Phase 2 Study Of Autologous T Cells Engineered To Express an Anti-CD19 Chimeric Antigen Receptor (CART-19) Following First-line Autologous Stem Cell Transplantation for High-risk Multiple Myeloma
Phase: PHASE2
Conditions: Multiple Myeloma
Sponsor: University of Pennsylvania

CART-19 post-ASCT in Multiple Myeloma 
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Phase 2 Study Of Autologous T Cells Engineered To Express an Anti-CD19 
Chimeric Antigen Receptor (CART-19) Following First-line Autologous Stem Cell 
Transplantation for High-risk Multiple Myeloma 
Principal Investigator 
Alfred L. Garfall, MD 
Department of Medicine & Abramson Cancer Center 
Perelman School of Medicine, University of Pennsylvania 
Philadelphia, Pennsylvania 19104 
Scientific Advisor 
Department of Pathology and Laboratory Medicine 
Perelman School of Medicine, University of Pennsylvania 
Medical Director 
Funding Sponsors 
Novartis Pharmaceuticals Corp 
One Health Plaza 
East Hanover, NJ 07936 
National Institutes of Health 
Protocol Numbers 
UPCC 19416; 
Study Product 
CD19 redirected autologous T cells (muCART-19-T Cells) 
Sponsor Cell Manufacturing- 
University of Pennsylvania 
Correlative Laboratory Team 
Biostatistician: 
Date 
V1.02-26-2016 
V2.05-03-2016 
V3.04-11-2017 
NCT02794246

CART-19 post-ASCT in Multiple Myeloma 
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STUDY SUMMARY
Title 
Phase 2 Study of Autologous T Cells Engineered To Express an Anti-CD19 
Chimeric Antigen Receptor (CART-19) Following First-line Autologous Stem 
Cell Transplantation for High-risk Multiple Myeloma 
Short Title 
CART-19 post-ASCT for Multiple Myeloma 
Phase 
Phase 2 
Methodology 
This will be a single-arm, open-label study. Patients will be enrolled during 
induction therapy for multiple myeloma, prior to standard-of-care 
consolidation with autologous stem cell transplantation (ASCT). T cells will 
be harvested for T cell manufacturing prior to ASCT, and CART-19 will be 
infused at day ~60 post-ASCT, 3 days after lymphodepleting 
chemotherapy. The primary endpoint is progression-free survival (PFS) 
after ASCT. As detailed below, the study is powered to detect an increase 
in two-year PFS to ~75% from a baseline expectation of 55% based on 
historical data. Secondary endpoints will evaluate CART-19 persistence and 
function, minimal residual disease, immune correlative endpoints, and 
associations of progression-free survival (PFS) with CART-19 persistence 
and clinical and biologic characteristics of multiple myeloma. 
Study Duration 
The study will accrue subjects over 2-3 years. Patients will be followed for 
two years post-ASCT.   
Study Center(s) 
Single-center at the University of Pennsylvania 
Objectives 
The primary objective is to evaluate PFS in high-risk multiple myeloma 
patients treated with CART-19 post-ASCT. 
Secondary objectives are to: 

Describe the incidence and nature of adverse events attributable
to CART-19 at this dose, schedule, and clinical setting, with specific
attention to adverse events that emerge after initiation of
maintenance lenalidomide.

Describe response rate and depth-of-response using both standard
clinical criteria (IMWG) and MRD assessments.

Evaluate expansion, persistence, phenotype, function, and homing
of CART-19 cells manufactured and administered in this low-target
clinical setting.

Evaluate PFS and depth-of-response in the subset of patients, if
present, with long-term (>6 months) in vivo persistence of CART-
19 cells.

Evaluate PFS and depth-of-response in clinically and biologically
defined subsets of multiple myeloma patients (e.g., subsets with
certain cytogenetic abnormalities, clinical stage, multiple myeloma
plasma cell immunophenotype, or gene expression profile).

Describe CART-19 manufacturing feasibility in this clinical setting
and the features (dose, cellular phenotype) of the manufactured
product.

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Number of Subjects 
Up to 25 evaluable subjects. An evaluable subject will be defined as a 
subject who receives CART-19 cells at a dose of 1-5x108 transduced cells. 
Diagnosis and Main 
Inclusion Criteria 
The target population includes patients between the ages of 18 and 70 
(inclusive) with multiple myeloma exhibiting high-risk prognostic features 
(adverse cytogenetic features or R-ISS stage 3) who, following initial 
therapy with lenalidomide, bortezomib, and dexamethasone, are 
candidates for autologous stem cell transplantation and post-transplant 
maintenance lenalidomide.  
Study Product, Dose, 
Route, Regimen 
CART-19 cells will be administered as a single intravenous infusion. The 
target dose of CAR-expressing cells will be 1-5x108 cells. CART-19 cells will 
be infused three days after administration of cyclophosphamide 1.5 g/m2 
as lymphodepleting chemotherapy.  
Duration of 
administration 
CART-19 cells will be administered as a single dose. 
Reference therapy 
There will be no control arm in this study. Outcomes will be compared to 
historical expectations for PFS post-ASCT for high-risk multiple myeloma 
patients. 
Statistical Methodology 
The study has been powered to detect an improvement in PFS in this high-
risk population in comparison to historical expectations. Historical 
expectations were derived from the recently published “revised ISS” (R-
ISS) staging system; R-ISS stage 3 patients who underwent ASCT in this 
study had a two-year post-ASCT PFS of approximately 55%. With sample 
size of 25 subjects, this study has 80% power to detect an increase in two-
year PFS to 75.5% compared to this historical expectation. This calculation 
was based on assumption for exponential survival for PFSs, 2 years of 
recruitment, and additional 2 years of follow-up after enrollment. The 
distribution of PFS will be estimated by Kaplan-Meier method and median 
PFS will be computed. Point estimate of two-year PFS will be tested 
against 55% using a one-sided test at 0.05 level. The study has been 
structured to enable comparison to the high-risk subgroups from the 
BMTCTN 0702 and the DFCI/IFM 2009 studies, both of which are studies 
employing contemporary treatment regimens from which data will be 
available over the next 1-2 years. 
Secondary endpoints are descriptive in nature.  
 
 

CART‐19 post‐ASCT in Multiple Myeloma 
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transmitted, reproduced, published, or used by other persons without prior written authorization from the 
regulatory sponsor. 
 
Figure 1: Study Schema  
 
CART‐19 mfg/
storage
Enroll‐
ment
Apheresis
Stem‐cell
Mobilization/
Collection
High‐dose
Melphalan
+ ASCT
Day +60
Lymphodepleting
Chemotherapy
Cyclophosphamide
1.5 g/m2
CART‐19 infusion
1‐5x10^8
Day +90
Maint.
Revlimid
Follow for PFS
RVD x 4‐6
CART‐19 mfg/
storage
Enroll‐
ment
Apheresis
Stem‐cell
Mobilization/
Collection
High‐dose
Melphalan
+ ASCT
Day 
Lymphodepleting
Chemotherapy
Cyclophosphamide
1.5 g/m2
CART‐19 infusion
1‐5x10^8
Day +90
Maint.
Revlimid
Follow for PFS
RVD x 4‐6
+57
Day +60

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regulatory sponsor. 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ..................................................................................................................... 8 
1. 
INTRODUCTION ...................................................................................................................... 11 
1.1 
Background .............................................................................................................................. 11 
1.2 
Investigational Agent ............................................................................................................... 14 
1.3 
Pre-clinical data ....................................................................................................................... 16 
1.4 
Clinical data ............................................................................................................................. 16 
1.4.1 
Previous Clinical Data With CART-19 Cells ................................................................. 16 
1.4.2 
Autologous CART-19 cells in multiple myeloma ......................................................... 18 
1.5 
CART-19 Dose/Setting Rationale and Risks/Benefits .............................................................. 20 
1.5.1 
Dose and Schedule Rationale ..................................................................................... 20 
1.5.2 
Setting Rationale ........................................................................................................ 21 
1.5.3 
Risks/Benefits ............................................................................................................. 21 
1.5.4 
Potential benefits ....................................................................................................... 25 
2. 
OBJECTIVES ............................................................................................................................. 25 
3. 
STUDY DESIGN ........................................................................................................................ 26 
3.1 
General Design ........................................................................................................................ 26 
3.2 
Primary Study Endpoint ........................................................................................................... 27 
3.3 
Secondary Study Endpoints ..................................................................................................... 27 
4. 
SUBJECT SELECTION AND WITHDRAWAL.................................................................................. 29 
4.1 
Inclusion Criteria ...................................................................................................................... 29 
4.2 
Exclusion Criteria ..................................................................................................................... 31 
4.3 
Subject Recruitment and Screening ........................................................................................ 31 
4.4 
Early Withdrawal of Subjects .................................................................................................. 32 
4.4.1 
When and How to Withdraw Subjects ....................................................................... 32 
4.4.2 
Data Collection and Follow-up ................................................................................... 33 
5. 
STUDY DRUG .......................................................................................................................... 33 
5.1 
Description .............................................................................................................................. 33 
5.2 
Patient Eligibility to Receive CART-19 Cells ............................................................................. 34 
5.3 
Treatment Regimen ................................................................................................................. 35 
5.3.1 
High-dose Melphalan and Autologous Stem Cell Transplantation ............................ 35 
5.3.2 
Lymphodepleting Chemotherapy ............................................................................... 35 
5.3.3 
CART-19 Infusion ........................................................................................................ 36 
5.3.4 
Maintenance Lenalidomide ........................................................................................ 36 
5.4 
Preparation and Administration of Study Drug ....................................................................... 36 
5.5 
Infusion of CART-19 Product ................................................................................................... 37 
5.6 
Prior and Concomitant Therapy .............................................................................................. 38 
6. 
STUDY PROCEDURES ............................................................................................................... 38 
6.1 
Screening/Enrollment.............................................................................................................. 39 
6.2 
Enrollment ............................................................................................................................... 39 

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6.3 
General information concerning samples obtained for laboratory correlative studies ......... 39 
6.4 
Apheresis ................................................................................................................................. 40 
6.5 
Pre-ASCT evaluation ................................................................................................................ 41 
6.6 
ASCT (Day 0) ............................................................................................................................ 41 
6.7 
Pre-infusion visit ...................................................................................................................... 41 
6.8 
Lymphodepleting Chemotherapy ............................................................................................ 42 
6.9 
CART-19 Cell Infusion (Day 60 +7 days) ................................................................................... 42 
6.10 Post-CART19 infusion Evaluations ........................................................................................... 42 
6.11 Day +28 Post CART-19 Infusion (±3 days) ................................................................................ 42 
6.12 Maintenance lenalidomide ..................................................................................................... 43 
6.13 Month 4 (±7 days) ................................................................................................................... 43 
6.14 Months  5 + 6 (± 7 days) .......................................................................................................... 43 
6.15 Months 8, 11, + 14 (± 14 days) ................................................................................................ 43 
6.16 Month 20 (± 14 days) .............................................................................................................. 43 
6.17 Two year post-ASCT (Month 24 ± 14 days) ............................................................................. 43 
6.18 Long-term Follow-up ............................................................................................................... 43 
7. 
STATISTICAL PLAN ................................................................................................................... 44 
7.1 
General Design Issues .............................................................................................................. 44 
7.2 
Sample Size .............................................................................................................................. 44 
7.3 
Subject Population(s) for Analysis ........................................................................................... 44 
7.4 
Statistical Analysis of Endpoints .............................................................................................. 45 
7.4.1 
Stopping rule for maintenance lenalidomide discontinuation ................................... 45 
8. 
SAFETY AND ADVERSE EVENTS ................................................................................................ 46 
8.1 
Definitions ............................................................................................................................... 46 
8.2 
Recording of Adverse Events ................................................................................................... 47 
8.3 
Reporting of Serious Adverse Events ...................................................................................... 52 
8.3.1 
Investigator Reporting: Notifying the Penn IRB ......................................................... 52 
8.3.2 
Investigator Reporting: Notifying the DSMC of the Abramson Cancer Center 
(ACC) ........................................................................................................................... 54 
8.3.3 
Investigator Reporting: Notifying the IBC .................................................................. 54 
8.3.4 
FDA Notification by Sponsor ....................................................................................... 54 
8.4 
Toxicity Management, Stopping Rules, and Study Termination ............................................. 55 
8.4.1 
Criteria for Stopping the Study ................................................................................... 56 
8.4.2 
General Toxicity Management Considerations .......................................................... 56 
8.5 
Protocol Exceptions and Deviations ........................................................................................ 60 
8.6 
Medical Monitoring ................................................................................................................. 61 
8.7 
Independent Data and Safety Monitoring Board .................................................................... 61 
9. 
DATA HANDLING AND RECORDKEEPING .................................................................................. 62 
9.1 
Confidentiality ......................................................................................................................... 62 
9.2 
Source Documents .................................................................................................................. 62 
9.3 
Case Report Forms .................................................................................................................. 63 
9.4 
Records Retention ................................................................................................................... 63 
10. 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................. 63 
10.1 Study Monitoring Plan ............................................................................................................. 63 
10.2 Auditing and Inspecting ........................................................................................................... 63 

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11. 
ETHICAL CONSIDERATIONS ...................................................................................................... 64 
12. 
STUDY FINANCES .................................................................................................................... 64 
12.1 Funding Sources ...................................................................................................................... 64 
12.2 Conflict of Interest ................................................................................................................... 64 
12.3 Subject Stipends or Payments ................................................................................................. 64 
12.4 Study Discontinuation ............................................................................................................. 64 
13. 
PUBLICATION PLAN ................................................................................................................. 65 
14. 
REFERENCES ........................................................................................................................... 66 
APPENDIX 1:  SCHEDULE OF EVALUATIONS ....................................................................................... 71 
APPENDIX 2:  NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL CLASSIFICATION ....................... 76 
 
 
 

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LIST OF ABBREVIATIONS 
aAPC 
Artificial APC 
ACC 
Abramson Cancer Center 
AE 
Adverse event 
ALL 
Acute lymphoblastic leukemia 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
APC 
Antigen presenting cell 
ASCT 
Autologous stem cell transplantation 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATG 
Anti-thymocyte globulin 
B-ALL 
B-lineage acute lymphoblastic leukemia 
BUN 
Blood urea nitrogen 
cAIX 
Carbonic anhydrase IX 
CAR 
Chimeric antigen receptor 
CART-19 cells 
CD19 redirected autologous T cells 
CBC 
Complete blood count 
CCI 
Center for Cellular Immunotherapies 
CD 
Cluster of differentiation 
CD137 
4-1BB co-stimulatory molecule 
CFR 
Code of federal regulations 
CHOP 
Children’s Hospital of Philadelphia 
CRi 
Complete Response with incomplete marrow recovery 
CI 
Confidence Interval 
CIR 
Chimeric immune receptor, interchangeable with CAR 
CLL 
Chronic lymphocytic leukemia 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CR 
Complete Response 
CRF 
Case report form 
CRP 
C-reactive protein 
CRS 
Cytokine release syndrome 
CSR 
Clinical study report 
CTC 
Common toxicity criteria 
CTL 
Cytotoxic T lymphocyte 
CTRC 
Clinical and translational research center 
 
 

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DFS 
Disease free survival 
DIC 
Disseminated intravascular coagulation  
DMC 
Data monitoring committee  
DMSO 
Dimethyl sulfoxide 
DSMB 
Data and Safety Monitoring Board 
DSMP 
Data safety monitoring plan 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report forms 
EDC 
Electronic data capture 
EKG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GMP 
Good Manufacturing Practices 
GVHD 
Graft versus host disease 
HACA 
Human anti-chimeric antibody 
HAMA 
Human anti-murine antibody 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
HLH 
Hemophagocytic lymphohistiocytosis 
HUP 
Hospital of the University of Pennsylvania 
IBC 
Institutional Biosafety Committee 
Ig 
Immunoglobulin 
IMWG 
International Myeloma Working Group 
IRB 
Institutional Review Board 
IVIG 
Intravenous immunoglobulin 
IWCLL 
International Workshop Group on Chronic lymphocytic leukemia 
kDa 
Kilodalton 
MAS 
Macrophage activation syndrome 
MED 
Minimal efficacious dose 
MEDRA 
Medical dictionary for regulatory activities 
MHC 
Major histocompatibility complex 
MM 
Multiple Myeloma 
MOI 
Multiplicity of infection 
MOP 
Manual of procedures 
MRD 
Minimal residual disease 

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mTOR 
Mammalian target of Rapamycin 
MUGA 
Multiple gated acquisition scan 
NaCl 
sodium chloride 
NHL 
Non-Hodgkin’s Lymphoma 
PBMC 
Peripheral blood mononuclear cells 
PDCS 
Product Development & Correlative Sciences laboratory 
PDL 
Product Development Laboratory 
PFS 
Progression free survival 
PHI 
Protected health information 
PID 
Patient identification number 
PLL 
Prolymphocytic leukemia 
PR 
Partial Response 
Q-PCR 
Quantitative polymerase chain reaction 
Q-RT-PCR 
Quantitative reverse transcriptase polymerase chain reaction 
RAC 
NIH Office of Biotechnology Recombinant DNA Advisory Committee 
RCR/L 
Replication competent retrovirus/lentivirus 
RIC 
Reduced intensity conditioning 
R-ISS 
Revised International Staging System for Multiple Myeloma  
RVP 
Respiratory virus panel 
scFv 
Single chain variable fragment 
SCID 
Severe combined immunodeficiency 
SCT 
Stem cell transplant 
SLL 
Small lymphocytic lymphoma 
STR 
Short tandem repeat analysis 
SUSAR  
Suspected unexpected serious adverse reaction 
Tcm 
Central Memory T cells 
TCR 
T cell receptor 
TCRζ 
Signaling domain found in the intracellular region of the TCR zeta, gamma and 
epsilon chains 
TCSL 
Translational Correlative Studies Laboratory 
Tem 
Effector memory T cells 
TLS 
Tumor lysis syndrome 
Treg 
Regulatory T cells 
UPenn 
University of Pennsylvania 
VSV-G 
Vesicular Stomatitis Virus, Glycoprotein 
Vβ 
A rearranged T cell specific gene that can be used to determine clonality of a T cell 
population 

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1. 
INTRODUCTION 
This is a single-arm, open-label phase-2 study in which autologous T cells transduced with an anti-CD19 
chimeric antigen receptor (CART-19 cells) will be infused to patients with high-risk multiple myeloma 
approximately 60 days after completion of first-line therapy. Approximately 30 days after CART-19 
infusion, subjects will begin standard-of-care maintenance therapy with low-dose lenalidomide. First-line 
therapy will consist of standard induction/initial therapy with lenalidomide, bortezomib, and 
dexamethasone followed by consolidation with high-dose melphalan and autologous stem cell 
transplantation (ASCT). Subjects will enroll during induction therapy, undergo leukapheresis for CART-19 
manufacturing, subsequently undergo hematopoietic stem cell harvesting and ASCT, and then receive 
CART-19 and maintenance lenalidomide. The primary objective is to assess progression-free survival (PFS); 
secondary objectives are to describe the maximum depth-of-response, in vivo CART-19 persistence and 
activity in this clinical setting, and association of these parameters and other correlative analyses with 
PFS. The rationale for CART-19 in this setting is based on data implicating CD19+ components of the 
myeloma clone as having unique drug-resistant and myeloma-propagating properties and clinical data 
from a completed pilot study suggesting that CART-19 can improve PFS after ASCT.  
1.1 
Background  
Multiple myeloma. Multiple myeloma is a hematologic malignancy in which clonal plasma cells 
accumulate in the bone marrow and extramedullary sites. Potential clinical complications of multiple 
myeloma include the development of painful, lytic bone lesions, anemia and other cytopenias, increased 
susceptibility to infection, hypercalcemia, renal impairment due to toxicity of the secreted monoclonal 
immunoglobulin, and compromise of organs infiltrated by extramedullary plasmacytomas. In the United 
States, there are approximately 25,000 new cases of multiple myeloma diagnosed annually and 
approximately 11,000 deaths attributed to multiple myeloma annually. The lifetime risk is 1 in 143 in the 
United States. The median age at diagnosis is 69, and over one-third of patients are diagnosed before age 
651. Though nearly all multiple myeloma patients respond to modern initial therapy with substantial 
decrease in the disease burden and improvement in the presenting complications, development of 
resistance to therapy is nearly inevitable. Nearly all patients eventually succumb to complications of 
treatment-refractory disease.  
 
Autologous stem-cell transplantation for multiple myeloma. Based on follow-up of patients diagnosed in 
2007, five-year survival for multiple myeloma patients is 45%1. Survival has improved considerably over 
the last 20 years coinciding initially with the widespread adoption of ASCT as consolidation following 
initial/induction therapy and, more recently, with the availability of modern anti-myeloma 
pharmaceuticals such as thalidomide, lenalidomide, bortezomib, carfilzomib, and others. ASCT entails a 
single myeloablative dose of melphalan (140-200 mg/m2) followed 1-2 days later by infusion of autologous 
hematopoietic stem cells, which are collected and stored prior to melphalan infusion, to facilitate 
hematopoietic reconstitution. ASCT is typically undertaken in multiple myeloma patients following an 
initial period of induction therapy. The initial phase-three studies of ASCT in multiple myeloma established 
an overall survival advantage compared to continuous standard-dose cytotoxic chemotherapy2,3. More 
recently, the overall survival advantage with HDM + ASCT was confirmed in a phase-3 study of patients 
treated with modern initial (i.e., lenalidomide- rather than chemotherapy-based) and salvage therapies4. 
Therefore, ASCT is a standard-of-care for eligible (i.e., <70 years of age and adequate cardiopulmonary 
function for high-dose chemotherapy) multiple myeloma patients, and multiple myeloma is the most 
common indication for ASCT worldwide. Though the optimal timing of ASCT for multiple myeloma is 

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domains: either CD28 and TCRζ or 4-1BB and TCRζ. Novel CAR designs incorporating three signaling 
domains (third-generation CARs) and other modifications are in pre-clinical and early clinical 
development. CAR-transduced T cells represent a promising immunotherapy approach to cancer. Several 
clinical studies using CART-19 (as detailed below) and other CD19-directed CAR T cells have demonstrated 
impressive responses in patients with advanced B cell malignancies12. These studies have demonstrated 
the capacity of CAR T cells to induce not only initial clinical responses but also long-term immunologic 
memory, manifest as long-term in vivo persistence of the CAR T cells and durable elimination of both 
neoplastic and non-neoplastic target cells such as, in the case of CART-19, normal CD19+ B cells. Studies 
of CAR T cells against other targets in a range of cancers are ongoing.  
 
CAR T cells for multiple myeloma. Several CAR T cell targets have been explored for use in multiple 
myeloma. Targets in pre-clinical or early clinical development include B cell maturation antigen (BCMA), 
CD38, CD138, kappa light chain, Lewis-Y antigen, and CS113. In particular, phase-1 studies of anti-BCMA 
CAR T cells are ongoing at the National Institutes of Health and the University of Pennsylvania. As 
described below, a pilot clinical study of CART-19 in patients with advanced multiple myeloma has been 
conducted at the University of Pennsylvania. 
 
CD19 as an immunotherapy target in multiple myeloma. CART-19, also referred to as murine CTL019 
(muCTL019), is a CAR directed against CD19, a cell surface protein expressed on almost all B lineage cells. 
Physiologic, non-neoplastic plasma cells are mostly CD19+, but the most terminally differentiated, long-
lived plasma cells are CD19-negative14. The dominant population of neoplastic plasma cells in multiple 
myeloma patients is CD19-negative in almost all cases15. CART-19 alone would therefore not be expected 
to have efficacy as monotherapy in multiple myeloma. Rather, the rationale for CD19-directed therapy in 
multiple myeloma is the presence of CD19 on minor subsets of the multiple myeloma clone that may have 
unique disease-propagating properties (i.e., cancer stem-cell properties). It is hypothesized that these 
disease-propagating subsets resist standard MM therapies, even those to which the dominant plasma cell 
population is sensitive, and facilitate repopulation of the neoplastic plasma cell population with 
progressively therapy-resistant cells. Though a discrete and consistent definition of the myeloma-
propagating subset has been elusive, subsets of cells with phenotypes along the spectrum between CD19+ 
B lymphocytes and terminally differentiated CD19-negative plasma cells have been consistently identified 
in multiple myeloma patients; in general, the less differentiated subsets have exhibited enhanced drug 
resistance and disease-propagating capacity in xenotransplantation models and in vitro clonogenicity 
assays16. Thus, in patients whose neoplastic plasma cell population has been successfully depleted with 
conventional multiple myeloma therapies, elimination of CD19+ cells with CART-19 may prevent or delay 
progression by depleting the less differentiated myeloma-propagating populations.  
 
Post-ASCT maintenance lenalidomide. The development of well tolerated oral anti-myeloma agents such 
as lenalidomide led to investigation of low-dose maintenance therapy in clinical settings where active 
observation had been the standard approach. Maintenance therapy has been most intensely studied in 
the post-ASCT period, which is typically a period of long-term (months-to-years) disease stability. 
Lenalidomide is a thalidomide derivative with anti-myeloma activity that has been attributed to multiple 
mechanisms of action, including direct effects on myeloma plasma cells and immunomodulatory effects. 
Lenalidomide is FDA-approved for treatment of relapsed/refractory multiple myeloma, but it has been 
extensively studied as a first-line therapy and in the post-ASCT maintenance setting. Low-dose post-ASCT 
maintenance lenalidomide roughly doubles PFS and, in one study, significantly prolonged overall 
survival4,17,18. Post-ASCT maintenance is widely utilized in the United States and has been incorporated 

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Signaling through the cytosolic domain of a CAR comprised of a scFv-TCRζ single chain construct does not 
fully replicate the multichain TCR signaling complex 36,37. Chimeric receptors bearing TCRζ signaling 
modules are sufficient to trigger sustained proliferation in T cell hybridomas and clones but are not 
sufficient to drive proliferation or cytokine production in peripheral T cells 36. 4-1BB is a T cell co-
stimulatory receptor induced by TCR activation, and evokes various T cell responses 38. 4-1BB signals are 
critical for long term proliferation of CD8 cells, and CD28 is essential for sustained CD4 cell proliferation 
39,40. Second-generation CARs comprised of TCRζ and either CD28 or 4-1BB signaling modules substantially 
improve the function and proliferation of T cells 41,42.  
1.3 
Pre-clinical data 
Extensive literature supports the use of engineered T cells for tumor immunotherapy in rodent tumor 
models43. Others have used electroporation or retroviral vectors to create anti-CD19 CAR T cells and have 
shown in vivo safety and efficacy of adoptively transferred T cells in immunodeficient mouse models 44,45. 
The incorporation of signaling modules such as CD28 and 4-1BB in 2nd generation CARs increases potency 
of the engineered T cells in pre-clinical studies 41,46-51. The pre-clinical data supporting CART-19 has been 
published 52,53. These data support the efficacy of CART-19 in treatment of CD19+ malignancies. They do 
not apply directly to multiple myeloma, in which the dominant neoplastic cell population does not express 
CD19. Nonetheless, these pre-clinical data indicate that anti-CD19 CAR T cells can stringently deplete 
CD19+ populations, which is directly relevant to the proposed mechanism of action in multiple myeloma. 
Use of CART-19 in multiple myeloma has not been specifically modeled pre-clinically. Nonetheless, as 
detailed above and reviewed elsewhere16, extensive pre-clinical and in vitro analysis of patient samples 
supports the use of CD19-directed therapy in multiple myeloma. 
1.4 
Clinical data 
1.4.1 Previous Clinical Data With CART-19 Cells 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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expansion was observed, likely due to the infusion just four days after high-dose melphalan, but the 
overlapping toxicity of CART-19 and ASCT was excessive. In contrast, with the 10-fold lower cell dose (1-
5x107 CART-19 cells) and longer gap (12-14 days) between lymphodepleting chemotherapy and CART-19 
infusion on 
, only minimal in vivo CART-19 expansion was observed, and no subjects 
developed long-term CART-19 persistence. In the studies of CLL, NHL, and ALL, many patients have 
developed long-term CART-19 persistence with infusion of 1-5x108 CART-19 cells within one week of non-
myeloablative-dose lymphodepleting chemotherapy without synergistic toxicity between the 
chemotherapy regimen and CART-19. This study therefore adopts the dose and schedule used on the CLL, 
NHL, and ALL studies. CART-19 cells will be given at a dose of 1-5x108 CAR-expressing cells three days after 
lymphodepletion with cyclophosphamide at 1.5 g/m2. This lymphodepleting regimen is in use in ongoing 
studies of anti-BCMA and anti-mesothelin CAR T cells. 
 
Our prior experience with manufacturing anti-CD3/CD28-stimulated autologous T cells from lymphocytes 
harvested in the pre-ASCT period supports the feasibility of this target dose in this patient population20,26-
28,55-57. 
1.5.2 Setting Rationale 
The rationale for administering CART-19 cells after first-line ASCT in multiple myeloma is rooted in the 
proposed mechanism-of-action described above for CART-19 in myeloma. Since CART-19 is hypothesized 
to prevent progression after effective standard anti-myeloma therapy, it is most likely to be effective early 
in the disease course, when the myeloma is sensitive and has been optimally cytoreduced by the 
accompanying standard anti-myeloma therapy. ASCT-eligible multiple myeloma patients typically achieve 
their lowest lifetime disease burden following first-line therapy and consolidative ASCT, especially when 
this line of therapy incorporates the combination of lenalidomide, bortezomib, and dexamethasone 
(RVD), which is the most effective standard first-line therapy for multiple myeloma. The post-RVD/post-
ASCT period is therefore the optimal window for evaluation of CART-19. 
1.5.3 Risks/Benefits 
Safety information outlined in the risk section is largely representative of the murine CART-19 experience. 
1.5.3.1 
T cell proliferation 
Participation in this study will expose the patient to genetically engineered autologous T cells. T cell 
proliferation could be uncontrolled; however we have not observed this in our pre-clinical models or in 
any CART-19 patient treated so far. In this case, corticosteroids and chemotherapy would be given to 
eradicate the CAR cells; this has been effective in previous cases58.  
1.5.3.2 
Immunogenicity  
Since we are using a murine-derived ScFv, it is possible the cells may be immunogenic and that the patients 
will have an immune response directed against the scFv; this has not had clinical consequences in previous 
trials of CART-19. If an immune response to the cells occurs, it is possible that the cells will be rejected. 
Three of 3 subjects developed HAMA and loss of T cell engraftment in the Lamers study58, but this has 
generally not been observed in patients with B cell malignancies.  
1.5.3.3 
Hypogammaglobulinemia and B/plasma cell aplasia 
Transient or permanent host B and plasma cell depletion and hypogammaglobulinemia has been observed 
with CART-19 cells, since normal B cells and a subset of normal plasma cells express CD19.  This can be 

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natural killer cell activity. Other findings include variable degrees of hepatic dysfunction ranging from mild 
transaminase elevation up to signs of acute liver failure and coagulopathy and DIC. A pathologic feature 
of MAS is the presence of hemophagocytic CD163+ macrophages (HPC) in bone marrow or lymph-node 
aspirates. 
 
Diagnosis is based on the fulfillment of criteria established in 200460 for HLH associated with autosomal 
recessive disorders (familial HLH, fHLH).  
A diagnosis of non-familial HLH/MAS is made by having 5/8 criteria: 
 
Fever 
 
Splenomegaly 
 
Cytopenias (affecting 2 or more lineages in the peripheral blood; hemoglobin <9 g/dL, platelets 
<100,000/uL, absolute neutrophil count <1000/uL) 
 
Fasting triglycerides >265 mg/dL , Fibrinogen < 1.5 g/L 
 
Hemophagocytosis in bone marrow or spleen or lymph nodes  
 
Low or absent NK-cell activity 
 
Ferritin  > 500 mcg/L 
 
Soluble CD25R > 2400 U/L 
 
Additional clinical features that support the diagnosis include neurologic symptoms and cerebrospinal 
ﬂuid pleocytosis, conjugated hyperbilirubinemia, transaminitis, hypoalbuminemia and hyponatremia. 
Typically, high fevers, cytopenias, and, hemophagocytosis in the bone marrow is observed (though 
marrow specimens at the time of the reaction are not often taken). Soluble CD25R and NK cell activity are 
not standard tests, though samples are taken for retrospective CD25R analysis. Therefore, patients may 
not meet strict definition of HLH/MAS, but given the constellation of findings, and the consistent, dramatic 
elevation in ferritin (which has a very short differential diagnosis), this is indeed the reaction associated 
with the CRS.   
 
At this time it is still unknown whether CRS/MAS is beneficial or harmful to the antitumor response. 
Research correlative studies have shown that IL-6 levels were extraordinarily high during the CRS, 
prompting us to use an anti-IL6 receptor antibody tocilizumab to treat the CRS/MAS. We have treated 
multiple adult patients with tocilizumab for CRS and MAS on the CLL/ALL trials. In most of the patients, 
this treatment resulted in rapid (within hours) resolution of high fevers, and continuous improvement in 
hypotension and hypoxia over hours to several days, and all showed improvement in biochemical 
evidence of CRS and MAS within 48 hours. Adult patients were initially treated with tocilizumab 4mg/kg x 
1. Subsequently, the dose was raised to 8mg/kg. It is unclear if early treatment will negate the antitumor 
response. Treatment and timing of treatment of this toxicity will be at the discretion of the patient’s 
physician and the study investigator; generally, treatment will be initiated if the syndrome progresses 
towards hemodynamic instability or other signs of critical illness requiring intensive care.  A guide for 
managing CRS/MAS is described in section 8.4.2. 
 
Pediatric ALL patients treated with CART-19 on 
 have experienced a similar CRS and MAS. 
 experienced a severe CRS and had high fevers, hypotension, acute vascular leak syndrome 
and acute respiratory distress. The patient was treated with etanercept and tocilizumab, as described in 
Grupp et al., NEJM, 201332, and all associated adverse events resolved. 
 and 
5 
developed CRS after receipt of just the first dose of CART-19, which consisted of only 10% of total planned 
dose.
103 received the 10% and 30% doses, respectively, and experienced a mild CRS after the 

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10% dose, with no CRS experienced after the 30% dose. None of these patients experienced sufficiently 
severe CRS to require treatment with steroids or cytokine blockade (i.e., there was no more than a 
transient oxygen requirement and no hypotension requiring vasopressor support). 
 
Unknowns: At this time there are still several unknowns regarding the observed CRS after CART19 
infusion. It is unknown which patient factors (including type of disease; disease burden; prior therapies; 
genetic predisposition) correlate with severity of CRS.  It is also unknown if cell dose correlates with 
severity of clinical CRS and if the duration and intensity of the CRS correlates with disease response.  It is 
evident that responding patients have had CRS; it remains unknown if abrogating the CRS with anti-
cytokine directed therapy abrogates anti-tumor responses. 
 
Grading of CRS: The Common Toxicity Criteria (i.e., CTCAE) grading system was originally developed to 
capture a cytokine syndrome occurring during infusional therapy; therefore, it is inadequate to capture 
the delayed CRS that occurs after CAR T cell infusion.  We propose to modify the CTCAE grading specifically 
to capture toxicity for protocols using CAR T cells. MAS/HLH signs and symptoms are a manifestation of 
CRS and will therefore not be graded separately (See Table 8-1 in Section 8.1).   
1.5.3.7 
Risk of tumor lysis syndrome (TLS) related to cytoreductive chemotherapy or 
CAR T cells   
The risk of tumor lysis syndrome (TLS) is dependent on the disease and burden of disease.  This risk is 
generally lower in multiple myeloma patients compared to those with other hematologic malignancies, 
but is present.  Compared to other CART-19 studies, the risk of TLS in this protocol is expected to be low 
because neoplastic multiple myeloma plasma cells do not typically express CD19 and the overall burden 
of these cells in the post-ASCT period is low. Nonetheless, patients will be closely monitored both before 
and after chemotherapy and CART-19 cells for laboratory evidence of TLS (serum measurements of 
potassium, uric acid, phosphate, calcium, and creatinine). TLS resulting in renal insufficiency, or rapidly 
rising uric acid, or evidence of organ dysfunction will be managed with intravenous fluids and rasburicase 
as needed and determined by the treating physicians. Appropriate clinical therapy will be administered 
should any significant tumor lysis occur. Prophylactic administration of allopurinol is at the discretion of 
the clinical investigator.  
1.5.3.8 
Risks of cyclophosphamide 
In over 10% of patients, cyclophosphamide causes dermatologic reactions (alopecia beginning 3-6 weeks) 
and may cause sterility; thrombocytopenia and anemia are less common than leukopenia with an onset 
at 7 days, nadir at 10-14 days, and recovery at 21 days. Rates of neutropenic fever range from 5 – 20%61-
64 at the dose used in this protocol (1.5 g/m2). Nausea and vomiting occur more frequently with large 
doses, usually beginning 6-10 hours after administration; subjects will be offered antiemetic prophylaxis 
and therapy. Acute hemorrhagic cystitis, believed to be a result of chemical irritation of the bladder by 
acrolein, a cyclophosphamide metabolite, occurs in 7% to 12% of patients and has been reported in up to 
40% of patients in some series. Patients will be encouraged to drink plenty of fluids during and after 
therapy (most adults will require at least 2 L/day), and void frequently. With large IV doses, IV hydration 
is recommended. The use of mesna and/or continuous bladder irrigation is not indicated for doses <2 
g/m2. Less frequent reactions (1-10%) such as facial flushing, headache, and skin rush may occur. Nasal 
congestion occurs when IV doses are administered too rapidly (large doses via 30-60 minute infusion); 
patients experience runny eyes, rhinorrhea, sinus congestion, and sneezing during or immediately after 
the infusion. If needed, a decongestant or decongestant/antihistamine (eg, pseudoephedrine or 
pseudoephedrine/triprolidine) can be used to prevent or relieve these symptoms. 

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1.5.3.9 
Replication-competent lentivirus (RCL)  
It is theoretically possible that RCL may be generated during the manufacturing phase or subsequently 
after infusion into the patient. However, an RCL resulting from the production phase is highly unlikely 
since elements are incorporated in the design of the vector system that minimize vector recombination 
and generation of RCL. Furthermore, the vector used to transduce the product undergoes sensitive assays 
for detection of RCL before it can be used in the manufacturing process. Nevertheless, generation of an 
RCL following infusion remains a theoretical possibility. The consequences of such recombination events 
in subjects without a known lentiviral infection are unknown, and therefore subjects with coexistent HIV 
infection are excluded from participation in this study in order to minimize this possibility. The 
development of RCL could pose a risk to both the subject and their close contact(s), and therefore, 
monitoring for RCL will be conducted during the course of the trial. RCL assessment (Q-PCR for VSV-G) in 
subjects’ samples will be performed prior to treatment (as a baseline) and after T cell infusion in 
accordance with the Schedule of Evaluations in Appendix 1; this assessment will continue on the long-
term follow-up (LTFU) protocol according to the FDA guidance. If the tests are negative during the first 
year post-CART19 infusion, the  Month 20 sample (18 months post-CART19)  will be archived in a 
temperature monitored and alarmed freezer at -80°C at the Translational and Correlative Studies 
Laboratory (TCSL). 
1.5.3.10 Risks of ASCT and potential interaction with CART-19 
High-dose melphalan and autologous stem cell transplantation is a standard-of-care procedure in this 
population. Risks of melphalan are described in the package insert. Subjects will sign a separate standard-
of-care consent for ASCT. The risks of ASCT are acceptable in this population based on the significant 
overall survival benefit that has been repeatedly demonstrated for this procedure in this patient 
population (see section 1.1). Based on the ~60-day interval between ASCT and CART-19 infusion in this 
protocol, adverse interactions between ASCT complications and CART-19 risks are not expected. 
1.5.4 Potential benefits 
This trial will enroll patients with high-risk multiple myeloma. As described in section 1.1, the prognosis 
for this condition is poor. Given our preliminary clinical data suggesting that CART-19 may prolong 
responses to standard multiple myeloma therapy even in exceptionally refractory and high-risk patients, 
the risks and potential benefits of participation in this study are well balanced. 
2. 
OBJECTIVES 
The primary objective is to evaluate PFS in high-risk multiple myeloma patients treated with CART-19 
post-ASCT. 
Secondary objectives are to: 
 
Describe the incidence and nature of adverse events attributable to CART-19 at this dose, 
schedule, and clinical setting, with specific attention to adverse events that emerge after 
initiation of maintenance lenalidomide. 
 
Describe response rate and depth-of-response using both standard clinical criteria (IMWG) and 
MRD assessments. 
 
Evaluate expansion, persistence, phenotype, function, and homing of CART-19 cells 
manufactured and administered in this low-target clinical setting.  

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 
Evaluate PFS and depth-of-response in the subset of patients, if present, with long-term (>6 
months) in vivo persistence of CART-19 cells. 
 
Evaluate PFS and depth-of-response in clinically and biologically defined subsets of multiple 
myeloma patients (e.g., subsets with certain cytogenetic abnormalities, clinical stage, multiple 
myeloma plasma cell immunophenotype, or gene expression profile).  
 
Describe CART-19 manufacturing feasibility in this clinical setting and the features (dose, cellular 
phenotype) of the manufactured product. 
3. 
STUDY DESIGN 
3.1 
General Design 
This is a single-arm, single-center, open-label study to evaluate post-ASCT administration of CART-19 cells, 
followed by maintenance lenalidomide, as a therapy to prolong response to ASCT in patients with high-
risk multiple myeloma. Figure 1 presents the study schema. The target population includes patients with 
high-risk multiple myeloma as defined by clinical and cytogenetic features who are receiving or have 
recently completed induction/initial therapy with a combination of lenalidomide, bortezomib, and 
dexamethasone (RVD) and for whom standard-of-care ASCT is planned by their treating physician. 
Enrollment and mononuclear cell apheresis to harvest T cells for CART-19 manufacturing will take place 
prior to standard-of-care hematopoietic stem cell mobilization and collection. Screening and enrollment 
procedures will consist of medical record review for eligibility, standard multiple myeloma response 
assessment, bone marrow aspiration/biopsy, and testing to confirm medical fitness for ASCT. Subjects will 
then undergo stem cell mobilization and collection and standard-of-care ASCT. Approximately 60 days 
post-ASCT, subjects will receive lymphodepleting chemotherapy with cyclophosphamide 1.5 g/m2 and, 
three days later, 1-5x108 CART-19 cells. At approximately day 90 post-ASCT, subjects will begin standard-
of-care maintenance therapy with lenalidomide. A stopping rule will monitor for excess discontinuation 
of lenalidomide maintenance due to adverse events. The target cell dose for this protocol is 1-5 x 108 
transduced cells. Subjects with a manufactured cell dose that is less than the protocol-specified dose will 
be scored as a manufacturing failure. These subjects will receive their cell infusion, provided that the 
manufactured dose is above the 
minimum acceptable dose for infusion (2x107 CART-19 cells) and all 
other manufacturing release criteria are met. The subjects that are infused with ≥2x107-<1x108 CART-19 
cells will be considered non-evaluable for the primary endpoint but will be included in analysis of 
secondary endpoints. Both primary efficacy evaluable and non-evaluable patients will be followed in 
the same manner according to the Schedule of Study Procedures for all evaluations, including clinical, 
research (correlative) and safety. 
 
Following CART-19 infusion, subjects will be followed for toxicity, PFS, and secondary endpoints that will 
assess depth of response (including MRD assessments) and in vivo persistence and activity of CART-19 
cells. Bone marrow sampled pre-ASCT and pre-/post-CART-19 infusion will be analyzed to evaluate  
trafficking of CART-19 cells to bone marrow, the immunophenotype of multiple myeloma plasma cells, 
presence of minimal residual disease, and other laboratory correlative studies. PFS will be compared to 
historical results reported in similar populations to preliminarily assess whether CART-19 provides clinical 
benefit in this setting and decide whether phase-3 evaluation of this approach is warranted. Since long-
term persistence of CART-19 (>6 months) is expected to develop in some patients, PFS will also be 
examined in this sub-group, along with other clinically and biologically defined sub-groups, to preliminarily 
explore whether clinical benefit from CART-19 is restricted to certain sub-groups.  

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The study is expected to enroll 25 patients over 2-3 years. The study is powered to detect an increase in 
two-year PFS to ~75% from a baseline expectation of 55% based on previously reported cohorts.  
3.2 
Primary Study Endpoint 
Proportion of patients alive and progression-free (PFS) two years after ASCT. Progression will be defined 
by IMWG criteria (Table 5).  
3.3 
Secondary Study Endpoints 
 
Adverse events: Occurrence of adverse events and their attribution to CART-19 in this 
patient population and clinical setting will be described. Adverse events and criteria for 
their attribution are defined in Section 8. 
 
Incidence of discontinuation of lenalidomide maintenance due to adverse events: This 
will be monitored continuously, and a stopping rule will operate throughout the study to 
pause new enrollments if the incidence exceeds historical expectations. Details of the 
stopping rule and its assumptions/rationale are described in Section 7.  
 
Anti-myeloma responses: Full multiple myeloma response assessments will take place 
pre-ASCT, prior to CART-19 infusion, approximately two months after CART-19 infusion, 
and two years post-ASCT. Responses will be categorized by IMWG criteria (Table 4)65 and 
using MRD assessment techniques. MRD assessment will be by flow cytometry and, 
when sufficient sample is available and when subjects are MRD-negative by flow 
cytometry, using immunoglobulin sequencing.  
 
Exploratory analysis of PFS and depth-of-response in clinically and biologically defined 
subgroups. The following parameters will be analyzed in all subjects and correlated in 
exploratory fashion with PFS and depth-of-response in an attempt to preliminarily 
identify sub-groups that are most likely to benefit from CART-19 therapy and to better 
understand the mechanism-of-action of CART-19 in multiple myeloma: 
 
CART-19 persistence and activity: Presence of CART-19 cells in peripheral blood and bone 
marrow will be assessed by flow cytometry and qPCR. Time points for these evaluations 
are described in the schedule of events (Appendix 1). As an in vivo measure of CART-19 
activity, the presence of normal CD19+ B cells will be assessed at the same time points 
that CART-19 persistence is assessed. 
 
Plasma cell CD19 expression: Flow cytometry will be performed on all bone marrow 
samples to analyze CD19 expression on multiple myeloma plasma cells at pre- and post-
CART-19 time points.  
 
Multiple myeloma gene expression profile: Gene expression profiling (GEP) by RNA-seq 
will be performed on sorted multiple myeloma cells, if available, from the pre-ASCT 
sample. The multiple myeloma GEP-based sub-type will be determined for each patient 
with reference to established GEP sub-types from the MMRF CoMMpass study66. When 
possible, CD19+ subsets of multiple myeloma plasma cells will be separately sorted and 
subjected to GEP. 
 
Manufacturing feasibility: The proportion of enrolled subjects from whom CART-19 is 
successfully manufactured at the target dose will be described. 

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Table 4: Response criteria 
Response 
subcategory 
Response criteriaa 
Stringent 
Complete 
Response 
(sCR) 
 
CR as defined below plus: 
     Normal FLC ratio and 
     Absence of clonal cells in bone marrowb by immunohistochemistry or 
immunofluorescencec    
Complete 
Response 
(CR) 
Negative immunofixation on the serum and urine and Disappearance of any soft 
tissue plasmacytomas and ≤5% plasma cells in bone marrowb 
Very Good 
Partial 
Response 
(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 < 100 mg per 24 h 
Partial 
Response 
(PR) 
≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by 
≥90% or to <200 mg per 24 h. 
If the serum and urine M-protein M-protein are unmeasurable,d a ≥ 50% decrease in 
the difference between involved and uninvolved FLC levels in required in place of 
the M-protein criteria  
Stable 
Disease 
(SD) 
Not meeting criteria for CR, VGPR, PR or progressive disease 
Abbreviations: CR, complete response; FLC, free light chain; PR, partial response; SD, stable disease;  
sCR, stringent complete response; VGPR, very good partial response. 
aAll response categories require two consecutive assessments made at any time before the institution of any new therapy; all 
categories also require no known evidence of progressive or new bone lesions if radiographic studies were performed.  
Radiographic studies are not required to satisfy these response requirements. 
bConfirmation with repeat bone marrow biopsy not needed. 
cPresence/absence of clonal cells is based upon the κ/λ ratio.  An abnormal κ/λ ratio by immunohistochemistry and/or 
immunofluorescence require a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an 
abnormal clone is κ/λ of >4:1 or <1:2. 
dRefer to inclusion criterion #7 for definition of measurable disease. 
 

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Table 5: Criteria for progression 
Progressive diseasea requires Increase of ≥25% from baseline in any one or more of the following: 
 
Serum M-component (the absolute increase must be ≥0.5 g/dL)b 
 
Urine M-component (the absolute increase must be ≥200 mg/24 h) 
 
Only in patients without measurable serum and urine M-protein levels, the difference between 
involved and uninvolved FLC levels, in which case the absolute increase must be ≥10 mg/dL. 
 
Bone marrow plasma cell percentage, if the absolute % is ≥10%. 
 
Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in 
the size of existing bone lesions or soft tissue plasmacytomas. 
 
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.65 mmol/L that can 
be attributed solely to the plasma cell proliferative disorder. 
a All relapse categories require two consecutive assessments made at any time before classification as relapse or disease 
progression and/or the institution of any new therapy. 
b For progressive disease, serum M-component increases of ≥1 g/dL are sufficient to define relapse if starting M-component is 
≥5 g/dL. 
4. 
SUBJECT SELECTION AND WITHDRAWAL 
4.1 
Inclusion Criteria  
1. Subjects must be age 18-70, inclusive, at time of enrollment. 
2. Subjects must have ECOG performance status of 0-2. 
3. Subjects must have a confirmed diagnosis of active multiple myeloma according to IMWG 
criteria, summarized below in Table 6. For circumstances not encompassed by this summary of 
the diagnostic criteria, reference can be made to the full publication of the IMWG criteria67. In 
addition, subjects must have “high-risk” multiple myeloma according to one of the following 
criteria: 
a. Any of the following high-risk cytogenetic features, documented by FISH or metaphase 
karyotyping: deletion 17p, t(4;14), t(14;16), t(14;20). 
b. Standard-risk cytogenetics but elevated LDH and beta-2-microglobulin > 5.5 mg/L (i.e., 
R-ISS stage III).  
4. At time of enrollment, subjects must be within 9 months of initiation of systemic therapy for 
multiple myeloma.  
5. Requirements for pre-enrollment therapy: Subjects must have received or be receiving, at time 
of enrollment, “RVD” therapy (combination therapy with lenalidomide, bortezomib, and 
dexamethasone). Patients must have received ≤6 cycles of RVD at time of enrollment and must 
not have progressed (by IMWG criteria65) on RVD. Patients may have received other regimens 
prior to RVD if such therapy was limited to ≤3 cycles. Patients may have received radiation 
therapy prior to enrollment. Patients must not have received infusional chemotherapy (e.g., 
VTD-PACE or similar regimen) prior to enrollment unless such infusional chemotherapy 
consisted of a single cycle prior to initiation of standard RVD. 
6. Subjects must be eligible for ASCT and to receive a melphalan dose of 200 mg/m2 as defined by 
the following criteria:  
a. Left ventricular ejection fraction ≥ 40%,  
b. AST/ALT ≤2.5 times the upper limit of normal 

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c. Total bilirubin ≤1.5 mg/dL, unless hyperbilirubinemia is attributable solely to Gilbert’s 
syndrome. 
d. Estimated (by CKD-EPI or Cockgroft-Gault equations) or calculated CrCl ≥40 ml/min.  
e. DLCO ≥50% of predicted (corrected or uncorrected for anemia and/or alveolar volume). 
7. Subjects must have measurable disease by standard serum and urine tests to enable post-
transplant monitoring for progression-free survival. Any of the following criteria are sufficient to 
define measurable disease. 
a. Serum M-spike ≥ 0.5 g/dL 
b. 24 hr urine M-spike ≥ 200mg 
c. Involved serum FLC ≥ 50 mg/L with abnormal ratio 
d. For IgA multiple myeloma, total serum IgA level elevated above normal range. 
Note: Measurable disease does not need to be documented at enrollment but can be based on 
historical lab results obtained at or since diagnosis with multiple myeloma. For example, a 
patient who does not have measurable disease at enrollment due to complete remission after 
induction therapy is eligible if the disease was previously measurable by one of the above 
criteria.  
8. Subjects must have signed written, informed consent. 
9. Subjects of reproductive potential must agree to use acceptable birth control methods, as 
described in protocol Section 4.3. 
Table 6 
IMWG Criteria for Diagnosis of Multiple Myeloma 
Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma* and 
any one or more of the following myeloma defining events:  
 
Evidence of end organ damage that can be attributed to the underlying plasma cell 
proliferative disorder, specifically:  
 
Hypercalcaemia: serum calcium >0·25 mmol/L (>1 mg/dL) higher than the upper limit of 
normal or >2·75 mmol/L (>11 mg/dL). 
 
Renal insufficiency: creatinine clearance <40 mL per min† or serum creatinine >177 
μmol/L (>2 mg/dL) 
 
Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or a 
haemoglobin value <100 g/L 
 
Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT‡ 
 
Any one or more of the following biomarkers of malignancy:  
 
Clonal bone marrow plasma cell percentage* ≥60% 
 
Involved:uninvolved serum free light chain ratio§ ≥100 
 
>1 focal lesions on MRI studies ¶ 
*Clonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, or 
immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in 
case of a disparity between the aspirate and core biopsy, the highest value should be used. †Measured or estimated by 
validated equations. ‡If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to 
distinguish from solitary plasmacytoma with minimal marrow involvement. §These values are based on the serum Freelite 
assay (The Binding Site Group, Birmingham, UK). The involved free light chain must be ≥100 mg/L. ¶Each focal lesion must 
be 5 mm or more in size. 

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4.2 
Exclusion Criteria  
Subjects must not: 
1. Be pregnant or lactating. 
2. Have inadequate venous access for or contraindications to leukapheresis. 
3. Have any active and uncontrolled infection. 
4. Any uncontrolled medical or psychiatric disorder that would preclude participation as outlined. 
5. Have NYHA Class III or IV heart failure (see Appendix 2), unstable angina, or a history of recent 
(within 6 months) myocardial infarction or sustained (>30 seconds) ventricular 
tachyarrhythmias.   
6. Have undergone allogeneic stem cell transplantation. 
7. Have received prior gene therapy or gene-modified cellular immunotherapy.  
8. Have active auto-immune disease, including connective tissue disease, uveitis, sarcoidosis, 
inflammatory bowel disease, or multiple sclerosis, or have a history of severe (as judged by the 
principal investigator) autoimmune disease requiring prolonged immunosuppressive therapy. 
9. Have prior or active central nervous system (CNS) involvement (e.g. leptomeningeal disease, 
parenchymal masses) with myeloma. Screening for this (e.g. with lumbar puncture) is not 
required unless suspicious symptoms are present.   
10. Have a contraindication to post-ASCT maintenance lenalidomide. 
11. Have active infection with HIV (negative HIV 1/2 antibody screen), hepatitis C (negative hepatitis 
C antibody screen), or hepatitis B (negative hepatitis B surface antigen). Any positive serologies 
for HIV or viral hepatitis should be confirmed with appropriate confirmatory testing before 
concluding that an active infection is present. Subjects with positive hepatitis core antibody are 
also excluded since the effect of long-term B cell depletion on the risk of hepatitis B reactivation 
is unknown. 
12. Patients with a known history or prior diagnosis of optic neuritis or other immunologic or 
inflammatory disease affecting the central nervous system.  
4.3 
Subject Recruitment and Screening 
Subjects will be identified through the clinical practices of the investigator or sub-investigators and 
through referrals from outside hospitals and physicians. The study will be publicized on clinicaltrials.gov, 
and via University of Pennsylvania or Abramson Cancer Center press releases. No direct-to-patient 
advertising will be performed.   
 
Female subjects of reproductive potential (women who have reached menarche and who have not been 
post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 
months, or have not undergone a sterilization procedure such as hysterectomy, bilateral oophorectomy, 
or bilateral tubal ligation) must have a negative serum or urine pregnancy test at the time of enrollment 
and a negative serum pregnancy test at the Pre-Infusion Visit. 
 
Due to the high-risk nature of this study, while enrolled, all subjects must agree not to participate in a 
conception process (e.g., active attempt to become pregnant or to impregnate or donate sperm for 
artificial insemination or in vitro fertilization). Additionally, if participating in sexual activity that could lead 
to pregnancy, the subject must agree to use at least one reliable method of contraception during 
participation in this protocol. 

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Acceptable birth control includes one of the following methods: 
 
Condoms (male or female) with or without a spermicidal agent 
 
Diaphragm or cervical cap with spermicide 
 
Intrauterine device (IUD) 
 
Hormone-based contraception 
Subjects who are not of reproductive potential (women who have been postmenopausal for at least 24 
consecutive months or have undergone hysterectomy, salpingotomy, and/or bilateral oophorectomy or 
men who have documented azoospermia) are eligible without requiring the use of contraception.   
 
Acceptable documentation of sterilization, azoospermia, or menopause consists of written or oral 
attestation by a physician or a physician’s staff in one of the following formats: 
 
Physician report/letter   
 
Operative report or other source documentation in the subject’s medical record (a laboratory 
report of azoospermia is required to document successful vasectomy)  
 
Discharge summary 
 
Laboratory report of azoospermia  
 
Follicle stimulating hormone measurement elevated into the menopausal range 
4.4 
Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Subjects who enroll but do not receive CART-19 cells will be prematurely discontinued from the study, will 
not be followed, and will be replaced in the study. Reasons for premature discontinuation prior to receipt 
of CART-19 cells may include, but are not limited to, the following: 
1. The subject is lost to follow-up.   
2. The principal investigator judges that the subject, prior to CART-19 infusion, is too ill to continue. 
3. Patient noncompliance with study therapy and/or clinic appointments 
4. Pregnancy is documented prior to CART-19 infusion. 
5. Voluntary withdrawal: a subject may remove himself/herself from the study at any time without 
prejudice.   
6. Significant and rapid progression of malignancy, requiring alternative medical, radiation or 
surgical intervention including, but not limited to, the development of CNS metastasis if this 
occurs prior to the CART-19 T-cell infusion. 
7. A serious adverse event that requires the subject to be withdrawn from the trial if the SAE occurs 
prior to the CART-19 T-cell infusion.   
8. Technical difficulties are encountered in the T cell genetic modification and expansion procedure 
that precludes the generation of clinical cell doses that meet all Quality Control release criteria as 
specified by FDA. 
9. Termination of the study by the Principal Investigator, the Sponsor, the Funding Sponsor, the IRB, 
ACC CTSRMC, ACC DSMC, DSMB, or the Food and Drug Administration.’’ 
 
Reasons for discontinuation of subjects after receipt of CART-19 cells may include, but are not limited to, 
the following: 
1. The subject is lost to follow-up. 
2. Voluntary withdrawal: a subject may remove himself/herself from the study at any time.   

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3. Disease progression of targeted malignancy 
4. Receipt of alternative treatment for their targeted disease 
5. Termination of the study by the Principal Investigator, the Sponsor, the Funding Sponsor, the 
IRB, ACC CTSRMC, ACC DSMC, DSMB, or the Food and Drug Administration. 
 
The reasons for discontinuation (for example, voluntary withdrawal, toxicity, death) must be recorded on 
the case report form. Final study evaluations will be completed at the time of discontinuation 
4.4.2 Data Collection and Follow-up  
Follow-up data collection after gene-modified cell therapy clinical trials is specified by FDA.  As long as 
subjects have detectable cells transduced with the lentiviral vector, they should be followed for toxicity, 
immune reactions, and any long-term adverse events.  Subjects who complete the 2 year follow-up as 
part of this protocol or discontinue participation early for any reason, will be encouraged to enroll in a 15-
year long-term follow-up protocol to further evaluate long term adverse events related to the study 
product.  Once subjects are enrolled on the long-term follow-up protocol, all follow-up data collection 
under this protocol will be discontinued. 
 
In the event that a subject cannot return to the study site for follow-up visits because of subject 
preference or geographical concerns, the subject’s primary care physician and/or local oncologist will be 
asked to provide information from the subject’s medical record to the study team at protocol defined 
time points (including the results of any routine care examinations and/or laboratory assessments), and 
assist in the collection of protocol required blood samples (if applicable), which will be sent to the 
University of Pennsylvania for protocol-required analysis.  The subject and local provider will also be 
contacted via telephone by a member of the study team to assess any potential toxicity. 
 
In numerous previous cell therapy trials at the University of Pennsylvania, loss of follow-up is estimated 
to occur in less than 5% of cases. Every effort will be made to contact subjects who appear to be lost to 
follow-up in order to at least obtain survival data. In the event a subject fails to complete the follow-up 
requirements, documentation of all attempts to contact the subject includes at least 3 telephone contacts 
(on different days and at different times of the day), and a certified letter. 
5. 
STUDY DRUG 
5.1 
Description 
CART-19 cells are autologous T cells that have been engineered to express an extracellular single chain 
antibody (scFv) with specificity for CD19 linked to an intracellular signaling molecule consisting of a 
tandem signaling domains comprised of the TCRζ signaling module linked to the 4-1BB costimulatory 
domain. The CART-19 cells are cryopreserved in infusible cryomedia and will be administered as one bag. 
Each bag will contain an aliquot (volume dependent upon dose) of cryomedia containing the following 
infusible grade reagents: 31.25% Plasmalyte-A, 31.25% dextrose (5%), 0.45% NaCl, up to 7.5% DMSO, 1% 
dextran 40, 5% human serum albumin.  
 
Expected toxicities associated with infusion of CART-19 cells include transient fever, chills nausea, rigors, 
hypotension, tumor lysis syndrome, and cytokine release syndrome. In order to minimize these events, 

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patients will receive premedication as instructed below. Toxicities that could potentially occur but are 
unprecedented are primarily related to the gene transfer and are described in the Risk and Benefit section 
(refer to section 1.5) and the Investigator Brochure. These include generation of a replication competent 
lentivirus (RCL), insertional oncogenesis, and uncontrolled proliferation of the CART-19 cells.  
5.2 
Patient Eligibility to Receive CART-19 Cells 
CART-19 infusion will be scheduled to occur 60 (± 7) days post-ASCT, and lymphodepleting chemotherapy 
will be scheduled for 3 (± 1) days prior to CART-19 infusion.  
Subjects must meet the following criteria to receive CART-19 cells:  
1. Disease response: Between enrollment and infusion, subjects must not have developed new 
disease complications or symptoms that would, in the opinion of the investigator, render it 
unsafe to proceed with CART-19 infusion. 
2. Subjects should not experience a significant change in performance or clinical status compared 
to status at screening/enrollment that would, in the opinion of the investigator, render it unsafe 
to proceed with CART-19 infusion. 
3. Female patients of child-bearing potential must not be pregnant as assessed by a negative 
serum beta-HCG test drawn within 7 days prior to CART-19 infusion. 
4. All subjects must undergo a Respiratory Virus Panel (RVP) within 10 days prior to the planned 
CART-19 infusion. If the patient is positive for influenza, Tamiflu® or equivalent should be 
administered per package insert. The patient must complete treatment prior to receiving 
cyclophosphamide and CART-19 cells. The test does not need to be repeated prior to the first 
CART-19 cell infusion; however if influenza signs and symptoms are present, the CART-19 cell 
infusions should be delayed until the patient is asymptomatic.  If the patient is positive for 
another virus on the RVP, the cyclophosphamide and CART-19 cell infusion will be delayed for at 
least 7 days to be sure clinical symptoms of a viral infection do not develop.  If clinical symptoms 
develop, the cyclophosphamide and CAR T cell infusion will be delayed until resolution of these 
symptoms. 
5. Subjects who develop laboratory abnormalities identified during routine care that in the opinion 
of the treating investigator or PI may make it unsafe to receive CART-19 cells may have their 
infusion delayed until both the treating investigator and PI determine that it is appropriate to 
proceed with the CART-19 cell infusion. 
6. Subjects experiencing toxicities from ASCT or lymphodepleting cyclophosphamide may have 
their CART-19 cell infusions delayed until these toxicities have resolved at the investigator 
discretion. If a subject’s CART-19 cell infusion is delayed > 4 weeks from the lymphodepleting 
cyclophosphamide, the cyclophosphamide dosing should be repeated.  
7. The specific toxicities warranting delay of T cell infusions include: 
a. Pulmonary: Requirement for supplemental oxygen to keep saturation greater than 95% 
or presence of radiographic abnormalities on chest x-ray that are progressive 
b. Cardiac: New cardiac arrhythmia not controlled with medical management 
c. Hypotension requiring vasopressor support 
d. Active Infection: Positive blood cultures for bacteria, fungus, or virus within 48 hours of 
CART-19 cell infusion. 
Administration of lymphodepleting chemotherapy and infusion of CART-19 cells may be delayed up to 4 
weeks from the originally scheduled date to address any factors that make a subject ineligible for CART-

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19 infusion. Delay of lymphodepleting chemotherapy and CART-19 infusion beyond 4 weeks from the 
scheduled date is acceptable only with approval of the Sponsor.  
5.3 
Treatment Regimen 
5.3.1 High-dose Melphalan and Autologous Stem Cell Transplantation 
HDM + ASCT will be carried out as follows: 
 
Melphalan dosing: Subjects will receive HDM at a dose of 200 mg/m2 unless dose-reduction is 
required due to new disease-related complications (e.g., new acute kidney injury) that develop 
between enrollment and HDM for which dose reduction is indicated. Melphalan will be 
administered as a single dose on day -2 or -1, or in two divided doses, according to standard 
institutional practice. Melphalan dose is based on ideal body weight (IBW) for patients who 
weigh 100-120% of their IBW. For patients who weigh less than 100% of their IBW, dosing 
should be based on actual body weight (ABW). For patients who weigh more than 120% of their 
IBW, dosing should be based on the adjusted ideal body weight (AIBW). Melphalan dose may be 
rounded-down to the nearest vial size per local institutional practice.  
 
Ideal Body Weight Formulas:  
o Males IBW = 50 kg + (2.3 kg x number of inches greater than 60)  
o Females IBW = 45.5 kg + (2.3 kg x number of inches greater than 60)  
o For patients less than 5 feet, subtract 2.3 kg/inch  
 
Adjusted Ideal Body Weight Formula: AIBW = IBW + [(0.25) x (ABW - IBW)]  
 
Anti-emetic prophylaxis will be given per standard institutional practice.  
 
Peripheral blood stem cell infusion: At least 24 hours will elapse between completion of 
melphalan infusion and stem cell reinfusion. The typical dose of hematopoietic stem cells is 
≥2x106 stem cells per kg of actual body weight. All subjects on this study must receive at least 
this dose, but the actual dosage will be chosen in accordance with standard institutional 
practice. The graft may not be CD34+ selected or otherwise manipulated to remove myeloma or 
other cells. Cryopreservation and thawing of stem cells will be conducted in accordance with 
FACT standards and local institutional practice. 
 
Filgrastim will be administered at a dose of 5 mcg/kg/day subcutaneously or intravenously 
beginning between days +3 and +5 post-ASCT until the ANC is ≥500/µl for two consecutive days. 
Filgrastim dose may be rounded to accommodate pre-formulated doses. 
 
Prophylaxis against infections: Anti-fungal prophylaxis with fluconazole will be initiated peri-
transplant and will continue until post-ASCT neutrophil recovery. HSV/VZV prophylaxis with 
acyclovir or valacyclovir will be initiated according to local institutional practice and continue 
until six months post-ASCT. Pneumocystis and anti-bacterial prophylaxis is not required by this 
protocol but may be utilized at the discretion of the treating investigator. 
Details of HDM + ASCT not specified above will be conducted in accordance with the site’s local 
institutional practices and the preferences of the treating investigator. 
5.3.2 Lymphodepleting Chemotherapy 
Cyclophosphamide will be administered at a dose of 1.5 g/m2 intravenously as a single infusion, 3 days (± 
1 day) prior to CART-19 infusion. Cyclophosphamide is commonly used in the treatment of myeloma, and 
this dose has been safely used for many years to mobilize autologous stem cells in myeloma and 
lymphoma 61-64 as well as in patients receiving CAR T cell therapies69. Although the chemotherapy is not 

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Vital signs (temperature, pulse, blood pressure, and oxygen saturation by pulse oximetry) will be 
measured within 10 minutes prior, within 10 minutes after the infusion, and then every 15 minutes for 
the first hour and then every hour for the next 2 hours, until these signs are satisfactory and stable. In the 
event that an infusion takes longer than 15 minutes, vital signs will be taken every 15 minutes until the 
infusion is completed. If the subject’s vital signs are not satisfactory and stable three hours post-CART-19 
infusion, vital signs will continued to be monitored at a minimum of every hour or as clinically indicated 
until stable. The subject will be discharged after the physician managing their care on the day of the 
infusion has determined that they are in satisfactory condition. 
5.6 
Prior and Concomitant Therapy 
All prescription and nonprescription medication, vitamins, herbal and nutritional supplements, taken by 
the subject during the 30 days prior to enrollment will be recorded at the screening visit. At every visit 
following CART-19 infusion until the subject discontinues participation on the protocol, concomitant 
medications will be recorded in the medical record and on the appropriate CRF.  Any additions, deletions, 
or changes of these medications will be documented. The following guidelines will be followed regarding 
concomitant therapy while on-study. 
 
Supportive care during and after ASCT is discussed in section 5.3.1.  
 
GM-CSF should be avoided due to potential to worsen CRS symptoms. G-CSF is the preferred 
myeloid growth factor over GM-CSF, if medically indicated. G-CSF was used in some patients on 
 immediately after CART-19 infusion and did not precipitate CRS. 
 
Steroids or other immunosuppressant drugs should NOT be used within 14 days prior to 
leukapheresis. GM-CSF or G-CSF must not be used 14 days prior to apheresis, as it may increase 
neutrophils in the collected product and make it difficult to process.  
 
Patients should not have received systemic chemotherapy within 2 weeks prior to apheresis. No 
anti-myeloma therapy will be administered between ASCT and lymphodepleting chemotherapy. 
Patients should not have received treatment with monoclonal antibodies within 4 weeks prior to 
apheresis.  
 
Steroids or other immunosuppressant drugs should NOT be used as pre-medication for CART-19 
infusion (refer to Section 5.4) or following CAR T cell infusion unless under life threatening 
circumstances. 
Note: According to the HUP institutional guidance, dexamethasone is part of the prophylactic 
anti-emetic regimen administered before cyclophosphamide; thus, dexamethasone is allowed to 
be administered as a prophylactic anti-emetic therapy on the day of cyclophosphamide 
administration.  
 
Patients with severe signs and symptoms attributable to cytokine release syndrome (i.e. CRS) 
should be managed with administration of tocilizumab or other anti-cytokine directed therapies 
(Refer to Section 8.4.2 for administration details).  
6. 
STUDY PROCEDURES 
The study consists of (1) a screening phase, (2) an ASCT and CART-19 manufacturing phase consisting of 
apheresis and preparation of the CART-19 cell product along with standard-of-care ASCT, (3) a treatment 

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phase consisting of lymphodepleting chemotherapy, infusion of CART-19 cells, and initiation of 
maintenance lenalidomide, and (4) a follow-up phase. Schedule of evaluations and interventions are 
included in Appendix 1. 
6.1 
Screening/Enrollment 
Subjects who have signed an informed consent form will undergo a medical record review and screening 
procedures to assess eligibility in accordance with the Schedule of Evaluations in Appendix 1. Testing for 
assessment of eligibility consists of standard-of-care procedures in this patient population. All screening 
procedures must be performed within four weeks of enrollment.   For the purposes of this study and in 
order to standardize the timing of study windows, enrollment will be defined as the date eligibility is 
confirmed by the Principal Investigator.    
6.2 
Enrollment 
To enroll a subject on this study, provide the documents listed below to:  
 
Protocol Monitor and Sponsor Project Manager 
 
 
 
Documents required: 
1. Complete Enrollment Form 
2. Copy of signed patient consent and HIPAA form 
3. Source documentation to verify eligibility (including patient past medical history, laboratory, 
radiological reports, physical exam, concomitant medications and any other source 
documentation to support that the patient meets eligibility criteria and has completed all 
required screening assessments). 
Assignment of subject numbers will occur at consent, will be in ascending order (i.e. 19416-XX), and no 
numbers will be omitted. Subject numbers will be used on all study documentation. 
 
Upon informed consent completion and receipt of screening and eligibility documentation, the Sponsor 
Protocol Monitor will review and provide documentation that the monitoring visit for eligibility has been 
completed. This documentation must be received prior to cell product manufacturing.   
 
Once the monitoring visit for eligibility has been completed, the site will schedule the patient for 
apheresis/T cell production. If T cells have already been collected during a previous apheresis, it is not 
necessary to repeat the apheresis procedure.  
6.3 
General information concerning samples obtained for laboratory 
correlative studies 
The following guidelines will be followed for collection of samples for research correlative studies:  
 
For molecular studies (Q-PCR, RNAseq and Q-RT-PCR), immune phenotyping and functional assays, 
peripheral blood and marrow samples will be collected in purple-top (K2EDTA) tubes. For cytokine 
analyses peripheral blood and marrow samples will be collected in red-top (no additive) tubes. Samples 

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will be delivered, processed, and frozen as per SOP to the Translational and Correlative Studies Laboratory 
(TCSL) (University of Pennsylvania).  Samples will be stored in the TCSL at the University of Pennsylvania 
for storage and bulk analyses.  Documentation for sample receipt, processing, and storage and primary 
data from the research analyses will be collected and stored in the TCSL.    
 
Correlative testing at this and future time points may include (but is not limited to) flow cytometry to 
measure both benign and malignant plasma cell populations, as well as CD19 expression on these cells, 
and T cell subsets within the bone marrow compartment. Deep sequencing of immunoglobulin heavy 
chain gene to assess for presence of the multiple myeloma clonotype and the normal B cell repertoire 
may also be performed. 
 
If a clinical test or procedure is performed for clinical indications, surplus material acquired during this 
procedure may be utilized for research correlative analysis if the subject agrees to such use of these 
materials in the informed consent document. For example, if a lumbar puncture is performed to evaluate 
neurologic symptoms, surplus CSF not required for clinical testing may be used for correlative analysis to 
test for presence of CART-19 cells in CSF.  
Post-infusion evaluations are specified in the Schedule of Events in Appendix 1. Additional details are 
provided in the sections below.  
 
At any time point, if serum and urine studies for multiple myeloma indicate CR, a bone marrow biopsy 
and aspiration maybe performed at or before the next study evaluation to confirm CR and conduct MRD 
testing. Likewise, if serum and urine studies for multiple myeloma indicate progression, bone marrow 
biopsy and aspiration may be performed at or before the next study evaluation to assess the 
immunophenotype and genetics of disease progression and assess for CART-19 cell persistence in bone 
marrow. Bone marrow aspirate from procedures to confirm CR or evaluate progression will be obtained 
for laboratory correlative studies.  
6.4 
Apheresis 
A large volume apheresis procedure is carried out at the Hospital of the University of Pennsylvania 
apheresis center. PBMC are obtained for CAR T cells during this procedure. From a single leukapheresis, 
the intention is to harvest at least 5 x 109 white blood cells to manufacture CART-19 cells. If a single 
apheresis does not yield the adequate number of cells for manufacturing, then subjects can undergo an 
additional apheresis as needed. Baseline blood leukocytes for FDA look-back requirements and for 
research are also obtained and cryopreserved (1 x 108 cells from apheresis to TCSL and 1-2 x 109 to PDL, if 
available after cells required for manufacturing are obtained). The cell product is expected to be ready for 
release approximately 3-4 weeks later. GM-CSF or G-CSF should not be used 14 days prior to apheresis, 
as it may increase neutrophils in the collected product and make it difficult to process. Chemotherapy, 
steroids or other immunosuppressant drugs should not be used within 14 days prior to leukapheresis. 
Treatment with monoclonal antibodies should not be used within 28 days prior to leukapheresis. 
 
A lymphocyte subset analysis (CD3, CD4, CD8 counts) will be performed to confirm that the patient has 
an absolute CD3 count of ≥150/µl. If the absolute CD3 count is <150/µl, it is recommended that the 
leukapheresis procedure be delayed until their ALC is ≥500/µl or absolute CD3 count is ≥150/µl.  
 
 
 

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Historical Apheresis Sample 
Cryopreserved historical apheresis products collected from the patient prior to study entry are usable for 
CART-19 manufacturing if collected at an appropriately certified apheresis center and the product meets 
adequate mononuclear cell yields, these cells may be used as the source of cells for CART-19 cell 
manufacturing.  If a historical apheresis product is not available, an apheresis procedure (as described 
above) will be performed for cell procurement after study eligibility has been confirmed. 
6.5 
Pre-ASCT evaluation 
Within 4 weeks of ASCT, but after apheresis and hematopoietic stem cell collection, subjects will undergo 
a full multiple myeloma response evaluation to assess response to induction therapy, assess pre-ASCT 
disease burden, and obtain samples for correlative analysis. 
This evaluation will consist of the following testing and procedures: 
 
Serum protein electrophoresis and immunofixation 
 
Quantitative immunoglobulins (IgG, IgM, IgA) 
 
Urine protein electrophoresis and immunofixation from a 24-hour collection 
 
CBC and comprehensive metabolic panel 
 
Serum free light chain analysis 
 
Bone marrow biopsy and aspiration, for standard anatomic pathology and research correlative 
analysis. 
 
Research peripheral blood draw 
 
Imaging: If the treating investigator feels advanced imaging (PET-CT, CT, or MRI) is necessary for 
adequate characterization of the subject’s response to induction therapy, these modalities will 
be performed. If not, a standard skeletal survey will be performed. 
6.6 
ASCT (Day 0) 
Following apheresis, subjects will undergo standard-of-care ASCT according to the guidelines set forth in 
section 5.3.1. This will include, if not already performed, mobilization and collection of autologous 
hematopoietic stem cells. This study does not specify a particular regimen for mobilizing stem cells. 
Subjects will undergo routine, standard-of-care monitoring post-ASCT, and this monitoring is not specified 
by this protocol.  
6.7 
Pre-infusion visit  
Subjects will undergo the following work-up 3-7 days prior to CART-19 infusion (~Day +55 ± 2d) including: 
a) Current medical conditions and physical examination including an assessment of vital sign, 
performance status, and concomitant medications.  
b) Complete blood count and differential 
c) Chemistry panel, consisting of the following tests: Glucose, BUN, Creatinine, Sodium, 
Potassium, Chloride, Calcium, Total Protein, Albumin, Total Bilirubin, Alk Phos, AST, ALT, Mg, 
Phos, LDH, Uric Acid. 
d) Myeloma re-staging labs (SPEP/immunofixation, quantitative immunoglobulins, serum free 
light chains, 24 hour urine for total protein, UPEP/immunofixation) 
e) Imaging: If the treating investigator feels advanced imaging (PET-CT, CT, or MRI) is necessary 
for adequate characterization of the subject’s response to ASCT, these modalities will be 
performed. If not, a standard skeletal survey will be performed. 

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f) Serum pregnancy test (females of childbearing potential only) 
g) Baseline screens for HLH/MAS: ferritin, triglycerides, haptoglobin and CRP 
h) Coagulation factors:  PT, PTT, INR, fibrinogen, D-dimer 
i) 
Respiratory virus panel by nasal swab (within 10 days prior to the first CART-19 infusion) 
j) 
Research blood draw for baseline molecular (including VSV-G), cytokine, and cellular 
assessments. These results are not required before CART-19 administration.    
k) Bone marrow aspirate and core biopsy. Samples will be sent for routine anatomic pathology. 
Additionally, bone marrow aspirate will be taken for correlative/exploratory studies. 
If CART-19 infusion is re-scheduled between the pre-infusion visit and CART-19 infusion, the pre-infusion 
evaluations, with the exception of the bone marrow biopsy, will be repeated within 3-7 days prior to the 
re-scheduled CART-19 infusion.  
6.8 
Lymphodepleting Chemotherapy 
Patients will undergo lymphodepleting chemotherapy 3 days (± 1d) prior to CART-19 infusion in 
accordance with the Schedule of Evaluations in Appendix 1. If >48 hours have passed since patient’s last 
blood work, a complete blood count with differential, and full chemistry panel  should be repeated prior 
to chemotherapy. Chemotherapy should be delayed if there is concern that on the scheduled day of CART-
19 infusion that the subject will not satisfy criteria for CART-19 infusion specified in section 5.2.  
 
Treatment can be given through a peripheral IV as an outpatient in the Perelman Center for Advanced 
Medicine (PCAM) chemotherapy unit.  At the discretion of the investigator, some patients may require 
hospitalization for the cyclophosphamide administration. In this event, the hospitalization will not be 
recorded as an SAE. Intravenous hydration with normal saline is required, as is anti-emetic pre-
medication. All patients will be given Zofran 24 mg and Dexamethasone 12mg pre-cyclophosphamide, and 
Zofran 8 mg PO BID on days 1 and 2 after cyclophosphamide.  
6.9 
CART-19 Cell Infusion (Day 60 +7 days) 
CAR T cell infusion will begin 3 days (± 1 day) after completion of lymphodepleting chemotherapy. Prior 
to infusion, subjects will undergo tests and procedures in accordance with the schedule of events in 
Appendix 1, including CD3, CD4, and CD8 counts. Criteria outlined in section 5.2 will be reviewed to verify 
all criteria for CART-19 infusion are satisfied. Section 5.2 also specifies parameters for delay of CART-19 
infusion. Subjects will be premedicated and receive CART-19 cells as described in section 5.4.  Subjects 
will be infused and premedicated as described in section 5.4 and monitored post-infusion as described in 
section 5.5. 
6.10 Post-CART19 infusion Evaluations  
Subjects will return to the clinic  4, 7, 10, 14, and 21 days (± 1 day) post CART-19 infusion for evaluations 
in accordance with the Schedule of Evaluations in Appendix 1.  
6.11 Day +28 Post CART-19 Infusion (±3 days) 
Subjects will undergo evaluations in accordance with the Schedule of Evaluations in Appendix 1 
approximately 28 days (± 1 days) after the CART-19 infusion.  Samples for correlative analyses will also be 

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obtained as detailed in the Schedule of Evaluations, including a 60 mL blood draw for research purposes 
and to archive T cells for analysis. 
6.12 Maintenance lenalidomide 
Lenalidomide will be initiated at the standard-of-care dose and schedule of 10 mg daily beginning at 
approximately day 90 post-ASCTand at least 4 weeks post-CART19.   
6.13 Month 4 (±7 days)  
Subjects will undergo evaluations in accordance with the Schedule of Evaluations in Appendix 1 
approximately 60 days after CART-19 infusion (month 4 post-ASCT).  
6.14  Months  5 + 6 (± 7 days)  
Subjects will undergo evaluations in accordance with the Schedule of Evaluations in Appendix 1 
approximately 3 and 4 months post CART-19 infusion (months 5 + 6 post-ASCT). Standard testing for 
multiple myeloma progression should be performed with SPEP, UPEP from a 24-hour collection, 
quantitative immunoglobulin measurements, and serum free light chain analysis. Advanced imaging, 
however, if required to track a subject’s disease, does not need to be performed at monthly intervals, and 
the frequency can be decided by the treating investigator based on standard clinical practice.  
6.15 Months 8, 11, + 14 (± 14 days)  
Subjects will undergo additional follow-up evaluations in accordance with the Schedule of Evaluations in 
Appendix 1 till Month 14 post-ASCT.  This includes standard testing for multiple myeloma progression 
(SPEP, UPEP from a 24-hour collection, quantitative immunoglobulin measurements, and serum free light 
chain analysis). Advanced imaging, however, if required to track a subject’s disease, does not need to be 
performed at each study visit, and the frequency can be decided by the treating investigator based on 
standard clinical practice.  
6.16 Month 20 (± 14 days) 
Subjects will undergo an additional safety follow-up visit at Month 20 in accordance with the Schedule of 
Evaluations in Appendix 1.   
6.17 Two year post-ASCT (Month 24 ± 14 days) 
Two years post-ASCT, subject will complete their Month 24/End of Study Visit, in accordance with the 
Schedule of Evaluations in Appendix 1.  Subjects will be seen by a treating investigator and queried about 
any new symptoms that may represent adverse events. Subjects will undergo a full multiple myeloma 
response evaluation at this visit.   
6.18 Long-term Follow-up   
After subjects’ complete or prematurely discontinue participation in this study, subjects will be asked to 
participate in a separate 15 year long-term follow-up destination protocol. 

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7. 
STATISTICAL PLAN 
7.1 
General Design Issues 
This is a single-arm, single-center, open-label study to assess the effect of post-ASCT CART-19 therapy on 
post-ASCT PFS. This study will also assess whether the addition of CART-19 post-ASCT improves PFS 
compared to historical post-ASCT outcomes in patients with high-risk multiple myeloma.  
 
Historical expectations for post-ASCT PFS are derived from the recently published validation of the R-ISS 
staging system6. This study aggregated long-term survival outcomes from several studies of first-line 
therapy for multiple myeloma to derive the R-ISS; the constituent studies involved first-line regimens that 
incorporated “novel agents” (“-imids” such as lenalidomide or thalidomide and/or bortezomib) and, for 
subjects <65 years of age, ASCT and post-ASCT maintenance therapy. The publication presented 
separately the outcomes for subjects <65 years of age according to R-ISS stage. Among subjects who were 
progression-free at time of ASCT, 2-year post-ASCT PFS in this cohort was approximately 55%. An increase 
in 2-year PFS from 55% to ~75% is deemed a clinically meaningful improvement for the purposes of sample 
size and power calculations.  
 
Though this historical cohort is used for the sample size determination below, the first-line regimens used 
differ significantly from the RVD regimen employed in the current study. For interpretation of PFS on this 
study, historical data from more contemporary cohorts such as the BMTCTN 0702 study or the DFCI/IFM 
2009 studies may be utilized. Since these studies have not yet reported outcomes, they cannot be used 
to design this study. Results are expected to emerge from these studies over the next 1-2 years, however, 
and, when available, may be used for historical comparison to PFS observed on this protocol.  
7.2 
Sample Size 
The sample size has been chosen to enable comparison to historical controls. Assuming a historical 2-year 
PFS of 55% in this population, the following table depicts the minimal detectable effect size with a sample 
size of 25 patients, 80% power, and alpha of 0.05 and 0.1 using a one-sided test. The calculation assumed 
a two years of recruitment and additional two years of follow-up, and exponential PFS distribution. 
 
N 
Alpha Two-year PFS 
 
25 
0.05 
75.5% 
 
25 
0.1 
72.5% 
7.3 
Subject Population(s) for Analysis 
 
The Enrolled Set comprises all patients who sign an informed consent form and are enrolled in 
the study, excluding screen failure patients.  
 
The Efficacy Evaluable Set comprises all patients who receive the CART-19 cells at the target cell 
dose (1-5x108 transduced cells).  Subjects with a manufactured cell dose that is less than the 
protocol-specified dose will be scored as a manufacturing failure. These subjects will receive 
their cell infusion, provided that the manufactured dose is above the 
 minimum acceptable 
dose for infusion (2x107 CART-19 cells) and all other manufacturing release criteria are met. The 
subjects that are infused with ≥2x107-<1x108 CART-19 cells will be considered non-evaluable for 

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the primary endpoint but will be included in analysis of secondary endpoints.  The Efficacy 
Evaluable Set will be used for the primary efficacy endpoint analysis.  
 
The Full Analysis Set (FAS) comprises all patients who received the CART-19 cells. This set 
includes both primary efficacy evaluable and non-evaluable patients as defined above. The Full 
Analysis Set will be used for the secondary efficacy, safety and correlative endpoints or other 
exploratory analyses.  
7.4 
Statistical Analysis of Endpoints 
The primary endpoint is progression-free survival (PFS). PFS is defined as time between the ASCT to the 
date of the first documented disease progression (see Table 5 for definition) or death due to any cause. If 
a patient has not progressed or died at the date of the analysis cut-off, PFS is censored at the last adequate 
assessment date or date of lost to follow-up.  If a patient receives a new anticancer therapy without 
evidence of progression, PFS will be censored. The survival function will be estimated using the Kaplan-
Meier method and one-sided 95% confidence interval for 2-year survival probability will be computed. If 
the 55% historic 2-year PFS does not fall into this confidence interval, we will reject the null hypothesis and 
conclude the 2-year PFS in the current trial is statistically significant above the historic value. Median 
survival time along with the associated 95% confidence intervals will be presented if appropriated.  
 
For secondary endpoints, incidence and severity of AEs will be summarized and tabulated by system organ 
class, preferred term and maximum toxicity grade (based on CTCAE v4.03). Changes or abnormal 
laboratory values and vital signs from time of infusion will be summarized descriptively. Response rate 
will be computed with confidence intervals. Descriptive statistics will be calculated for other correlative 
endpoints. Persistence and trafficking of CART-19 to blood or bone marrow over time will be presented 
graphically and by clinical outcomes if appropriate. Statistical methods appropriate for longitudinal data 
will be implemented. Subgroup analysis of PFS will be determined using appropriate parametric or non-
parametric statistics. Statistical tests if performed will be limited to avoid the inflation of type I error rate.  
7.4.1 Stopping rule for maintenance lenalidomide discontinuation 
As described in section 1.1, we expect maintenance lenalidomide to be well tolerated after CART-19 
infusion. To monitor for evidence that maintenance lenalidomide is not tolerable after CART-19, however, 
the stopping rule described here will monitor for lenalidomide discontinuation due to adverse events and 
pause the study if discontinuation is substantially in excess of baseline expectations such that there is a 
high probability that the true discontinuation rate will be above the maximum tolerated rate of 30%. 
Baseline expectations for lenalidomide discontinuation are derived from the CALGB 100104 study, which 
was a randomized, double-blind trial comparing maintenance lenalidomide after ASCT to placebo. In this 
study, 23 of 231 (10%) subjects in the lenalidomide arm discontinued maintenance therapy due to adverse 
events (Figure S1b in McCarthy et al.18). A Bayesian stopping rule will be applied with every 3 patients. 
Given a sample size of 25 evaluable subjects, the trial will be paused if lenalidomide discontinuation within 
1 year of ASCT are observed in 3 out of 3 patients, ≥4 out of 6, ≥5 out of 9, ≥6 out of 12, ≥7 out of 15, ≥8 
out of 18, ≥9 out of 21, and ≥10 at any time. Our calculation assumed a prior of beta(0.6, 5.4) which 
corresponds to a 10% prior event rate. However, because the impact of receiving CART-19 infusion on 
lenalidomide discontinuation rate is currently unknown, we conservatively selected the values of hyper-
parameter in the prior distribution such that evidence of the observed discontinuation rate will outweigh 
over the prior rate by approximately five folds. Based on this stopping rule, the probability to stop early is 

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around 71%.If this stopping rule is triggered, new enrollments will be paused, and the study will be either 
terminated or amended to address the excess discontinuation of maintenance lenalidomide. 
8. 
SAFETY AND ADVERSE EVENTS 
8.1 
Definitions 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. Intercurrent illnesses or injuries should be regarded as adverse 
events. 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
 
fatal 
 
life-threatening 
 
requires or prolongs hospital stay 
 
leads to a persistent or significant disability or incapacity or substantial disruption of the ability 
to conduct normal life functions 
 
a congenital anomaly or birth defect 
 
an important medical event 
Note that hospitalizations that meet the following criteria should not be reported as serious adverse 
events: 
 
Routine treatment or monitoring of the studied indication, not associated with any deterioration 
in condition, such as preplanned study visits and preplanned hospitalizations for study procedures 
or treatment administration 
 
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication 
under study and has not worsened since signing the informed consent 
 
Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition. 
 
Note that treatment on an emergency outpatient basis that does not result in hospital admission and 
involves an event not fulfilling any of the definitions of a SAE given above is not a serious adverse event.  
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance. They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above. For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
Unexpected adverse events 
An adverse event is considered unexpected if the event severity and/or frequency is not described in 
the investigator brochure or protocol (in the absence of an investigator brochure).  Please refer to the 

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investigator brochure for additional detail related to severity and/or frequency of a particular event.   
Related adverse events 
An adverse event is considered related to participation in the research if there is a reasonable possibility 
that an event was caused by an investigational product, intervention, or research-required procedures.  
For the purposes of this study, "reasonable possibility" means there is evidence to suggest a causal 
relationship.  
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from 
the initiation of any study procedures to the end of the study treatment follow-up.  For this study, adverse 
events will be reported starting at the time of administration of lymphodepleting chemotherapy and will 
continue until the subject is off-study or until two years post-ASCT.  
 
If a subject is taken off study within 30 days of the T-cell infusion, all SAEs experienced within 30 days 
after the T-cell infusion should be reported to the sponsor. Any SAEs experienced after this 30-day period 
should be reported to the sponsor if the investigator suspects a causal relationship to the study treatment.  
Preexisting Condition/General Physical Examination Findings 
A preexisting condition is one that is present at the start of the study.  At screening, any clinically 
significant abnormality should be recorded as a preexisting condition on the medical history eCRF.  During 
the course of the study, a preexisting condition should be recorded as an adverse event if the frequency, 
intensity, or the character of the condition worsens.  Preexisting conditions that improve should also be 
recorded appropriately. 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met:  
 
The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
 
The abnormality suggests a disease and/or organ toxicity 
 
The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
Laboratory abnormalities that meet the criteria for Adverse Events should be followed until they have 
returned to normal or an adequate explanation of the abnormality is found. When an abnormal laboratory 
or test result corresponds to a sign/symptom of an already reported adverse event, it is not necessary to 
separately record the lab/test result as an additional event. A Grade 3 or 4 event (severe) as per CTCAE 
does not automatically indicate a SAE unless it meets the definition of serious as defined below and/or as 
per investigator’s discretion.  Whenever possible, a diagnosis, rather than a symptom should be provided 
(i.e. anemia instead of low hemoglobin).  
8.2 
Recording of Adverse Events 
Safety will be assessed by monitoring and recording potential adverse effects of the treatment using the 
Common Toxicity Criteria version 4.03 at each study visit. Subjects will be monitored by medical histories, 
physical examinations, and blood studies to detect potential toxicities from the treatment.  If CTCAE 

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grading does not exist for an adverse event, the severity of mild, moderate, severe, life-threatening, and 
death, corresponding to Grades 1-5, will be used whenever possible. 
 
At each contact with the subject, the investigator must seek information on adverse events by non-
directive questioning and, as appropriate, by examination. Adverse events may also be detected when 
they are volunteered by the subject during the screening process or between visits, or through physical 
examination, laboratory test, or other assessments. Information on all adverse events should be recorded 
in the source documentation. All clearly related signs, symptoms, and abnormal diagnostic procedures 
results should be recorded in the source document, though should be grouped under one diagnosis.  To 
the extent possible, adverse events should be recorded as a diagnosis, and symptoms used to make a 
diagnosis recorded within the diagnosis event.  Do not list symptoms if a diagnosis can be assigned. 
 
All adverse events occurring during the adverse event reporting period (defined in Section 8.1 above) 
must be recorded.  
 
As far as possible, each adverse event should be evaluated to determine: 
1. The severity grade (CTCAE v4.03 Grade 1-5) 
2. Its duration (start and end dates) 
3. Its relationship to the study treatment- [Reasonable possibility that AE is related: No (unrelated/ 
not suspected) or Yes (a suspected adverse reaction)].  If yes (suspected)- is the event possibly, 
probably or definitely related to the investigational treatment?  
4. Expectedness to study treatment- [Unexpected- if the event severity and/or frequency is not 
described in the investigator brochure or protocol (in the absence of an investigator brochure)]. 
5. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
6. Whether medication or therapy taken (i.e. no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.1. 
 
All adverse events should be treated appropriately. If a concomitant medication or non-drug therapy is 
given, this action should be recorded. Once an adverse event is detected, it should be followed until its 
resolution or until it is judged to be permanent, and assessment should be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome.  
 
Adverse events that occur concurrently with the progression of malignancy but that are not related to 
disease progression (i.e. deep vein thrombosis or hemoptysis) will be reported as an adverse event as 
described above.  Progression of malignancy resulting in death should be reported as a serious adverse 
event.  
 
Serious adverse events that are still ongoing at the end of the adverse event reporting period must be 
followed to determine the final outcome. Any serious adverse event that occurs after the adverse event 
reporting period and is considered to be possibly related to the study treatment or study participation 
should be recorded and reported. 

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Grading System of Cytokine Release Syndrome (CRS) 
 A protocol specific grading system (Table 8-1) has been developed to capture cytokine release syndrome 
(CRS) in CAR T-cell protocols.  Please refer to section 1.5 for additional detail on CRS in CAR T-cell therapy.  
 
For the purposes of reporting and grading on clinical trials using CAR T cells, we will use the following 
grading for CRS Toxicity.  The start date of CRS is a retrospective assessment of the date of onset of 
persistent fevers and/or myalgia consistent with CRS and not explained by other events (i.e. sepsis). The 
stop date of CRS is defined as the date when the patient has been afebrile for 24 hours and off 
vasopressors for 24 hours.  For the purposes of defining the CRS start date, a fever is defined as a 
temperature of 100.4⁰F/38⁰C. 
 

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Table 8-1:  CRS Grading Criteria 
CRS Toxicity Grade (Modified) 
1 
2 
3 
4 
5 
Mild reaction: 
Treated with 
supportive care 
such as anti-
pyretics, anti-
emetics 
Moderate 
reaction requiring 
IV fluids or 
parenteral 
nutrition; some 
signs of organ 
dysfunction (i.e. 
grade 2 creatinine 
or grade 3 liver 
function tests 
[LFTs] related to 
CRS and not 
attributable to 
any other 
condition).  
Hospitalization for 
management of 
CRS related 
symptoms 
including fevers 
with associated 
neutropenia.  
More severe reaction: 
Hospitalization required for 
management of symptoms 
related to organ 
dysfunction including grade 
4 LFTs or grade 3 creatinine 
related to CRS and not 
attributable to any other 
conditions.  This excludes 
management of fever or 
myalgias.  Includes 
hypotension treated with 
IVFs* or low-dose pressors, 
coagulopathy requiring 
fresh frozen plasma (FFP) 
or cryoprecipitate, and 
hypoxia requiring 
supplemental oxygen (nasal 
cannula oxygen, high flow 
oxygen, Continuous 
Positive Airway Pressure 
[CPAP] or Bilateral Positive 
Airway Pressure [BiPAP].  
Patients admitted for 
management of suspected 
infection due to fevers 
and/or neutropenia may 
have grade 2 CRS. 
Life-threatening 
complications such 
as hypotension 
requiring high dose 
pressors (See Table 
8-2), or hypoxia 
requiring 
mechanical 
ventilation 
Death 
*CRS Grade 3 language clarification: “hypotension treated with intravenous fluids” is further defined as 
hypotension requiring multiple fluid boluses for blood pressure support. 
 

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Table 8-2 
High Dose Vasopressor Use 
Definition of “High-Dose” Vasopressors 
Vasopressor 
Dose for ≥ 3 hours 
Norepinephrine monotherapy 
≥ 0.2 mcg/kg/min 
or ≥ 20 mcg/min (if institutional practice is to use flat dosing) 
Dopamine monotherapy 
≥ 10 mcg/kg/min 
or ≥ 1000 mcg/min (if institutional practice is to use flat dosing) 
Phenylephrine monotherapy 
≥ 2 mcg/kg/min 
or ≥ 200 mcg/min (if institutional practice is to use flat dosing) 
Epinephrine monotherapy 
≥ 0.1 mcg/kg/min 
or ≥ 10 mcg/min (if institutional practice is to use flat dosing) 
If on vasopressin 
High-dose if vaso +  Norepinephrine Equivalent (NE) of >0.1 
mcg/kg/min (or 10 mcg/min) (using Vasopressin and Septic Shock 
Trial (VASST) formula) 
If on combination vasopressors 
(not vasopressin) 
Norepinephrine equivalent of ≥ 0.2 mcg/kg/min  
(or ≥ 20 mcg/min) (using VASST formula) 
Vasopressin and Septic Shock Trial (VASST) Equivalent Equation: 
Norepinephrine equivalent dose = [norepinephrine (mcg/min)] + [dopamine (mcg/kg/min) ÷ 2] + 
[epinephrine (mcg/min)] + [phenylephrine (mcg/min) ÷10]  
Criteria from Russell et al, 200870. 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to the 
regulatory sponsor within 24 hours of learning of its occurrence. The pregnancy must be followed up to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator to the regulatory sponsor. Pregnancy follow-up should be recorded on the same form and 
must include an assessment of the possible relationship to the study treatment of any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
 
Pregnancy outcomes must be collected for the female partners of any males who took study treatment in 
this study. Consent to report information regarding these pregnancy outcomes should be obtained from 
the mother.   
 
 
 
 

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8.3 
Reporting of Serious Adverse Events 
Every SAE, regardless of suspected causality, occurring during the adverse event reporting period defined 
in Section 8.1 above must be reported to the sponsor within 24 hours of learning of its occurrence.  The 
original SAE notification may take place by email to meet the 24-hour reporting window.  However, within 
3 business days of knowledge of the event, the investigator must submit a complete SAE form to the 
Sponsor along with any other diagnostic information that will assist the understanding of the event.  The 
Investigator will keep a copy of this SAE Form on file at the study site.   
 
Follow-up information on SAEs should be reported when updates are available, as a follow-up to the initial 
SAE form, and should include both the follow-up number and report date.  New information on ongoing 
serious adverse events should be provided promptly to the sponsor. The follow-up information should 
describe whether the event has resolved or continues, if there are any changes in assessment, if and how 
it was treated, and whether the patient continued or withdrew from study participation. 
Report serious adverse events by email to: 
Attention: Clinical Safety Manager or designee  
 
 
 
 
At the time of the initial report, the following information should be provided: 
1. Study identifier 
2. Subject number 
3. A description of the event 
4. Date of onset 
5. Current status 
6. Whether study treatment was discontinued 
7. The reason the event is classified as serious 
8. Investigator assessment of the association 
between the event and study treatment 
9. Expectedness relative to investigational 
product(s) 
8.3.1 Investigator Reporting: Notifying the Penn IRB 
This section describes the requirements for safety reporting by investigators who are Penn faculty, 
affiliated with a Penn research site, or otherwise responsible for safety reporting to the IRB. The IRB 
requires expedited reporting of those events related to study participation that are unforeseen and 
indicate that participants or others are at increased risk of harm.  The IRB will not acknowledge safety 
reports or bulk adverse event submissions that do not meet the criteria outlined below.  The IRB requires 
researchers to submit reports of the following problems within 10 working days from the time the 
investigator becomes aware of the event: 
 Any adverse event (regardless of whether the event is serious or non-serious, on-site or off-site) 
that occurs any time during or after the research study, which in the opinion of the principal 
investigator is: 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately reflected in the 
protocol-related documents, such as the IRB-approved research protocol, any applicable investigator 
brochure, and the current IRB-approved informed consent document and other relevant sources of 
information, such as product labeling and package inserts.) 
AND 

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Related to the research procedures (An event is “related to the research procedures” if in the opinion of 
the principal investigator or sponsor, the cause of the event was deemed probably or definitely related to 
the investigational product or procedure that was performed for the purposes of the research.) 
 
Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the IRB.   This 
will include a written report of the event (including a description of the event with information regarding 
its fulfillment of the above criteria, follow-up/resolution and need for revision to consent form and/or 
other study documentation). 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
 
Reporting Deaths:  more rapid reporting requirements 
Concerning deaths that occur during the course of a research study, the following describes the more 
rapid reporting requirement of the Penn IRB for specific situations: 
 Report the event within 72 hours when the death is unforeseen (unexpected) and indicates 
participants or others are at increased risk of harm. 
For reportable deaths, the initial submission to the IRB may be made by contacting the IRB Director or 
Associate Director. 
 
Other Reportable events: 
For clinical drug trials, the following events are also reportable to the IRB: 
 Any adverse experience that, even without detailed analysis, represents a serious unexpected 
adverse event that is rare in the absence of drug exposure (such as agranulocytosis, hepatic 
necrosis, Stevens-Johnson syndrome). 
 Any adverse event that would cause the sponsor to modify the investigators brochure, protocol 
or informed consent form, or would prompt other action by the IRB to assure protection of 
human subjects. 
 Information that indicates a change to the risks or potential benefits of the research, in terms of 
severity or frequency. For example:  
– An interim analysis indicates that participants have a lower rate of response to treatment 
than initially expected. 
– Safety monitoring indicates that a particular side effect is more severe, or more frequent 
than initially expected. 
– A paper is published from another study that shows that an arm of your research study is of 
no therapeutic value. 
 Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic used in 
a research protocol. 
 Breach of confidentiality 
 Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard 
to a research participant. 
 Incarceration of a participant when the research was not previously approved under Subpart C 
and the investigator believes it is in the best interest of the subject to remain on the study. 
 Complaint of a participant when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 

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 Protocol violation (meaning an accidental or unintentional deviation from the IRB approved 
protocol) that in the opinion of the investigator placed one or more participants at increased risk, 
or affects the rights or welfare of subjects. 
8.3.2 Investigator Reporting: Notifying the DSMC of the Abramson Cancer Center 
(ACC) 
All events that meet the ACC DSMC definition of reportable AE’s must be promptly entered into Velos.   
The DSMC requires AE/SAE submission as follows:  
 
Unless covered by exclusions below, grade 3 or higher events must be reported within 10 days 
of knowledge of the adverse event. 
Exceptions: 
o Grade 3 and 4 events that are typical in the disease population – with the exception of 
those that could be symptoms/early indicators of any of the toxicities defined in the 
Toxicity Management section of the protocol, signs/symptoms of an allergic response, 
severe hypotensive crisis or any other reaction to the infusion.  
o All grade 3 or 4 events that are judged by a study investigator to be clearly unrelated to 
protocol therapy. 
o Grade 3 or 4 events that are probably or definitely related to progression of disease as 
judged by the study investigator.  
o Grade 3 or 4 events that are probably or definitely related to an FDA approved agent. 
 
All unexpected deaths within one business day of knowledge  
 
All others deaths within 30 days of knowledge. Deaths of subjects off-study for greater than 30 
days from the last study treatment/intervention are not reportable unless a longer time frame is 
specified in the protocol.  
 
In the event of a grade 4 or 5 unexpected event regardless of attribution, the study team must meet or 
have a teleconference within 24 business hours of knowledge of the event to have a thorough 
discussion of the event. These types of events will not be vetted via e-mail. The sponsor should not be 
involved in discussions about attribution. The PI and Research Coordinator will schedule a meeting with 
the study team to discuss the grade 4 or 5 unexpected event. Meeting minutes capturing the review of 
any ongoing investigations of the grade 4 or 5 unexpected event, including next steps in the 
management of the subject and any proposed changes to the protocol will be documented 
appropriately. 
8.3.3 Investigator Reporting: Notifying the IBC 
Notify the Institutional Biosafety Committee of serious adverse events according to institutional 
requirements.  
8.3.4 FDA Notification by Sponsor 
The study sponsor is required to report certain study events in an expedited fashion to the FDA. These 
written notifications of adverse events are referred to as IND safety reports. The sponsor must report an 
IND safety reports as described in:   

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http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227
351.pdf 
The following describes the safety reporting requirements by timeline for reporting an associated type 
of event: 
 
Within 7 Calendar Days 
Any study event that is: 
o Unexpected fatal or life-threatening suspected adverse reaction. 
o Expected and unexpected Grade 3 or higher events of cytokine release syndrome per 
the modified CRS grading scale in Table 8-1 
o All fatal events occurring within 30 days of T-cell infusion, regardless of attribution and 
expectedness  
 
Within 15 Calendar Days 
Any study event that is: 
o unexpected 
o Suspected adverse reaction that is serious, but not fatal or life-threatening 
-or- 
o a previous adverse event that was not initially deemed reportable but is later found to 
fit the criteria for reporting (reporting within 15 calendar days from when event was 
deemed reportable). 
Any finding from tests in laboratory animals that: 
– suggest a significant risk for human subjects including reports of mutagenicity, teratogenicity, 
or carcinogenicity or reports of significant organ toxicity at or near the expected human 
exposure. 
Increase in rate of occurrence of serious suspected adverse reactions: 
o any clinically important increase in the rate of a serious suspected adverse reaction over 
that listed in the protocol or investigator brochure. 
Additional Reporting Requirements 
Sponsors are also required to review all adverse events to make a causality determination on the basis of 
information from investigators and report these findings to the FDA in accordance with 21 CFR 312.32. 
If the adverse event does not meet expedited reporting requirements, the Sponsor will report the SAE as 
in the IND Annual Report. 
8.4 
Toxicity Management, Stopping Rules, and Study Termination 
It is expected that AEs will occur frequently in this population based on the underlying hematologic 
malignancy and that these can be SAEs. Therefore, there is no specific occurrence of SAEs that define a 
stopping rule, but the review of SAEs will form the basis for potential early stopping of the study. Only 
unexpected SAEs that are related to the CART-19 cells would lead to study termination (as defined below).  
 
Premature termination of the clinical trial may occur because of a regulatory authority decision, change 
in opinion of the IRB, ACC DSMC, or the DSMB, determination that there are problems in the cell product 
generation, as a result of safety concerns, or at the discretion of the Sponsor or study investigators. 
Additionally, recruitment may be stopped for reasons of particularly low recruitment, protocol violations, 
or inadequate data recording. 

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8.4.1 Criteria for Stopping the Study 
The study will be stopped if: 
 
Any subject develops uncontrolled T cell proliferation that does not respond to management. 
 
Premature study termination may occur if the Investigator, Study Funder, Sponsor, DSMB, IRB, 
ACC DSMC or any independent review board or regulatory body decides for any reason that 
subject safety may be compromised by continuing the study. 
 
Premature study termination may occur if the Sponsor or Study Funder decides to discontinue 
the development of the intervention to be used in this study. 
Subject accrual will be paused in the event of any death within 30 days of CART-19 infusion or if the 
stopping rule described in section 7.4.1 regarding excess lenalidomide discontinuation is triggered. 
Accrual will be held until an investigation is performed and the safety data is evaluated by the DSMB and 
applicable changes implemented (as appropriate). The results of DSMB review must be reviewed by the 
Sponsor, FDA, IRB, and ACC DSMC before additional enrollment may take place. If all parties are in 
agreement as to the event resolution, then the pause will be lifted. 
8.4.2 General Toxicity Management Considerations 
 
Replication-competent lentivirus (RCL): Information on the risks of RCL is contained in Section 
1.5.3.9. Regulatory agencies and the gene therapy community have previously discussed measures 
to be taken should an RCL be confirmed in a subject. However, because the probability and 
characteristics of an RCL are unknown, no guidelines have been put in place. Nevertheless, all agree 
that the subject must be isolated until an understanding of how to manage the subject becomes 
clear. Some considerations are  
o Intensive follow-up of subject in consultation with gene therapy experts, study 
investigators, FDA and NIH. 
o Inform local public health officials and CDC. 
o Identify sexual partners and provide appropriate counseling and intervention. 
RCL will be monitored by a suitable Q-PCR DNA assay for detection of the lentivirus (for example: 
HIV gag DNA or VSV-G DNA). If a positive RCL DNA assay result is obtained, the PI will be informed 
and the subject rescheduled for a retest for the DNA test.  If the second DNA test is positive, then 
infusions of subsequent patients will be temporarily halted.  The patient will undergo a blood draw 
for isolation of HIV from his/her cells.  The virus will be sequenced and compared to sequences of 
the transfer vector and packaging constructs, as well as to available HIV sequences to determine 
the origin of the virus.  Determination of the origin of the virus can be easily performed by 
evaluation for HIV accessory genes such as vif, vpr and vpu which are not present in the packaging 
constructs.  If the sequence is derived from wt-HIV then infusions for all subjects can resume, and 
the patient will be referred to treatment for HIV.  If an RCL is confirmed, or the virus cannot be 
isolated from the blood draw, the patient will be scheduled for apheresis and will undergo a full 
biological RCL testing for detection and/or characterization of the RCL.   
 
Clonality and insertional oncogenesis: Four of nine treated patients in a gene therapy trial for X-
linked Severe Combined Immunodeficiency (SCID) developed T cell leukemia 31-68 months post-
treatment. The T cell leukemias were attributable to clonal expansion conferred by 
gammaretroviral vector integration sites in the CD34+ bone marrow stem cell modification 
(Hacein-Bey-Abina et al., 2008). This represents the most severe adverse event caused by vector 

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integration. However, there is also evidence for retroviral vector integration site dominance in a 
gene therapy trial of -thalassaemia without malignancy (Cavazzana-Calvo et al., 2010). The 
lentiviral vector used for CART-19 manufacturing is part of a vector class that may have a lower risk 
for integration in or near oncogenic regions than oncoretroviral vectors (Montini et al., 2009). As 
of May 2015, none of the patients treated with CART-19 have developed a new malignancy, T cell 
or otherwise, related to lentiviral vector integration. Subjects will be monitored for evidence of 
unexpected CART-19 expansion by CART-19 transgene quantitation by qPCR and clinical 
monitoring for malignancy by complete blood count (CBC) as part of the study design. If an 
unexpected pattern of CART-19 cell expansion is observed (i.e. CART-19 cell expansion in the 
absence of CD19+ target), subjects will be closely monitored clinically for new malignancies, 
particularly T cell, and further studies, including insertion site analysis, will be considered to 
investigate the molecular basis of the expansion. Investigators should consult with the Regulatory 
Sponsor if an unexpected pattern of CART-19 expansion and/or a new malignancy arises. Subjects 
will continue to be similarly monitored for clonality and insertional oncogenesis when enrolled on 
the 
long 
term 
follow-up 
protocol.   
 
 
Uncontrolled T cell proliferation. CART-19 cells could proliferate without control of normal 
homeostatic mechanisms. It is expected that the T cells will proliferate in response to signals from 
the malignant tumor or normal B and plasma cells. This could be beneficial or harmful depending 
on the extent of proliferation. Clonal dominance of adoptively transferred T cells has been 
associated with tumor reduction in adoptive transfer trials25. If uncontrolled T cell proliferation 
occurs, subjects may be treated with corticosteroids. Subjects will be treated with pulse 
methylprednisolone (2 mg/kg i.v. divided q8 hr x 2 days), followed by a rapid taper.  
 
B cell depletion. It is possible that B cell depletion and hypogammaglobulinemia will occur. This is 
common with anti-CD20 directed therapies71. In the event of clinically significant 
hypogammaglobulinemia (i.e. systemic infections or prolonged periods with total serum IgG levels 
<500 mg/dL), consideration will be given to intravenous immunoglobulin (IVIG) by established 
clinical dosing guidelines to restore normal levels of serum immunoglobulin levels, as has been 
done with Rituximab. Determination about IVIG therapy will be made on a case-by-case basis based 
on each patient’s medical history, current condition, and risk of adverse reaction to IVIG.  
 
Infusion reaction. Acetaminophen and diphenhydramine hydrochloride may be repeated every 6 
hours as needed. A course of non-steroidal anti-inflammatory medication may be prescribed if the 
patient continues to have fever not relieved by acetaminophen. It is recommended that patients 
not receive corticosteroids at any time, except in the case of a life threatening emergency, since 
this may have an adverse effect on CART-19 cells. 
 
Febrile reaction. In the event of febrile reaction, an evaluation for infection should be initiated, and 
patients managed appropriately with antibiotics, fluids and other supportive care as medically 
indicated and determined by the treating physician.  In the event that the patient develops sepsis 
or systemic bacteremia following CAR T cell infusion, appropriate cultures and medical   
management should be initiated. If a contaminated CART-19 T cell product is suspected, the 
product can be retested for sterility using archived samples that are stored in the 
.  
Consideration of a cytokine release syndrome (see below) should be given.   
 
Macrophage activation syndrome (MAS).  Based on the observations of subjects treated on UPENN 
protocol 
, there is some concern for macrophage activation syndrome (MAS).  

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Treatment and timing of treatment of this toxicity will be at the discretion of the patient’s physician 
and the study investigator.  Suggested management might include: if the subject has a fever greater 
than 101°F that lasts more than 2 consecutive days and there is no evidence of infection (negative 
blood cultures, CXR or other source), tocilizumab 8 mg/kg can be considered.  The addition of 
corticosteroids and anti-TNF therapy can be considered at the physician’s discretion. 
 
Cytokine Release Syndrome (CRS) / Macrophage Activation Syndrome (MAS)  
Selective tocilizumab therapy has been utilized (described below) to manage CRS/MAS toxicity 
without precluding CAR T cell expansion in patients. Please note, steroids or other 
immunosuppressant drugs should NOT be used as pre-medication for CART-19 cell therapy but 
may be considered in the management of CRS.  
 
The moderate to severe cases of CRS observed required intervention with single dose tocilizumab 
with or without high dose corticosteroids, between 2 and 9 days after T cell infusion to date. This 
resulted in rapid reversal of the high persistent fevers and hemodynamic instability associated with 
CRS in most but not all patients. 
Given the dramatic clinical improvement of patients after treatment with anti-cytokine therapy, 
patients with moderate to severe cytokine toxicities should be managed with administration of 
tocilizumab.  
 
Tocilizumab should be used as a single, weight-based dose of 8 mg/kg at the time of hemodynamic 
instability. This management approach is designed to avoid life-threatening toxicities, while 
attempting to allow the CART-19 cells to establish a proliferative phase that appears to correlate 
with anti-tumor efficacy. Thus, the timing of the tocilizumab should be individualized, in close 
consultation with the Principal Investigator and/or expert consultants for the trial.  Steroids have 
not always been effective in this setting and may not be necessary given the rapid response to 
tocilizumab. Because steroids will interfere with CART-19 cell function and efficacy, if used, they 
should be rapidly tapered.  
 
Upon developing the prodrome of high-persistent fevers following CART-19 cell infusion, patients 
should be followed closely. Infection and tumor lysis syndrome work-up should be immediately 
undertaken. The pharmacy should be notified of the potential need for tocilizumab. Patient 
management in an intensive care unit may be required and the timing is dependent upon local 
institutional practice. In addition to supportive care, tocilizumab may be administered in cases of 
moderate to severe CRS, especially if the patient exhibits any of the following: 
o Hemodynamic instability despite intravenous fluid challenges and moderate stable 
vasopressor support 
o Worsening respiratory distress, including pulmonary infiltrates, increasing oxygen 
requirement including high-flow O2, and/or need for mechanical ventilation.  
o Any other signs or symptoms of rapid deterioration despite medical management 
The recommended dosing for tocilizumab is 8 mg/kg i.v. single dose. Not all Grade 4 CRS reactions 
following CAR T cell infusions have been immediately treated with tocilizumab and decisions are, 
in part, based upon the rapidity of the syndrome onset and the individual patient’s physiologic 
reserve. 
 

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Other anti-cytokine therapies, such as repeat administration of tocilizumab or use of siltuximab 
or etanercept, may also be considered if the patient does not respond to the initial dose of 
tocilizumab.  If the patient experiences ongoing CRS despite administration of anti-cytokine 
directed therapies, anti T-cell therapies such as cyclophosphamide, ATG, or alemtuzumab may be 
considered.   
 
CRS has been associated with biochemical and physiologic abnormalities consistent with MAS.  
Moderate to extreme elevations in serum C-reactive protein (CRP) and ferritin have been seen 
with CART-19 associated CRS, however the magnitude and kinetics vary greatly between 
individual patients.  CRS management decisions should be based upon clinical signs and symptoms 
and response to interventions, not these laboratory values per se.  Refer to Figure 8-1 below for 
a CRS Management Algorithm.  
 
In all cases of CRS, we will perform serum cytokine analysis at baseline using a 30-plex Luminex 
assay. This analysis will be repeated at all time-points collected during the event until its clinical 
resolution. This analysis will be batched and not available in real time; thus, it will not be used for 
clinical decisions. We will report these results to FDA. 
 
 

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Figure 8-1 
CRS Management Algorithm 
 
 
 
 
 
Tumor Lysis Syndrome. TLS resulting in renal insufficiency, or rapidly rising uric acid, or evidence 
of organ dysfunction will be managed with intravenous fluids and rasburicase as needed and 
determined by the treating physicians. Appropriate clinical therapy will be administered should 
any significant tumor lysis occur. Prophylactic administration of allopurinol is at the discretion of 
the clinical investigator. 
8.5 
Protocol Exceptions and Deviations 
Exception 
A one time, intentional action or process that departs from the approved study protocol, intended for 
one occurrence. If the action disrupts the study progress, such that the study design or outcome 
(endpoints) may be compromised, or the action compromises the safety and welfare of study subjects, 
advance documented approval from the Regulatory Sponsor, IRB, ACC DSMC, and other local regulatory 
review committees per institutional guidelines is required. Approval from the Regulatory Sponsor must 
be received prior to submission to the IRB, ACC DSMC, and other applicable regulatory review committees 
for approval.   

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No exception would be granted if the action disrupts the study progress, such that the study design or 
outcome (endpoints) may be compromised, or the action compromises the safety and welfare of study 
subjects.  
 
Exceptions to eligibility will not be granted for this study. 
 
Deviation 
A one time, unintentional action or process that departs from the IRB and ACC CTSRMC approved study 
protocol, involving one incident and identified retrospectively, after the event occurred. If the impact on 
the protocol disrupts the study design, may affect the outcome (endpoints) or compromises the safety 
and welfare of the subjects, the deviation must be reported to the Regulatory Sponsor and ACC DSMC 
within 5 business days, and the IRB within 10 business days of PI knowledge.  
Any departure from the protocol that meets the following criteria should be submitted: 
 
Impacts subject safety 
 
Impacts the integrity of the study design or outcome 
 
Based on the PI’s judgment is reportable 
Other deviations should be explained in a memo to file (such as a subject missing a visit is not an issue 
unless a critical/important treatment or procedure was missed and must have been done at that specific 
time).  
 
Include the following information on the Sponsor supplied exception/deviation form:  protocol number, 
subject study number, description of the exception/deviation from the protocol, and rationale.  Ensure all 
completed exception/deviation forms are signed by the Principal Investigator (or sub-investigator) and 
submitted to the Sponsor Project Manager for review.    
Attention: Sponsor Project Manager  
 
 
 
The Sponsor Project Manager will submit the exception and/or deviation request to the Regulatory 
Sponsor or designee for review and approval/acknowledgement.  Once approval of the exception request 
or acknowledgement of the deviation has been granted by the Regulatory Sponsor or designee, the 
exception or deviation will be submitted to the IRB, ACC DSMC and all other applicable committees for 
review and approval. 
8.6 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site. This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above. Medical monitoring will include a regular assessment of the number and type of serious adverse 
events. 
8.7 
Independent Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) comprised of four individuals including physicians with 
experience in oncology and/or gene transfer therapy will be assembled and will work under a charter 

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specifically developed for safety oversight of this study. The DSMB will provide guidance/advice to the 
Regulatory Sponsor. The DSMB will evaluate patient-subject safety as specified in the DSMB Charter. 
The DSMB will meet approximately every 6 months. If necessary, additional meeting of the DSMB may be 
held if safety issues arise in between scheduled meetings. 
 
It is envisioned that the DSMB may make four types of recommendations, namely: 
• 
No safety or efficacy issues, ethical to continue the study as planned 
• 
Serious safety concerns precluding further study treatment, regardless of efficacy 
• 
Overwhelming evidence for futility, recommend stopping the study. 
• 
Recommendation to continue the study but proposing an amendment to the protocol (e.g., 
incorporate an additional safety assessments) 
A sponsor representative will share the outcome of the DSMB meeting with the PI via email, for 
submission to local regulatory review committees as required per institutional policy.  
9. 
DATA HANDLING AND RECORDKEEPING 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
 
What protected health information (PHI) will be collected from subjects in this study 
 
Who will have access to that information and why 
 
Who will use or disclose that information 
 
The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
9.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents   Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. 
 
The investigator must maintain source documents for each subject in the study, consisting of case and 
visit notes (hospital or clinical medical records) containing demographic and medical information, 

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laboratory data, electrocardiograms and the results of any other tests or assessments. All information 
recorded on the eCRFs must be traceable to source documents in the patient’s file. The investigator must 
also keep the original signed informed consent form, and a signed copy must be given to the patient. 
9.3 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study. All 
data requested on the CRF must be recorded. All entries will be entered into an electronic 
data capture system (EDC) via VELOS. The Principal Investigator is responsible for assuring that the data 
entered into eCRF is complete, accurate, and that entry and updates are performed in a timely manner. 
9.4 
Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after the last 
approval of a marketing application in their country and until there are no pending or contemplated 
marketing applications in their country or at least 2 years have elapsed since the formal discontinuation 
of clinical development of the investigational product.  These documents should be retained for a longer 
period if required by an agreement with the sponsor.  In such an instance, it is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer need to be retained.  
10. STUDY MONITORING, AUDITING, AND INSPECTING 
10.1 Study Monitoring Plan 
This study will be monitored according to the Sponsor Data and Safety Monitoring Plan.   
Interim Monitoring Visits will be conducted during the course of the study. The Monitors will assure that 
submitted data are accurate and in agreement with source documentation; verify that investigational 
products are properly stored and accounted for, verify that subjects’ consent for study participation has 
been properly obtained and documented, confirm that research subjects entered into the study meet 
inclusion and exclusion criteria, and assure that all essential documentation required by Good Clinical 
Practices (GCP) guidelines are appropriately filed. 
 
At the end of the study, Monitors will conduct a close-out visit and will advise on storage of study records 
and disposition of unused investigational products. 
 
The investigator will allocate adequate time for such monitoring activities. The Investigator will also 
ensure that the monitor or other compliance or quality assurance reviewer is given access to all the above 
noted study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), 
and has adequate space to conduct the monitoring visit. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, study 
data etc.).  The investigator will ensure the capability for inspections of applicable study-related facilities 
(e.g. pharmacy, diagnostic laboratory, etc.). 

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CONFIDENTIAL 
This document is confidential and the property of the University of Pennsylvania.  No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorization from the 
regulatory sponsor. 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
 
Please notify the Sponsor in real-time if an audit/inspection notice is received. 
11. ETHICAL CONSIDERATIONS 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA 
Title 21 part 312 and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the study conduct.  
The decision of the IRB concerning the conduct of the study will be made in writing to the investigator and 
a copy of this decision will be provided to the sponsor before commencement of this study.   
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.  The consent 
form will be submitted with the protocol for review and approval by the IRB for the study.  The formal 
consent of a subject, using the IRB-approved consent form, must be obtained before that subject is 
submitted to any study procedure.  This consent form must be signed by the subject and the investigator-
designated research professional obtaining the consent.  
 
The protocol is listed under clinicaltrials.gov. 
12. STUDY FINANCES 
12.1 Funding Sources 
This study will be funded by Novartis Pharmaceuticals and the National Institutes of Health (NIH). 
12.2 Conflict of Interest 
 All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on Conflicts 
of Interest Related to Research.   
12.3 Subject Stipends or Payments 
There is there is no subject stipend/payment for participation in this protocol. 
12.4 Study Discontinuation 
The study may be discontinued at any time by the IRB, the Sponsor, the FDA, or other government 
agencies as part of their duties to ensure that research subjects are protected. 

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transmitted, reproduced, published, or used by other persons without prior written authorization from the 
regulatory sponsor. 
13. PUBLICATION PLAN 
Publication of the results of this trial will be governed by University of Pennsylvania policies. Neither the 
complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided by the sponsor for the purposes of performing the study, will be published or passed 
on to any third party without the consent of the study sponsor.  Any investigator involved with this study 
is obligated to provide the sponsor with complete test results and all data derived from the study.  
 
 

CART-19 post-ASCT in Multiple Myeloma 
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transmitted, reproduced, published, or used by other persons without prior written authorization from the 
regulatory sponsor. 
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transmitted, reproduced, published, or used by other persons without prior written authorization from the 
regulatory sponsor. 
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This document is confidential and the property of the University of Pennsylvania.  No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorization from the 
regulatory sponsor. 
35. 
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positive tumor cells by human T lymphocytes engineered to express chimeric T-cell receptor 
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chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in 
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43. 
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CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect. Blood 
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with cancer-specific chimeric single chain and two chain TCR. Gene Therapy 2000;7:1369-77. 
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both primary and costimulatory signaling in T cells from a single gene product. Journal of 
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CD28 signaling selectively enhances survival and proliferation in genetically modified activated 
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transmitted, reproduced, published, or used by other persons without prior written authorization from the 
regulatory sponsor. 
52. 
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transmitted, reproduced, published, or used by other persons without prior written authorization from the 
regulatory sponsor. 
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persons without prior written authorization from the regulatory sponsor. 
determined based on the screening value. The HCV RNA test is not required if documentation of a negative result of a HCV RNA test 
performed within 60 days prior to screening is provided. 
3. Chemistry Panel- Glucose, BUN, Creatinine, Sodium, Potassium, Chloride, Calcium, Total Protein, Albumin, Total Bilirubin, ALK PHos, AST, 
ALT, MG, Phos, LDH, Uric Acid 
4. Performed at the Month 5 visit only. 
5. Pre-donor evaluation of peripheral veins to determine whether apheresis can be performed without central venous access.  If central 
venous access is felt to be necessary, catheter placement will be arranged.  
6. Enrollment and mononuclear cell apheresis to harvest T cells for CART-19 manufacturing will take place prior to standard-of-care 
hematopoietic stem cell mobilization and collection.  Cryopreserved historical apheresis products collected from the patient prior to 
study entry are usable for CART-19 manufacturing if collected at an appropriately certified apheresis center and the product meets 
adequate mononuclear cell yields, these cells may be used as the source of cells for CART-19 cell manufacturing.  If a historical apheresis 
product is not available, an apheresis procedure will be performed for cell procurement after study eligibility has been confirmed.  
Please see section 6.4 for additional information.  
7. Vital sign assessments include weight, temperature, pulse, blood pressure and oxygen saturation by pulse oximetry.  Height will be 
collected at screening only.  On the day of the CART-19 infusion, vital signs will be measured within 10 minutes prior, within 10 minutes 
after the infusion, and then every 15 minutes for the first hour, and then every hour for the next 2 hours until these signs are 
satisfactory and stable.  If the subject’s vital signs are not satisfactory and stable three hours post CART-19 infusion, vital signs will 
continue to be monitored at a minimum of every hour or as clinically indicated until stable.  The subject will be discharged after the 
physician managing their care on the day of the infusion has determined that they are in satisfactory condition.  
8. Female of child-bearing potential only. 
9. Serum (1ml SST) or urine pregnancy test may be performed within 14 days prior to enrollment.  A serum pregnancy test will be 
performed at the pre-infusion visit (~Day + 55 ± 2d). 
10. Research bone marrow aspirates and blood draws should be sent to Translational and Correlative Studies Laboratory.   TCSL has 
requested labs be delivered to TCSL as soon as drawn. If required to keep research labs after hours, please keep red tops upright, purple 
tubes should be room temperature on rotating platforms. In the event that something unexpected occurs, research sample collection 
may be done as necessary, not to exceed 3 tablespoons of blood twice in one week time window, in addition to the protocol-specified 
time points. This would be done at the PI’s discretion. 
11. Collected at the time of apheresis (if performed).  
12. If the treating investigator feels advanced imaging (PET-CT, CT or MRI) is necessary for adequate characterization of the subject’s 
response, these modalities will be performed per routine care.  If not, a standard skeletal survey will be performed.  
13. Melphalan will be administered as a single dose on day -2 or -1, or in two divided doses, according to standard institutional practice.  
Please see Section 5.3.1 for complete details regarding melphalan administration and ASCT. 

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14. Pre-infusion visit to occur 3-7 days prior to the CART-19 infusion.  If the CART-19 infusion is re-scheduled between the pre-infusion visit 
and CART-19 infusion, the pre-infusion evaluations, with the exception of the bone marrow biopsy, will be repeated within 3-7 days prior 
to the re-scheduled CART-19 infusion. 
15. Lymphodepleting chemotherapy will be administered 3 days +/- 1 day prior to CART-19 infusion.  Please see Section 6.8 for additional 
information.  
16. Cyclophosphamide will be administered at a dose of 1.5 g/m2 intravenously as a single infusion.  Administration of lymphodepleting 
chemotherapy and infusion of CART-19 cells may be delayed up to 4 weeks from the originally scheduled date to address any factors 
that make a subject ineligible for CART-19 infusion. Delay of lymphodepleting chemotherapy and CART-19 infusion beyond 4 weeks from 
the scheduled date is acceptable only with approval of the Sponsor.  Please refer to Section 5.2 for complete details. 
17. If performed within 48 hours of the visit, these do not need to be repeated. 
18. To be performed prior to the CART-19 infusion and 1-2 hours post-infusion.  Pre-infusion samples: ~25mL PBMC and ~5mL serum; Post-
infusion Samples: ~5mL PBMC and ~2mL serum. 
19. To be performed at the D14 post-CART19 visit only. 
20. A 60 ml blood draw (collected in purple top tubes) will be performed.  
21.  Optional; performed if clinically appropriate as determined by the treating investigator. 
22. Lenalidomide will be initiated at the standard-of-care dose and schedule of 10 mg daily beginning at approximately day 90 post-ASCT 
and at least 4 weeks post-CART19.  Before maintenance lenalidomide is initiated, toxicities of CART-19 and lymphodepleting 
chemotherapy must be resolved to Grade < 2 and stabilized in the judgment of the treating investigator.  Maintenance lenalidomide may 
be withheld, delayed or dose-reduced at the discretion of the treating investigator if there are clinical contraindications to beginning 
maintenance therapy on the usual dose and schedule. 
23. RCL testing – VSV-g PCR will be performed at Months 5, 8 and 14 visits (Months 3, 6 and 12 post-CART19 infusion). Blood will be 
collected at Month 20 (Month 18 post-CART19 infusion) and will be archived if all tests in the first year post-CART19 infusion are 
negative.