerization with a small molecule 
drug, Rimiducid (AP1903) which cross-links the FKBP12 domains, initiating the apoptotic pathway 
of the T cell(122). T lymphocytes transduced with the IC9 system were shown in-vitro to retain their 
immune potential and can be eliminated with exposure to the dimerizing drug with high specificity 
and potency(122). The dimerizer drug, Rimiducid, has no reported effects on cells other than those 
engineered with the suicide gene.(124) The transgene is made from human products thus conferring 
low immunogenicity potential.(121, 124) Maximal killing occurred at about 0.3 ng/ml.(122) Pre-
clinical studies with CAR T cells show that T cells engineered with the IC9 transgene were able to 
be eliminated within 3 days or less of administration; however, in the clinical setting, GVHD was 
controlled much faster than 3 days in some patients. (121, 125) An advantage of this system is that 
it utilizes endogenous apoptotic pathways, resulting in rapid elimination of the transduced cells.(121, 
122) 
In the clinical setting, the IC9 system has been shown to be safe and efficacious in a trial to rapidly 
control graft-versus-host-disease in patients who underwent stem cell transplantation for 
leukemia.(121) Five patients who had undergone haploidentical allogeneic stem cell transplantation 
for relapsed acute leukemia were treated with T cells engineered with the IC9 system. (121) These 
T cells propagated in vivo showing that the expression of IC9 did not inhibit survival or in vivo 
expansion of the transduced cells. Skin GVHD (four patients) and liver GVHD  (one patient) 
developed in four patients; a single dose of dimerizing drug eliminated more than 90% of the 
modified T cells within 30 minutes after administration, which resulted in the end of GVHD in those 
patients without recurrence. (121) The dimerizing drug had no effect on the endogenous CD3+CD19-
negative untransduced T-cell population or on other blood counts. (121) Within 24 hours of infusion, 
GVHD abnormalities began to resolve and normalized within 24-48 hours after infusion.(121) No 
evidence of an immune response to the transgenic T cells was found.(121)  
The four patients who developed GVHD in the clinical trial received 0.4 mg/kg of the dimerizing 
agent Rimiducid as a 2-hour infusion. (121) In a different study, pharmocokinetic data showed that 
the plasma concentration following administration of Rimiducid doses ranging from 0.01 to 1.0 
mg/kg resulted in plasma concentrations of 10 to 1275 ng/ml with plasma levels falling to 18% of 
the maximum half an hour after infusion and 7% of the maximum 2 hours after the infusion.(121, 
122) At these concentrations, pre-clinical studies showed little variation in the induction of apoptosis 
among patients with consistent elimination of more than 90% of IC9-expressing cells.3 The terminal 
half life of Rimiducid is 5 hours (in vivo). (121)   
1.2.9 Anti-SLAMF7 CAR development and preclinical testing 
The suicide gene plus anti-SLAMF7 CAR construct to be assessed in this protocol contains the IC9 
suicide gene, which is made up the of an FKBP12 dimerization domain and a caspase 9 domain, as 


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
22 
described in section 1.2.8, followed by a thosa asigna virus 2A (T2A) ribosomal skip domain 
followed by an anti-SLAM F7 CAR. The antigen recognition domain of the CAR is a single chain 
variable fragment from the murine Luc90 antibody. The anti-SLAMF7 CAR contains the hinge and 
transmembrane regions of the human CD8α molecule, the signaling moiety of the CD28 
costimulatory molecule, and the signaling domains of the CD3ζ molecule.  The CAR is designated 
Luc90-CD828Z (Figure 3). The clinical gene therapy vector encoding IC9-Luc90-CD828Z is 
MSGV1, which has been used in many prior clinical trials at the NCI.(126)  
 
Figure 3 
 
 
After transductions, we found high levels of cell surface expression of the Luc90-CD828Z anti-
SLAMF7 CAR on the transduced T cells as shown in the representative example in Figure 4. 
Figure 4 
 
Figure 4 shows Luc90-CD828Z CAR expression on T cells from a multiple myeloma patient 5 days 
after transduction with gammaretroviruses encoding the Luc90-CD828Z.  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. Staining of untransduced T cells is also shown. The plots are gated 
on live, CD3+ lymphocytes. 
We also performed a series of in vitro assays to assess the function of anti-SLAMF7-CAR-
expressing T cells, and we found that Luc90-CD828Z-CAR-expressing T cells exhibited SLAMF7-
specific activities including CD107a upregulation and cytokine production in vitro.  These 
experiments showed that anti-SLAMF7-CAR-expressing T cells are activated in a SLAMF7-
specific manner. 
 
Caspase9
FKBP12               
T2A
CD3ζ
Luc90 scFv
CD28
SS
CD8α
IC9-Luc90-CD828Z       Untransduced
CD3
CAR+


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
23 
Figure 5 
 
Figure 5 shows upregulation of CD107a, which indicates degranulation and correlates with 
cytotoxicity when Luc90-CD828Z CAR-expressing CD8+ T cells (top row)  or CD4+ T cells (bottom 
row) were cultured with the SLAMF7-expressing cell line MM.1S.  CD107a was not upregulated 
when Luc90-CD828Z-CAR-expressing T cells were cultured for 4 hours with the SLAMF7-negative 
control cell line NGFR-K562.  Untransduced T cells did not upregulate CD107a when cultured with 
either MM.1S or NGFR-K562 (not shown).  The plots are gated on live CD3+ lymphocytes.   
T cells transduced with IC9-Luc90CD828Z suicide gene plus CAR construct and T cells 
transduced with the Luc90CD828Z CAR alone both produced large amounts of IFNγ when they 
were cultured overnight with the SLAMF7-expressing cell lines SLAMF7-K562 and MM.1S 
(Table 2 
).  In contrast, the anti-SLAMF7 CAR-expressing T cells produced only background levels of IFNγ 
when they were cultured with the SLAMF7-negative target cell lines NGFR-K562 and CCRF-
CEM.  The anti-SLAMF7-CAR-transduced T cells also made minimal IFNγ when cultured 
without any target cell.  As expected, untransduced T cells and T cells expressing the anti-CD19 
CAR Hu19-CD828Z released only low levels of IFNγ in response to all target cells. The 
experiment depicted in Table 2 
 consisted of culturing the T cells with the indicated target cell lines overnight and then performing 
a standard IFNγ enzyme-linked immunosorbant assay (ELISA) to detect IFNγ in the culture 
supernatant. 
IC9-Luc90-CD828Z
+MM.1S
IC9-Luc90-CD828Z
+NGFR-K562
IC9-Luc90-CD828Z
+MM.1S
IC9-Luc90-CD828Z
+NGFR-K562
CD107a
CD107a
CD8
CD8
CD4
CD4


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
24 
Table 2 
 
A second ELISA experiment performed in a similar manner utilizing T cells from a different 
patient is shown in Table 3 
.  In the experimental results shown in Table 3 
, four different types of effector T cells from the same multiple myeloma patient were evaluated, 
untransduced T cells, T cells expressing the Hu19-CD828Z anti-CD19 CAR, T cells expressing the 
Luc90-CD828Z anti SLAMF7 CAR, and T cells expressing the IC9 suicide gene  plus Luc90-
CD828Z plus. The untransduced T cells and T cells expressing the anti-CD19 CAR expressed only 
background levels of IFNγ against all target cells. T cells expressing either Luc90-CD828Z or IC9-
Luc90-CD828Z specifically recognized SLAMF7 as shown by the high levels of IFNγ released when 
the CAR-expressing T cells were cultured with the SLAMF7+ target cells SLAMF7-K562; in 
contrast, the CAR-expressing T cells produced much lower levels of IFNγ when cultured with the 
SLAMF7-negative target cell lines A431-H9, Panc10.05, U251, COLO205, HEPG2, A549, TC71, 
and 624. T cells alone made low levels of IFNγ for all T cell types evaluated.   
Table 3 
 
Table 4 
 shows ELISA results from an experiment in which effector T cells were cultured in the presence of 
soluble SLAMF7 protein at concentrations ranging from 0 ng/mL to 200 ng/mL.  Effector T cells 
used in this experiment were T cells from the same patient transduced with one of 2 anti-SLAMF7 
CARs, either Luc90-CD828Z or Luc63-CD828Z. Untransduced T cells were also assessed.  Target 
cells used in this experiment were either SLAMF7-RPMI (RPMI8226 cells transduced with the 
SLAMF7 gene) or NGFR-K562 cells, which are SLAMF7-negative. The T cells and target cells 
were cultured together overnight, and IFNγ was measured in the culture supernatant by a standard 
ELISA assay.  The presence of soluble SLAMF7 protein did not block recognition of the RPMI8226 
SLAMF+ target cells. SLAMF7 protein also did not cause nonspecific activation of the T cells.  All 
numbers are pg/mL IFNγ. The concentration of soluble SLAMF7 added is shown in ng/mL. 
T cells
SLAMF7-
K562
MM.1S
NGFR-
K562
CCRF-CEM
T cells 
alone
%CAR+
Untransduced
231.4
170.5
138.2
64.7
4.9
Hu19-CD828Z
57.0
68.6
48.1
39.0
38.6
58.2
Luc90-CD828Z
90780.1
22519.4
22.9
19.2
18.6
83.0
IC9-Luc90-CD828Z
76955.3
30188.4
32.9
14.2
21.1
50.2
Target 
cells
T cells
SLAMF7-K562 A431-H9
Panc
10.05
U251
COLO205 HEPG2
A549
TC71
624
T cells %CAR+
Untransduced
598.0
48.4
395.2
165.4
48.4
41.2
17.9
28.8
31.0
44.4
0.3
Hu19-CD828Z
521.8
129.5
367.3
173.3
74.2
398.4
87.5
247.1
144.6
89.4
29.9
IC9-Luc90-
CD828Z
77961.3
423.8
390.6
217.1
496.6
212.2
349.0
722.1
662.7
215.7
42.0
Luc90-CD828Z
104728.5
509.7
526.3
227.5
749.0
196.8
447.9
522.9
823.2
247.5
68.1


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
25 
Table 4 
 
Figure 4 presents the results of a 4-hour cytotoxicity assay in which MM.1S cells were used as target 
cells for either Hu19-CD828Z anti-CD19 negative-control T cells, or T cells transduced with the 
anti-SLAMF7 CAR Luc90-CD828Z, or T cells transduced with the IC9 suicide gene and Luc90-
CD828Z CAR (IC9-Luc90-CD828Z).  MM.1S is SLAMF7+ and CD19-negative. The graph gives 
specific cytotoxicity of MM.1S cells relative to the negative-control SLAMF7-negative CCRF-CEM 
cell line.  T cells expressing either Luc90-CD828Z or IC9 plus Luc90-CD828Z were able to cause 
specific cytotoxicity of the SLAMF7+ cell line. 
Figure 6 
 
Anti-SLAMF7-CAR-transduced T cells also proliferated in a SLAMF7-specific manner. Figure 7 
shows a carboxyfluorescein diacetate,succinimidyl ester (CFSE) proliferation assay in which anti-
SLAMF7-CAR-transduced T cells were cultured for 4 days with either SLAMF7-K562 cells or 
SLAMF7-negative NGFR-K562 cells.  In a series of experiments, we compared 2 CAR plus suicide 
gene constructs. In Luc90-CD828Z-IC9, the sequence of the CAR is followed by the IC9 suicide 
gene. In IC9-Luc90-CD828Z, the suicide gene sequence comes first and is followed by the CAR 
gene. CFSE was diluted to a greater degree, indicating more proliferation, when the T cells 
transduced with either of the CAR plus suicide gene constructs were cultured with SLAMF7-K562 
target cells (open histogram in Figure 7) compared to when T cells were cultured with SLAMF7-
negative NGFR-K562 target cells (solid red histogram in Figure 7).  The solid red histogram 
representing culture of anti-SLAMF7 CAR T cells with NGFR-K562 cells is smaller than the open 
Target 
cells
T-cells
SLAMF7 
RPMI
0 ng/ml
SLAMF7 
RPMI  
50 ng/mL
SLAMF7 
RPMI  
200 ng/mL
NGFR
K562 
0 ng/mL
NGFR 
K562    
50 ng/mL
NGFR K562 
200 ng/mL
T cells
0 ng/mL
T cells
50 ng/mL
T cells
200 ng/mL
Luc90-CD828Z
23538
23315
21301
267
223
224
172
160
41
Luc63-CD828Z
3495
2873
3083
191
98
83
20
22
30
Untransduced
504
451
501
564
433
507
23
22
25
Targets alone
5
5
5
5
200 ng/mL soluble SLAMF7 
alone: 6
2 0 : 1
6 . 7 : 1
2 . 2 : 1
0 . 7 : 1
0
2 5
5 0
7 5
1 0 0
E : T   R a t i o
%
 C y t o t o x i c i t y
H u 1 9 - C D 8 2 8 Z
L u c 9 0 - C D 8 2 8 Z
I C 9 - L u c 9 0 - C D 8 2 8 Z


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
26 
histogram representing culture of anti-SLAMF7 T cells with SLAMF7-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.(127)  In multiple experiments, we consistently found equivalent 
in vitro proliferation of T cells expressing Luc90-CD828Z-IC9 compared with T cells expressing 
IC9-Luc90-CD828Z. 
Figure 7 
We established MM.1S human multiple myeloma cell line tumors in immunodeficient mice.  We 
allowed sizable tumors to develop over 7  days, and then we treated the mice with a single 
intravenous infusion of T cells transduced with either the anti-SLAMF7 CAR Luc90-CD828Z or T 
cells transduced with Luc90-CD828Z plus the IC9 suicide gene. Control groups included mice 
treated with untransduced T cells or T cells transduced with the anti-CD19 CAR Hu19-CD828Z. 
After infusion of anti-SLAMF7-CAR T cells, dramatic regressions of all tumors occurred between 
day 6 and day 18 after the T cell infusion. In contrast, tumors continued to increase in size in all 
untreated mice and mice treated with the T cells expressing the Hu19-CD828Z anti-CD19 CAR. 
Mice receiving anti-SLAMF7-CAR T cells survived while untreated mice and mice receiving T cells 
expressing the anti-CD19 CAR Hu19-CD828Z developed large tumors that required that the mice 
be euthanized (Figure 8 ). In the experiments depicted in Figure 8, anti-SLAMF7-CAR T cells were 
infused on Day 0, and no other treatments were administered, and there were 5 mice in all groups. 
Figure 8 
 
Luc90-CD828Z-IC9
IC9-Luc90-CD828Z
D a y s  a f t e r  T  c e l l  i n f u s i o n
P e r c e n t  S u r v i v a l
0
6
1 2
1 8
2 4
3 0
3 6
0
2 0
4 0
6 0
8 0
1 0 0
H u 1 9 - C D 8 2 8 Z
I C 9 - L u c 9 0 - C D 8 2 8 Z
L u c 9 0 - C D 8 2 8 Z
U n t r e a t e d
0
3
6
9
1 2
1 5
1 8
2 1
2 4
2 7
3 0
3 3
3 6
0
2 0 0
4 0 0
6 0 0
8 0 0
1 0 0 0
D a y s  a f t e r  T  c e l l  i n f u s i o n
T u m
o r  V o l u m
e  i n  m
m
3
U n t r e a t e d
H u 1 9 - C D 8 2 8 Z
I C 9 - L u c 9 0 - C D 8 2 8 Z
L u c 9 0 - C D 8 2 8 Z


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
27 
 
 
We conducted in vitro experiments to demonstrate the activity of AP1903 (Rimiducid) against T 
cells expressing both the Luc90-CD828Z CAR and the inactivated caspase 9 (IC9) suicide gene. We 
transduced T cells with MSGV-IC9-Luc90-CD828Z and then exposed them to graded 
concentrations of AP1903 in vitro for 6 hours prior to performing flow cytometry (Figure 9). 
Application of AP1903 caused a rapid disappearance of CAR+ T cells, and most of the residual T 
cells were apoptotic as indicated by their annexin V+ status (Figure 9). In a human clinical trial, the 
mean peak serum concentrations of AP1903 achieved with a single dose of 0.5 mg/kg of AP1903 
was 626 ng/mL(122), so the in vitro concentrations that we assessed were substantially lower than 
clinically-achievable concentrations. 
Figure 9 
 
 
1.2.10 Anti-SLAMF7 Therapy in MM: 
Elotuzumab, a humanized IgG1 kappa monoclonal antibody, in combination with lenalidomide and 
dexamethasone is an FDA approved therapy shown to have activity in MM in clinical trials.(117, 
118, 128) Elotuzumab exerts it’s effect through several mechanisms: elotuzumab impairs MM cell 
adhesion and exerts direct effects on primary MM cell survival in vitro; it mediates antibody-
dependent cellular cytotoxicity mediated through NK cell interaction; and it directly activates NK 
cells through SLAMF7 receptor ligation.(9, 10, 129-131) In pre-clinical studies, elotuzumab did not 
exhibit cytotoxicity against NK cells.(9, 10, 129-131)  
CD3
CD3
CAR+
0 ng/mL                         1 ng/mL                       10 ng/mL                      100 ng/mL
0 ng/mL                           1 ng/mL                      10 ng/mL                      100 ng/mL
Annexin V
Rimiducid (AP1903) eliminates >90% of IC9-Luc90-CD828Z CAR T cells only 6 hours after exposure


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
28 
As a single agent, elotuzumab did not result in objective responses in a phase 1 trial in heavily 
pretreated MM.(132) At doses of 10 mg/kg and 20 mg/kg elotuzumab, SLAMF7 receptors on bone 
marrow-derived myeloma cells were consistently saturated.(132) Lower dose groups exhibited more 
variation of target cell saturation.(132) No opportunistic viral or fungal infections were seen on any 
dose of elotuzumab used in this phase 1 trial.(132) Transient decreases in absolute lymphocyte 
counts were observed after the first elotuzumab infusion only and resolved by day 7 of follow-
up.(132) The transient decrease in lymphocytes (both SLAMF7 positive and negative NK cells, 
CD8+ T cells, CD4+ T cells and B cells) coincided with increase in IP-10 a chemokine that stimulates 
migration of activated T cells and NK cells.(132) There was no evidence of lymphocyte depletion 
associated with repeated dosing of elotuzumab and cytotoxicity was observed against MM cells but 
not against autologous NK cells.(132)  
In a phase 3 trial, the combination of elotuzumab, lenalidomide and dexamethasone versus 
lenalidomide and dexamethasone in patients with relapsed refractory MM, resulted in a 30% 
decrease in the risk of disease progression or death.(117, 118, 131-133) The 1-year PFS rate in the 
elotuzumab cohort was 68% versus 57% in the control group.(117, 118, 131-133) The PFS was 
maintained at the 3 year extended follow up with a trend toward improved overall survival.(117, 
118, 131-133)  
In a phase 2 trial comparing bortezomib plus dexamethasone with the combination plus elotuzumab, 
PFS was statistically significantly longer in the elotuzumab group with a 28% reduction in the risk 
of progression of death.(118)  
Results from pre-clinical work and clinical trials involving elotuzumab offer proof of principle that 
SLAMF7 may be a suitable target for future targeted T-cell therapy.  
1.2.11 Pre-clinical studies utilizing anti-SLAMF7 CAR T cells 
Several pre-clinical studies utilizing an anti-SLAMF7 CAR T-cell have been carried out.(10, 11, 13, 
116) These studies show that T cells engineered to target SLAMF7 can be expanded and have 
activity in eradicating MM cells. 
Several groups shown that MM cells from patients with untreated MM as well as relapsed/refractory 
MM express high, uniform levels of SLAMF7 on their surface despite prior proteasome inhibitor or 
immunomodulatory therapy.(9-11, 13, 116) Mathur et al and Wang et al report that >90% of MM 
cases they tested uniformly express SLAMF7.(11, 13)  
Chu et al engineered an anti-SLAMF7 CAR with a CD28 costimulatory domain that was able to kill 
SLAMF7+ cells in MM cell lines, primary myeloma cells and mouse models.(116) The antigen 
density of SLAMF7+ determined the rate of killing in their experiments; in cell lines where 
SLAMF7 was expressed at low levels (RPMI8226), the anti-SLAMF7 CARs were not as effective 
at killing.(116) However, in cell lines with high expression of SLAMF7 (NCI-H929 and IM9) and 
in primary MM cells from patients with relapsed disease, the anti-SLAMF7 CAR was able to kill 
SLAMF7+ cells with high efficiency.(116) Furthermore, in a mouse model, anti-SLAMF7 CAR T 
cells suppressed growth and prolonged mouse survival; 44 days after treatment, their group observed 
a 100% survival rate for IM9 bearing mice receiving anti-SLAMF7 CAR T-cell infusion as 
compared with 28.6% of the control mice receiving mock T cells.(116)  
Gogishvili et al created and tested anti-SLAMF7 CAR T cells with a CD28 costimulatory domain 
that was able to exert rapid and specific high level cytolysis of all SLAMF7+ myeloma targets in 


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
29 
vitro with cell lines and primary MM cells from patients with either untreated or relapsed/refractory 
disease.(10) The anti-SLAMF7 CAR was able to eradicate systemic myeloma in a xenograft mouse 
model that was sustained until the end of the 8-week observation period.(10)  
Hypothesizing that T cells collected from MM patients are associated with anergy, Mathur et al have 
devised a system to engineer allogeneic anti-SLAMF7 CD4+ and CD8+ CAR T cells.(11) In order 
to decrease the potential for GVHD potentially associated with allogeneic CAR-T cells, Mathur et 
al have used gene editing technology to knock out endogenous TCR genes.(11) To further limit 
toxicity, they have included an elimination gene for safety that is activated by rituximab 
administration.(11) In pre-clinical studies, anti-SLAMF7 allogeneic T cells proliferate when co-
cultured with myeloma cell lines and primary myeloma tumors but not in co-culture with control 
cells.(11) The anti-SLAMF7 allogeneic T cells eradicated established MM and induced durable 
remissions in mouse models.(11)   
Finally, Wang et al sought to enhance the immune functions of anti-SLAMF7 CAR T cells by 
expanding the CAR T cells in the presence of lenalidomide in vitro.(13) Their pre-clinical results 
demonstrate that lenalidomide enhanced antitumor activity and persistence of the adoptively 
transferred anti-SLAMF7 CAR T cells in vivo mouse model including improving cytotoxicity, 
memory maintenance, Th1 cytokine production and immune synapse formation.(13)   
Due to the expression of SLAMF7 on lymphocyte subsets and the toxicity potential with eradicating 
these lymphocytes with anti-SLAMF7 therapy, Gogishvili et al conducted a series of experiments 
aimed at determining the fratricide potential that could occur with anti-SLAMF7 CAR-T 
therapy.(10) They first demonstrated expression of the SLAMF7 protein on a fraction of naive and 
memory CD4+ and CD8+ T cells, NK and NKT cells, monocytes, and B cells that were obtained 
from the peripheral blood of MM patients.(10) After co-culture of autologous anti-SLAMF7 CAR 
T cells, they used flow-cytometry cytotoxicity assays to assess the fratricide potential.(10) They 
found that in each lymphocyte subset, a population of SLAM+high and SLAM-/low cells existed. 
Furthermore, engineered T cells reverted to a SLAMF7-/low state. CD8+ SLAMF7-negative CAR T 
cells induced fratricide of SLAMF7+high cells but spared the SLAMF7-/low fraction of cells.(10) These 
SLAMF7-/low CD4 and CD8 lymphocytes were viable and functional based on IFN-gamma secretion 
after stimulation.(10) Their experiments demonstrated that on average 17.3% of NK cells, 35.4% of 
CD8+ T cells, 66.5% of B cells, and 85% of CD4+ T cells were viable at the end of the fratricide 
assay with SLAMF7-CAR T cells incubated with cell lines and primary MM cells.(10) Furthermore, 
they found that the SLAMF7-/low T cells were able to respond to specific antigens including CMV 
after incubation with anti-SLAMF7 CAR T cells.(10) Their data suggests that although anti-
SLAMF7 CAR T-cell therapy may deplete lymphocytes that express high levels of SLAMF7, a 
subset of effector immune cells might be preserved that will provide protection against common 
pathogens including cytomegalovirus (CMV).(10) Similarly, Chu et al demonstrated that although 
their engineered anti-SLAMF7 CAR T cells were able to kill high SLAMF7 expressing MM cell 
lines, the CAR-T cells were unable to effectively kill cell lines that expressed low levels of 
SLAMF7.(116)   
 
1.2.12 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.  Only patients with multiple myeloma who 


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
30 
have persisting or relapsed myeloma despite at least 3 prior lines of therapy will be enrolled. The 
risks of the study fall into six categories.   
The first category is chemotherapy-related toxicity that could cause cytopenias. As with any 
chemotherapy that causes neutropenia and thrombocytopenia, this chemotherapy could cause 
toxicities such as infections and bleeding. CAR T cells might also cause cytopenias. 
The second category of toxicity is cytokine-release-type toxicities such as high fevers, tachycardia, 
transient abnormalities of liver function and hypotension. These cytokine-release-type toxicities 
have been detected in other clinical trials of CAR T cells during the first two weeks after anti-CD19 
CAR T cells and anti-BCMA CAR T cells were infused.(4, 5, 134) 
A third category of potential toxicities are neurological toxicities such as delirium, obtundation, 
myoclonus, seizures, headache and transient focal neurological toxicities including aphasia and focal 
paresis. In previous anti-CD19 CAR trials, cytokine-release toxicities and neurological toxicities 
have been limited in duration with toxicities generally resolving within 2 days to 3 weeks.(5, 41, 74, 
135, 136) In the NCI anti-BCMA trial, neurologic toxicities were limited to confusion or delirium 
in the setting of high fevers and one case of encephalopathy and muscle weakness of all extremities 
consistent with critical illness polyneuropathy/polymyopathy.(5) In most cases, these toxicities have 
been transient with toxicities generally resolving within 2 days to 2 weeks.   
The fourth category of toxicity is direct damage to normal tissues by the CAR T cells.  This could 
happen because of unexpected cross-reactivity of the CAR T cells with proteins other than SLAMF7 
in vivo. This trial will be one of the first in human trials testing anti-SLAMF7 CAR T cells in 
patients. Although SLAMF7 is highly expressed in almost all cases of MM it has very limited or 
absent expression on normal tissues aside from leukocytes.(9, 10, 110, 112, 113)  Hematopoietic 
stem cells do not express SLAMF7.(111) SLAMF7 is not expressed on the surface of normal organ 
epithelial tissue such as lung, kidney, stomach, brain, breast, spleen, prostate, skeletal muscle, testis, 
liver, ovary, heart, thymus and small intestine epithelial tissue.(9) We have performed extensive 
testing of the MSGV-IC9-Luc90CD828Z CAR T cells by culturing them with a variety of human 
cell lines and have not seen recognition of cell lines that did not express SLAMF7. In addition, we 
did not find any evidence of cross-reactivity in our cell line data or immunohistochemistry data from 
the NIH Department of Pathology.  
A fifth category of toxicity that may be caused by anti-SLAMF7 T cells is impairment of normal 
immunity because SLAMF7 is expressed on leukocytes such as CD8+ T cells, natural killer (NK) 
cells, B cells, plasma cells, some monocytes, NKT cells, and some dendritic cells.(5, 9, 10, 110, 112, 
113) NK cell deficiencies are associated with severe, potentially life-threatening viral infections 
caused typically by members of the Herpesviridae (VZV, HSV, CMV, EBV) and Papillomaviridae 
(HPV) families.(137) Additionally, NK cells have potent cytotoxic activity against malignant cells 
and NK cell defects are linked to ineffective tumor surveillance and clearance. We have included a 
suicide gene in this trial in large part to allow elimination of anti-SLAMF7 CAR T cells in case 
depletion of recipient immune cells leads to infections.  
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.(43, 


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31 
44)  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, 33, 138, 139) 
The potential benefits to subjects enrolling on this trial include the possibility that the anti-SLAMF7-
CAR T cells can cause a significant anti-myeloma effect. Many patients enrolled on trials of anti-
CD19 CAR T cells and anti-BCMA CAR T cells obtained complete remissions of their advanced 
malignancies; there is a chance that recipients of the CAR-SLAMF7 T cells that are being evaluated 
in this protocol could 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 that might help future patients. 
1.2.13 Toxicity 
Cytokine Release Syndrome:  
The primary acute toxicity observed to date with B cell malignancy-targeted and BCMA-targeted 
CAR T cells has been CRS, and this protocol will grade CRS as defined by Lee et al. (2019).(102) 
For this protocol, a CRS is defined as a constellation of symptoms which may include (but are not 
limited to) fever, chills, hypotension, dyspnea, hypoxia, confusion, mental status changes, seizures, 
myalgias, nausea and vomiting, and laboratory abnormalities including elevated AST, ALT, 
bilirubin, D-dimers, ferritin, urea and/or creatinine. Treatment of a CRS will follow the guidelines 
in Appendix C of this protocol.(102) Any subject with a fever ≥100.0°F should have a work up for 
CRS. The work-up of a CRS should include hospitalization, evaluation for an infectious etiology 
(e.g., blood cultures, urine culture, chest X-ray, as required), and have blood drawn for CAR+ T cells 
and cytokine assessments along with study-outlined clinical laboratory tests.  
Immune cell depletion:  
Potential toxicities may arise from the impairment of normal immunity with anti-SLAMF7 CAR T-
cell therapy because SLAMF7 is expressed on leukocytes such as CD8+ T cells, natural killer (NK) 
cells, B cells, plasma cells, some monocytes, NKT cells, and some dendritic cells.(5, 9, 10, 110, 112, 
113)  
NK Cell Depletion: NK cells are lymphocytes of the innate immune system that mediate cytotoxic 
killing via germline encoded activation receptors.(140) SLAMF7 is expressed on all NK cells; 
however, it is expressed on CD56dimNK cells uniformly and at a higher level than on 56brightNK 
cells.(9, 112, 114, 120, 141) CD56dimNK cells comprise about 90% of circulating NK cells and are 
thought to be the mature subset of NK cells; they have the most potent cytotoxic effects.(140, 142) 
CD56brightNK cells are thought to represent immature NK cells that are precursors of the CD56dim 
subset; CD56brightCD16- NK cells cultured in the presence of skin fibroblasts differentiate into and 
have the characteristic phenotype and functional features of peripheral blood CD56dimNK cells.(140, 
142) Gogishvili et al observed that 17% of NK cells were still viable after incubation with anti-
SLAMF7 CAR T cells.(10) Hematopoietic stem cells do not express SLAMF7. Thus, in the presence 
of peripheral destruction of NK cells by anti-SLAMF7 CAR T cells, the bone marrow should be able 
to produce new NK cells. In addition, CD56brightNK cells may differentiate into cytotoxic NK cells 
with appropriate stimulation.(140, 142) 
Although it is unclear to what level NK cell depletion will occur with anti-SLAMF7 CAR T-cell 
therapy, there is a risk of clinically relevant NK cell deficiency occurring with this therapy. NK cells 


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are important for protection against viral infections and in tumor cell surveillance; recently, their 
importance in immunoregulation and coordination of immunity has been elucidated.(140) NK cell 
deficiencies are associated with severe, potentially life-threatening viral infections caused by 
typically benign members of the Herpesviridae (VZV, HSV, CMV, EBV) and Papillomaviridae 
(HPV) families.(137) Additionally, NK cells have potent cytotoxic activity against malignant cells 
and NK cell defects are linked to ineffective tumor surveillance and clearance.(143)  During 
malignant transformation of cells, host-stress molecules are upregulated; NK cells can recognize 
these antigens, leading to destruction of the transformed cell. (143) 
Therapeutic approaches to NK cell depletion focus on monitoring for viral infections and malignant 
transformation as well as prophylactic treatment with antiviral drugs that target the Herpesviruses 
such as acyclovir, ganciclovir and related agents.(137) Prior to enrollment, all patients will be 
screened for current HSV/CMV/EBV infections by history and through laboratory work. Once 
enrolled, patients will have CMV PCR checked prior to treatment initiation, once a week during 
required hospitalization and at each follow-up appointment. Patients will be treated with standard 
anti-viral agents. If a patient were to have a severe infection from a member of either the 
Herpesviridae or Papillomaviridae families associated with NK cell deficiency the patient will be 
treated with Rimiducid, the dimerizer drug, that will signal apoptosis of the active anti-SLAMF7 
CAR T cells.  
CD8+ T-cell depletion:  Depletion of CD8+ T cells may occur with anti-SLAMF7 therapy. 
Gogishvili et al observed that 35.4% of CD8+ T cells were still viable after incubation with anti-
SLAMF7 CAR T cells.(10) In addition, the viable T cells were found to have specificity and able to 
exact killing of viral pathogens such as CMV.(10) Depletion of CD8+ T cells may reduce the capacity 
for cytotoxic killing of pathogens.  
Monocyte and dendritic cell depletion:  A small subset of monocytes and some dendritic cells 
express SLAMF7. We do not anticipate a complete depletion of monocytes from anti-SLAMF7 CAR 
T cell therapy; however, patients will be carefully monitored for signs of infections. Peripheral 
monocytes will be measured daily during hospitalization and at each follow-up visit.  
B cell depletion: A potential toxicity caused by anti-SLAMF7 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, 41)  We do not expect the same level of B cell 
depletion as prior anti-CD19 CAR T-cell trials as only a fraction of B-cells express SLAMF7. 
Hypogammaglobulinemia in patients treated with anti-CD19 CAR T-cell trials were routinely 
infused with intravenous immunoglobulins.(4)   
1.2.14 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 CAR-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.(14, 16, 144)  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.(14, 16, 34, 35, 144, 145)  Administering 


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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 
and other mechanisms.(14, 16, 145, 146)  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.(14)  Experiments in a murine xenograft model showed that 
regulatory T cells could impair the anti-tumor efficacy of anti-CD19 CAR T cells.(102)  Myeloid 
suppressor cells have been shown to inhibit anti-tumor responses.(146)  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.(15)   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.(15)  
Strong suggestive evidence of enhancement of the activity of adoptively-transferred T cells has been 
generated in humans.(20, 39, 147)  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.(39, 42)  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, 41, 60)   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, 40, 41, 147, 148)  Both cyclophosphamide and 
fludarabine are highly effective at depleting lymphocytes.(147, 148)  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.(149)  Multiple cycles of this regimen can be tolerated by heavily pretreated 
leukemia patients.(74, 149)    
The chemotherapy regimen that will be used in this protocol is cyclophosphamide 300 mg/m2 and 
fludarabine 30 mg/m2 given daily on days -5 to -3 followed by an infusion of CAR T cells on day 
0.(5)  This same chemotherapy regimen has been used in previous clinical trials. 
 
1.2.15 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-SLAMF7 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.(150-152)  Second, in the setting of allogeneic 
transplantation, relapsed malignancy is often treated with infusions of allogeneic donor lymphocytes 
(DLIs).(153, 154)  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’.(153, 154)  


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The starting CAR T-cell dose of 0.66x106 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.  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.(74)  NCI protocol 14-C-0168, a trial of anti-
BCMA CAR T cells had an MTD of 9x106 CAR+ T cells/kg.(5)  NCI protocol number 16-c-0054, a 
trial of anti-CD19 CAR T cells started at a dose of 0.66x106 CAR T cells/kg, and the maximum 
dose administered on this trial was 6x106 CAR T cells/kg. A multicenter trial of anti-BCMA CAR 
T cells conducted by bluebird bio and Celgene Inc. determined that a flat dose of 150-450 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.   
 
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 canceled or delayed until eligibility criteria are met. 
2.1.1 Inclusion Criteria 
2.1.1.1 Multiple Myeloma criteria 
• SLAMF7 expression must be detected on malignant plasma cells from either bone marrow 
or a plasmacytoma by flow cytometry or immunohistochemistry.  A specific quantitative 
level of SLAMF7 expression for eligibility is not specified, but patients with multiple 
myeloma cells that are negative for SLAMF7 by flow cytometry and immunohistochemistry 
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 SLAMF7 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 SLAMF7 staining, otherwise new biopsies will need to be 
performed for determination of SLAMF7 expression. 
• SLAMF7 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 CAR-SLAMF7 T-cell infusion 
in all patients undergoing a second CAR-SLAMF7 T-cell infusion on this clinical trial.   
• Bone marrow plasma cells must make up less than or equal to 50% of total bone marrow 
cells based on a bone marrow biopsy performed within 24 days of the start of protocol 
treatment. 
• Patients must have received at least 3 different prior treatment regimens for multiple 
myeloma 
• Must have prior exposure to an immunomodulatory drug (IMiD) such as lenalidomide and a 
proteasome inhibitor 


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35 
• Patients must have measurable MM as defined by at least one of the criteria below. 
 Serum M-protein greater or equal to 0.6 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 1.5 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 
• 
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 in the past 14 
days.  
• Hemoglobin greater than or equal to 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 


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36 
must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo or 
cytopenias).  
• 
Because this protocol requires collection of autologous blood cells by leukapheresis in order 
to prepare CAR-SLAMF7 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 14 days 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. 
• 
Patients receiving prior gene therapy outside of NIH will not be eligible. Patients who 
previously received CAR T-cell therapy at the NCI will be potentially eligible. 
 
2.1.2 Exclusion criteria:  
2.1.2.1 Patients who are receiving any other investigational agents. 
2.1.2.2 Patients on any anticoagulants except aspirin 
2.1.2.3 Patients that require urgent therapy due to tumor mass effects or spinal cord compression. 
2.1.2.4 Patients that have active hemolytic anemia. 
2.1.2.5 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.    
2.1.2.6 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. 
2.1.2.7 Active systemic infections (defined as infections causing fevers or requiring anti-microbial 
treatment), active coagulation disorders or other major uncontrolled  illnesses of the 
cardiovascular, respiratory, endocrine, renal, gastrointestinal, genitourinary, neurologic, 
psychiatric, or immune system, history of myocardial infarction, active cardiac 
arrhythmias, active obstructive or restrictive pulmonary disease. 
2.1.2.8 Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency 
Disease).  
2.1.2.9 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 14 days prior to either the required leukapheresis or within 14 days prior to CAR T-


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37 
cell infusion (and at any time after the CAR T cell infusion unless approved by the Principal 
Investigator or an Associate Investigator). 
2.1.2.10 History of severe immediate hypersensitivity reaction to any of the agents used in this study. 
2.1.2.11 Patient unwilling to undergo intensive care unit treatment including mechanical ventilation, 
cardiopulmonary resuscitation, vasoactive drugs, and hemodialysis. 
2.1.2.12 History of allogeneic stem cell transplantation 
2.1.2.13 Patients with currentspinal cord compression (without intradural myeloma involvement. 
2.1.2.14 Patients who have a history (or current evidence) of cerebrospinal fluid multiple myeloma, 
or intra-dural central nervous system masses. 
2.1.2.15 Patients with active autoimmune skin diseases such as psoriasis or other active autoimmune 
diseases such as rheumatoid arthritis. 
2.1.2.16 Patients must not have required supplemental oxygen within the past month unless it was 
for a resolved infection. 
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 forums, or from other patients through 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 prior to obtaining informed consent 
Minimal risk activities that may be performed before the subject has signed a consent include the 
following:  
• Email, written, in person or telephone communications with prospective subjects  
• Review of existing medical records to include H&P, laboratory studies, etc.  
• Review of existing MRI, x-ray, or CT images 
• Review of existing photographs or videos 
• Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes. 
2.2.2 Screening activities performed after a consent for screening has been signed 
Note: Screening evaluation testing/procedures are conducted under the separate screening protocol, 
01-C-0129 (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):  


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• 
Complete history and physical examination, including weight, vital signs, ECOG, details 
about the exact size and location of any evaluable lesions that exist.  
• 
Confirmation of diagnosis of MM by the NCI Laboratory of Pathology and confirmation of 
SLAMF7 expression on malignant plasma cells from either bone marrow or a plasmacytoma 
by flow cytometry or immunohistochemistry.  The sample used for this SLAMF7 expression 
analysis can come from any time prior to enrollment on the protocol. 
• 
Bone marrow aspirate and biopsy; specifically ask for SLAMF7 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 (2-4 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.  
• 
Flow cytometry staining of bone marrow or plasmacytoma cells for SLAMF7 should be 
performed by Dr. Stetler-Stevenson’s lab (NCI Laboratory of Pathology). 
• 
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)  
• 
MRI of the brain 
• 
CT scans of areas with possible lesions/plasmacytomas. This may include areas such as the 
head, neck, chest, abdomen and pelvis. (performed only if necessary, to document 
measurable malignancy in the event of no other miserable disease in blood, urine and bone 
marrow). 
• 
Venous assessment for apheresis (Valid for up to 6 months before apheresis collection, does 
not need to be performed if cells have been previously collected) 
• 
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, order Hepatitis B core antibody, and hepatitis B surface antigen. 
• 
EKG 
• 
Echocardiogram 


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39 
• 
(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  
• 
24-hour urine collection with immunofixation electrophoresis as clinically indicated 
• 
Glucose-6-phosphate dehydrogenase (G6PD) deficiency screening 
• 
TSH, T4, and T3 
• 
Serum Cortisol 
• 
PT/PTT 
• 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 here. 
2.4 
TREATMENT ASSIGNMENT PROCEDURES FOR THE REGISTRATION PURPOSES ONLY: 
Cohorts:  
Number Name 
Description 
1 
Cohort 1 
Subjects enrolled to determine the MTD  
2 
Cohort 2 
Subjects enrolled after the MTD has been 
identified 
 
Arms:  
Number Name 
Description 
1 
Conditioning 
chemotherapy plus CAR 
T-cells dose escalation 
Patients will receive escalating doses (up to 4 planned) of Anti-
SLAMF7-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 


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40 
Number Name 
Description 
2 
Conditioning 
chemotherapy plus CAR 
T-cells expansion phase 
MTD dose of Anti-SLAMF7- 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-SLAMF7 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 SLAMF7 expression will be an important part of the eligibility 
screening.  Patients enrolled on the study will undergo leukapheresis, and anti-SLAMF7-CAR-
expressing T cells will be generated by transducing the patient’s T cells with a gamma retrovirus 
encoding the anti-SLAMF7 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-SLAMF7-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 3 years. 
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-SLAMF7 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-SLAMF7-expressing 
T cells (7-9 days); cryopreservation 
Pretreatment staging/Baseline 
Infusion of recipient with 
Anti-SLAMF7-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 3 years post-infusion. 
Outpatient or inpatient 
cyclophosphamide plus fludarabine 
conditioning chemotherapy 
Patient Eligibility 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): 
o Non-cardiac and non-neurologic Grade 3 toxicities possibly or probably or definitely 
related to the CAR T cells and lasting more than 9 days with exceptions below. 
o Grade 4 toxicities possibly or probably or definitely related to the CAR T cells. 
o Grade 5 toxicities possibly or probably or definitely related to CAR T cells. 
o Grade 3 hypotension or hypoxia (Appendix F) occurring in the setting of grade 3 CRS (as 
graded according to Appendix F) and lasting more than 72 hours will be a DLT for the 
first 2 subjects on study.  
o Grade 3 cardiac and neurologic adverse events lasting more than 72 hours will be DLTs 
except for those included in the list below.  
 
The following grade 3 and 4 toxicities will not be DLTs: 
o Neutropenia (ANC≤500/µL) lasting 10 days or less is not a DLT 
o Neutropenia with an ANC>500/mL is not a DLT 
o Anemia (Hgb<8 g/dL) lasting 10 days or less is not a DLT 
o Anemia with Hgb greater than or equal to 8 g/dL is not a DLT even if blood transfusions 
are required 
o Transfusion-dependent thrombocytopenia lasting 28 days or less is not a DLT 
o Thrombocytopenia that is not transfusion-dependent is not a DLT 
o Hypotension requiring continuous treatment with 3 µg/minute or less of norepinephrine 
for 72 hours or less is not a DLT.   
o Grade 3 hypotension or hypoxia occurring in the setting of CRS (Appendix F) lasting 
more than 72 hours in patients treated after the first two patients on study will not be a 
DLT.  
o Fever is not a DLT. 
o All cytopenias except neutropenia, anemia, and thrombocytopenia are not DLTs 
o Asymptomatic electrolyte disturbances regardless of grade are not DLTs 
o Prolonged QT interval as long as ventricular arrhythmias do not occur is not a DLT 
o Grade 3 creatine kinase elevation is not a DLT 


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o Infections controlled by antibiotics are not DLTs 
o Grade 3 concentration impairment is not a DLT  
o Grade 3 dysesthesia is not a DLT  
o Grade 3 dysphasia is not a DLT  
o Grade 3 headache is not a DLT  
o Grade 3 memory impairment is not a DLT  
o Grade 3 paresthesia is not a DLT  
o Grade 3 syncope (only 1 uncomplicated resolved event) is not a DLT  
o Grade 3 atrial fibrillation is not a DLT  
o Grade 3 sinus bradycardia is not a DLT  
o Grade 3 sinus tachycardia is not a DLT  
3.1.4 Dose Escalation 
The trial will be a dose-escalation with 4 dose levels based on the patient’s actual bodyweight.  Each 
dose will be limited to the number of cells that would be administered up to a 120 kg patient.  
 
Dose Escalation Schedule 
Dose Level 
Dose of IND Agent  
Level -1 
0.3x106 Anti-SLAMF7-CAR + T cells per kg of recipient 
bodyweight 
Level 1 
0.66x106 Anti-SLAMF7-CAR + T cells per kg of recipient 
bodyweight 
Level 2 
2.0x106 Anti-SLAMF7-CAR + T cells per kg of recipient 
bodyweight  
Level 3 
6.0x106 Anti-SLAMF7-CAR + T cells per kg of recipient 
bodyweight  
Level 4 
12.0x106 CAR+ T cells per kg of recipient bodyweight 
 


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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.  
There will be a 28-day interval between the first and second patient treated on study. A minimum of 
14 days will elapse between the second and third patient on the first dose level. After completing the 
1st dose level, we will contact the FDA about potentially having a 14-day interval between the first 
and second patient on subsequent dose levels on a case by case basis.  
If sufficient cells cannot be grown to meet the criteria for the assigned dose level, the treatment will 
be cancelled.  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. If insufficient cells are left over from the first cell 
production attempt, a second apheresis will be needed. 
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.   
Any dose level with 3 treated patients and no DLTs can be expanded to 6 patients at the PI’s 
discretion to better understand toxicity of this dose level prior to proceeding to the next higher dose 
level. After the 6 patients are treated, the dose can be escalated to the next higher dose level if 0/6 
or 1/6 DLTs occur. If 2 or more DLTs occur, the cell dose must be reduced to the next lower dose 
level. 
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 an 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 an MTD has not been reached, the highest achievable dose 
level will be declared the maximum feasible dose.   
Dose escalation will follow the rules outlined in the Table below: 
 
Number of Patients with 
DLT 
at 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 


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Number of Patients with 
DLT 
at a Given Dose Level 
Escalation Decision Rule 
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: 
o Patients may have a delay in planned treatment if they have active infections defined as 
infections causing fevers or infections requiring intravenous 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.   
o 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 15 to 20 - liter leukapheresis will be processed in the Department of 
Transfusion Medicine (DTM) Dowling Apheresis Clinic according to DTM standard operating 


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46 
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.  
3.3.2 Anti-SLAMF7-CAR-expressing T-cell preparation 
After cells are obtained by apheresis, further cell processing to generate 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.  Peripheral blood 
mononuclear cells will be isolated. Sufficient cells for a complete cell production 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, Room: 3W-3808, Phone: 240-858-3755 for 
cryopreservation at 100 to 300 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 gamma retroviruses encoding the 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 CAR will be determined by flow cytometry, 
and this percentage of CAR 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 3.7.2, any remaining cryopreserved 
pretreatment PBMC collected on this protocol will either be disposed of or 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) and possible use in research.   
3.3.3 Conditioning chemotherapy and CAR-SLAMF7 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 
cyclophosphamide on day -
5, -4, -3 
Daily x 3 doses on days -5, -
4, -3 
 


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Anti-SLAMF7-CAR T cells Variable.  
One-time dose on day 0 
 
3.3.3.2 Detailed treatment plan 
Note that patients must meet still meet protocol enrollment criteria with the exception that a 
platelet count as low as 50,000/µL is allowed based on laboratory results from 7 days or less 
and physical examination within 3 days or less before chemotherapy starts. 
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% (see 11.3.6).  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:  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  using 
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.  
Days 1 to 9: Mandatory minimal 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 
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 Appendix C. 


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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 Rimiducid administration  
Rimiducid may be administered a under the following conditions at the discretion of the Principal 
Investigator: 
• Significant herpes virus infections such as cytomegalovirus infections, herpes zoster, or other 
significant viral infections in the setting of a peripheral blood NK cell count less than the 
lower limit of normal as determined on lymphocyte phenotyping (TBNK) performed at the 
NIH Department of Laboratory Medicine. “Significant” will be determined by the Principal 
Investigator. 
• Significant organ damage possibly, probably or definitely attributable to CAR T cells. 
“Significant” will be determined by the Principal Investigator. 
• Severe cytokine-release syndrome not responsive to high-dose corticosteroids of 200 mg of 
methylprednisolone within 1 hour. If a participant has Cytokine Release Syndrome that 
improves after the Rimiducid is given, methylprednisolone will be discontinued. 
• Neutrophil count <500/µL lasting 7 to 9 days (Rimiducid can be given anywhere from 7 to 
9 days of neutrophil count<500/µL) 
• Transfusion-dependent thrombocytopenia lasting 21 to 23 days (Rimiducid administered 
anytime between 21 and 23 days of transfusion dependence) 
• Bleeding due to thrombocytopenia or life-threatening infections in the setting of neutropenia. 
Infusion of Rimiducid: 0.4 mg/kg of Rimiducid is infused in 100 mL of normal saline over 2 hours. 
Patients <50 kg or >150 kg, may have different volume than 100 mL but will still be infused over 2 
hours. 
A second dose of Rimiducid will be given when 2 criteria are met: 1. An indication for a 1st dose of 
Rimiducid persists at least 48 hours after the first dose. 2. CAR T cells are still detected in the 
patient’s blood 1 day after the first dose of Rimiducid. 
 
Premedication for Rimiducid Infusion: Patients will receive acetaminophen 650 mg orally and 
diphenhydramine 12.5 mg IV approximately 30-60  minutes prior to start of Rimiducid infusion. 
3.3.5 Potential repeat treatment 
Retreatment will only be considered on a case by case basis after consultation with the IRB and FDA 
and after the maximum tolerated or maximum administered dose is determined. 


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3.4 
PROTOCOL EVALUATION 
3.4.1 Baseline evaluations and interventions 
Bone marrow aspirate and biopsy must be performed within 24 days prior to 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 SLAMF7, 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 
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 through 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. 
SLAMF7 immunohistochemical staining is performed in the NIH Dept. of Laboratory Medicine 
with the anti-SLAMF7 antibody clone 3B3, LSBio part number LS-C340266. 
 
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 another device. 
• Physical exam with vital signs and oxygen saturation 
• PET scan in all patients to measure boney disease and soft tissue plasmacytomas for safety 
reason.  
• CT scans of neck, chest, abdomen and pelvis in all patients. CT scans of other locations will 
be performed clinically to image only areas of previously known plasmacytomas. If area of 
known plasmacytoma was imaged at the NIH within 14 days, CT scan of that area will not 
be repeated.  
• MRI only if needed to define measurable multiple myeloma plasmacytomas staging or spine 
lesions that not evaluable completely by CT) 
• 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  
• 24-hour urine collection for urine protein 
• Serum immunofixation electrophoresis 


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• Blood CMV PCR 
• 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 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, Room: 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 
Figg 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)  
• β2-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) 
  


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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 after completion of the 
CAR T cell infusion and every 4 hours otherwise unless otherwise clinically indicated. 
• Daily physical exam 
• CBC twice a day from day 0 until day 9 with differential every 24 hours. 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 
• Immunoglobulin free light chains day 9 (+/- 1 day) after infusion 
• Serum immunofixation electrophoresis (if patient had a measurable M-protein prior to 
treatment) day 9 (+/- 1 day) 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 (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.) All twice daily labs can be reduced to once daily after 9 days 
following CAR T-cell infusion. 
• 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 Figg 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 14 days after infusion of CAR-SLAMF7 -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 Figg 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 may be stored refrigerated on the nursing unit and 
processed first thing Monday morning at the latest. Send to the Figg lab; For sample pick-
up, page 102-11964. 
• Rimiducid Administration Research Blood:  Draw the below samples immediately before 
Rimiducid administration, 1 day post Rimiducid , and 3 days post Rimiducid 
• 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, Room: 3W-3808,  Phone: 240-858-3755  


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• 1 SST tube (8 mL) of Research Blood will be obtained for serum collection.  Send 
to the Figg lab; For sample pick-up, page 102-11964. 
 
3.4.3 Post-infusion outpatient evaluation 
After completion of therapy the patient will be followed for potential complications related to CAR- 
T-cell infusion. The patient will be seen at the NIH in follow-up to evaluate disease status and late 
problems related to a CART-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 CART-cell infusion. After 12 months, the patient will be seen every 6 months 
(+/- 30 days) up to three years. After 3 years total follow-up, patients will be, transferred to the long-
term follow-up protocol 15-C-0141. 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, Room: 
3W-3808, Phone: 240-858-3755  
 
• 1 SST tube (8 mL) of Research Blood will be obtained for serum collection.  Send to the 
Figg 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. 
• Rimiducid Administration Research Blood:  Draw the below samples immediately before 
Rimiducid administration, 1 day post Rimiducid, and 3 days post Rimiducid 
 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, Room: 3W-3808, Phone: 240-858-3755.  
 1 SST tube (8 mL) of Research Blood will be obtained for serum collection.  Send 
to the Figg lab; For sample pick-up, page 102-11964. 
• PET scans will be performed at 3 and 12, 24 and 36 months after cell-infusion.  
• CT scans of areas with tumors/plasmacytomas will be performed at 1, 2, 4, 6, 9, 12, 18, 24, 
30 and 36 months after CAR T-cell infusion (only to evaluate known soft-tissue 
plasmacytomas ). This may include areas such as the head, neck, chest, abdomen and pelvis. 
CT scans will NOT be performed in areas where there are no known tumor plasmacytomas 
at baseline unless clinically indicated or if there is concern for a new plasmacytoma that 
would constitute progressive disease.  
• MRIs will be performed to evaluate tumors not evaluable completely by CT, especially to 
follow measurable myeloma staging or spine lesions  
• Physical exam with vital signs and oxygen saturation 


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53 
•  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 β2-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.  SLAMF7 and 
BCMA staining must be requested for the flow cytometry. Also, request flow cytometry for 
anti-SLAMF7 CAR T cells.  SLAMF7, BCMA immunohistochemistry should also be 
requested on the bone marrow biopsy. Specifically ask for SLAMF7, 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 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.  SLAMF7 and 
BCMA staining must be requested for the flow cytometry. Also, request flow cytometry for 
anti-SLAMF7 CAR T cells.  SLAMF7 and BCMA immunohistochemistry should also be 
requested on the bone marrow biopsy.  This may also be performed at day +30 if 
clinicallyindicated.Specifically ask for SLAMF7, 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. 
• At the 6-month follow-up appointment, a bone marrow aspirate and biopsy will be 
performed.  Aspirate must be sent for flow cytometry to the lab of Dr. Maryalice   Stetler-
Stevenson.  SLAMF7 and BCMA staining must be requested for the flow cytometry. Also, 
request flow cytometry for anti-SLAMF7 CAR T cells. SLAMF7 and BCMA 
immunohistochemistry should also be requested on the bone marrow biopsy.  Specifically 


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54 
ask for SLAMF7, 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. 
• At all time-points, bone marrow biopsies might be done to evaluate for MM progression or 
to investigate cytopenias. 
• For each bone marrow aspirate performed, send one tube of bone marrow aspirate to the 
Surgery Branch Cell Production Facility (SB-CPF), Bldg. 10, Room: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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55 
 
3.5 
STUDY CALENDAR 
 
 
Inpatient 
Follow up 
Proceduresa  
Screening 
Baseline 
Day 
0 
Post 
Cell
s 
whil
e 
inptc 
Day+
14 (+- 
1 
day) 
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 
3 years post 
CAR cells.  
Clinical Assessments 
 
History and PE 
X 
Xb 
Xc 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital 
signs, 
O2 
saturation 
X 
X 
Xc 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Performance Score 
(ECOG) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Lesion Location  
(If applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pathology 
Confirmation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory 
Assessments 
 
CBC with differential  X 
X 
Xc 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sodium, Potassium 
Chloride, CO2, 
Creatinine, Glucose, 
BUN, Albumin, 
Calcium, 
Magnesium, 
Phosphorus, 
Alkaline 
Phosphatase, ALT, 
X 
X 
Xc 
Xc 
XX 
X 
X 
X 
X 
X 
X 
X 
X 


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Inpatient 
Follow up 
Proceduresa  
Screening 
Baseline 
Day 
0 
Post 
Cell
s 
whil
e 
inptc 
Day+
14 (+- 
1 
day) 
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 
3 years post 
CAR cells.  
AST, T. Bilirubin, D. 
Bilirubin, LDH, 
Total Protein, CK, 
Uric Acid 
Serum C-reactive 
protein 
 
X 
Xc 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT/PTT 
X 
X 
Xc 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fibrinogen 
 
X 
Xc 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ionized calcium 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TBNK  
 
X 
X 
Xd 
(D7
) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis (culture 
prn) 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMV PCR (Blood) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Anti-CMV, HSV, 
EBV, T.cruzi, 
toxoplasmosis 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
PCR for HCV and 
HBV; antibody test 
for HIV, HTLV-I/II, 
T.cruzi, West Nile, 
RPR 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
TSH, T4, T3 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Inpatient 
Follow up 
Proceduresa  
Screening 
Baseline 
Day 
0 
Post 
Cell
s 
whil
e 
inptc 
Day+
14 (+- 
1 
day) 
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 
3 years post 
CAR cells.  
G6PD 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Cortisol 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ABO typing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
B2-HCG (serum or 
urine in women of 
childbearing 
potential) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
MM Lab Assessments 
 
β2-microglobulin 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
24 hr urine with 
immunofixation 
electrophoresis and 
urine 24 hour 
protein 
X 
X 
 
 
X 
X 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Serum 
immunoglobulin free 
light chains  
X 
X 
 
Xh 
(D9
) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum 
immunofixation 
electrophoresis 
X 
X 
 
Xh 
(D9
) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Radiological 
Assessments 
 
CT scan of disease 
affected areas 
Xz 
Xy 
 
 
 
Xi 
Xi 
 
    Xi 
Xi 
Xi 
   Xi 
              Xi 
PET scan 
 
Xw
, 
 
 
 
 
   
Xv 
       
   
 
   X w  


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Inpatient 
Follow up 
Proceduresa  
Screening 
Baseline 
Day 
0 
Post 
Cell
s 
whil
e 
inptc 
Day+
14 (+- 
1 
day) 
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 
3 years post 
CAR cells.  
Brain MRI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 MRI 
Xi 
Xi  
 
 
 
Xj 
Xj 
Xj 
 Xj  
 Xj 
 Xj 
 Xj 
 Xj 
Other 
Specific 
Assessments 
 
250 
microgram 
cosyntropin test 
 
Xk 
 
 
 
 
 
 
 
 
 
 
 
EKG, 
echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
RCR, Gene Therapy 
Follow Up 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
Xl 
Central 
Venous 
catheter placement 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Venous Assessment 
for Apheresis 
X
m 
 
 
 
 
 
 
 
 
 
 
 
 
Response Evaluation 
 
Bone 
marrow 
aspirate/biopsyn, o, p   
 
Xq 
 
 
X 
Xx 
X 
 
 
X 
 
 
 
Research Blood  
 
Xr 
Xs,, t 
Xs,  t Xt, u 
Xt, u 
Xt,, u 
Xt,, u 
Xt,, u 
Xt,, u 
Xt,, u  
Xt, u 
Xt,, u 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a. see section 2.2 and section 3.3.1 for details 
b. Medical history not required at baseline 
c. see section 3.4.2 for details of testing during hospitalization 


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d. TBNK is performed on D7 
e. 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 
f. 
only if DNA testing is not available, order Hepatitis C antibody, order Hepatitis B core antibody, and hepatitis B surface antigen. 
g. Urine electrophoresis can be omitted after D30 if not needed for staging 
h. Draw immunoglobulin free light chains and serum immunofixation electrophoresis on day 9 after CAR T-cell infusion 
(electrophoresis if M-protein at baseline). 
i. 
if useful for response assessment to evaluate known multiple myeloma plasmacytomas that identified at screening or baseline clinically 
except for day 30 and 120.Note: only day 30 and day 120 CT scan will be done on patients who had known plasmacytoma 1.5 cm.  
j. 
MRIs will be done only to evaluate tumors not evaluable completely by CT, especially to establish measurable myeloma   
k. only if clinical suspicion of adrenal insufficiency 
l. 
see section 3.4.3 for details 
m. Venous assessment valid for 6 months before cell collection  
n. bone marrow biopsy will include flow cytometry, SLAMF7 expression, cytogenetics (pretreatment bone marrow aspirate only), 
amyloid staining (pretreatment bone marrow biopsy only), research samples, and molecular studies of each sample.  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. 
o. Additional bone marrow biopsies and aspirates might be needed if clinicallyindicated due to low blood counts or for myeloma 
response assessment. 
p. A bone marrow aspirate and biopsy with flow cytometry will also be performed to confirm suspected complete remission.  
q. Bone marrow biopsy does not need to be repeated for baseline if done previously within 24 days 
r. 
Baseline Research Blood (See section 3.4.1) 
s. 
Inpatient Research Blood (See section 3.4.2) 
t. 
Rimiducid Administration Research Blood (See section 3.4.2 and 3.4.3) 
u. Follow up Research Blood (See section 3.4.3) 
v. PET research scan to evaluate MM in all patients  
w. To measure boney disease and soft tissue plasmacytomas for safety reason   
x. Only if clinicallyindicated 
y. CT scan of neck, chest, abdomen and pelvis in all patients for to measure plasmacytoma staging  will not be repeated if done within 
14 days of protocol treatment start 
z. CT scan of areas with possible lesions/plasmacytomas (this research scan only be done p erfo rm edper   if needed to establish measurable 
disease). If outside CT scans of plasmacytomas are available within 30 days, we can use these images to establish measurable 
disease.  


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61 
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 protocol.  Physical examinations 
will be performed and documented annually for 5 years following cell infusion to evaluate 
long-term safety.  After 3 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 or <0.1% of PBMC (whichever is higher).  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.   
• S+L- culture-based replication-competent retrovirus testing will be conducted on the 
infusion CAR T cells of all patients 
3.7 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to 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. 
3.7.1 Criteria for removal from protocol therapy 
Note that the treatment consists of a conditioning chemotherapy regimen followed by a T-cell 
infusion. Off-treatment criteria applies to eligibility for potential repeat treatments; and also, 
cancellations of treatment for toxicity arising any time before the cell infusion.  
Patients will be taken off treatment for the following: 
• Any DLT makes patients ineligible for repeat treatments. 
• 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 within 1 day, the patient 
can proceed on treatment, otherwise the patient must come off treatment.   
• The patient receives any other treatment for multiple myeloma except bisphosphonates and 
treatment on this protocol.  Bisphosphonates are allowed when administered to prevent 
osteopenia more than 2 months after the 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 


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• Investigator discretion 
• Positive pregnancy test 
3.7.2 Off-Study Criteria 
Patients will be taken off study for the following (all patients coming off study must enroll on the 
long-term gene therapy follow-up protocol 15-c-0041): 
• The patient completes the study upon reaching 3 years after CAR T-cell infusion. 
• The patient completes a safety visit 30 day after last administration of study treatment (only 
for patients who have received chemotherapy but will not receive a cell infusion) 
• The patient voluntarily withdraws 
• There is significant patient noncompliance 
• PI discretion 
• Death 
• Development of progressive or relapsed multiple myeloma after CAR T cell infusion. 
• The patient receives any anti-myeloma therapy except bisphosphonates.  Bisphosphonates 
are allowed 2 months or more after the CAR T-cell infusion. 
• The patient no longer meets the eligibility criteria for the protocol after enrolling but before 
start of the chemotherapy conditioning regimen.  In this case, treatment will be delayed 
until the patient meets eligibility criteria, or if the patient will never likely meet eligibility 
criteria, the patient will be removed from the study. An exception to this is that a platelet 
count of 50,000 or more is considered adequate to start chemotherapy. This platelet level 
is slightly lower than that required for initial protocol enrollment. 
3.8 
PROTOCOL 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 attributable 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 amendment of the 
protocol approved/reviewed by the FDA and NIH Intramural 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 NIH Intramural IRB. 


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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 400 mg/dL will receive intravenous 
immunoglobulin replacement as needed to maintain an IgG level above 400 mg/dL.  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 38.3 C 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. 
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. 


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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 GUIDELINES 
Guidelines for management of common CAR toxicities including cytokine release syndrome 
(CRS) and neurologic toxicity are in section Appendix C. Rimiducid will be given as described in 
Section 3.3.4. 
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 
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 CAR-SLAMF7 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.  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 SST tubes will 
be sent to Figg lab; For sample pick-up, page 102-11964An apheresis is required to obtain 
cells used to prepare the 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 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 
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 


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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 tto the Figg lab; For sample pick-up, page 
102-11964. 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 CAR T-cell infusion. After the 
12-month follow-up appointment patients will return for follow-up every 6 months up until 
3 years after infusion.  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.  
 1 SST tube (8 mL) of Research Blood will be obtained for serum collection.  The 
SST tubes will be sent to Figg lab. For sample pick-up, page 102-11964. 
NOTE: After 1-year research blood collected will be reduced to 4 CPT tubes at each visit. 
• At the 2-week, 2 months and 6- 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 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 months after infusion, and 
CAR+ T cell analysis will continue until the CAR+ T cell level drops to undetectable levels 
or levels reach <0.1% of PBMC. The absolute number of CAR+ PBMC will be estimated 
by multiplying the percentage of CAR+ PBMC by the absolute number of lymphocytes 
plus monocytes per microliter of blood.  Ex vivo immunological assays might be used to 
measure the SLAMF7-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.  
• Serum cytokine levels will also be measured by enzyme-linked immune sorbent or similar 
assays.  


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• A human anti-mouse ELISA assay will be performed retrospectively on serum collected 
before administration of anti-SLAMF7 CAR T cells and 2 to 3 months after anti-SLAMF7 
CAR T-cell administration for all patients who previously received treatment involving 
any CAR derived from a murine antibody including previous treatment with the IC9-
Luc90-CD828Z CAR used in this study. 
• 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. Blood does not need to be banked for gene-therapy 
monitoring after the 12-month post-infusion 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 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 
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 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 Biospecimen collection with Rimiducid administration:  
If Rimiducid is infused, we will collect research blood (6 CPT tubes and 1 SST tube) for 
monitoring CAR T-cell levels immediately before the infusion and 1 day and 3 days after the 
infusion.  
5.1.6 Additional biopsies and additional blood draws 
Patients might be asked to undergo biopsies or additional blood draws for research purposes. 
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 
research biopsies are optional, and patients can participate in this trial whether or not they agree to 
undergo biopsies for research purposes.  These biopsies will only be performed if minimal 


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67 
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. 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. 
5.1.7 Future studies  
Blood and tissue specimens collected during 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 Samples Sent to Figg 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. 
o Record the date and exact time of draw on the tube. Blood tubes may be kept in the 
refrigerator until pick-up.  
o For sample pick-up, page 102-11964. 
o For immediate help, call 240-760-6180 (main Blood Processing Core number) or, if 
no answer, 240-760-6190 (main clinical pharmacology lab number). 
o For questions regarding sample processing, contact the Blood Processing Core (BPC) 
at NCIBloodcore@mail.nih.gov or 240-760-6180. 
o The samples will be processed, barcoded, and stored in the Figg lab until requested by 
the investigator. 
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. 
5.2.2 Sample Storage, Tracking and Disposition 
 
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 Blood 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. 


A b bre vi ate d Titl e:  A nti -S L A M F 7 C A R T c ells f or M M  
V ersi o n D at e:  A pril 1 4, 2 0 2 0  
 
6 8  
Sa m ples will n ot b e s e nt o utsi d e NI H wit h o ut a p pr o priate a p pr o vals a n d/ or a gre e m e nts, if 
re q uire d.  
5. 2.2.1  Sa m ples Ma n a ge d b y Dr. Fi g g’s Bl o o d Pr o c essi n g C ore ( B P C)  
5. 2.2.1. 1  B P C C o nta ct I nf or m ati o n  
Ple as e e -m ail N CI Bl o o d c ore @ m ail. ni h. g o v at le ast 2 4 h o urs b ef ore tra ns p orti n g s a m ples  (t h e 
Fri d a y b ef ore is pref erre d).  
F or s a m ple pic k u p, p a ge 1 0 2 -1 1 9 6 4.  
F or i m m e diate h el p, c all 2 4 0 -7 6 0 -6 1 8 0 ( m ai n bl o o d pr o cessi n g c ore n u m ber) or, if n o a ns w er, 
2 4 0 -7 6 0 -6 1 9 0 ( m ai n cli nic al p h ar m ac ol o g y la b n u m ber).  
F or q u esti o ns re gar di n g s a m ple pr oc essi n g, c o nta ct N CI Bl o o d c ore @ m ail. ni h. g o v.  
5. 2.2.1. 2  Sa m ple D ata C olle cti o n  
All s a m ples s e nt t o t h e Bl o o d Pr o c essi n g C ore ( B P C) ( Dr. Fi g g’s  la b) will b e b arc o d e d, wit h data 
e ntere d a n d st ore d i n t h e L A Bra d or (a k a La b Sa m ples) utiliz e d b y t h e B P C. T his is a s e c ure 
pr o gra m , wit h a c c ess t o L A Bra d or li mite d t o d efi n e d Fi g g la b p ers o n n el, w h o are iss u e d i n di vid ual 
us er a c c o u nts. I nstallati o n of L A Bra d or is  li mite d t o  c o m p uters s p e cifie d b y Dr.  Fi g g.  T h ese 
c o m p uters all h a v e a p ass w or d restricte d l o gi n s cre e n. All Fi g g  la b p ers o n n el wit h a c c ess t o p atie nt 
i nf or m ati o n c o m plete t h e NI H o nli n e Pr ote cti o n of H u m a n S u bje cts c o urs e, i n t h e re q uire d ti me 
fra m e.  
L A Bra d or cre ates a u ni q u e b arc o d e I D f or e v er y s a m ple a n d s a m ple b o x, w hic h c a n n ot b e trace d 
b a c k t o p atie nts wit h o ut L A Bra d o r a c cess. T h e d ata re c or de d f or e a c h s a m ple i n cl u des t h e p atie nt 
I D, n a m e, trial n a m e/ pr ot o c ol n u m b er, ti m e dra w n, c y cle ti m e p oi nt, d os e, m aterial t y p e, as w ell 
as b o x a n d fre e z er l o c ati o n. Patie nt d e m o gra p hics ass o ciate d wit h t h e cli nic al c e nter p atie nt 
n u m b er are pr o vi d e d i n t h e s yste m. F or e a c h s a m ple, t h ere are n otes ass o ciate d wit h t h e pr o c essin g 
m et h o d ( d ela y i n s a m ple pr o cessi n g, st ora ge c o n diti o ns o n t h e w ar d, etc.).  
Sa m ple b ar -c o d es are li n k e d t o p atie nt d e m o gra p hics a n d li mite d cli nic al i nf or m at i o n. T his 
i nf or m ati o n will o nl y b e pr o vi de d t o i n v esti gat ors liste d o n t his pr ot o c ol, via re gistere d us e of the 
L A Bra d or. It  is  critic al  t h at t h e  s a m ple re m ai ns li n k e d t o p atie nt i nf or m ati o n s u c h as ra c e, a ge, 
d ates of dia g n osis a n d d e at h, a n d hist ol o gic al  i nf or m ati o n a b o ut t h e t u m or, i n  or d er t o  c orrelate 
ge n ot y p e wit h t h es e v aria bles.  
5. 2.2.1. 3  Sa m ple St ora ge  
Barc o d e d s a m ples  are  st ore d i n  b arc o d e d b o x es i n  a  l o c k e d fre e z er at  eit h er -2 0 or -8 0 C 
a c c or di n g t o sta bilit y re q uire m e nts. T h es e fre ez ers are l o c ate d o ns ite i n t h e B P C a n d off site at N CI 
Fre d eric k Ce ntral Re p osit or y Ser vic es i n Fre d eric k, M D. Visit ors t o t h e la b orat or y are re q uire d to 
b e a c c o m p a nie d b y la b orat or y staff at all ti m es.  


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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 in LABrador. 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 
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.  
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting the 
rights to use the material. 
If, at any time, a patient 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.  
5.2.3 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 Lab matrix. 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 Lab matrix with identification and storage location. Access to 
the stored specimens will be restricted. Access to Lab matrix 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. 
5.2.4 Protocol Completion/Sample Destruction 
All specimens obtained in the protocol are used as defined in the protocol.  
If the patient withdraws consent, the participant’s data will be excluded from future distributions, 
but data that 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. 
 
5.2.5 Samples for Genetic/Genomic Analysis 
No genetic/genomic analysis will be performed. 


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6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system, C3D and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts.  All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
All ongoing AEs, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. Document 
AEs from the first study intervention, Study Day 1, through the end of treatment. Beyond 30 days 
after the last intervention, only adverse events which are serious and related to the study 
intervention need to be recorded. 
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
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. 
• Grade 2 adverse events that will be recorded: 
a. Adverse events regardless of attribution will be recorded for the first year after the 
infusion. 
b. Unexpected events that are possibly, probably, or definitely related to the research 
will be recorded after the first year. 
• All grade 3, 4, and 5 adverse events will be recorded regardless of attribution. 
• All serious events regardless of attribution 
  


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6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
What data will be shared? 
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) 
_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 
Genomic data will not be generated. 
6.4 
RESPONSE CRITERIA 
Responses will be categorized by using the International Uniform Response Criteria for Multiple 
myeloma 2016 updated version.(155)  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 disease(24) 
Any one or combination of these abnormalities defines measurable disease:  


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• Serum M-protein greater or equal to 0.6 g/dL (6 g/L).  
• Urine M-protein greater or equal to 200 mg/24 h. 
• Serum FLC assay: involved FLC level greater or equal to10 mg/dL (100 mg/L) provided 
serum FLC ratio is abnormal. 
• Presence of a biopsy-proven plasmacytoma 
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. 
• 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 or MRI 
scans by measuring target lesions with the sums of the products of the diameters method. 
For purposes of defining CR, masses greater than 1.5 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 


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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;  
• 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 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). 
• If serum and urine M-protein are not measurable and serum FLC assay is also not 
measurable, 50% or greater reduction in plasma cells is required in lieu of M-protein 
evaluation (provided baseline bone marrow plasma cell percentage was 30% or greater) 
6.4.2.6 Stable Disease (SD)  


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• 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. 
6.4.2.7 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 
o Only in patients without measurable M-protein, 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 one 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 lesion 1.5 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) 
Flow MRD-negative-Absence of aberrant clonal plasma cells in the bone marrow by flow 
cytometry using EuroFlow standard operating procedures or equivalent (which includes NCI 
Dept. of Pathology multicolor flow); must have sensitivity of one in 105 nucleated cells. 
Sequencing MRD-negative-absence of clonal plasma cells by next generation sequencing on 
bone marrow aspirate with a method with sensitivity of 1 in 105 nucleated cells. 


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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 here. 
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 here. 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 here.  
7.3 
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the 
Clinical Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut 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 CAR-SLAMF7 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 CAR-SLAMF7 -expressing T cells, but are not fatal 


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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 Annual Reports to IBC 
Within 60 days after the one-year anniversary of the date on which the IBC approved the initial 
protocol, and after each subsequent anniversary until the trial is completed, the Principal 
Investigator (or delegate) shall submit the information described below.  Alternatively, the IRB 
continuing review report can be sent to IBC in lieu of a separate report.  Please include the IBC 
protocol number on the report. 
7.4.2.1 Clinical Trial Information  
A brief summary of the status of the trial in progress or completed during the previous year. The 
summary is required to include the following information:  
• the title and purpose of the trial  
• clinical site 
• the Principal Investigator 
• clinical protocol identifiers participant population (such as disease indication and general 
age group, e.g., adult or pediatric);  
• the total number of participants planned for inclusion in the trial; the number entered into 
the trial to date whose participation in the trial was completed; and the number who 
dropped out of the trial with a brief description of the reasons  
• the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, 
or fully completed,  
• if the trial has been completed, a brief description of any study results.  
7.4.2.2 Progress Report and Data Analysis 
Information obtained during the previous year's clinical and non-clinical investigations, 
including:  
• a narrative or tabular summary showing the most frequent and most serious adverse 
experiences by body system 
• a summary of all serious adverse events submitted during the past year 
• a summary of serious adverse events that were expected or considered to have causes not 
associated with the use of the gene transfer product such as disease progression or 
concurrent medications 
• if any deaths have occurred, the number of participants who died during participation in 
the investigation and causes of death 
• a brief description of any information obtained that is pertinent to an understanding of the 
gene transfer product’s actions, including, for example, information about dose-response, 
information from controlled trials, and information about bioavailability.  


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7.5 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
7.5.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular 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 and response data on each patient to ensure 
safety and data accuracy. The principal investigator 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 NIH Intramural 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 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 


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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 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. 
• 
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 


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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 
sponsor. 
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 to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form and 
instructions 
can 
be 
found 
at:   
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842  
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 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
8.4.1 Reporting by CCR to Bellicum Pharmaceuticals Inc. 
All events listed below must be reported in the defined timelines to CCRsafety@mail.nih.gov.  
The CCR Office of Regulatory Affairs will send all reports to the manufacturer as described below. 
Rimiducid is provided under NCI CTA# 01096-18 with Bellicum Pharmaceuticals Inc. Data 
sharing with Bellicum Pharmaceuticals Inc. must be carried out as follows: 
• An annual report of all patients receiving Rimiducid. This report will consist of a brief 
summary of each patient’s Grade 2 or greater adverse events and multiple myeloma 
responses after the date of Rimiducid administration (report to Paul Woodard, MD of 
Bellicum, Inc. at pwoodard@bellicum.com).  
• Communications with the FDA related to Rimiducid must be shared within 10 calendar 
days. Report to this email address: BellicumSafety@pharmalex.com. Also send to Paul 
Woodard, MD of Bellicum, Inc. at pwoodard@bellicum.com.  


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• Pregnancies must be reported to BellicumSafety@pharmalex.com. Also send a copy to 
Paul Woodard, MD of Bellicum, Inc. at pwoodard@bellicum.com. 
8.4.2 Reporting by Study Team to Bellicum Pharmaceuticals Inc. 
• SAEs possibly or definitely related to Rimiducid must be reported within 24 hours of 
the sponsor becoming aware of the SAE. Study team will report to this email address: 
BellicumSafety@pharmalex.com. Back-up reporting is to this phone number: 1-617-
315-4825. Also, report to Paul Woodard, MD of Bellicum, Inc. at 
pwoodard@bellicum.com. 
• Any use of Rimiducid must be reported within 3 calendar days and must include the 
following 
(report 
to 
Paul 
Woodard, 
MD 
of 
Bellicum, 
Inc. 
at 
pwoodard@bellicum.com.) by Principal Investigator: 
o Patient age, sex, malignancy, brief history including indication for Rimiducid 
o Dose of CAR T cells received by the patient and percentage of infused cells 
expressing the CAR 
o Blood CAR T-cell levels before and after Rimiducid administration (may take 
longer than 3 days to obtain these results). 
o Blood cytokine levels before and after Rimiducid administration (may take 
longer than 3 days to obtain these results). 
o Timing and nature of Grade 2 or greater AEs within the first 3 days after 
Rimiducid administration.     
 
8.5 
REPORTING PREGNANCY  
8.5.1 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 (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented. 
8.5.2 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 (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 


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congenital abnormality) occurring from the date of the first dose until (120 days) after the last dose 
should, if possible, be followed up and documented. 
8.6 
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 in expedited manner to the FDA in accordance 
to 21 CFR 312.32.  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 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 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 CAR-expressing T cells, and to measure persistence, 
function, and gene expression of CAR-expressing T cells. In addition, the efficacy of Rimiducid 
at inducing apoptosis of the SLAMF7 expressing CAR T cells and mitigating toxicity including 
severe infections will be assessed.  


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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 24 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 36. The trial uses a dose-escalation design, with 4 dose levels and a -1 dose level if 
needed.  The number of CAR+ T cells transferred for each dose level is as follows:  
 
Dose level -1 0.3x106 CAR+ T cells per kg of recipient bodyweight 
Dose level 1 0.66x106 CAR+ T cells per kg of recipient bodyweight 
Dose level 2 2.0x106 CAR+ T cells per kg of recipient bodyweight  
Dose level 3 6.0x106 CAR+ T cells per kg of recipient bodyweight  
Dose level 4 12.0x106 CAR+ T cells per kg of recipient bodyweight 
 
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 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 because 
no retreatments will be allowed until the optimal CAR T-cell dose is established. Use of Rimiducid 
will be recorded and used in descriptive statistics.  


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10.3 POPULATIONS FOR ANALYSES 
Toxicity Analysis: All patients will be evaluable for toxicity from the time of Anti-SLAMF7-CAR 
T cell infusion.  Toxicity data will be collected for all patients. 
Response Analysis - Intention to treat: any subjects who enroll onto the trial and provide consent 
and who receive at least one cycle of treatment will be included in analyses 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 3.8. 
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 CAR-transduced T cells will be evaluated by a quantitative measure 
(flow cytometry and/or quantitative PCR) in all patients.  Serum cytokine 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 


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of a pilot study which may be used to guide parameters for study in future protocols if warranted. 
Efficacy of Rimiducid will be assessed by resolution of clinical toxicity and by evaluating 
elimination of CAR+ T cells by monitoring blood CAR T-cell levels by qPCR and/or flow 
cytometry. 
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 
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 COLLABORATIVE AGREEMENTS 
11.1 CLINICAL TRIAL AGREEMENT 
Rimiducid is provided under a Clinical Trial Agreement (CTA) NCI CTA# 01096-18 with 
Bellicum Pharmaceuticals Inc. 
12 HUMAN SUBJECTS PROTECTIONS  
12.1 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 gender and ethnic aspects of clinical research on the other hand.  If 
differences in outcome that correlate to gender 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. 
• The upper age limit of this protocol will be 73 years of age. CAR T-cell therapies often 
result in patients being admitted to intensive care units due to cytokine-release syndrome. 
These critically ill patients often need vasopressor drugs and occasionally need mechanical 


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ventilation among other intensive care interventions. The mortality of critically-ill patients 
progressively increases with age above 20 years as shown in the Acute Physiology and 
Chronic Health Evaluation (APACHE) IV: Hospital mortality assessment for today’s 
critically ill patients.(156) Because mortality of critically-ill patients reaches >10% at age 
70 (Table 6 of the cited paper). Because CAR toxicity is very unpredictable and based on 
my extensive past experience treating patient with CAR T cells on phase I clinical trials, I 
choose to not enroll patients over the age of 73. 
12.2 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.   
12.3 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 
research participation (section 10.4 ), 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 as needed for the following: an independent assessment 
of whether an individual has the capacity to provide consent; assistance in identifying and 
assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint 
a surrogate.  For those subjects that become incapacitated and do not have pre-determined 
substitute decision maker, the procedures described in NIH HRPP SOP 14E for appointing a 
surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not 
have a legal guardian or durable power of attorney, will be followed.  
12.4 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 clinical trial is being performed to evaluate a 
genetically-modified T-cell therapy for multiple myeloma, which is an almost always incurable 
disease.(21)  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 six 
categories.   
The first category is chemotherapy-related toxicity that could cause cytopenias. 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, 
transient abnormalities of liver function and hypotension. These cytokine-release-type toxicities 


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have been detected in other clinical trials of CAR T cells during the first two weeks after anti-
CD19 CAR T cells and anti-BCMA CAR T cells were infused.(4, 5, 134) 
A third category of potential toxicities are neurological toxicities such as delirium, obtundation, 
myoclonus, seizures, headache and transient focal neurological toxicities including aphasia and 
focal paresis. In previous anti-CD19 CAR trials, cytokine-release toxicities and neurological 
toxicities have been limited in duration with toxicities generally resolving within 2 days to 3 
weeks.(5, 41, 74, 135, 136) In the NCI anti-BCMA trial, neurologic toxicities were limited to 
confusion or delirium in the setting of high fevers and one case of encephalopathy and muscle 
weakness of all extremities consistent with critical illness polyneuropathy/polymyopathy.(5) In 
most cases, these toxicities have been transient with toxicities generally resolving within 2 days to 
2 weeks.   
The fourth 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-SLAMF7 CAR with proteins other than 
SLAMF7 in vivo. This trial will be one of the first in human trials testing anti-SLAMF7 CAR T 
cells in patients with multiple myeloma who have failed at least three previous lines of therapy. 
Although SLAMF7 is highly expressed in almost all cases of MM it has very limited or absent 
expression on normal tissues aside from leukocytes.(9, 10, 110, 112, 113)  Hematopoietic stem 
cells do not express SLAMF7.(111) SLAMF7 is not expressed on the surface of normal organ 
epithelial tissue such as lung, kidney, stomach, brain, breast, spleen, prostate, skeletal muscle, 
testis, liver, ovary, heart, thymus and small intestine epithelial tissue.(9) We have performed 
extensive testing of the MSGV-iCasp9-Luc90CD828Z CAR T cells by culturing them with a 
variety of human cell lines and have not seen recognition of cell lines that did not express 
SLAMF7. In addition, we did not find any evidence of cross-reactivity in our cell line data or 
immunohistochemistry data from the NIH Department of Pathology.  
A fifth category of toxicity that may be caused by anti-SLAMF7 CAR T cells is impairment of 
normal immunity because SLAMF7 is expressed on leukocytes such as CD8+ T cells, natural killer 
(NK) cells, B cells, plasma cells, some monocytes, NKT cells, and some dendritic cells.(5, 9, 10, 
110, 112, 113) NK cell deficiencies are associated with severe, potentially life-threatening viral 
infections caused typically by benign members of the Herpesviridae (VZV, HSV, CMV, EBV) 
and Papillomaviridae (HPV) families.(137) Additionally, NK cells have potent cytotoxic activity 
against malignant cells and NK cell defects are linked to ineffective tumor surveillance and 
clearance. We have included a suicide gene in this trial in large part to allow elimination of anti-
SLAMF7 CAR T cells in case depletion of recipient immune cells leads to infections. Greater 
detail about the depletion of leukocyte subsets is provided below. 
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.(43, 44)  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, 33, 138, 139) 
The potential benefits to subjects enrolling on this trial include the possibility that the CAR T cells 
can cause a significant anti-myeloma effect. Many patients enrolled on trials of anti-CD19 CAR T 
cells and anti-BCMA CAR T cells obtained complete remissions of their advanced malignancies; 


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there is a chance that recipients of the CAR T cells that are being evaluated in this protocol could 
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 by 
aiding in the development of new therapies might help future patients. 
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.   
The risks associated with biopsies are pain and bleeding at the biopsy site. In order to minimize 
pain, local anesthesia will be used. Rarely, there is a risk of infection at the sampling site.  
12.4.1 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 seven (7) CT neck +CAP, two (2) CT-
Guided biopsies and three (3)18FDG-PET/CT scans in the first year of the study. 
The total additional radiation dose for research purposes will be approximately 15.6 rem in the 
first year of the study. Being exposed to too much radiation can cause harmful side effects such 
as an increase in the risk of cancer. 
Most patients will obtain much less than the maximum levels of radiation exposure since CT scans 
will only be carried out in patients who have measurable plasmacytomas after baseline assessment. 
In addition, CT imaging will be modified based on plasmacytoma locations. For example, many 
patients will not receive any post-infusion neck CTs since many patients do not have baseline neck 
involvement with myeloma. Most activity of CAR T cells occurs in the first 3 months after 
infusion, so we need to assess the onset of myeloma responses carefully during this time-period. 
Note that our imaging practices are similar to those in the largest multicenter anti-BCMA CAR 
study, the bb2121 trial .(157) The radiation exposure on this study is in fact, less than what is 
outlined in the Raje et al. study.  
 
12.5 CONSENT PROCESS AND DOCUMENTATION 
The informed consent document will be provided to the participant or consent designee(s) (e.g., 
the parent/guardian if participant is a minor, 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 in a 
private area (e.g., clinic consult room) or remotely (e.g., via telephone or other NIH approved 
remote platforms) per discretion of the designated study investigator and with the agreement of 
the participant/consent designee(s).  


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Permission for additional biopsies for research will be obtained from patients at the time of the 
biopsy procedure. The research nurse, Principal Investigator or his designee is responsible for 
obtaining written informed consent from the patient. 
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 CAR-SLAMF7 GENE  
13.1.1 Cells manufacturing 
The retroviral vector supernatant (MSGV1-IC9-Luc90CD828Z) (encoding a CAR directed against 
SLAMF7 with the iCasp9 suicide gene system 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 including the 5' LTR from the 
murine stem cell virus (promoter), packaging signal including the splicing donor (SD) and splicing 
acceptor sites,  the anti-SLAMF7  CAR protein containing a signal peptide from human CD8-
alpha signal sequence, a single-chain variable fragment antigen recognition domain derived from 
the murine Luc90 antibody, CD8-alpha (hinge and transmembrane domains), CD28 (cytoplasmic 
region), and CD3-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 Fisher Biosciences, Rockville, MD. Both storage facilities are equipped with 
around-the-clock temperature monitoring. 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 
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 Source 
After cells are obtained by apheresis, further cell processing to generate CAR-expressing T cells 
will occur in the DTM according to standard operating procedures (SOPs).  Either freshlycollected 
cells or cryopreserved cells can be used to initiate the cell-preparation process. 
13.1.3 Toxicities 
Please refer to section 1.2.13. 
13.1.4 Administration procedures:  
Please see section 3.3 3.1.4.Potential Drug Interactions 
There are no known drug interactions.  
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 


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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 
Fludarabine is administered as an IV infusion in 100 mL 0.9% sodium chloride, USP over 30 
minutes.   
13.3 RIMIDUCID  
13.3.1 Source  
Rimiducid will be supplied by a CTA from Bellicum Inc. 
13.3.2 Toxicity  
No serious adverse events occurred during the Phase 1 study in volunteers.(122) The incidence of 
adverse events was very low following each treatment, with all adverse events being mild in 
severity. Only one adverse event was considered possibly related to AP1903. This was an episode 
of vasodilatation, described as “facial flushing” for 1 volunteer at the 1.0 mg/kg AP1903 level. 
This event occurred at 3 minutes after the start of infusion and resolved after 32 minutes’ duration. 
All other adverse events reported during the study were considered by the investigator to be 
unrelated or to have improbable relationship to the study drug. These events included chest pain, 
flu syndrome, halitosis, headache, injection site pain, vasodilatation, increased cough, rhinitis, 
rash, gum hemorrhage, and ecchymosis.(122) 
13.3.3 Formulation and preparation  
This information is from the Rimiducid “Guidance for Investigators” from Bellicum, Inc. The 
Rimiducid for Injection is packaged in 3 ml Type 1 clear glass serum vials. The contents of each 
vial are composed of the labeled content 10 mg (2 ml) of Rimiducid drug substance dissolved in a 
sterile, endotoxin free, 25% Solutol HS 15/Water for Injection solution at an Rimiducid 
concentration of 5 mg/ml and at pH 5.0 – 7.5. Each vial is stoppered with a Teflon© coated serum 
stopper and a yellow flip-off seal.  
 


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The primary product label (applied directly to the vial) for Rimiducid for Injection will contain the 
following information: product name, Rimiducid for Injection; the manufacturer’s lot number; 
product concentration, 5 mg/ml; volume of solution available in the vial; total Rimiducid contents 
of the vial (10 mg); a statement, “For IV Infusion Following Dilution, contains no preservatives” 
and the IND notation, “Caution: New Drug-Limited by Federal Law to Investigational Use”. The 
product will be labeled according to the requirement of each competent authority.  
 
Rimiducid is formulated in 25% Solutol HS 15, a non-ionic surfactant. Prior to administration, 
rimiducid is diluted in normal saline, which may lead to the formation of micro-micelles. Micelles of 
polyethoxylated pharmaceutical surfactants, such as Solutol, are known to activate complement, 
leading to anaphylactoid-like reactions or pseudoallergy. Such responses may be the result of the 
activation of mast cell and subsequent degranulation (Szebeni 2001).  
 
Bellicum recommends that patients are pre-medicated using standard procedures for the prevention of 
infusion reactions prior to administration of rimiducid. Such pre-treatment regimens would typically 
be administered thirty minutes to one hour prior to the infusion of rimiducid.  
Rimiducid for Injection must be warmed to room temperature prior to dilution.  
 
Drug interactions: Rimiducid is an investigational new drug and while there are no known verified 
drug interactions, investigators should be aware that potential unknown interactions and adverse effects 
may occur. It should be noted that rimiducid is an inhibitor of CYP3A4 and CYP2C8 and therefore, 
co-administration of rimiducid with other substrates of CYP3A4 and CYP2C8 could lead to elevated 
concentrations of these concomitant medications. However, a drug/drug interaction study was 
conducted to evaluate the potential interaction of rimiducid with substrates of CYP3A4 using the probe 
midazolam. This study indicated that following a single IV dose of 0.5 mg/kg or less, rimiducid is 
unlikely to alter the clearance of co-administered CYP3A4 substrates. 
 
Rimiducid was tested in normal, healthy people at doses 2.5-fold greater than those used in the 
clinical trials using gene modified cells (Covance Study No. 1711-1). A side effect noted was facial 
flushing (redness) in one person. Although not observed in patients to date, rimiducid was 
associated with modest elevations of hepatic transaminases, bilirubin and alkaline phosphatase in 
the acute and subacute non-human primate study. It is possible that other side effects may occur.  
In the Bellicum BP-PC-001 trial, one patient exhibited an adverse event of cytokine mediated release 
or hypersensitivity like reaction upon infusion of rimiducid and one patient experienced urticaria and 
flushing, which resolved with antihistamine administration. None of these AEs were considered 
serious.  
Rimiducid for Injection is incompatible with materials containing plasticizer or DEHP and materials 
sterilized with ethylene oxide.  
 
Rimiducid (AP1903) with iCasp9 Switch suspected unexpected serious adverse reaction 
(SUSARs): Currently, no SUSARs have been reported under this program. For regulatory reporting 
purposes, there are currently no adverse events expected.  
The Rimiducid for Injection vials must be stored at 5°C ± 3°C (41°F ± 5°F) in a limited access, 
qualified refrigerator, preferably without light (but not required to protect from light). Prior to 
administration, the calculated dose will be diluted to 100 mL in 0.9% normal saline for 
infusion.(121, 122) 


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13.3.4 Administration procedures:  
For use, the Rimiducid will be diluted prior to administration. Rimiducid is administered via I.V. 
infusion at the target dose diluted in normal saline with volume as appropriate for age of patient to 
be administered over 2 hours, using a DEHP-free saline bag and solution set.  
 
Rimiducid for Injection (0.4 mg/kg) in a total volume of 100 ml of Rimiducid plus normal saline 
will be administered via IV infusion over 2 hours, using a non-DEHP, non-ethylene oxide 
sterilized infusion set and an infusion pump. For patients <50 kg or >150 kg, a volume of 
administration of Rimiducid different than 100 mL is allowed (121, 122) 
Note: Recommendations include premedication per institutional standards (acetaminophen and 
antihistamine) 30 minutes prior to infusion for prevention of potential hypersensitivity to the 
Solutol HS 15 or rimiducid.   
Dose reduction for renal impairment: Rimiducid is thought to be cleared by non-renal means. Dose 
adjustments for hepatic or renal insufficiency have not been established. 
 
 


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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 C3D database: 
 
A. Patient Enrollment 
 
• Date of birth, age, gender, race, ethnicity 
• Height 
• Weight 
• ECOG 
• Date of original diagnosis 
• Plasmacytoma present: Yes or No 
• Tumor Histology and date of confirmation 
• SLAMF7 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 SLAMF7 
results 
• Findings of consultations done at screening 
 
B. Study Drug administration and response for each course of therapy given 
• Dates anti-SLAMF7-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 C3D 
 
         
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 


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results, serum protein, urine albumin, serum calcium (including ionized), ESR and 
CRP results. MRI, X-ray, and CT scan results will only be reported if they were 
used for staging. 
D. Adverse Events 
Please see section 6.1.1 Adverse 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. 
 
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 regardless of 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. 


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
109 
 
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.  
• Systolic blood pressure less than 75% 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 in patients weighing 30 kg or more, infused IV over 1 hour (dose should 
not exceed 800 mg); it may be infused up to three additional times if there is no clinical 
improvement in signs and symptoms after the first dose. The interval between consecutive 
doses should be at least 8 hours.  


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110 
• 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 µg/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%. 
• 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 “Tocilizumab 
administration” 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 Rimiducid should 
be administered, 1000 mg of methylprednisolone can be considered. 


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
111 
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. 
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. CARTOX-10 scale (Appendix E) will be administered daily in patients and used to monitor 
for aphasia/dysphasia in patients.  
5. 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. Tocilizumab may be concurrently given with steroids if the patient has evidence of 
CRS in addition to neurological toxicity 
1. Inability of patient to follow simple commands such as “squeeze my fingers”. 
2.  Any generalized seizure 
3. Somnolence severe enough to potentially limit airway protection 
4. Obtundation and stupor  
5. Ataxia severe enough to preclude ambulation 
6. Disorientation to person or place that persists longer than 48 hours 
7. Neurologic toxicity lasting more than 2 hours that is severe enough to interfere with 
activities of daily living (ADLs) 
8. Cerebral edema 
 
 
 


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
112 
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 has been 
signed  
 
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.  
 


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
113 
7.  Measure and record baseline vital signs, 
respiratory and circulatory assessments. 
 
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. 
 
 
 
 
 


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
114 
 
 
 
 
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.  
 
 
 
 
 
 


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
115 
15.5 APPENDIX E:   CARTOX (ADAPTED FROM NEELAPU ET AL, 2018):  
- 
One point is assigned for each task. Normal function defined by overall score 
of 10.  
- 
TASKS:  
 Orientation to year, month, city, hospital and President of country 
(maximum 5 points) 
 Name three objects (ex: point to clock, pen, button) (maximum of 3 
points) 
 Write a standard sentence (1 point) 
 Count backwards from 100 in tens (1 point) 
 
 


Abbreviated Title: Anti-SLAMF7 CAR T cells for MM 
Version Date: April 14, 2020 
 
116 
15.6 APPENDIX F:   CYTOKINE RELEASE SYNDROME GRADING ASSESSMENT (ADAPTED FROM 
LEE ET AL, 2019).  
Grade 1 CRS:  
- 
Fever and:  
- 
Constitutional symptoms 
Grade 2 CRS:  
- 
Fever and:  
- 
Hypotension; responds to fluids. 
- 
Hypoxia requiring low flow nasal cannula or blow-by. 
Grade 3 CRS:  
- 
Fever and;  
- 
Hypotension: requires pressor +/- vasopressin)  
Hypoxia: requiring high-flow nasal cannula, facemask, nonrebreather mask or venturi mask. Grade 
4 CRS:  
- 
Fever and;  
- 
Positive pressure  
- 
 
- 
Multiple Pressors 
 

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/14/2020
Page 1 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:    James N. Kochenderfer, M.D. 
STUDY TITLE: 
A Phase I Clinical Trial of T-cells Expressing an anti-
SLAMF7 CAR for Treating Multiple Myeloma
STUDY SITE:  
NIH Clinical Center
Cohort:                                                Standard Treatment consent
Consent Version: 
04/14/2020
WHO DO I CONTACT ABOUT THIS STUDY? 
James Kochenderfer, MD. by phone at 240-760-6062 or Email: kochendj@mail.nih.gov 
                         
           
KEY INFORMATION ABOUT THIS RESEARCH 
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study. 
You are being asked to take part in a research study at the National Institutes of Health (NIH). This 
section provides the information we believe is most helpful and important to you to in making your 
decision about participating in this study. Additional information that may help you make a 
decision can be found in other sections of the document. Taking part in research at the NIH is your 
choice.
You are being asked to take part in this study because you have been diagnosed with multiple 
myeloma, a blood cell cancer, that has not been controlled with standard therapies …
The purpose of this study to determine if a personalized immune treatment is safe.
The use of anti-SLAMF7 CAR T cells and Rimiducid used in this study is considered 
investigational, which means that it has not been approved by the U.S. Food and Drug 
Administration (FDA) to treat Multiple Myeloma.  However, the FDA has given us permission to 
use anti-SLAMF7 CAR T cells in this study.
There are other drugs that may be used to treat your disease, and these can be prescribed/given by 
your regular cancer doctor, even if you are not in this study.  These may include, for instance, 
dexamethasone, standard chemotherapy or tocilizumab.  While all the other therapies have their 
own side effects, CAR T-cell therapy can cause cytokine release syndrome (CRS) which is 
associated with high-fevers and feeling very sick, which may be different than some of the 
therapies, and it is expected that if the CAR T-cells cause cytokine-release syndrome,  Patients 
sometimes need  to go the an intensive care unit for close observation and intensive treatments.  
If you decide to join this study, here are some of the most important things that you should know 
that will happen:
IRB NUMBER: 19C0102
IRB APPROVAL DATE: 06/16/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/14/2020
Page 2 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
First, we will separate and collect your T cells from your blood. Your whole blood will go through 
a machine that separates blood into different parts (this will take 3-4 hours). Your T cells will be 
grown with viruses that carry the CAR genes that lead cells to recognize SLAM7, a protein often 
found in blood cells. The viruses will put the CAR gene into your collected T cells. These CAR T 
cells will then be grown in a laboratory at the NIH for 7 to 9 days.
You will be given three days of low-dose standard chemotherapy before getting the CAR T cells. 
Chemotherapy creates an environment in your body where the T cells will be active and multiply. 
You will receive your CAR T cells by an intravenous (IV) infusion while in the hospital at the 
NIH three days after chemotherapy. You will be in the hospital for at least 9 days or longer, if 
there are complications.
You may experience side effects from taking part in this study. Some can be mild or very serious, 
temporary, long-lasting, or permanent, any may include death. Some of the most important side 
effects that you may have include:
•
Cytokine release syndrome (CRS): Cytokines are substances released from cells that can cause 
many side effects such as fever, fast heart rate, low blood pressure etc.
•
Tumor lysis syndrome (rapid breakdown of tumor that can cause side-effects such as fast heart 
rate, possible kidney damage that will most likely be temporary, shortness of breath etc.)
•
Headache
•
Temporary muscle weakness or difficulty speaking
•
Temporary decreased kidney function
•
Tiredness, fever, chills
•
Increased risk of infection 

May have rare incidence of increased risk of cytomegalovirus (CMV) and Epstein-bar virus 
(EBV) infections. 
•
Temporary changes in liver function tests
•
Temporary abnormal heart rhythm
•
Prolonged (a month or more) low blood counts including low white blood cells (leading to 
infection) and platelets (leading to bruising)
To increase the safety of this therapy, we have included a safety switch that can stop the CAR T 
cells with a medication. The medication is called Rimiducid. We will stop your CAR T cells if you 
develop severe side effects that are not controlled by standard medications or if you have a severe 
or life-threatening viral infection. There may be other serious situations where we will decide to 
give you the medication to stop the CAR T cells.
You will be seen often during the study. You will have laboratory, and imaging tests to see how 
you are doing and to assess your disease. We will also collect required samples from you (such as: 
blood and bone marrow biopsies).
IRB NUMBER: 19C0102
IRB APPROVAL DATE: 06/16/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/14/2020
Page 3 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
After you finish your CAR T cell treatment we would like to see you at the NIH Clinical Center 
monthly for 4 months then at 6, 9 and 12 months, and finally every 6 months up to 3 years to assess 
your health and to determine what impact, if any, the cell therapy had on your disease.
After the study follow-up period has ended, long-term follow up will be requested. During the 
long-term follow-up, we would like to contact you one time each year until 15 years after your 
CAR T-cell infusion.
Just as we do not know what side-effects you might have, we cannot know if you may benefit from 
taking part in this study. If you do not benefit, this study and the results from our research may 
help others in the future.
We will cover the cost for some of your expenses, such as travel, lodging and/or meals. Someone 
will work with you to review your costs of taking part and what we will support.
You are free to stop participating in the trial at any time. If you decide to stop, the study doctor 
may ask you to agree to certain tests to make sure it is safe for you to stop.
The remaining document will now describe more about the research study. This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information described in this document. Some people have personal, religious, or ethical 
beliefs that may limit the kinds of medical or research treatments they would want to receive (such 
as blood transfusions). Take the time needed to ask any questions and discuss this study with NIH 
staff, and with your family, friends, and personal health care providers.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research. 
WHY THIS STUDY IS BEING DONE?
This is a research study. The purpose of this research study is to see if it is safe to give anti-SLAM7 
CAR T cells T cells to people with multiple myeloma 
We are asking you to join this research study because you have been diagnosed with multiple 
myeloma that has not been controlled with standard therapies, meaning that the cancer cells are 
growing despite your prior treatments or, if you did achieve a remission, the cancer has come back 
after your most recent treatment.
IRB NUMBER: 19C0102
IRB APPROVAL DATE: 06/16/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/14/2020
Page 4 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Anti-SLAM7 CAR T cells and Rimiducid are considered investigational, which means that they 
have not been approved by the U.S. Food and Drug Administration (FDA) to treat multiple 
myeloma. There may be other standard therapies your myeloma will respond to.  
WHAT WILL HAPPEN DURING THE STUDY?
Before you begin the study
If you decide to take part in this study, before receiving treatment, you will have several tests 
performed to check whether the trial is suitable for you. This is called the Screening Period. Your 
doctor will review your medical history and the drugs that you are currently taking to determine 
whether you can participate in this trial. 
Some of these tests or procedures are part of regular care and may be done even if you are not 
being considered to join the study. If you have had some of these tests or procedures recently, 
they may or may not have to be repeated.  These tests will be performed on a separate screening 
protocol# 01C0129 and include a medical history and physical examination, routine blood tests, 
pregnancy test in women who can have children (pregnant women are not allowed to take part), 
blood tests for viruses, taking a sample of your bone marrow, scans to assess your disease and 
tests of your heart function.  We may also need to collect all your urine over a 24-hour period.  
During the study therapy
Once it is determined that you are eligible to participate in the study, and you agree to participate 
by signing the study consent, you will undergo an apheresis procedure that will remove cells from 
your blood. Apheresis is a procedure for obtaining certain blood cells, such as white blood cells, 
without removing most blood cells. It is a process people undergo for routine platelet donations. 
Some people need an IV (intravenous catheter, a small plastic tube that is put into a vein) inserted 
into each arm for this collection and some people need a temporary special apheresis “central line” 
just for the one-day collection.
Next, we will manipulate your cells in a laboratory so that they can recognize your multiple 
myeloma. Specifically, we will genetically modify your T cells and grow them in the laboratory 
so that they can recognize and destroy cells that have a certain protein, signaling lymphocyte 
activation molecule 7 (SLAMF7) on the surface. Your multiple myeloma cells express the 
SLAMF7 protein on the surface. This SLAMF7 protein will serve as a target for the anti-SLAMF7 
T cells. Most of your normal cells do not express SLAMF7; however, they are present in normal 
plasma cells and NK cells, parts of your immune system. To prevent too much damage to your 
normal cells, the T cells will be genetically modified to encode a gene for a “safety switch” protein 
in addition to the SLAMF7 protein. This safety switch can be turned on by giving an infusion of a 
drug called Rimiducid. We have incorporated this safety switch to stop toxicity of this therapy. By 
turning on the safety switch, the genetically modified T cells that recognize your multiple myeloma 
cells will no longer function and will die. Rimiducid, the drug that turns on the safety switch, will 
only be infused in certain circumstances: severe infections not controlled by antibiotics or antiviral 
medications, prolonged low blood counts with and without complications and severe cytokine 
release syndrome. There may be other severe instances where the medication will be infused. 
This study will be conducted as a “dose escalation”. The purpose of dose escalation is to determine 
the safe dose of anti-SLAMF7 T cells. There are four dose levels of anti-SLAMF7 T cells. The 
IRB NUMBER: 19C0102
IRB APPROVAL DATE: 06/16/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/14/2020
Page 5 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
first patients enrolled get the smallest dose and the dose is increased when a level has been 
determined to be safe. You can discuss this with the study doctors to find out which dose of anti-
SLAMF7 T cells you will be receiving. 
After you have had cells removed from your blood, you will receive 2 FDA approved drugs 
(chemotherapy) named cyclophosphamide and fludarabine. These drugs will be given to you 
through a “central line” (or tube) placed in a large vein in your arm or chest once a day for 3 days. 
The two drugs are given one after the other with each infusion lasting about 30 minutes. The 
purpose of the chemotherapy is to enhance the activity of the anti-SLAMF7 T cells. This is a 
standard chemotherapy regimen that is often used to treat certain types of leukemia. The 
chemotherapy can be administered on an outpatient basis, which means hospital admission is not 
necessary.
Three days after the chemotherapy ends, you will be admitted to the hospital as an inpatient where. 
you will receive the anti-SLAMF7 T cells. The anti-SLAMF7 T cells will be given to you as a 
single intravenous (IV) infusion. You will need to have a “central line”, and IV catheter (or tube) 
placed in a large vein in your arm or chest for this infusion. This may be the same “central line” 
that was used for the chemotherapy. You will receive the commercially-available, common drugs 
acetaminophen and diphenhydramine as premedications prior to the CAR T cells. All patients that 
participate in this study will be required to stay in the hospital for close observation and testing for 
at least 9 days after the cell infusion, and patients must stay within 60 minutes driving distance for 
2 weeks after the cell infusion. This is because in our experience with similar treatments we have 
noticed side-effects including fevers, fatigue, low blood pressure, and others that have been most 
severe between 6 and 9 days after cell infusion. You may have to stay in the hospital longer to 
manage these side effects if they occur. During this time-period, you must be willing to agree to 
intensive care treatment that can include drugs that support your blood pressure, chest 
compressions, a machine to assist your kidneys, and being attached to a breathing machine.
You will be closely watched during the anti-SLAMF7 cell infusion for signs of a reaction. While 
other types of genetically-modified T cells have been administered to many patients, infusion of 
anti-SLAMF7 T cells is a new approach that is being evaluated in this protocol. There is always a 
chance that we will not be able to genetically-modify your cells or be able to grow the cells in the 
laboratory. If we are not able to successfully prepare the minimum number of cells that we believe 
are needed to help control the tumor in our first attempt to produce the cells, we will make a second 
attempt to produce the cells if you give us permission to do so even if you have already received 
the chemotherapy part of the protocol at the time. This second attempt to produce cells will 
probably not be necessary. If a second attempt to produce cells is necessary, it might require a 
second apheresis.
For patients who still have disease after receiving anti-SLAMF7 T cells the first time, repeated 
infusions might be possible. In order for a repeat infusion to be possible, you must not have 
experienced severe side effect with your first infusion, and you must meet the original eligibility 
requirements for enrollment on the trial. Repeat treatments will also include the same 
chemotherapy as the first treatment. A maximum of 2 total treatments can be given to any one 
patient. 
IRB NUMBER: 19C0102
IRB APPROVAL DATE: 06/16/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/14/2020
Page 6 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Blood will be drawn frequently during your treatment.  Most of the blood draws will be to monitor 
your health during and after the cell infusion. 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 samples will be used to study how your immune 
system is affected by the cell therapy. If a cancer is suspected, but not definite, you may have 
subsequent evaluation here at NIH or at your home institution per standard of care.  These might 
include additional testing such as, bone marrow biopsies, or other imaging tests.
Additional research testing
In addition to performing the tests described above, we will also do tests for purposes of research. 
These are being done to help us to find out if you have cancer, evaluate your emotional and 
physical wellbeing, and to study possible markers in your blood.
The studies include:

Imaging Assessments: 
a computed tomographic scan (CT) that produces a picture of your body using a small 
amount of radiation (if you are not pregnant and do not have allergy to CT contrast) 
Positron emission tomography (PET)/CT scans which combine two different types of 
scanners to get better image of your tumor before starting the study treatment, 
approximately 1 scan/year.

Tumor Sampling: In very rare instance, before or after of cell therapy, we may ask your 
permission to perform a research biopsy of your cancer if we can safely perform a biopsy 
without general anesthesia or significant risk of danger or discomfort to you, a sample may 
be removed through a surgical procedure or with a needle biopsy. The specific details 
would be described to you by the surgeon and you will be asked to sign a separate consent 
for the procedure. The biopsy will be performed under sterile conditions to prevent 
infections.   We may also ask your permission to perform a biopsy for research. The tissue 
from this biopsy will be used to determine whether there is evidence of an immune response 
to the tumor or to determine if a newly discovered tumor is actually multiple myeloma. 
Any biopsies would only be performed with your permission, and if the biopsy is 
determined to be safe by the Principle Investigator of this trial and the additional physician 
or physicians that would actually perform the biopsy. Some of the samples may be used 
for other or future research conducted by the investigational team or other researchers.  
This future research might directly study malignancy of the same type that you have, or it 
could focus on other areas of research.
When you are finished taking the drugs (treatment)
You will need to come for a clinic visit two weeks after your cell infusion, for blood work, urine 
tests, and a brief visit with one of our doctors. You will also need to return to clinic for evaluation 
of your overall health and your multiple myeloma 1, 2, 3, 4, 6, 9 and 12 months after the cell 
infusion. These visits will also include a health and multiple myeloma assessment including blood 
test, urine tests, and possible disease imaging. You will have imaging done using PET scan at 2, 
4, 6, 12, 18, 24, 30 and 36 months after cell-infusion.  If you have a certain type of multiple 
myeloma tumor, you may also need to have imaging done using a CT scan at your visits.
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After 12 months, follow up for patients with ongoing responses, which means the multiple 
myeloma has not progressed, will continue every 6 months for up to 3 years after your T-cell 
infusion. At the follow-up visits we will evaluate your general health, and we will assess your 
multiple myeloma. Blood will be drawn at all follow-up visits. Note that all these follow-up visits 
are only required for patients with ongoing responses. 
If your multiple myeloma progresses, you will be removed from the study to pursue other options. 
As long as your multiple myeloma does not progress, we ask that you do not take any other 
treatments. We also ask that you do not take any corticosteroid medications such as prednisone or 
dexamethasone. If you do take other treatments including corticosteroids, we will not be able to 
interpret the results of the anti-SLAMF7 T cells, and you will be removed from the study. You 
will then be followed by your home oncologist who will receive a detailed summary of your case 
and blood tests and other investigations that need to be performed and potential problems that may 
arise. We encourage early communication of any problems with us so that we can assist in deciding 
the best treatment approach.
Gene Therapy Long Term Follow up (Retroviral Vectors) 
You will be followed on a separate NCI protocol# 15C0141 if you leave the CAR protocol. There 
will be a consent process for the separate protocol. Because we do not know the long-term side 
effects of gene therapy, we will ask you to take part in long term follow up for the next 15 years. 
The Food and Drug Administration (FDA) requires that people who receive gene therapy be 
watched even after they complete the study. We will ask you questions about your health and ask 
you to have a physical exam every year. We will also collect your blood over the next several 
years. If you return to your referring doctor after treatment here we will ask you to have your 
doctor send us a copy of your physical exam and your blood samples. We will collect blood 
samples right after you receive the cells, and at 3, 6 and 12 months after treatment, and then every 
year after that (2 teaspoons each time). This testing will help us learn if the cells have grown or 
changed in your body. For this reason, we ask that you continue to provide us with a current address 
and telephone number, even after you complete this research study. At the time of your death, no 
matter the cause, we may request permission for an autopsy in order to obtain vital information 
concerning the safety of this experimental therapy approach. Please discuss this request with your 
family to inform them of your wishes.
HOW LONG WILL THE STUDY TAKE?
If you agree to take part in this study, your involvement is expected to last for 3 years: 

You may be seen in the clinic two weeks after your cell infusion, for blood work, urine 
tests, and a brief visit with one of our doctors. Then to return to clinic for evaluation of 
your overall health and your multiple myeloma 1, 2, 3, 4, 6, 9 and 12 months after the cell 
infusion 

After 12 months, follow up for patients with ongoing responses, which means the multiple 
myeloma has not progressed, will continue every 6 months for up to 3 years after your T-
cell infusion. 
Your involvement on the Gene Therapy Long Term Follow Up Study will be 15 years once you 
are off treatment in this study.
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HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
We plan to have approximately 36 people participate in this study at the NIH. 
WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
Risks of Study Drugs
Because the SLAMF7 protein is found on normal plasma cells as well as on your cancer, the anti-
SLAMF7 T cells might cause a fleeting or prolonged decrease in the number of normal plasma 
cells. SLAMF7 is also found on a proportion of other immune cells of the body that fight 
infections-NK cells, CD8+ T cells, dendritic cells, monocytes and B cells. NK cells and CD8+ T 
cells play important roles controlling viral infections while plasma cells make antibodies that are 
involved in protection against infections. We do not know if a decrease in these cells will cause 
problems with infections and several steps can be taken to deal with an increased risk of infection 
or actual infections. These include giving antibiotics or antiviral therapy, antibodies intravenously, 
which is a standard treatment given to many patients with immune deficits or turning on the safety 
switch by administering the drug Rimiducid to stop the CAR T cells from functioning.
The anti-SLAMF7 T cells we will be giving you are exposed to a type of virus (retrovirus) in order 
to insert the anti-SLAMF7 gene that gives the T cells the ability to recognize multiple myeloma. 
Although this retrovirus is not active, there is the rare possibility that it may cause infection. This 
has never happened to any of the hundreds of patients who received T cells that were modified 
with similar viruses. The anti-SLAMF7 T cells could also cause you to develop another type of 
cancer in your blood cells, although we think this is very unlikely because it has never happened 
in the hundreds of patients who have received genetically-modified T cells. 
Patients who have received CAR T cells aimed at targets other than SLAMF7 have experienced a 
variety of side-effects. Most of these patients have developed fever and fatigue that can last for up 
to 2 weeks after cell infusion. Some patients that have received similar treatments have developed 
low blood pressure. In a minority of patients low blood pressure and  a temporary decrease in 
kidney function also occurred. In some other clinical trials aimed at different targets, patients 
developed temporary confusion, headaches, or weakness. One patient developed severe, but 
temporary, muscle twitching. Three patients developed a temporary inability to speak, which 
resolved completely after a few days. Rarely patients developed a temporary decrease in heart 
function. Heart function has almost always subsequently returned to normal levels. Less likely, 
patients developed tumor lysis syndrome, which is a release of toxic substances from tumor cells 
that are being destroyed. Tumor lysis syndrome is very rare, and has not caused no long-term 
problems for the patients on CAR T-cell studies at the NIH. Patients at risk of tumor lysis syndrome 
on the anti-SLAMF7 T-cell study will receive medication to prevent this complication. In addition, 
the safety switch can be turned on which we anticipate will control these side-effects. 
Chemotherapy is part of this protocol. The chemotherapy part of this study can cause decreased 
blood count, nausea, and hair loss. The decreased blood counts due to chemotherapy can lead to 
infections and bleeding.
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Potential risks of anti-SLAMF7 T cells infusion include:
Likely:
Less Likely:
Rare:

Fever 

Chills 

Fatigue

Low 
immunoglobulin 
levels ( susceptibility 
to infection)

Headache

General feeling of being unwell (malaise)

Temporary decreased kidney function

Temporary weakness or difficulty 
speaking

Low blood pressure

Fainting

Tumor lysis syndrome (rapid breakdown 
of tumor that can cause side-effects)

Possible intensive care unit 
admission

Fast heart rate

Possible kidney damage that will 
most likely be temporary

Possible breathing problems that 
might in rare cases require 
mechanical ventilation 
(breathing machine)

Cytokine release syndrome (release of 
substances from T cells that can cause 
many side-effects) including

Fever

Fast heart rate

Low Blood Pressure

Possible intensive care unit 
admission

Rare cases, death.

Temporary decreased cardiac function, or 
abnormal heart rhythms

Prolonged (a month or more) low blood 
counts including low white blood cells and 
platelets

Temporary changes in bleeding tests

Temporary changes in liver function tests 

Muscle pain, 
twitching

Death

Permanent kidney 
damage

Other neurologic 
problems

Coma 

Temporary liver 
damage

Extreme 
weakness of the 
arms and legs

Muscle damage

Long-term 
debilitation

Difficulty 
breathing

Increased risk of 
cytomegalovirus 
(CMV) 
and 
Epstein-bar virus 
(EBV) infections. 
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Likely:
Less Likely:
Rare:

Temporary low calcium, phosphorous, 
albumin in the blood

Increased risk of infection
There is no information available at this time to guide us in how humans might respond to this 
type of cell infusion. As this is a new experimental therapy, side effects that we do not anticipate 
that may cause your condition to worsen may be encountered. 
Potential risks of cyclophosphamide:
Likely:
Less Likely:
Rare:

Low blood counts 
Nausea and vomiting 
Painful and bloody urination 
Sterility 
Water retention
Hair Loss
Heart damage 
Secondary leukemia (a 
different type of cancer) 
Skin rash
Bleeding
Potential risks fludarabine:
Likely:
Less Likely:
Rare:
Low blood counts
Long-term reduction of 
lymphocyte counts which 
could increase the risk of 
infection.
Infection
Damage to the nervous 
system 
Causing seizures, coma, 
vision loss, and even 
death 
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Likely:
Less Likely:
Rare:
Inflammation in the lungs
Kidney damage 
Potential risks Rimiducid:
Likely:
Less Likely:
Rare:
Facial flushing
Allergic reactions 
including anaphylactoid-
like reactions or 
pseudoallergy
Liver injury
Fevers
Urticaria 

Nervous system 
disorders such as 
confusion
Gene Therapy Risk of Cancer and Other Diseases: 
The risks of gene therapy causing new disease are unknown. It is possible that the gene therapy 
may cause an immune system, blood, or neurological disorder, or cause a new cancer in your blood 
cells to develop. It is unknown if you will develop any of these disorders, but you need to be aware 
of this possible risk. Children in France and England received gene therapy for a particular disease 
of the immune system. The disease these children had was very different from the disease that you 
have. These children did not receive CAR T cells, they received a different type of cells. In these 
children, stem cells were genetically modified (in contrast to the research offered in this trial where 
T cells are genetically modified). Most of the children were cured, but 5 out of 22 children 
developed leukemia and one died. Experts who examined this case thought that the gene therapy 
caused the leukemia in these children. To monitor you for this risk we will be testing your blood 
as previously described. 
Procedure Risks
Blood draws:
Side effects of drawing blood include pain and bruising in the area where the blood was drawn, 
lightheadedness, or rarely fainting due to transient lowering of blood pressure. If you feel dizzy, 
you should lie down for a few minutes to avoid hurting yourself if you fall. Infection at the blood-
drawing site could also occur. 
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Central Intravenous Catheter: 
In order to receive this treatment, you will need to have a central venous catheter. This catheter is 
placed under the skin of the chest wall and enters a major vein in the chest. There are several types 
of catheters including those which must be removed after each cycle of chemotherapy (temporary 
type) and those which may be kept for the duration of therapy (permanent type). These options 
will be discussed with you. The risks associated with placing some catheters include pain, 
bleeding, infection and collapsed lung. The long-term risks of the catheter include infection, and 
clotting of your veins. If these occur, it may be necessary to remove the catheter. These risks will 
be explained to you in more detail at the time of insertion.
Bone marrow aspiration and biopsy:
A bone marrow biopsy is performed by inserting a needle into a bone of the hip. In the aspiration 
part of the procedure, a small amount of liquid bone marrow is removed, and in the biopsy part, a 
tiny solid piece of bone marrow is removed. You may feel a pressure sensation when the needle is 
being inserted and a pulling sensation and brief pain as the marrow is withdrawn. The amount of 
marrow taken is very small and will not change your body's ability to form blood cells. Potential 
complications of this procedure are local bleeding, pain at the site, and infection. Both are very 
rare. Bleeding can be stopped by applying local pressure and an infection can be treated with 
antibiotics.
Risks from MRI, PET, and CT scan
You may have allergic reaction to contrast used to perform MRI or CT scan. 
You may feel uncomfortable to stay still for about an hour during an MRI.
For radiation risk associated with CT scans and PET scans, please, see next paragraph. 
What are the risks of radiation from being in the study? 
During your participation in this research study, you will be exposed to radiation from CT scans 
of your neck, chest, abdomen and pelvis, CT-Guided biopsies and 18FDG-PET/CT scans.  The 
amount of radiation exposure you will receive from these procedures is equal to approximately 
15.6 rem. A rem is a unit of absorbed radiation. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT scans, CT-Guided biopsies and 18FDG-PET/CT scans that you get in this study will 
expose you to the roughly the same amount of radiation as 52 years’ worth of background 
radiation. Being exposed to too much radiation can cause harmful side effects such as an increase 
in the risk of cancer.  The risk depends on how much radiation you are exposed to. Please be aware 
that about 40 out of 100 people (40%) will get cancer during their lifetime, and 20 out of 100 
(20%) will die from cancer. The risk of getting cancer from the radiation exposure in this study is 
1.6 out of 100 (1.6%) and of getting a fatal cancer is 0.8 out of 100 (0.8%).
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Please tell your doctor if you have had any radiation exposure in the past year, either from other 
research studies or from medical tests or care, so we can make sure that you will not receive too 
much radiation. Radiation exposure includes x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body. 
You may not participate in this study if you are pregnant. If you can become pregnant, we will 
perform a pregnancy test before exposing you to radiation. You must tell us if you may have 
become pregnant within the previous 14 days because the pregnancy test is unreliable during that 
time
What are the risks related to pregnancy? 
If you are able to become pregnant, we will ask you to have a pregnancy test before beginning this 
study. You will need to practice an effective form of birth control before starting study treatment, 
during study treatment, and for at least 4 months after your last research treatment (the restricted 
period). If you become pregnant, there may be unknown risks to the fetus or unborn child, or risks 
that we did not anticipate. There may be long-term effects of the treatment being studied that could 
increase the risk of harm to a fetus. You must tell the study doctor if your birth control method 
fails during the restricted period,. If you think or know you have become pregnant during the 
restricted period,, please contact the research team member identified at the top of this document 
as soon as possible. 
If you are a sexually active person with a partner able to become pregnant, it is important that your 
partner not become pregnant during the restricted period,. There may be unknown risks to a fetus 
or risks we did not anticipate. You and your partner must agree to use birth control if you want to 
take part in this study. If you think your partner has become pregnant during the restricted period,, 
please contact the research team member identified at the top of this document as soon as possible.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
You might not benefit from being in this study. However, the potential benefit could include 
shrinking of your multiple myeloma if the cell infusion is accepted by your body or lessening of 
your symptoms, such as pain, that are caused by the cancer. 
Are there any potential benefits to others that might result from research?
In the future, other people might benefit from this study because the knowledge gained from this 
study may help in developing treatments for those who have this cancer.
WHAT OTHER OPTIONS ARE THERE FOR ME?
Before you decide whether or not to be in this study, we will discuss other options that are 
available to you. Instead of being in this study, you could:

choose to be treated with other forms of chemotherapy, antibody-drug therapy (such as 
daratumumab), radiation, stem cell or bone marrow transplantation, or immune therapies.
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
choose to take part in a different study, if one is available

choose not to be treated for cancer but you may want to receive comfort care to relieve 
symptoms.
You should discuss with your doctor your other choices and their risks and benefits.
DISCUSSION OF FINDINGS
New information about the study
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places.
Return of research results
We do not plan to return research results to you. A summary of the research results will be posted 
on Clinicaltrials.gov at completion of the study.
EARLY WITHDRAWAL FROM THE STUDY 
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if you have side effects from the treatment that your doctor thinks are too severe

if you develop problems such as an infection or other severe illness during or after the 
protocol chemotherapy before the CAR T-cell infusion

if you become pregnant

if you need to receive any other treatment for your disease

if the study doctor decides to end the study

if new information shows that another treatment would be better for you. 

if you do not follow the study rules
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Bellicum Pharmaceuticals, 
Inc. -the manufacturer of Rimiducid - or designated representatives. If you withdraw your consent 
and leave the trial, any samples of yours that have been obtained for the study and stored at the 
NCI can be destroyed upon request. However, any samples and data generated from the samples 
that have already been distributed to other researchers or placed in the research databases cannot 
be recalled and destroyed.
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CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY 
Some of your health information, and/or information about your specimen, from this study will 
be kept in a central database for research. Your name or contact information will not be put in 
the database. Your test results will be identified by a unique code and the list that links the code 
to your name will be kept separate from your sample and health information. Your information 
may be given out if required by law. For example, certain states require doctors to report to health 
boards if they find a disease like tuberculosis. However, the researchers will do their best to 
make sure that any information that is released will not identify you.
Will my medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private. However, we cannot guarantee total privacy. Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

Qualified representatives from Bellicum Pharmaceuticals, Inc, the pharmaceutical 
company that produces Rimiducid
This study is protected by a Certificate of Confidentiality (Certificate). With this certificate, 
researchers may not release or use data or information about you except in certain circumstances. 
Please refer to the Other Important Information section near the end of this consent form for 
more information on this type of protection.
WILL YOU SAVE MY SPECIMENS OR DATA FOR USE IN OTHER RESEARCH 
STUDIES?
As part of this study, we are obtaining data and specimens (such as: blood, bone marrow 
biopsies) from you. We plan to use these specimens and data for studies going on right now, as 
well as studies in the future. These studies may provide additional information that will be 
helpful in understanding multiple myeloma, or other diseases or conditions. This could include 
studies to develop other research tests, treatments, drugs, or devices, that may lead to the 
development of a commercial product by the NIH and/or its research or commercial partners. 
There are no plans to provide financial compensation to you if this happens. Also, it is unlikely 
that we will learn anything from these studies that may directly benefit you. By agreeing to let 
us use your specimens and data, you give the NIH any rights you may have in the specimens and 
data.
We may share your specimens and data with other researchers. They may be doing research in 
areas similar to this research or in other unrelated areas. These researchers may be at NIH, other 
research centers and institutions, or industry sponsors of research. 
In addition to the use and sharing of your specimens and data described above, we might remove 
any information from your specimens and data that can identify you such as name, address, or 
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medical record number, and then use the specimens and data for additional research studies at 
the NIH or other places. If we do this, we might not contact you to ask your permission or 
otherwise inform you.
If you change your mind and do not want us to store and use your specimens and data for future 
research, you should contact the research team member identified at the top of this document. 
We will do our best to comply with your request but cannot guarantee that we will always be 
able to destroy your samples. For example, if some research with your specimens and data has 
already been completed, the information from that research may still be used. Also, for example, 
if the specimens and data have been shared already with other researchers, it might not be 
possible to withdraw the samples and data. 
Please place your initials in the blank next to Yes or No for each of the questions below:
My specimens and data (blood and bone marrow) may be stored and used for future research as 
described above.
_____ Yes
_____ No
Initials
Initials
My specimens and data (blood and bone marrow) may be shared with other researchers and used 
by these researchers for future research as described above.
_____ Yes 
_____ No
Initials
Initials
How Long Will My Samples and Data be Stored by the NIH?
Your specimens and data will be stored at NIH indefinitely.
Risks of Storage and Sharing of Samples and Data
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or someone may gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your data or 
samples.
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COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will I receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will I receive reimbursement or direct payment by NIH as part of my participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses. Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid. Someone will work 
with you to provide more information.
Will taking part in this research study cost me anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

If some tests and procedures are performed outside the NIH Clinical Center, 
you may have to pay for these costs if they are not covered by your insurance 
company.

Medicines that are not part of the study treatment will not be provided or paid 
for by the NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be 
provided by the NIH Clinical Center.
CONFLICT OF INTEREST(COI) 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a COI Guide. You may ask your research team for a copy 
of the COI Guide or for more information. Members of the research team who do not work for 
NIH are expected to follow these guidelines or the guidelines of their home institution, but they 
do not need to report their personal finances to the NIH.
The National Institutes of Health and the research team for this study have developed Anti-
SLAMF7 CAR being used in this study. This means it is possible that the results of this study 
could lead to payments to NIH. By law, the government is required to share such payments with 
the employee inventors. You will not receive any money from the development of Anti-SLAMF7 
CAR.
Bellicum Pharmaceuticals, Inc is providing the drug Rimiducid for this study to NIH. No 
NIH employee involved in this study receives any payment or other benefits from Bellicum 
Pharmaceuticals, Inc.
IRB NUMBER: 19C0102
IRB APPROVAL DATE: 06/16/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/14/2020
Page 18 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
OTHER IMPORTANT INFORMATION 
Confidentiality 
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified. In most cases, the NIH will not release any 
information about your research involvement without your written permission. However, if you 
sign a release of information form, for example, for an insurance company, the NIH will give the 
insurance company information from your medical record. This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
any information that shows your identity before sharing them. You should be aware that there is a 
slight possibility that someone could figure out the information is about you. 
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). NIH researchers must use this Certificate to legally refuse to disclose 
information that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings, for example, if there is a court subpoena. NIH researchers will 
use the Certificate to resist any demands for information that would identify you, except as 
explained below.
There are several circumstances in which the Certificate does not provide protection. These include 
when information: 
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is necessary for your medical treatment and you have consented to this disclosure; 
4. is for other research;
5. is disclosed with your consent 
In addition, identifiable, sensitive information collected or compiled during research and protected 
by this Certificate cannot be admissible as evidence or used for any purpose in any action, suit, or 
proceeding without your consent. You should understand that a Certificate does not prevent you 
from voluntarily releasing information about yourself or your involvement in this research. If an 
insurer, medical care provider, or other person obtains your written consent for us to disclose the 
research information, then the researchers will not use the Certificate to withhold that information.
IRB NUMBER: 19C0102
IRB APPROVAL DATE: 06/16/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/14/2020
Page 19 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures.
The protections of the Certificate apply to all copies of the identifiable, sensitive information 
collected or compiled during the research. Therefore, if an NIH investigator shares a copy of your 
identifiable, sensitive information with any other investigator or institution (whether a collaborator 
on this study, or researcher conducting secondary research in the future) that party must generally 
agree to comply with the disclosure restrictions under the Certificate described above. 
Additionally, the Federal Privacy Act generally protects the confidentiality of your NIH medical 
records. In some cases, the Privacy Act protections differ from the Certificate of Confidentiality. 
For example, sometimes the Privacy Act allows release of information from your medical record 
without your permission, for example, if it is requested by Congress. However, NIH will only 
release information from your medical record if it is permitted by both the Certificate of 
Confidentiality and the Privacy Act.
Policy Regarding Research-Related Injuries 
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
Problems or Questions
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Jim 
Kochenderfer, M.D., Building 10, Room 12C121, telephone: 240-760-6062.You may also call the 
Clinical Center Patient Representative at 301-496-2626, or the NIH Office of IRB Operations at 
301-402-3713, if you have a research-related complaint or concern.
Consent Document 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 19C0102
IRB APPROVAL DATE: 06/16/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/14/2020
Page 20 of 20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: 
Witness:
Signature of Witness*
Print Name of Witness
Date
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 19C0102
IRB APPROVAL DATE: 06/16/2020