Conditions: Smoldering Multiple Myeloma
Keywords: Smoldering Multiple Myeloma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
This research study is evaluating a new drug called "nivolumab" as a possible treatment for smoldering multiple myeloma in order to prevent or postpone development of active multiple myeloma.

\- Patients with smoldering multiple myeloma do not have symptoms but are at risk for progressing to active multiple myeloma. Multiple myeloma is a cancer of the plasma cell, which is an important part of the immune system. Patients with active multiple myeloma generally require treatment.

Detailed description:
* This research study is a Phase II clinical trial, which tests the effectiveness of an investigational drug(s). The investigational drugs used in this research study are;

  * nivolumab
  * lenalidomide
  * dexamethasone.
* Preliminary experience suggests that the combination of lenalidomide and dexamethasone may prevent or postpone smoldering multiple myeloma (SMM) from becoming active multiple myeloma. The purpose of this research study is to determine if the addition of nivolumab may improve the rate of prevention in combination with lenalidomide and dexamethasone.
* "Investigational" means that the FDA (the U.S. Food and Drug Administration) has not approved the combination of nivolumab, lenalidomide and dexamethasone as a treatment regimen.
* Lenalidomide is an immunomodulatory drug derived from thalidomide. Lenalidomide works by stopping blood flow to your cancer cells and signaling your cancer cells to die off. The FDA has approved lenalidomide for the treatment of many types of cancer including multiple myeloma, and myelodysplastic syndromes.
* Dexamethasone, also FDA approved, is a type of steroid and is usually combined with other chemotherapy for the treatment of blood cancers, such as myeloma and leukemias.
* Nivolumab is approved by the FDA for some lung cancers, some skin cancers, some kidney cancers, and Hodgkin lymphoma. It is currently being evaluated for use in the treatment of several other types of cancers. Nivolumab may kill or stop cancer cells from growing by blocking a signal in the cells allowing the immune system to fight the cancer. This drug is a human monoclonal antibody, which is a molecule that is made in a laboratory that is designed to act identically to cells in the immune system.

Arms:
arm 1: * A treatment cycle is defined as 28 consecutive days.
* Participants will receive 6 cycles of induction therapy followed by 6 cycles of maintenance therapy with lower doses of lenalidomide and no dexamethasone for a total of 12 months.

Interventions: intervention 1: Nivolumab intervention 2: Lenalidomide intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Intravenous, predetermined dosage, Days 1 and 15 during cycles 1-12 and intervention 2: Oral, predetermined dosage, Days 1-21 of cycle 1-12 intervention 3: Oral, Days 1, 8, 15 of cycle 1-6

Protocol document:
Prot_SAP_000.pdf: 
 
 
Protocol Title: 
 
Phase II Trial of the PD-1 Antibody Nivolumab in Combination with Lenalidomide and 
Low Dose Dexamethasone in Patients with High-Risk Smoldering Multiple Myeloma 
 
 
NCT #: NCT02903381 
 
IRB Approval Date:  01/23/2018


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Local Protocol #:16-242 
BMS Protocol #: CA209-607 
TITLE: Phase II Trial of the PD-1 Antibody Nivolumab in Combination with 
Lenalidomide and Low Dose Dexamethasone in Patients with High-Risk Smoldering 
Multiple Myeloma 
Coordinating Center: 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02115 
Phone: 617-632-4198 
Fax: 617-582-8608 
Principal Investigator (PI):   Irene M. Ghobrial, MD 
Dana-Farber Cancer Institute 
Irene_Ghobrial@dfci.harvard.edu 
Statistician: 
Project Manager: 
Lorenzo Trippa 
Alexandra Savell 
Dana-Farber Cancer Institute 
Dana-Farber Cancer Institute 
ltrippa@partners.org 
AlexandraE_Savell@dfci.harvard.edu 
Chia-Jen Liu, MD, PhD 
Dana-Farber Cancer Institute 
Cliu35@partners.org  
Agent(s): Nivolumab, Bristol-Myers Squibb 
Lenalidomide, Celgene 
Dexamethasone, commercial 
IND #: 129255 
IND Holder: Irene M. Ghobrial, MD 
Original/ 11.0/ January 23rd 2018 


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CYCLES 1-6 
• 
• 
• 
Nivolumab days 1, 15 
Lenalidomide days 1-21 
Dexamethasone days 1, 8, 15 
Cycle Length: 28 days 
MAINTENANCE CYCLES 7-12 
• 
Nivolumab days 1,15 
• 
Lenalidomide days 1-21 
Cycle Length: 28 days 
Stop 
Therapy 
Event 
Monitoring 
up to 3 
years 
**At any time 
• 
Progression to Active Myeloma 
• 
Unacceptable Toxicity 
• 
Refusal 
• 
Alternative Therapy 
REGISTRATION 
SCHEMA 
**Disease Assessment: Day 1 of each cycle 


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Table of Contents 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ............................................................... 6 
PROTOCOL SUMMARY ........................................................................................................................ 10 
1. 
OBJECTIVES ................................................................................................................................... 13 
1.1 
STUDY DESIGN ........................................................................................................................... 14 
1.2 
NUMBER OF PATIENTS ............................................................................................................... 14 
1.3 
DURATION OF STUDY ................................................................................................................. 14 
1.4 
PRIMARY OBJECTIVES ................................................................................................................. 14 
1.5 
SECONDARY OBJECTIVES ........................................................................................................... 15 
2. 
BACKGROUND ............................................................................................................................... 15 
2.1 
MULTIPLE MYELOMA ................................................................................................................ 15 
2.2 
MGUS AND SMM CONSISTENTLY PRECEDES MULTIPLE MYELOMA ................................................... 16 
2.3 
MOLECULAR STUDIES IN MGUS AND SMM .............................................................................. 16 
2.4 
DEFINITION OF SMM AND MM .................................................................................................. 18 
2.5 
DEFINITIONS OF HIGH-RISK SMM ............................................................................................. 18 
2.6 
TREATMENT OF HIGH RISK SMM ............................................................................................... 19 
2.7 
NIVOLUMAB ............................................................................................................................... 19 
2.8 
PHARMACOKINETICS AND DRUG METABOLISM ......................................................................... 20 
2.9 
TRIAL RATIONALE ..................................................................................................................... 21 
2.10 
CORRELATIVE STUDIES BACKGROUND ....................................................................................... 21 
3. 
PARTICIPANT SELECTION ........................................................................................................ 24 
3.1 
ELIGIBILITY CRITERIA ................................................................................................................ 24 
3.2 
EXCLUSION CRITERIA ................................................................................................................. 27 
3.3 
INCLUSION OF WOMEN AND MINORITIES ................................................................................... 28 
4. 
REGISTRATION PROCEDURES ................................................................................................. 28 
4.1 
GENERAL GUIDELINES FOR DF/HCC AND DF/PCC INSTITUTIONS ............................................. 28 
4.2 
REGISTRATION PROCESS FOR DF/HCC AND DF/PCC INSTITUTIONS ......................................... 29 
4.3 
GENERAL GUIDELINES FOR OTHER INVESTIGATIVE SITES ......................................................... 29 
4.4 
REGISTRATION PROCESS FOR OTHER INVESTIGATIVE SITES ..................................................... 29 
5. 
TREATMENT PLAN ....................................................................................................................... 30 
5.1 
TREATMENT REGIMEN ............................................................................................................... 30 
5.2 
AGENT ADMINISTRATION........................................................................................................... 31 
5.3 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES .......................... 33 
5.4 
MANAGEMENT OF CLINICAL EVENTS ......................................................................................... 34 
5.5 
CRITERIA FOR TAKING A PARTICIPANT OFF PROTOCOL THERAPY ............................................ 36 
5.6 
DURATION OF FOLLOW UP ......................................................................................................... 37 
5.7 
CRITERIA FOR TAKING A PARTICIPANT OFF STUDY .................................................................. 37 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................................. 38 
6.1 
RECOMMENDED CRITERIA FOR BEGINNING OR DELAYING A SUBSEQUENT TREATMENT CYCLE 
38 
6.2 
NIVOLUMAB ............................................................................................................................... 38 
6.3 
LENALIDOMIDE .......................................................................................................................... 41 
6.4 
DEXAMETHASONE ...................................................................................................................... 46 
6.5 
DOSE DELAY GUIDELINES ......................................................................................................... 47 


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7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ........................................ 48 
7.1 
DEFINITIONS ............................................................................................................................... 48 
7.2 
EXPECTED TOXICITIES ............................................................................................................... 49 
7.3 
ADVERSE EVENT CHARACTERISTICS ......................................................................................... 52 
7.4 
EXPEDITED ADVERSE EVENT REPORTING .................................................................................. 52 
7.5 
DF/HCC EXPEDITED REPORTING GUIDELINES ........................................................................... 52 
7.6 
EXPEDITED REPORTING TO THE FOOD AND DRUG ADMINISTRATION (FDA) ............................ 55 
7.7 
EXPEDITED REPORTING TO BRISTOL-MYERS SQUIBB (BMS) .................................................... 55 
7.8 
EXPEDITED REPORTING TO HOSPITAL RISK MANAGEMENT ...................................................... 55 
7.9 
ROUTINE ADVERSE EVENT REPORTING ..................................................................................... 55 
8. 
PHARMACEUTICAL INFORMATION ....................................................................................... 56 
8.1 
NIVOLUMAB ............................................................................................................................... 56 
8.2 
LENALIDOMIDE .......................................................................................................................... 59 
8.3 
DEXAMETHASONE ...................................................................................................................... 60 
9. 
BIOMARKER, CORRELATIVE, MRD ASSESSMENT AND SPECIAL STUDIES ............... 61 
9.1 
MINIMAL RESIDUAL DISEASE ASSESSMENT (MRD) ................................................................... 62 
9.2 
BONE MARROW ASPIRATE SAMPLES ......................................................................................... 64 
9.3 
PERIPHERAL BLOOD SAMPLES ................................................................................................... 66 
9.4 
BUCCAL SWAB SAMPLES ........................................................................................................... 67 
10. 
STUDY CALENDAR ................................................................................................................... 68 
11. 
MEASUREMENT OF EFFECT ................................................................................................. 69 
11.1 
DEVELOPMENT OF SYMPTOMATIC DISEASE ............................................................................... 69 
11.2 
ANTITUMOR EFFECT .................................................................................................................. 69 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ................................................... 76 
12.1 
DATA REPORTING ...................................................................................................................... 76 
12.2 
DATA SAFETY MONITORING ...................................................................................................... 77 
13. 
STATISTICAL CONSIDERATIONS ........................................................................................ 77 
13.1 
STUDY DESIGN/ENDPOINTS........................................................................................................ 77 
13.2 
SAMPLE SIZE, ACCRUAL RATE AND STUDY DURATION ............................................................. 78 
13.3 
STRATIFICATION FACTORS ......................................................................................................... 78 
13.4 
INTERIM MONITORING PLAN ...................................................................................................... 78 
13.5 
STOPPING RULE FOR SAFETY ..................................................................................................... 78 
14. 
PUBLICATION PLAN ................................................................................................................ 79 
15. 
REFERENCES ............................................................................................................................. 80 
APPENDIX A: PERFORMANCE STATUS CRITERIA ...................................................................... 85 
APPENDIX B: SPECIMEN COLLECTION SCHEDULE ................................................................... 86 
APPENDIX C: SPECIMEN REQUISITION ......................................................................................... 87 
APPENDIX D: MANAGEMENT ALGORITHMS FOR ENDOCRINOPATHY, 
GASTROINTESTINAL, HEPATIC, RENAL, SKIN, NEUROLOGICAL, AND PULMONARY 
ADVERSE EVENTS DUE TO NIVOLUMAB ...................................................................................... 88 
APPENDIX E: DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER DATA AND 
SAFETY MONITORING PLAN ............................................................................................................. 93 
1. 
INTRODUCTION ............................................................................................................................ 96 
1.1 
PURPOSE ..................................................................................................................................... 96 


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1.2 
MULTI-CENTER DATA AND SAFETY MONITORING PLAN DEFINITIONS ..................................... 96 
2. 
GENERAL ROLES AND RESPONSIBILITIES .......................................................................... 97 
2.1 
DF/HCC SPONSOR ............................................................................................................................................... 97 
2.2 
COORDINATING CENTER ............................................................................................................ 97 
2.3 
PARTICIPATING INSTITUTION ..................................................................................................... 98 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ........................................ 98 
3.1 
PROTOCOL DISTRIBUTION .......................................................................................................... 99 
3.2 
PROTOCOL REVISIONS AND CLOSURES ...................................................................................... 99 
3.3 
INFORMED CONSENT REQUIREMENTS ........................................................................................ 99 
3.4 
IRB DOCUMENTATION ............................................................................................................. 100 
3.5 
IRB RE-APPROVAL ............................................................................................................................................ 100 
3.6 
PARTICIPANT CONFIDENTIALITY AND AUTHORIZATION STATEMENT ....................................... 100 
3.7 
DF/HCC MULTI-CENTER PROTOCOL REGISTRATION POLICY .................................................. 100 
3.8 
DF/HCC PROTOCOL CASE NUMBER ........................................................................................ 101 
3.9 
SAFETY ASSESSMENTS AND TOXICITY MONITORING .............................................................. 103 
3.10 
DATA MANAGEMENT ............................................................................................................... 103 
4. 
REQUISITIONING INVESTIGATIONAL DRUG ..................................................................... 104 
5. 
MONITORING: QUALITY CONTROL ..................................................................................... 104 
5.1 
ONGOING MONITORING OF PROTOCOL COMPLIANCE .............................................................. 104 
5.2 
MONITORING REPORTS ............................................................................................................ 105 
5.3 
ACCRUAL MONITORING ............................................................................................................ 105 
6. 
AUDITING: QUALITY ASSURANCE ........................................................................................ 105 
6.1 
DF/HCC INTERNAL AUDITS ........................................................................................................................... 106 
6.2 
AUDIT NOTIFICATIONS ............................................................................................................. 106 
6.3 
AUDIT REPORTS ........................................................................................................................ 106 
6.4 
PARTICIPATING INSTITUTION PERFORMANCE ........................................................................... 106 


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Common abbreviations used in oncology protocols are provided below. Program-specific or 
protocol-specific abbreviations must be added to this list, and unnecessary abbreviations 
removed, as applicable. Abbreviations that are retained should not be changed. 
Abbreviation 
Term 
5-HT3 
5-hydroxytryptamine 3 serotonin receptor 
AE 
adverse event 
ALL 
acute lymphoblastic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myelogenous leukemia 
ANC 
absolute neutrophil count 
API 
active pharmaceutical ingredient 
aPTT 
activated partial thromboplastin time 
Ara-C 
Cytarabine 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC24 hr 
area under the plasma concentration versus time curve from zero to 24 hours 
AUCinf 
area under the plasma concentration versus time curve from zero to infinity 
AUCτ 
area under the plasma concentration versus time curve from zero to next dose 
BCRP 
breast cancer resistance protein 
hCG 
beta-human chorionic gonadotropin 
BID 
bis in die; twice a day 
BM 
bone marrow 
BSA 
body surface area 
BUN 
blood urea nitrogen 
BZD 
Benzodiazepines 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CL 
clearance, IV dosing 
CLP 
plasma clearance 
CLTotal 
total clearance 
Cmax 
single-dose maximum (peak) concentration 
CNS 
central nervous system 


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Abbreviation 
Term 
CO2 
carbon dioxide 
CR 
complete remission 
CRM 
continual reassessment method 
CRP 
C-reactive protein 
CSF-1R 
colony-stimulating factor 1 receptor 
CT 
computed tomography 
Ctrough 
single-dose end of dosing interval (trough) concentration 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DLT 
dose-limiting toxicity 
DME 
drug metabolizing enzymes 
DNA 
deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
End of Study (visit) 
EOT 
End of Treatment (visit) 
EU 
European Union 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony stimulating factor 
GGT 
gamma glutamyl transferase 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practices 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
Hct 
Hematocrit 
HDPE 
high-density polyethylene 
hERG 
human ether-à-go-go related gene 
HIV 
human immunodeficiency virus 


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Abbreviation 
Term 
HNSTD 
highest nonseverely toxic dose 
IB 
Investigator’s Brochure 
IC50 
concentration producing 50% inhibition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
intravenous; intravenously 
IVRS 
interactive voice response system 
Ki 
inhibition constant 
KPS 
Karnofsky Performance Status 
LDH 
lactate dehydrogenase 
LFT 
liver function test(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
Millennium 
Millennium Pharmaceuticals, Inc., and its affiliates 
MRI 
magnetic resonance imaging 
MRU 
medical resource utilization 
MTD 
maximum tolerated dose 
MUGA 
multiple gated acquisition (scan) 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NPO 
nothing by mouth 
NYHA 
New York Heart Association 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease (disease progression) 
Pgp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PO 
per os; by mouth (orally) 
PR 
partial response 
PRO 
patient-reported outcome 
PSA 
prostate-specific antigen 


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Abbreviation 
Term 
QD 
quaque die; each day; once daily 
QID 
quater in die; 4 times a day 
QOD 
quaque altera die; every other day 
QOL 
quality of life 
QTc 
rate-corrected QT interval (millisec) of electrocardiograph 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SC 
Subcutaneous 
SD 
stable disease 
SmPC 
Summary of Product Characteristics 
t1/2 
terminal disposition half-life 
TGI 
tumor growth inhibition 
Tmax 
single-dose time to reach maximum (peak) concentration 
UK 
United Kingdom 
ULN 
upper limit of the normal range 
US 
United States 
Vz 
volume of distribution in the terminal phase 
WBC 
white blood cell 
WHO 
World Health Organization 


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PROTOCOL SUMMARY 
Study Title: Phase II Trial of the PD-1 Antibody Nivolumab in Combination with 
Lenalidomide and Low Dose Dexamethasone in Patients with High-Risk Smoldering 
Multiple Myeloma 
Phase: II 
Number of Patients: 41 
Study Objectives: 
Primary Objectives 
To determine the proportion of high risk smoldering multiple myeloma patients 
who are progression free at 2 years after receiving Nivolumab and lenalidomide+ 
dexamethasone combination therapy 
Secondary Objectives 
• To assess the response rate of the combination in these patients 
• To assess time to progression and progression free survival 
• To assess duration of response 
• To assess the safety of the combination 
• To examine molecular evolution of the tumor cells 
• To determine the role of immune cells in the progression of smoldering MM 
• To determine minimal residual disease (MRD) 
Overview of Study Design: 
This is a single arm phase II study using the combination of Nivolumab and lenalidomide 
+ low dose dexamethasone in patients with high risk smoldering multiple myeloma. The 
study is designed to examine novel therapeutic immunotherapy combinations in patients 
with smoldering MM. The trial will include a safety run in of 10 patients. If three of the 
ten patients experience a serious, unexpected adverse event during their first cycle of 
therapy, the study will be suspended temporarily until further safety review. 
Study Population: 
SELECT INCLUSION CRITERIA 
• Age  18 years. 
• Must meet criteria of high risk smoldering MM as described with one of the below 
criteria: 
o Bone marrow clonal plasma cells ≥10% and any one or more of the following: 
▪ Serum M protein ≥3.0g/dL 
▪ IgA SMM 
▪ Immunoparesis with reduction of two uninvolved immunoglobulin 
isotypes 
▪ Serum involved/uninvolved free light chain ratio ≥8 (but less than 


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100) 
▪ Progressive increase in M protein level (Evolving type of SMM)† 
▪ Bone marrow clonal plasma cells 50-60% 
▪ Abnormal plasma cell immunophenotype (≥95% of bone marrow 
plasma cells are clonal) and reduction of one or more uninvolved 
immunoglobulin isotypes 
* All patients should have four or six color flow cytometry performed on the baseline 
bone marrow sample, as feasible. Patients evaluated for eligibility by Spanish Criteria 
must have their result confirmed by four color flow cytometry. If four or six color flow 
cytometry is not available at the site, the baseline bone marrow must be sent to Dana- 
Farber Cancer Institute to confirm eligibility prior to enrollment. 
▪ High risk cytogenetics or FISH including t (4;14) or del 17p or 1q 
gain 
▪ Increased circulating plasma cells 
▪ MRI with diffuse abnormalities or 1 focal lesion 
▪ PET-CT with focal lesion with increased uptake without underlying 
osteolytic bone destruction 
† Increase in serum monoclonal protein by ≥10% on two successive evaluations within a 
6 month period 
• No evidence of CRAB criteria* or new criteria of active MM which including the 
following: 
o Increased calcium levels (corrected serum calcium >0.25 mmol/dL {1mg/dL) 
above the upper limit of normal or >2.75 mmol/dL {11mg/dL}); 
o Renal insufficiency (attributable to myeloma); 
o Anemia (Hb 2g/dL below the lower limit of normal or <10g/dL); 
o Bone lesions (lytic lesions or generalized osteoporosis with compression 
fractures) 
o No evidence of the following new criteria for active MM including the 
following: Bone marrow plasma cells ≥60%, Serum involved/uninvolved FLC 
ratio ≥100*, and MRI with more than one focal lesion (*except for light chain 
smoldering MM) 
* Participants with CRAB criteria that are attributable to conditions other than the disease 
under study may be eligible 
• 
ECOG Performance Status (PS) 0, 1, or 2. 
• 
The following laboratory values obtained  21 days prior to registration: 
o ANC  1000/L 
o PLT  50,000/L 
o Total bilirubin ≤ 1.5 mg/dL (If total is elevated check direct and if normal 
patient is eligible.) 
o AST  3 x institutional upper limit of normal (ULN) 
o ALT  3 x institutional upper limit of normal (ULN) 


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SELECT EXCLUSION CRITERIA 
• 
Symptomatic Multiple Myeloma or any evidence of CRAB criteria. Any prior therapy 
for Multiple Myeloma should also be excluded Bisphosphonates are not excluded. 
Patients who received prior therapy due to being incorrectly diagnosed as having overt 
multiple myeloma may not be excluded after discussion with the overall PI. 
• 
Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary 
therapy considered investigational. Prior therapy with bisphosphonate is allowed. 
Prior radiation therapy to a solitary plasmacytoma is allowed. 
• 
Autoimmune disease: Patients with a history of inflammatory bowel disease, 
including ulcerative colitis and Crohn’s Disease, are excluded from this study, as 
are patients with a history of symptomatic disease (eg, rheumatoid arthritis, systemic 
progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune 
pneumonitis, autoimmune vasculitis [eg, Wegener’s Granulomatosis]) and motor 
neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and 
Myasthenia, Gravis). Patients with Hashimoto’s thyroiditis are eligible to go on study. 
The Overall PI must be consulted to discuss any other autoimmune disorders not listed 
here to determine if the patient is eligible for the trial. 
Duration of Study: 5 years 


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1. OBJECTIVES 
Smoldering Multiple Myeloma (SMM) is a heterogeneous disease entity that includes patients 
who have a disease burden that is higher than that in patients with MGUS but who are not yet 
symptomatic1. The term SMM was first described by Greipp and Kyle et al in 19802 and was 
followed by many other descriptions terming it indolent MM3, or Durie Salmon Stage I4. It was 
not until 2003 that the International Myeloma Working Group (IMWG) described the exact 
definition of this disease. SMM was defined as serum M-protein ≥3 g/L and/or ≥10% 
monoclonal plasma cells in the bone marrow (BM), Table 15,6. While the incidence and 
prevalence of SMM in the population is not well defined, it has been estimated to represent 
approximately 8% to 20% of patients within the MM spectrum1. 
Most recently, the IMWG further re-defined the group of patients who meet criteria for treatment 
and included asymptomatic SMM patients who are likely going to have end-organ damage in the 
near future, previously defined as “ultra-high risk smoldering myeloma”. These include patients 
with bone marrow plasmacytosis ≥60% 7; an abnormal FLC-ratio ≥100 (involved kappa) or 
<0.01 (involved lambda) 8: and/or 2 or more focal bone marrow lesions detected by functional 
imaging including PET-CT and/or MRI 9,10. These patients should therefore not be considered 
SMM anymore but rather re-defined as patients with myeloma-defining events that require 
therapy. 
The overall risk of progression of SMM is 10% per year for the first 5 years and 3% per year for 
the next 5 years11. The most common factors used to stratify patients with SMM are the Mayo 
Clinic criteria11,12 and the Spanish PETHEMA criteria13. The Mayo Clinic criteria are based on 
the tumor burden defined by the serum protein level (by serum protein electrophoresis or light 
chain ratio) or by the percent bone marrow plasma cell involvement (see Table 2 )11,12, leading to 
risks of progression at 5 years of 25% for low risk, 51% for intermediate risk and 76% for high 
risk individuals who have 1, 2 or 3 risk factors respectively11,12. The risk stratification of the 
PETHEMA group is based on identifying the number of clonal plasma cells in the bone marrow 
by flow cytometry (≥95% ratio of abnormal neoplastic plasma cells to normal plasma cells) and 
reduction of uninvolved immunoglobulins, with 5 year-risk of progression being 4%, 46%, and 
72% for patients with 0, 1 or 2 risk factors, respectively13. 
The paradigm of therapy in Smoldering Multiple Myeloma (SMM) is changing as we develop 
better therapeutic agents that prevent end organ damage and improve survival of patients with 
multiple myeloma (MM)14-16. Indeed, recent studies of a phase III trial of lenalidomide and 
dexamethasone versus placebo showed improved response, progression free survival and overall 
survival in patients with high risk smoldering MM compared to placebo control17. Therefore, 
there is a need to examine novel therapeutic combinations in patients with high risk smoldering 
MM. 
Our overarching hypothesis is that early therapeutic interventions in patients with 
smoldering MM will prevent/delay progression to overt MM. We will examine the in vivo 
activity and safety of nivolumab and lenalidomide in patients with high-risk SMM. 


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14 
1.1 Study Design 
This is a phase II study using the combination of Nivolumab and lenalidomide + low dose 
dexamethasone in patients with high-risk smoldering multiple myeloma. The trial will include a 
safety run in of 10 patients. If three of the ten patients experience a serious, unexpected adverse 
event during their first cycle of therapy, the study will be suspended temporarily until further 
safety review. If any one of the study medications is permanently discontinued for any reason 
including toxicity, or FDA mandate, the patient may remain on the study at the discretion of the 
principal investigator. 
** As of September 2017, the trial has been put on partial clinical hold by the Food and Drug 
Administration: all patients are to discontinue nivolumab indefinitely, and no additional patients 
will be accrued to the trial. Participants may elect to remain on lenalidomide/dexamethasone or 
lenalidomide therapy alone for disease control after discussion with the overall PI. 
1.2 Number of Patients 
A total of 41 patients will be included on this study. Enrollment includes patients who receive 
the first day of therapy. 
1.3 Duration of Study 
A treatment cycle is defined as 28 consecutive days. 
Patients will receive 6 cycles of induction therapy followed by 6 cycles of maintenance therapy 
with lower doses of lenalidomide and no dexamethasone for a total of 12 months. 
During maintenance, if a patient experiences biochemical progression (≥ 25% increase and an 
absolute increase of ≥ 0.5g/dL from their nadir in their serum or urine m-spike or FLC with no 
CRAB features attributable to MM progression) high-dose dexamethasone may be re-added to 
the combination at a dose of 40mg oral given on days 1, 8, and 15 of a 28 day cycle after 
discussion with the overall PI. 
For all treatment cycles a +/- 7 day window is allowed for Nivolumab. For hold and delay 
guidelines for lenalidomide and dexamethasone, please refer to Table 17. The treatment plan is 
designed to be administered on an outpatient basis, however if necessary, may be given as 
inpatient. 
Patients will be followed for up to three years after discontinuation of therapy. 
1.4 Primary Objectives 
• To determine the proportion of high risk smoldering multiple myeloma patients who are 
progression free at 2 years after receiving Nivolumab and lenalidomide + dexamethasone 
combination therapy 


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1.5 Secondary Objectives 
• To assess the response rate of the combination in these patients 
• To assess time to progression and progression free survival 
• To assess duration of response 
• To assess the safety and tolerability of the combination 
• To examine molecular evolution of the tumor cells 
• To determine the role of immune cells in the progression of smoldering MM 
• To determine minimal residual disease (MRD) by Adaptive’s LymphoSIGHT sequencing 
platform. 
2. BACKGROUND 
2.1 Multiple Myeloma 
Multiple myeloma is a plasma cell neoplasm characterized by multifocal proliferation of clonal, 
long-lived plasma cells associated with an overproduction of monoclonal gammaglobulin 18. In 
2010 the International Myeloma Working Group (IMWG) defined monoclonal gammopathy of 
undetermined significance (MGUS) by the presence of serum M-protein < 3g/dL, clonal plasma 
cell population in the bone marrow < 10%, and the absence of end-organ damage such as 
hypercalcemia (serum calcium ≥ 11.5 mg/dL), renal insufficiency (serum creatinine ≥ 2 mg/dL), 
anemia (hemoglobin value below the lower limit of normal by more than 2 g/dL or hemoglobin 
value < 10 g/dL) and lytic bone lesions (CRAB features) that can be attributed to the plasma cell 
proliferative disorder 19. Smoldering multiple myeloma was defined by the presence of serum M- 
protein ≥ 3 g/dL or IgA> 2g/ dL or urinary monoclonal protein > 500 mg/ dL and/or clonal bone 
marrow plasma cells ≥ 10% and the absence of CRAB features clinically. 
In a large population based study in Olmsted County, MN, Kyle et al. analyzed serum samples of 
more than 75% of residents, 50 years or older, within the county 20. They identified MGUS in 
694 of 21,463 patients tested (3.2%). While the overall prevalence was noted to be 3.2% (95 % 
CI, 3.0 to 3.5), there was a significant age dependent increase in both sexes with the prevalence 
among persons 80 years of age or older 4 times as high as among those 50-59 years of age. Age- 
adjusted rates were higher in men (4.0 %, 95% C.I., 3.5 to 4.4) than in women (2.7%, 95% C.I., 
2.4 to 3.0). In a subsequent study on a majority of the same patients from Olmsted County, 
Dispenzieri, et al, used the free light chain assay (FREELITE) and showed that 0.8% of people 
older than 50 years had light chain-MGUS. The total MGUS prevalence including the light 
chain-MGUS cases was noted at 4.2% (95% C.I., 3.9 to 4.5%) 21. A limitation of both these 
studies was that 97.3% of the residents of Olmsted County were white. 
For SMM patients a M-protein ≥ 3 g/dL, a FLC ratio outside the range of 0.125 to 8, and ≥ 10% 
plasma cells in the bone marrow are considered as adverse factors in this model 11,12. The 5-year 
rate of progression in patients with 1, 2 and 3 risk factors was 25%, 51% and 76% respectively. 
The time to progression with these risk factors was 10, 5.1 and 1.9 years respectively. Recently 


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Rajkumar et al have proposed that SMM with >60% plasma cells progress to multiple myeloma 
within 2 years in 95% cases and should be treated at diagnosis even in the absence of symptoms.7 
Table 1: Mayo Clinic model for risk factors and % risk of progression for smoldering MM 
Model 
No. of Risk 
Factors 
5-Year Progression % 
Time to Progression 
(in years) 
Mayo Clinic Model 
1 
25 
10 
Risk Factors: 
2 
51 
5.1 
• 
M-protein ≥ 3.0g/dL 
• 
≥10% plasma cells in the BM 
• 
FLC ratio outside the range of 
0.125 to 8 
3 
76 
1.9 
2.2 MGUS and SMM consistently precedes multiple myeloma 
Since the early description of monoclonal gammopathy of undermined significance it was known 
that some cases of MGUS progressed to symptomatic myeloma but it was not clear whether all 
cases of myeloma are preceded by MGUS. In a study of more than 77,000 individuals, 55 to 74 
years of age, from a cancer screening trial, Landgren et al found 71 patients who developed 
multiple myeloma22. They performed serum protein electrophoresis, immunofixation and kappa- 
lambda free light chain assay on prediagnostic samples in these patients. The study showed that 
patients who eventually developed multiple myeloma consistently had MGUS in the years 
preceding development of multiple myeloma. Interestingly, in half the patients, there was a 
steady increase in the M-protein before the development of symptomatic myeloma, while in the 
other half the M-protein stayed fairly stable. A second study by Weiss et al found a monoclonal 
gammopathy in 27 of 30 patients (90%) in sera 2 or more years before the diagnosis of myeloma 
23. 
2.3 Molecular studies in MGUS and SMM 
A recent study using SNP-based arrays compared MGUS, SMM and MM samples 24. They 
found copy number abnormalities in all stages. The incidence of genomic imbalance did increase 
from a median of 5/case for MGUS to 7.5/case for SMM and 12/case for MM. The study also 
noted certain genomic changes that were exclusive to MM including 11q and 21q gains and 16q 
and 22q deletions. Interestingly, the study found these abnormalities in a small subclone in 
MGUS patients indicating that most if not all of the chromosomal changes may be already 
present at the MGUS state. These findings also support a possible role of ‘clonal tides’ in the 
evolution from precursor state to symptomatic myeloma as explained below. Two major 
pathways have been proposed as the early oncogenic events in the development of the myeloma 


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cell based on chromosomal abnormalities noted in MGUS, SMM and MM- the non-hyperdiploid 
and the hyperdiploid pathway. The main cytogenetic changes that have been observed in MGUS 
and SMM are indicated in the table below. 
Table 2: Cytogenetic abnormalities in MGUS, SMM and MM 
Cytogenetic Abnormality 
Involved Oncogene 
MGUS% 
SMM% 
MM% 
IgH Translocations 
See below 
40-50% 
40-50% 
50-70% 
t(11;14)(q13;q32) 
CCND1 
(Cyclin D1) 
10-25% 
10-25% 
15% 
t(4;14)(p16;q32) 
FGFR3 and MMSET 
2-9% 
3-13% 
10-15% 
t(14;16)(q32;q23) 
C-MAF 
2-5% 
2-5% 
2-5% 
Other IgH Translocations 
• t(6;14)(p21;q32) 
• t(14;20)(q32;q11) 
• etc. 
CCND3 (Cyclin D3), 
MAFB, etc. 
6-10% 
1-10% 
10% 
13q Deletion 
Unknown 
25-50% 
35-50% 
40-50% 
Hyperdiploidy 
Unknown 
40-50% 
40-50% 
40-50% 
Other molecular studies in MGUS and SMM included microRNA studies. MicroRNAs are single 
stranded RNA molecules that regulate gene expression posttranscriptionally and are being 
implicated in a large number of cancers 25. A study comparing miRNA profiles of normal PC, 
MGUS, SMM and MM found overexpression of mir-21, mir-106~25 and mir181a and mir181b 
in MGUS and MM compared to normal PCs 26. The study also found mir-32 and mir17~92 
clusters to be upregulated only in MM and not in any other forms. Mir 17~92 and Mir 106~25 
are known to have a role in B cell development as well as B cell lymphomas targeting PTEN, 
E2F1, Bcl2 and BIM 25,26. The mir17 cluster has been shown to upregulated by the transcription 
factor c-Myc, which is considered a late event in myeloma progression 27-29. 
With the advances in deep sequencing techniques, we are now able to study the whole genome of 
myeloma cells and compare that to the normal human genome. Several studies employing these 
techniques are beginning to shift our understanding of the pathogenesis of myeloma. These 
studies have revealed that the previously held dogma that cancer progression occurred through a 
linear cumulative acquisition of mutational changes may be too simplistic. A new model of 
clonal heterogeneity is beginning to emerge 30. In fact tumor evolution may indeed proceed like 
Darwinian evolution with tumor progression involving a branching process with coexistent 
clonal heterogeneity. In this model various subclones exist in a dynamic equilibrium, competing 
for limited resources and over time the subclonal populations ebb and flow under environmental 


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evolutionary pressures with alternating dominance of various subclones at different time points31- 
35. Most of these studies were done on patients with symptomatic multiple myeloma and as 
similar studies involving MGUS and SMM emerge, our understanding of the pathogenesis of 
myeloma from these precursor states will continue to evolve. It is possible that the progression 
from myeloma precursor state to symptomatic disease also involves ‘clonal tides’ with expansion 
of a subclone leading to progression. Several previous studies have identified clonal 
heterogeneity in a subset of MGUS patients24,36,37. 
2.4 Definition of SMM and MM 
The diagnosis of smoldering (asymptomatic) multiple myeloma (SMM)38,39 is based on: 
• Serum monoclonal protein (IgG, IgM, IgD or IgA) ≥3 g/dL or urinary monoclonal 
protein ≥500 mg per 24 h and/or clonal bone marrow plasma cells (BPMC) 10–60%. 
• Absence of myeloma defining events or amyloidosis 
• No evidence of the following CRAB criteria or other Myeloma defining events (MDE): 
o Increased calcium levels (corrected serum calcium >0.25 mmol/dL above the 
upper limit of normal or >2.75 mmol/dL) related to MM 
o Renal insufficiency (attributable to MM) 
o Anemia (Hb 2g/dL below the lower limit of normal or <10g/dL) related to MM 
o Bone lesions (lytic lesions or generalized osteoporosis with compression 
fractures) 
New MDE criteria that indicates overt MM and not SMM38,39 
The following criteria are now incorporated with the CRAB criteria to indicate that patients meet 
criteria for therapy as symptomatic or overt MM: 
• Bone marrow plasma cells >60% 
• Serum involved/uninvolved FLC ratio ≥100mg/L, provided the absolute level of the 
involved free light chain is at least 100 mg/L and repeated twice (except for monoclonal 
light chain smoldering MM and for those with stable serum light chains for 6 months.) 
• MRI with two or more focal lesion that is at least 5 mm or greater in size 
2.5 Definitions of High-Risk SMM 
Based on the new defined high risk criteria for smoldering myeloma based on 40 as described in 
table 3 below: 
Table 3 Bone marrow clonal plasma cells ≥10% and any one or more of the following: 
Serum M protein ≥3.0g/dL 
IgA SMM 
Immunoparesis with reduction of two uninvolved immunoglobulin isotypes 
Serum involved/uninvolved free light chain ratio ≥8 (but less than 100) 
Progressive increase in M protein level (Evolving type of SMM)† 
Bone marrow clonal plasma cells 50-60% 


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19 
Abnormal plasma cell immunophenotype (≥95% of bone marrow plasma cells are clonal) and 
reduction of one or more uninvolved immunoglobulin isotypes 
t (4;14) or del 17p or 1q gain 
Increased circulating plasma cells 
MRI with diffuse abnormalities or 1 focal lesion 
PET-CT with focal lesion with increased uptake without underlying osteolytic bone destruction 
Monoclonal light chain excretion of 500mg/24 hours or higher* 
† Increase in serum monoclonal protein by ≥10% on two successive evaluations within a 6 
month period 
* Monoclonal Light Chain Smoldering 
2.6 Treatment of high risk SMM 
In a randomized open-label phase 3 trial 17, 119 patients with high-risk smoldering myeloma 
were randomized to treatment or observation. Patients in the treatment group received an 
induction regimen (lenalidomide at a dose of 25 mg per day on days 1 to 21, plus dexamethasone 
at a dose of 20 mg per day on days 1 to 4 and days 12 to 15, at 4-week intervals for nine cycles), 
followed by a maintenance regimen (lenalidomide at a dose of 10 mg per day on days 1 to 21 of 
each 28-day cycle for 2 years). The primary end point was time to progression to symptomatic 
disease. Secondary end points were response rate, overall survival, and safety. After a median 
follow-up of 40 months, the median time to progression was significantly longer in the treatment 
group than in the observation group (median not reached vs. 21 months; hazard ratio for 
progression, 0.18; 95% confidence interval [CI], 0.09 to 0.32; P<0.001). The 3-year survival rate 
was also higher in the treatment group (94% vs. 80%; hazard ratio for death, 0.31; 95% CI, 0.10 
to 0.91; P=0.03). A partial response or better was achieved in 79% of patients in the treatment 
group after the induction phase and in 90% during the maintenance phase. Toxic effects were 
mainly grade 2 or lower. Early treatment for patients with high-risk smoldering myeloma delays 
progression to active disease and increases overall survival. (NCT00480363). 
2.7 Nivolumab 
2.7.1 Preclinical Experience 
Please refer to the current nivolumab Investigator’s Brochure (IB) and Safety Management 
Attachment located in Appendix D 
2.7.2 Clinical Experience 
Nivolumab is a fully human monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) 
that targets the PD-1 cell surface membrane receptor. Nivolumab inhibits the interaction of PD- 
1 with its ligands, PD-L1 and PD-L2, resulting in enhanced T-cell proliferation and interferon- 
gamma (IFN-γ) release in vitro. 
Nivolumab has demonstrated clinical activity as monotherapy in subjects with a variety of 
malignancies including lung, melanoma, renal cell carcinoma and in lymphomas, responses have 
been reported for diffuse large B-cell lymphoma, follicular lymphoma, and Hodgkin’s 


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lymphoma. (See IB for details). 
Approximately 4,000 subjects have received nivolumab monotherapy in single- or multiple-dose 
Phase 1/2/3 studies or studies with nivolumab in combination with other therapeutics 
(ipilimumab, cytotoxic chemotherapy, anti angiogenics, and targeted therapies). The safety 
profile is generally consistent across completed and ongoing clinical trials, with no maximum 
tolerated dose (MTD) reached at any monotherapy dose tested up to 10 mg/kg. There was no 
pattern in the incidence, severity, or causality of AEs to nivolumab dose level. The safety profile 
of nivolumab combination therapy varies with the agent combined with nivolumab, but is 
generally consistent with the safety profiles observed with either agent alone and, in some cases, 
the frequency of AEs may be greater than that observed with either agent alone. For nivolumab 
monotherapy and combination therapy, most high-grade events were manageable with use of 
corticosteroids or hormone replacement therapy. 
2.8 Pharmacokinetics and Drug Metabolism 
2.8.1 Flat Dose Regimen 
The safety and efficacy of 240 mg Q2W flat dose of nivolumab is expected to be similar to 3 
mg/kg Q2W dosing regimen. Using the PPK model, exposure of nivolumab at 240 mg flat dose 
is identical to a dose of 3 mg/kg for subjects weighing 80 kg, which is the approximate median 
body weight in nivolumab clinical trials. Across the various tumor types in the clinical program, 
nivolumab has been shown to be safe and well tolerated up to a dose level of 10 mg/kg, and the 
relationship between nivolumab exposure produced by 3 mg/kg and efficacy and safety has been 
found to be relatively flat. Given the similarity of nivolumab PK across tumor types and the 
similar exposures predicted following administration of 240 mg flat dose compared to 3 mg/kg, 
it is expected that the safety and efficacy profile of 240 mg nivolumab will be similar to that of 3 
mg/kg nivolumab. Hence, a flat dose of 240 mg nivolumab is under investigation. 
2.8.2 Shorter Infusion Duration 
Establishing that nivolumab can be safely administered using a shorter infusion time (30 
minutes) is under investigation. Previous clinical studies of nivolumab monotherapy have used a 
60-minute infusion duration wherein, nivolumab has been safely administered up to 10 mg/kg 
over long treatment periods. Infusion reactions including high-grade hypersensitivity reactions 
have been uncommon across nivolumab clinical program. In CA209010, a dose association was 
observed for infusion site reactions and hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% at 2 
mg/kg and 18.5% at 10 mg/kg). All the events were Grade 1-2 and were manageable. An 
infusion duration of 30 minutes for 3 mg/kg nivolumab (30% of the dose provided at 10 mg/kg) 
is not expected to present any safety concerns compared to the prior experience at 10 mg/kg 
nivolumab dose infused over a 60-minute duration. Overall, a change in safety profile is not 
anticipated with 30-minute infusion of nivolumab. 
Additional information on the background and development of nivolumab can be found on the 
Nivolumab Investigator’s Brochure. 


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2.9 Trial Rationale 
Based on the activity of lenalidomide and dexamethasone in patients with SMM and based on 
the data that progression of tumors is based on evasion and suppression of the host immune 
system, we believe that the combination of a PD-1 inhibitor with lenalidomide will induce high 
responses and delay development of symptomatic MM in patients with high risk Smoldering 
MM. 
Patients who develop symptomatic disease will receive induction therapy with standard 
therapeutic options for multiple myeloma including combinations such as those of proteasome 
inhibitors, immunomodulators and steroids or cyclophosphamide, proteasome inhibitors and 
dexamethasone. 
2.9.1 Dexamethasone effect on immune response 
The use of dexamethasone in this study may blunt the immune response to Nivolumab. However, 
all prior studies of lenalidomide and dexamethasone in smoldering myeloma have used the 
combination of both agents. Therefore, to assess the true significance of adding Nivolumab to 
this combination, we will not omit dexamethasone from the regimen. In addition, recent studies 
in MM have shown that pulse dexamethasone used in our regimens of myeloma does not 
significantly blunt the immune response41. Moreover, recent studies in relapsed myeloma have 
shown preliminary strong activity of immune-mediated antibodies in combination with 
lenalidomide and dexamethasone. Moreover, we will monitor for immune cell numbers and 
checkpoint regulation on immune cells at the start of therapy and during therapy to define the 
effect of these agents on immune regulation. If patients cannot tolerate dexamethasone, then dose 
reductions will be permitted as described in dose reduction/modification sections. 
2.9.2 Stem Cell Mobilization and Collection 
Patients who are eligible for stem cell collection and who intend to go on to transplant will have 
the option to collect stem cells during the course of therapy on this trial at the time of best 
response (PR,VGPR, or CR or at investigator’s discretion) or after 6 cycles of induction therapy, 
however, collection may be done at any time during the study after discussion with the Overall 
PI. Institutional guidelines should be followed in regards to stem cell mobilization and 
collection. Patients should be mobilized as soon as possible after stopping study treatment. 
Patients may delay resuming treatment for up to 3 weeks after collection is complete. 
Plerixafor should be utilized as a mobilization agent primarily; however cyclophosphamide or 
other agents may be used at the investigator’s discretion. Based on data using combination 
therapies for induction, there have been no major concerns regarding stem cell collections after 
treatment with these agents. 
2.10 Correlative Studies Background 
2.10.1 DNA and RNA sequencing of tumor cells 


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The "clonal evolution" model of cancer emerged amid ongoing advances in technology, 
especially in recent years during which next generation sequencing has provided ever higher 
resolution pictures of the genetic changes in cancer cells and heterogeneity in tumors where 
tumor progression proceeds in a branching rather than in a linear manner, leading to substantial 
clonal diversity and coexistence of wide genetic heterogeneity42,43. The genomic complexity in 
MM was recently corroborated by massive parallel-sequencing studies displaying the lack of a 
universal driving mutation30. Recent studies have shown intraclonal heterogeneity that occurs at 
different stages of progression in MM31,32. Most recently, exome sequencing confirmed that the 
heterogeneity observed in the transformation from MGUS/SMM to MM is likely to be an 
essential feature of clonal evolution and disease progression44,45. Point mutations such as N-RAS, 
K-RAS, MYC up-regulation46, and gain or loss of chromosome 1q or 1p seem to correlate with 
disease progression from MGUS and SMM29. A progressive increase in the incidence of copy 
number abnormalities from MGUS to SMM and to MM has been recently observed47. 
We plan to perform exome sequencing and RNA sequencing studies on tumor cells obtained at 
the time of screening as well as from subsequent bone marrow biopsy samples to examine clonal 
heterogeneity, resistant clones at best response and at time of end of study or tumor progression. 
The hypothesis is that clonal evolution and the progression/response of different clones in 
response to immunotherapy would be critical to better understand clonal evolution in MM and 
help in the development of future therapeutic options for patients with MM. 
The tumor research samples will be collected at the time of scheduled bone marrow biopsies. 
From these samples, high quality DNA (for tumor cells) and RNA for both exome sequencing 
and RNA sequencing will be obtained. In brief, BM aspirates will be obtained after informed 
consent. The tumor cells will be collected using CD138+ bead selection (over 90% purity based 
on prior publications)30,31. For samples that have a small fraction of plasma cells, we will use 
flow sorting for CD138/CD38/CD56 and CD19-ve to obtain a pure malignant plasma cell 
population based on prior published markers of malignant plasma cells48. Germline DNA will 
also obtained from a buccal swab from all patients. 
2.10.2 Exome sequencing of tumor cells 
Whole-exome capture libraries will be constructed from 100ng of tumor and normal DNA 
followed by shearing, end repair, phosphorylation and ligation to barcoded sequencing adapters. 
The DNA will be size-selected to exonic hybrid capture using SureSelect v2 Exome bait 
(Agilent, CA). Samples will be multiplexed and sequenced on Illumina HiSeq flowcells with the 
goal of an average depth of coverage of 100x. The resulting data will be analyzed with the 
current Illumina pipeline, which generates data files (BAM files). The details of the current 
analysis pipeline are published elsewhere30,49. Briefly, somatic single nucleotide variants are 
determined using the MuTect algorithm50. Indels and translocations are determined by the 
algorithms IndelLocator and dRanger, respectively. The MutSig algorithm identifies genes in 
which the observed mutations are inconsistent with what would be expected at random51. To 
accurately assess the significance of mutations, MutSig takes into account several covariates, 
which influence the background mutation model. These include the expression level of genes 
(for which published gene expression data of MM samples can be used), and other gene 
characteristics observed empirically to co-vary with mutation rate: local relative replication 


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time52, and open vs. closed chromatin status53. Focal as well as arm-level copy number variations 
will be determined based on whole exome sequencing and subsequent application of the GISTIC 
algorithm54. 
2.10.3 RNA sequencing of tumor cells. 
For RNA Sequencing, poly-A selection and cDNA synthesis will be performed, followed by 
library preparation, sequencing (76bp or 101bp paired reads), and sample identification with 
quality control. Details of experimental design are described in55,56-58. We will perform library 
construction using a non-strand specific Illumina TruSeq Protocol and sequence coverage to 
100M total reads. Analysis will be performed as described in the preliminary data and in 
previous studies56-58. 
2.10.4 Immune cell characterization in peripheral blood and bone marrow 
Peripheral blood and bone marrow derived mononuclear cells will undergo immunologic 
assessments to assess the impact of therapy on general measures of cellular immunity. We will 
determine the number of immune cells (T-regs, CD4 effector T cells, CD8 T-regs, CD8 effector 
T cells, NK, NKT, B cells, MSCs, M1 and M2 macrophages, Dendritic cells and MDSCs at 
screening and during therapy. These cells will be quantified using CyTOF. Each cell type will be 
defined by unique combinations of antibodies based on previous publications59,60. Regulatory T 
cells will be defined as CD4/CD25/FOXP3+ cells. Levels of naïve, effector and central memory 
cells will be quantified as CD45RA, CD45RO/CD62L-/CD27- and CD45RO/CD62L+/CD27+ 
cells, respectively. NK cells will be quantified by expression of CD56+ subsets. MDSCs will be 
quantified by CD33+/lineage-/DR- and CD11b/lineage-/DR- cells. We will also examine the 
percent expression of checkpoint regulators and how they are modulated with therapy. These 
checkpoint regulators include PD-1, Lag-3, Tim-3 and CTLA-4. 
2.10.5 RNA sequencing of immune cells during therapy 
We will dissect molecular alterations that occur in these cells during progression in MM and the 
role of therapy on these cells. We will obtain the T-regs, NK cells and MDSCs from the 
peripheral blood and bone marrow at the same time points described above. Similar samples will 
be obtained from the comparative untreated cohort. The cells will be isolated by flow sorting 
using single cell sequencing and submitted for RNA sequencing as described above. Single cell 
sequencing of immune cells has recently shown significant advances in understanding immune 
regulation of the tumor microenvironment. Therefore, we believe that these studies will help 
define the immune microenvironment in smoldering MM before and after therapy with a PD-1 
inhibitor. 
2.10.6 Cell free DNA to monitor genomic evolution 
Human cancers are caused by the accumulation of genetic alterations in cells. Of special 
importance is the sequence at which the genetic events arise, as early events likely result in 
common oncogenic dependency that represents favorable therapeutic targets. Non-invasive 
liquid biopsies, by means of circulating tumor cells (CTC) and circulating free DNA (cfDNA), 


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facilitate the continuous monitoring of genomic evolution. CTCs have been identified in solid 
tumors as well as in multiple myeloma (MM). Likewise, massive parallel sequencing of cfDNA 
has been shown to track genomic evolution of several types of cancer during the course of the 
disease. This could potentially complement current invasive biopsy approaches and constitute a 
new paradigm for monitoring clonal evolution in human cancers and provide the possibility for 
an early detection of known MM driver mutations that could predict risk of progression. CfDNA 
sequencing can be challenging because of the small fragment size of DNA in the peripheral 
blood (around 166bp), the low yield of DNA and the usual low allelic fraction of tumor-derived 
DNA among the cfDNA. Therefore, we developed two different approaches to sequence cfDNA. 
After high-speed centrifugation of frozen samples, to eliminate residual cells from plasma, 
cfDNA is extracted using the Qiagen circulating nucleic acid kit. As little as 5ng of cfDNA is 
then subjected to library preparation using the Kapa HyperPlus kit, which enables us to prepare 
libraries from small DNA fragments and minimal DNA yield. CfDNA libraries are qualified for 
further sequencing using ultra-low-pass whole genome sequencing (ULP-WGS). The ULP-WGS 
is a low cost approach developed by the Blood Biopsy Group to nominate samples containing 
sufficient fraction of tumor-derived DNA for whole exome sequencing (WES). Large numbers 
of cfDNA libraries are multiplexed and sequenced to an average of 0.1X genome-wide 
sequencing coverage. Samples with lower than 5% purity, not suitable for WES, are analyzed by 
a targeted deep sequencing approach for cfDNA to increase the sensitivity of detection of low 
allelic fraction mutations. Our custom amplicon set includes 109 genes exons to detect single 
nucleotide variants (SNVs). WES and targeted libraries are then sequenced on a HiSeq 4000. 
Mutations are called using MuTect in single-sample mode. All known germline variants are 
filtered out (1000 Genome Project Consortium release 2.2.2) and somatic SNVs are 
characterized for their presence in the Catalogue of Somatic Mutations in Cancer (COSMIC) 
database. All somatic SNVs are reviewed manually with Integrative Genomic Viewer (IGV) to 
validate their accuracy. We assess the reproducibility of our assay by running samples in 
duplicates, which show a high correlation between the 2 replicates in the same test run. 
3. PARTICIPANT SELECTION 
3.1 Eligibility Criteria 
3.1.1 Age  18 years. 
3.1.2 Must meet criteria of high risk smoldering MM based on the criteria 
described below: 
Definition of high-risk SMM: 
• Bone marrow clonal plasma cells ≥10% and ≤60% and any one 
or more of the following: 
o Serum M protein ≥3.0g/dL (IgA, IgG, IgM, or IgD) 
o IgA SMM 
o Immunoparesis with reduction of two uninvolved 
immunoglobulin isotypes 
o Serum involved/uninvolved free light chain ratio ≥8 (but 


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less than 100) 
▪ Free Light Chain Smoldering Myeloma patients as 
defined in section 2.4 are not excluded 
o Progressive increase in M protein level (Evolving type of 
SMM) 
▪ Increase in serum monoclonal protein by ≥10% on 
two successive evaluations within a 6 month period 
o Bone marrow clonal plasma cells 50-60% 
o Abnormal plasma cell immunophenotype (≥95% of bone 
marrow plasma cells are clonal) and reduction of one or 
more uninvolved immunoglobulin isotypes 
o t (4;14) or del 17p or 1q gain 
o Increased circulating plasma cells 
o MRI with diffuse abnormalities or 1 focal lesion 
o PET-CT with one focal lesion with increased uptake 
without underlying osteolytic bone destruction 
o Urine monoclonal light chain excretion ≥500 mg/24 hours 
3.1.3 ECOG Performance Status (PS) 0, 1, or 2 (Appendix A) 
3.1.4 The following laboratory values obtained  21 days prior to registration 
and confirmed prior to the first dose of study drug: 
• ANC  1000/L 
• PLT  50,000/L. Platelet transfusions to help patients meet eligibility 
criteria are not allowed within 3 days before study enrollment. 
• Total bilirubin ≤ 1.5 mg/dL (If total is elevated check direct and if 
normal patient is eligible.) 
• AST  3 x institutional upper limit of normal (ULN) 
• ALT  3 x institutional upper limit of normal (ULN) 
• WBC ≥2000/μL 
3.1.5 Ability to understand and willingness to sign a written informed consent 
before performance of any study-related procedure not part of normal 
medical care, with the understanding that consent may be withdrawn by the 
subject at any time without prejudice to future medical care. 


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3.1.6 Female patients who are postmenopausal for at least 1 year before the 
screening visit or are surgically sterile. Females of childbearing potential* 
must have a negative serum or urine pregnancy test with a sensitivity of at 
least 25 mIU/mL within 10 – 14 days and again within 24 hours prior to 
prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 
days as required by Revlimid REMS®) and must either commit to 
continued abstinence from heterosexual intercourse or begin TWO 
acceptable methods of birth control, one highly effective method and one 
additional effective method AT THE SAME TIME, at least 28 days before 
she starts taking lenalidomide. Females of reproductive potential must 
agree to follow instructions for method(s) of contraception for the duration 
of treatment with any study drug(s) plus 5 half-lives of study plus 30 days 
(duration of ovulatory cycle) for a total of 120 days after their last dose of 
lenalidomide (Revlimid). Women must not breastfeed. 
Female patients who are of childbearing potential must use contraception 
for 5 half-lives plus 30 days after their last dose of nivolumab for a total of 
5 months. 
* A female of childbearing potential is a sexually mature female who: 
• Has not undergone a hysterectomy (the surgical removal of the 
uterus) or bilateral oophorectomy (the surgical removal of both 
ovaries) or 
• Has not been naturally postmenopausal (amenorrhea following 
cancer therapy does not rule out childbearing potential) for at 
least 24 consecutive months (i.e., has had menses at any time 
during the preceding 24 consecutive months) 
3.1.7 All study participants must be registered into the mandatory Revlimid 
REMS® program, and be willing and able to comply with the requirements 
of the REMS® program. 
3.1.8 Females of reproductive potential must adhere to the scheduled pregnancy 
testing as required in the Revlimid REMS® program. 
3.1.9 Men must agree to use a latex condom during sexual contact with a female 
of childbearing potential even if they have had a successful vasectomy 
during the entire study treatment period and through 154 days after the last 
dose of lenalidomide (Revlimid) or agree to practice true abstinence when 
this is in line with the preferred and usual lifestyle of the subject. (Periodic 
abstinence [eg, calendar, ovulation, symptothermal, post-ovulation 
methods] and withdrawal are not acceptable methods of contraception.) 
Men who are sexually active with women who are of childbearing potential 
must adhere to contraception for a period of 5 half-lives plus 90 days for a 


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total of 7 months after their last dose of nivolumab. 
3.2 Exclusion Criteria 
3.2.1 No evidence of CRAB criteria* or new criteria of active MM which 
including the following: 
• Increased calcium levels (corrected serum calcium >0.25 mmol/dL 
{>1mg/dL} above the upper limit of normal or >2.75 mmol/dL 
{11mg/dL} ) related to MM 
• Renal insufficiency (attributable to MM) 
• Anemia (Hb 2g/dL below the lower limit of normal or <10g/dL) 
related to MM 
• Bone lesions (lytic lesions or generalized osteoporosis with 
compression fractures) 
• Bone marrow plasma cells >60% 
• Serum involved/uninvolved FLC ratio ≥100, provided the absolute 
level of the involved free light chain is at least 100 mg/L and repeated 
twice (light chain smoldering myeloma as described in section 2.4 is 
not an exclusion criteria). 
• MRI with two or more focal lesions that are at least 5 mm or greater in 
size 
*Participants with CRAB criteria that are attributable to conditions other 
than the disease under study may be eligible 
3.2.2 Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary 
therapy considered investigational. Prior therapy with bisphosphonate is allowed. 
Prior therapy for smoldering myeloma MM may not be an exclusion criterion, 
discussion with Principal Investigator must occur before enrolling patients with 
prior treatments. Prior radiation therapy to a solitary plasmacytoma is allowed. 
Patients who received prior therapy due to being incorrectly diagnosed as having 
overt multiple myeloma may not be excluded after discussion with the overall PI. 
3.2.3 Serious medical or psychiatric illness likely to interfere with participation in this 
clinical study. 
3.2.4 Diagnosed or treated for another malignancy within 2 years of enrollment, with 
the exception of complete resection of basal cell carcinoma or squamous cell 
carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after 
curative therapy. 
3.2.5 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 


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3.2.6 Autoimmune disease: Patients with a history of inflammatory bowel disease, 
including ulcerative colitis and Crohn’s Disease, are excluded from this study, as 
are patients with a history of symptomatic disease (eg, rheumatoid arthritis, 
systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, 
autoimmune pneumonitis, autoimmune vasculitis [eg, Wegener’s 
Granulomatosis]) and motor neuropathy considered of autoimmune origin (e.g. 
Guillain-Barre Syndrome and Myasthenia, Gravis). Patients with Hashimoto’s 
thyroiditis are eligible to go on study. 
3.2.7 Pregnant or nursing women will be excluded from the study because 
lenalidomide is an agent with the potential for teratogenic or abortifacient 
effects. 
3.2.8 History of severe allergic reactions attributed to compounds of similar chemical 
or biologic composition to Nivolumab or lenalidomide. 
3.2.9 Known seropositive for or active viral infection with human immunodeficiency 
virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who 
are seropositive because of hepatitis B virus vaccine are eligible. 
3.2.10 Major surgery within 4 weeks of enrollment. 
3.2.11 Myeloma-related central nervous system involvement. 
3.2.12 Known Amyloid involvement. 
3.2.13 Participation in other clinical trials, including those with other investigational 
agents not included in this trial, within 30 days of the start of this trial and 
throughout the duration of this trial. 
3.2.14 Prior CVA with persistent neurological deficit. 
3.2.13 Inability to tolerate thromboprophylaxis. 
3.3 Inclusion of Women and Minorities 
3.3.1 Both men and women of all races and ethnic groups are eligible for this trial. 
4. REGISTRATION PROCEDURES 
4.1 General Guidelines for DF/HCC and DF/PCC Institutions 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 


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An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible. 
4.2 Registration Process for DF/HCC and DF/PCC Institutions 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed. 
4.3 General Guidelines for Other Investigative Sites 
The Research Project Manager will enter eligible participants on study at DFCI. All sites should 
call or email the Research Project Manager, to ensure enrollment availability prior to consenting 
any patients. 
Following registration, participants should begin protocol therapy as soon as feasible. Issues that 
would cause treatment delays should be discussed with the Overall PI. If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study must be 
canceled. The Research Project Manager should be notified of cancellations as soon as possible. 
4.4 Registration Process for Other Investigative Sites 
To register a participant, the following documents should be completed by the research nurse or 
data manager and e-mailed to the Research Project Manager: 
• Copy of labs and clinical information that satisfy inclusion criteria 
• Signed participant consent form 
• HIPAA authorization form 
• Registration Form 
The research nurse or data manager at the participating site will then call or e-mail the Research 
Project Manager, to verify eligibility. To complete the registration process, the Research Project 
Manager will follow DF/HCC Standard Operating Procedure for Human Subject Research Titled 
Subject Protocol Registration (SOP #: REGIST-101) and register the participant on the protocol. 
The Research Project Manager will fax or e-mail the participant study number, and if applicable 
the dose treatment level, to the participating site. The coordinator will also call the research 
nurse or data manager at the participating site and verbally confirm registration 
Treatment may not begin without confirmation from the Coordinating Center that the 
participant has been registered. 


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NOTE: Registration with the coordinating center can only be conducted during the 
business hours of 8:00 AM and 5:00 PM Eastern Time Monday through Friday. Same day 
treatment registrations will only be accepted with prior notice and discussion with the study team 
at DFCI. 
5. TREATMENT PLAN 
5.1 Treatment Regimen 
Treatment will consist of 6 cycles of induction therapy followed by maintenance therapy for a 
total of 12 months. A treatment cycle is defined as 28 consecutive days. 
For treatment cycles 1 through 12, a +/- 7 day window for nivolumab dosing is allowed 
For further guidance on lenalidomide and dexamethasone holds and delays, please see Table 17. 
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant's malignancy. 
** As of September 2017, the trial has been put on partial clinical hold by the Food and Drug 
Administration: all patients are to discontinue nivolumab indefinitely, and no additional patients 
will be accrued to the trial. Participants may elect to remain on lenalidomide/dexamethasone or 
lenalidomide therapy alone for disease control after discussion with the overall PI. 
Induction Cycles 
Table 7: Nivolumab and Lenalidomide and Dexamethasone Combination (Cycles 1-6) 
Agent 
Pre-medications/ 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Nivolumab 
None 
240 mg 
Intravenous 
Days 1,15 
28 days 
Lenalidomide 
None 
25 mg 
Oral 
Days 1-21 of 
each cycle 
Dexamethasone 
Take with food; 
Recommended to be 
taken in the morning 
40 mg 
Oral 
Days 1, 8, 15 
Maintenance Cycles** 
Table 8: Nivolumab and Lenalidomide Combination (Cycles 7-12) 
Agent 
Pre-medications/ 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Nivolumab 
None 
240 mg 
Intravenous 
Days 1, 15 
28 days 
Lenalidomide 
None 
15 mg* 
Oral 
Days 1-21 of 


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each cycle 
* If patient was dose reduced during the induction phase for lenalidomide below 15mg, then 
maintenance phase starts at that dose reduction and not at the higher 15 mg dose. 
** During maintenance, if a patient experiences biochemical progression (≥ 25% increase and an 
absolute increase of ≥ 0.5g/dL from their nadir in their serum or urine m-spike or FLC with no 
CRAB features attributable to MM progression) high-dose dexamethasone may be re-added to 
the combination at a dose of 40mg oral given on days 1, 8, and 15 of a 28 day cycle after 
discussion with the overall PI. 
The participant will be requested to maintain a medication diary. The medication diary 
should be returned to clinic staff at the end of each cycle. 
5.2 Agent Administration 
The drugs may be administered in any order. 
5.2.1 Nivolumab 
5.2.1.1 
Administration 
Nivolumab will be administered at a dose of 240 mg as an intravenous infusion over 
60 minutes (+/- 10 minutes) every 2 weeks (Days 1 and 15 of each 28 day cycle). 
See section 8.1.7 for guidelines on drug preparation and section 8.1.8 for further guidelines for 
drug administration. 
Administer the infusion over 60 minutes (+/- 10 minutes) through an intravenous line containing 
a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 
micrometer). 
Do not co-administer other drugs through the same intravenous line. 
Flush the intravenous line at end of infusion. 
5.2.1.2 
Dose Delay or Interruption 
Please refer to section 6.2 of the protocol. 
5.2.2 Lenalidomide 
Lenalidomide will be obtained from commercial supply in this study. This may lead to added 
costs for the participant or the participant’s insurance company. 
Lenalidomide will be given as a single daily oral dose of 25 mg per day on days 1-21 followed 


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by a 7-day rest period for induction (cycles 1-6) and 15 mg per day on days 1-21 for maintenance 
(cycles 7-12) (if a patient was dose reduced during the induction phase for lenalidomide below 
15mg, then maintenance phase starts at that dose reduction and not at the higher 15 mg dose). 
Please refer to Table 17 for specific hold and delay instructions for lenalidomide. Dose 
modification guidelines are described in Section 6.3. 
Lenalidomide capsules should be swallowed whole, and should not be broken, chewed or 
opened. Administration of lenalidomide should be at approximately the same time each day. 
Drug may be taken with or without food. If a dose is missed and less than 12 hours has elapsed 
since the missed dose, the patient may take the dose for that day. If more than 12 hours has 
elapsed since missing a dose at the normal time, the patient should not take the dose, but take the 
next dose at the normal time on the following day. If a dose is missed, it should be taken as soon 
as possible on the same day. If a dose is vomited, the dose should not be made up and the 
participant should continue with the regular schedule of the drug at the next dose. A drug diary 
must be provided to participants to record oral administration of doses. 
Participants who take more than the prescribed dose of lenalidomide should be instructed to seek 
emergency medical care if needed and contact study staff immediately. Participants experiencing 
adverse events may need study treatment modifications (see Section 6.3). 
Lenalidomide related resources must be provided to all patients prior to receiving lenalidomide 
therapy as part of the Revlimid REMS program. For more information regarding program 
registration and drug ordering, refer to section 8.2. 
5.2.2.1 
Dose Delay or Interruption 
Please refer to section 6.3 of the protocol. 
5.2.3 Dexamethasone 
Dexamethasone will be obtained from commercial supply in this study. This may lead to added 
costs for the participant or the participant’s insurance company. 
Dexamethasone will be given as a single oral dose of 40mg on days 1, 8, and 15 of each 28 day 
cycle during the induction phase of this study (Cycles 1-6 only). 
Dexamethasone should be taken at approximately the same time each day. It is recommended 
that dexamethasone be taken in the morning to reduce insomnia. Each dose should be taken with 
food. If a dose of dexamethasone is vomited, the participant should continue with the regular 
schedule of the drug at the next dose. If a dose is missed and less than 12 hours has elapsed since 
the missed dose, the patient may take the dose for that day. If more than 12 hours has elapsed 
since missing a dose at the normal time, the patient should not take the dose, but take the next 
dose at the normal time on the following day. If a dose is missed, it should be taken as soon as 
possible on the same day. If a dose is vomited, the dose should not be made up and the 
participant should continue with the regular schedule of the drug at the next dose.. A drug diary 
must be provided to participants to record oral administration of doses. Dose modification 
guidelines are described in Section 6.3. 


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5.2.3.1 
Dose Delay or Interruption 
Please refer to section 6.4 of the protocol. 
5.3 General Concomitant Medication and Supportive Care Guidelines 
5.3.1 Medications and supportive care 
• Patients who experience worsening neuropathy from baseline should be observed 
for recovery, have dose reductions/delays as indicated in the protocol, and any 
supportive therapy or intervention may be initiated as appropriate at the discretion 
of the investigator. 
• Supportive measures consistent with optimal patient care may be given 
throughout the study. 
• Stem cell collection may be performed at the time of best response (PR, VGPR or 
CR or at the investigator’s discretion) or after 6 cycles of therapy for those who 
are transplant eligible, and/or who plan to pursue transplant in the future. The 
standard mobilization procedures of the treating institution should be followed. 
Plerixafor should be the preferred mobilization agent, though cyclophosphamide 
or other agent may be used at the investigator’s discretion. A delay of no more 
than 3 weeks is allowed between the end of collection and re-initiation of therapy 
especially if chemotherapy such as high dose cyclophosphamide was used for 
stem cell mobilization. Mobilization should occur as soon as possible after study 
treatment is stopped. 
• Use of white cell growth factors (Filgrastim or acceptable equivalent) is allowed 
for management of treatment-induced neutropenia at physician discretion. 
Filgrastim or equivalent should be given according to local institutional guidelines 
or per the package insert. Pegfilgrastim is not to be used in place of filgrastim. 
• Patients may be transfused with red cells and platelets as clinically indicated and 
according to institutional guidelines. 
• Patients may receive bisphosphonates per recommendations of myeloma therapy, 
or may follow local standard of care. A note should be placed about patients who 
are not receiving bisphosphonates, such as osteonecrosis of the jaw. 
• If nausea and/or vomiting is/are noted at any point in time, premedication with 
prochlorperazine or other antiemetics may be used before future doses. 
Antiemetics, including 5-HT3 serotonin receptor antagonists, may be used as 
needed at the discretion of the investigator. 


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• If nausea persists in spite of the use of standard antiemetics, additional symptom 
management should be initiated per institutional standard. 
• Loperamide or other antidiarrheal may be used for symptomatic diarrhea at 
discretion of the investigator. The dose and regimen will be according to 
institutional guidelines. IVF may be given to prevent volume depletion. 
• Thromboprophylaxis is recommended for all participants. Thromboprophylactic 
initiation and regimen choice is at the discretion of the treating physician or sites 
may follow the current package insert for Revlimid. It is recommended that if the 
platelet count falls below 30,000/mm3, thromboprophylaxis be held to minimize 
the risk of bleeding and then resumed when platelet counts are equal to or above 
30,000/mm3. 
• Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided with impaired 
renal function given reported NSAID-induced renal failure in patients with 
decreased renal function. 
• Patients may be at an increased risk of infection including reactivation of herpes 
zoster and herpes simplex viruses. Antiviral therapy such as acyclovir, 
valacyclovir, or other antivirals may be initiated as clinically indicated at the 
discretion of the treating investigator. Antivirals for other indications are also 
allowed. 
• The following procedures are prohibited during the study: 
o Any antineoplastic treatment with activity against MM, other than study 
drugs 
o Radiation therapy (note that, in general, the requirement for local radiation 
therapy indicates disease progression) 
5.4 
Management of Clinical Events 
5.4.1 Rash 
• Symptomatic measures such as antihistamines or corticosteroids (oral or 
topical) have been successfully used to manage rash and have been used 
prophylactically in subsequent cycles. The use of a topical, IV, or oral steroid 
(eg, prednisone ≤ 10 mg per day or equivalent) is permitted. 
• Management of a Grade 3 rash may require intravenous antihistamines or 
corticosteroids. Administration of lenalidomide (and/or other causative agent 


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35 
if given in combination) should be modified per protocol and re-initiated at a 
reduced level from where rash was noted. 
• In line with clinical practice, a dermatology consult that includes a biopsy of 
Grade 3 or higher rash or any SAE involving rash is recommended. 
Prophylactic measures should also be considered if a patient has previously 
developed a rash (eg, using a thick, alcohol-free emollient cream on dry areas 
of the body or oral or topical antihistamines). 
• A rare risk is Stevens-Johnson Syndrome, a severe and potentially life- 
threatening rash with skin peeling and mouth sores, should be managed 
symptomatically according to standard medical practice. Punch biopsies for 
histopathological analysis are encouraged at the discretion of the investigator. 
5.4.2 Thrombocytopenia 
• Blood counts will be monitored regularly as outlined in the protocol with 
additional testing obtained according to standard clinical practice. 
Thrombocytopenia may be severe but has been manageable with platelet 
transfusions according to standard clinical practice. Lenalidomide 
administration should be modified as noted as per dose modification 
recommendations in the protocol when thrombocytopenia occurs (see Section 
6.3). Therapy may be reinitiated at a reduced level upon recovery of platelet 
counts. 
• A rare risk is thrombotic thrombocytopenic purpura (TTP), a rare blood disorder 
where blood clots form in small blood vessels throughout the body 
characterized by thrombocytopenia, petechiae, fever, or possibly more serious 
signs and symptoms. TTP should be managed symptomatically according to 
standard medical practice. 
5.4.3 Neutropenia 
• Blood counts will be monitored regularly as outlined in the protocol with 
additional testing obtained according to standard clinical practice. Neutropenia 
may be severe but has been manageable. Growth factor support is not required 
but may be considered according to standard clinical practice. Lenalidomide 
administration should be modified as per dose modification recommendations in 
the protocol when neutropenia occurs (see Section 6.3). 
5.4.4 Pregnancy 
• Female patients participating in this study should avoid becoming pregnant, and 
male patients should avoid impregnating a female partner. Non-sterilized 
female patients of reproductive age group and male patients should use effective 
methods of contraception through defined periods during and after study 
treatment as specified below. 


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o Female patients must meet 1 of the following: 
▪ Postmenopausal for at least 1 year before the screening visit 
▪ Surgically sterile 
▪ If they are of childbearing potential, agree to practice 2 
effective methods of contraception from the time of signing of 
the informed consent form through 120 days after the last dose 
of lenalidomide ( Revlimid) of study drug 
• Women who are of childbearing potential, agree to 
practice contraception for a period of 5 months after 
their last dose of nivolumab 
▪ Agree to practice true abstinence, when this is in line with the 
preferred and usual lifestyle of the subject. 
• Periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal 
are not acceptable methods of contraception. 
• Male patients, even if surgically sterilized (ie, status postvasectomy) must 
agree to 1 of the following: 
o Practice effective barrier contraception during the entire study 
treatment period and through 154 days after the last dose of 
lenalidomide ( Revlimid) 
▪ Men receiving nivolumab who are sexually active with women 
of childbearing potential must adhere to contraception for a 
period of 7 months after the last dose of nivolumab 
o Agree to practice true abstinence, when this is in line with the 
preferred and usual lifestyle of the subject. 
▪ Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods for the female partner) and withdrawal 
are not acceptable methods of contraception. 
5.5 Criteria for Taking a Participant Off Protocol Therapy 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care. 
In the absence of treatment delays due to adverse event(s), treatment may continue for 12 cycles 
or until one of the following criteria applies: 
• Progression to overt Multiple Myeloma 
• Intercurrent illness that prevents further administration of treatment 


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• Unacceptable adverse event(s) 
• Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
• Participant decides to withdraw from the protocol therapy 
• General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
Participants will be removed from the protocol therapy when any of these criteria apply. The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
A Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form will be provided by the lead site. External sites should submit the 
form to the Research Project Manager. 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Irene Ghobrial at telephone number 617-632-4198. 
5.6 Duration of Follow Up 
Participants will be followed for 3 years after removal from protocol therapy or until progression 
to active symptomatic MM or need for new therapy, whichever occurs first. Participants 
removed from protocol therapy for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
5.7 Criteria for Taking a Participant Off Study 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
• Progression to active myeloma and subsequent treatment 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 


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A Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form will be provided by the lead site. External sites should submit the 
form to the Research Project Manager. 
6. DOSING DELAYS/DOSE MODIFICATIONS 
6.1 Recommended Criteria for Beginning or Delaying a Subsequent Treatment Cycle 
Patients must meet eligibility criteria on Cycle 1 Day 1 to begin treatment. There are no pre- 
treatment criteria to begin a new cycle of nivolumab. 
For a new cycle of treatment with lenalidomide to begin, the patient must meet the following 
criteria: 
• ANC must be ≥ 1,000/L. 
• Platelet count must be ≥ 50,000/L. 
• All other clinically significant, study drug related non hematologic toxicity must have 
resolved to ≤ Grade 1 or to baseline condition 
If the participant fails to meet the above-cited criteria for initiation of a new cycle of treatment 
on day 1 of the cycle, dosing of all medications should be delayed for 1 week. At the end of that 
time, the participant should be re-evaluated to determine whether the above criteria have been 
met. If the participant continues to fail to meet the above-cited criteria, delay therapy and 
continue to re-evaluate. The maximum delay for toxicity related to study treatment before 
treatment is permanently discontinued will be 3 weeks. If a delay of > 3 weeks is clinically 
necessary, and the patient is showing benefit from treatment, the patient may continue on 
study after discussion and approval by the Principal Investigator. 
If any one of the study medications is permanently discontinued for any reason including 
toxicity, or FDA mandate, the patient may remain on the study at the discretion of the principal 
investigator. 
6.2 Nivolumab 
No dose reductions for Nivolumab are allowed. If Nivolumab is held on Day 1 of a new cycle, 
treatment with Lenalidomide/Dexamethasone will also be delayed. If Nivolumab is held during 
any cycle on day 15, the treating investigator should decide if lenalidomide and/or 
dexamethasone will be skipped using recommended guidance for retreatment below. Nivolumab 
may be delayed for up to 21 days or 3 weeks. A delay of up to 14 days will be allowed for 
participants for non-AE related events (i.e.; vacation, family emergency, etc) after discussion 
with the overall PI. If an alternate treatment plan for a suspected nivolumab related toxicity is 
proposed and is not listed in Table 11, you must first discuss and obtain approval from the 
Overall PI. 
Dose delays and modifications will be made as indicated in the following table(s). The 


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descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.03 can be downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
* If any one of the study medications is permanently discontinued for any reason including 
toxicity, or FDA mandate, the patient may remain on the study at the discretion of the principal 
investigator. 
Table 11 Suggested Guidelines for Nivolumab Suspected Toxicity 
CTCAE 4.0 Category 
CTCAE Grade 
Nivolumab Action 
Pneumonitis 
(See Section 6.2.1 for 
management guidelines) 
Grade 1 
Continue to treat- Do NOT OMIT 
Grade 2 
Hold dose until resolved to ≤ Grade 1 
≥ Grade 3 
Permanently discontinue nivolumab 
Colitis 
(See Section 6.2.2 for 
management guidelines) 
Grade 1 
Continue to treat- Do NOT OMIT 
Grade 2 
or 
Grade 3 
Hold dose until resolved to ≤ Grade 1 
Grade 4 
Permanently discontinue nivolumab 
Increase 
in 
AST and/or ALT 
(See Section 6.2.3 for 
management guidelines) 
Grade 1 
Continue to treat- Do NOT OMIT 
Grade 2 
Hold dose until resolved to ≤ Grade 1 
≥ Grade 3 
Permanently discontinue nivolumab 
Increase 
in 
Blood Bilirubin 
(See Section 6.2.3 for 
management guidelines) 
Grade 1 
Continue to treat- Do NOT OMIT 
Grade 2 
Hold dose until resolved to ≤ Grade 1 
≥ Grade 3 
Permanently discontinue nivolumab 
Increase 
in 
Creatinine 
(See Section 6.2.4 for 
management guidelines) 
Grade 1 
Continue to treat- Do NOT OMIT 
Grade 2 
or 
Grade 3 
Hold dose until resolved to ≤ Grade 1 
Grade 4 
Permanently discontinue nivolumab 
All other related 
toxicities not listed 
previously in this table 
(See Section 6.2.6 for 
management guidelines) 
Grade 1 
Continue to treat- Do NOT OMIT 
Grade 2 
Continue to treat- Do NOT OMIT 
Grade 3 
Hold dose until resolved to ≤ Grade 1 
Recurrent Grade 3 
or 
Permanently discontinue nivolumab 


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Grade 4 
If the patient discontinues nivolumab, he or she does not need to come off protocol therapy 
6.2.1 Immune-Mediated Pneumonitis 
Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids at a dose of 
1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater pneumonitis, followed by 
corticosteroid taper. Permanently discontinue nivolumab for severe (Grade 3) or life-threatening 
(Grade 4) pneumonitis and withhold nivolumab until resolution for moderate (Grade 2) 
pneumonitis. 
6.2.2 Immune-mediated colitis 
Monitor patients for immune-mediated colitis. Administer corticosteroids at a dose of 1 to 
2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life- 
threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day 
prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more 
than 5 days duration; if worsening or no improvement occurs despite initiation of corticosteroids, 
increase dose to 1 to 2 mg/kg/day prednisone equivalents. Withhold NIVOLUMAB for Grade 2 
or 3 immune-mediated colitis. Permanently discontinue NIVOLUMAB for Grade 4 colitis or for 
recurrent colitis upon restarting NIVOLUMAB 
6.2.3 Immune-Mediated Hepatitis 
Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer 
corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater 
transaminase elevations, with or without concomitant elevation in total bilirubin. Withhold 
nivolumab for moderate (Grade 2) and permanently discontinue nivolumab for severe (Grade 3) 
or life-threatening (Grade 4) immune-mediated hepatitis. 
6.2.4 Immune-Mediated Nephritis and Renal Dysfunction 
Monitor patients for elevated serum creatinine prior to and periodically during treatment. 
Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by 
corticosteroid taper for life-threatening (Grade 4) serum creatinine elevation and permanently 
discontinue nivolumab. For severe (Grade 3) or moderate (Grade 2) serum creatinine elevation, 
withhold nivolumab and administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone 
equivalents followed by corticosteroid taper; if worsening or no improvement occurs, increase 
dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents and permanently discontinue 
nivolumab. 
6.2.5 Immune-Mediated Hypothyroidism and Hyperthyroidism 
Monitor thyroid function prior to and periodically during treatment. Administer hormone 
replacement therapy for hypothyroidism. Initiate medical management for control of 


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hyperthyroidism. There are no recommended dose adjustments of nivolumab for hypothyroidism 
or hyperthyroidism. 
6.2.6 Other Immune-Mediated Adverse Reactions 
Other clinically significant immune-mediated adverse reactions can occur. Immune-mediated 
adverse reactions may occur after discontinuation of nivolumab therapy. For any suspected 
immune-mediated adverse reactions, exclude other causes. Based on the severity of the adverse 
reaction, withhold nivolumab, administer high-dose corticosteroids, and if appropriate, initiate 
hormone-replacement therapy. Upon improvement to Grade 1 or less, initiate 
corticosteroid taper and continue to taper over at least 1 month. Consider restarting nivolumab 
after completion of corticosteroid taper based on the severity of the event 
6.2.7 Immune Mediated Cardiac Toxicity 
Cardiac * 
Management/Next Dose for Nivolumab 
≤ Grade 1 
Hold dose pending evaluation and observation.** Evaluate for signs 
and symptoms of CHF, ischemia, arrhythmia or myositis. Obtain 
history EKG, CK (for concomitant myositis), CK-MB. Repeat troponin, 
CK and EKG 2-3 days. If troponin and labs normalize may resume 
therapy. If labs worsen or symptoms develop then treat as below. 
Hold pending evaluation 
Grade ≥2 with suspected 
myocarditis 
Hold dose.** Admit to hospital. Cardiology consult. Rule out MI 
and other causes of cardiac disease. Cardiac Monitoring. Cardiac 
Echo. Consider cardiac MRI and cardiac biopsy. Initiate high dose 
methylprednisolone. If no improvement within 24 hours, add either 
infliximab, ATG or tacrolimus. Consult algorithm for more details. 
Resume therapy if there is a return to baseline and myocarditis is 
excluded or considered unlikely. 
Grade ≥2 with confirmed 
myocarditis 
Off protocol therapy. Admit to CCU (consider transfer to nearest 
Cardiac Transplant Unit). Treat as above. Consider high dose 
methylprednisolone 
Add ATG or tacrolimus if no improvement. Off treatment. 
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin 
**Patients with evidence of myositis without myocarditis may be treated according as “other event” 
Note: The optimal treatment regimen for immune mediated myocarditis has not been established. 
Since this toxicity has caused patient deaths, an aggressive approach is recommended. 
6.3 Lenalidomide 
Hematologic Toxicities: For adverse hematologic events that are considered possibly, probably 
or definitely related to Lenalidomide, the following criteria for retreatment and dose 
modification should be followed unless discussed and approved first by the overall principal 


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investigator. The treating investigator should determine the clinical significance of laboratory 
values and attribution to study medications before a treatment decision is made. All instances 
where lenalidomide is held, the dose will be considered missed, and will not be made up. 
Non Hematologic Toxicity: For adverse non hematologic events that are considered to be 
possibly, probably or definitely related to Lenalidomide, the following criteria for retreatment 
and dose modification should be followed unless discussed and approved first by the overall 
principal investigator. The treating investigator should determine the clinical significance of 
laboratory values or radiographic findings and attribution to study medications before a treatment 
decision is made. All instances where lenalidomide is held, the dose will be considered missed, 
and will not be made up. 
Dose delays and modifications should be made as indicated in the following table(s) unless first 
discussed with the Overall PI. The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for 
dose delays and dose modifications. A copy of the CTCAE version 4.0 can be downloaded from 
the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Table 12 Lenalidomide Hematologic Toxicities 
CTCAE 4.0 
Category 
CTCAE 
Grade 
Lenalidomide Dose Modification 
Grade 1 
or 
Continue to treat- Do NOT OMIT and DO NOT REDUCE therapy 
Grade 2 
Absolute 
Hold dose 
Neutrophil Count 
(ANC)1 
Grade 3 
Administer Filgrastim 
Resume at same dose when ANC is ≥ 1000 if neutropenia is the only 
hematologic toxicity 
If other hematologic toxicity ≥Grade 2 is present, reduce dose one level 
when ANC≥1000 
Hold dose 
Grade 4 
Administer Filgrastim 
Resume therapy at one dose level lower when ANC is ≥ 1000 
Neutropenia with 
Fever 
ANC <1000 and 
temperature ≥38.5o 
C or 101ºF 
Grade 3 
or 
Grade 4 
Hold dose 
Administer Filgrastim 
Reduce dose one level when ANC≥1000 
Thrombocytopenia 
Grade 1 
or 
Grade 2 
Continue to treat- Do NOT OMIT and DO NOT REDUCE therapy 


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Aspirin prophylaxis 
should be held if 
platelets are ≤50,000 
Grade 3 
or 
Grade 4 
Provide platelet transfusion support 
Redraw platelets 
If redrawn platelet value ≥ 50,000 -> Do NOT OMIT and DO NOT 
REDUCE therapy 
If redrawn platelet value <50,000 continue to transfuse at the discretion of 
the investigator and hold therapy until platelets are ≥ 50,000 on Day 1 or ≥ 
30,000 intracycle 
Resume therapy at one dose level lower when the patient’s platelets are ≥ 
50,000 on Day 1 or ≥ 30,000 intracycle 
Anemia 
Grade 1 
Grade 2 
Grade 3 
Continue to treat- Do NOT OMIT and DO NOT REDUCE therapy 
Transfuse at the discretion of treating investigator 
Grade 4 
Hold treatment 
Transfuse 
Resume treatment when hemoglobin ≥ 8.0 g/dL 
DO NOT REDUCE therapy 
1 ANC can be calculated two ways: From the percentage of neutrophils: White Blood Count (WBC) x total 
neutrophils (polys% + bands%) x 10. From the absolute number of cells: (Absolute polys + Absolute bands) x 10. 
Table 13 Lenalidomide Non Hematologic Toxicities 
CTCAE 4.0 
Category 
CTCAE 
Grade 
Lenalidomide Dose Modification 
Infection or Viral 
Illness with ANC1 
≥1000 
Including herpes 
zoster reactivation 
N/A 
Day 1 of Cycle: Delay cycle until infection/viral 
illness has resolved. Resume treatment at the same 
dose level. Do not dose reduce. 
Intracycle: Hold lenalidomide for a maximum of 21 
days to allow for recovery. Resume treatment at same 
dose level. 
If patient has delay of greater than 21 days, the patient 
must come off-study 


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Infection or Viral 
Illness with ANC1 
< 1000 
N/A 
Day 1 of Cycle: Delay cycle until infection/viral 
illness has resolved. Administer filgrastim or 
equivalent as indicated. 
Reduce one dose level when infection/virus has 
resolved, and ANC ≥1000 
Intracycle: Hold lenalidomide for a maximum of 21 
days. Reduce one dose level when infection/virus has 
resolved and ANC ≥ 500 
If patient has a delay of less than or equal to 21 days, 
dose reduce to next dose level. If patient has delay of 
greater than 21 days, the patient must come off-study 
Allergic reaction or 
hypersensitivity to 
Lenalidomide 
Including Rash 
related to 
Lenalidomide 
Grade 1 
Continue to treat- Do NOT OMIT and DO NOT 
REDUCE therapy 
Grade 2 
Continue to treat- Do NOT OMIT and DO NOT 
REDUCE therapy 
Grade 3 
or 
Grade 4 
Hold lenalidomide 
Follow at least weekly. 
If toxicity resolves to ≤ grade 2, restart at next lower 
dose level 
Renal/Metabolic 
For all grades, 
provide hydration and 
other supportive care 
as needed at the 
discretion of the 
treating investigator 
Grade 1 
Continue to treat- Do NOT OMIT and DO NOT 
REDUCE therapy 
Grade 2 
Hold Lenalidomide until < grade 2 and resume 
treatment at the same dose level 
If toxicity recurs, dose reduce one dose level at the 
treating investigator’s discretion 
Grade 3 
or 
Grade 4 
Hold Lenalidomide until < grade 2 and resume 
treatment with one dose level reduction 
If the toxicity remains ≥ grade 3, omit dose and restart 
at subsequent scheduled visit with one dose level 


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reduction 
If treatment-related toxicity occurs on day one of the 
cycle, the cycle will be delayed. 
Diarrhea, 
Constipation, 
Nausea, or Vomiting 
Grade 1 
Continue to treat- Do NOT OMIT and DO NOT 
REDUCE therapy 
Grade 2 
Treat at the discretion of the investigator 
Provide aggressive supportive care 
DO NOT REDUCE therapy 
Grade 3 
Hold Lenalidomide until toxicity resolves to < grade 2 
If the patient has received maximum supportive care, 
resume therapy with one dose level reduction 
Grade 4 
Hold Lenalidomide until toxicity resolves to < grade 2 
Resume therapy with one dose level reduction 
All other related 
toxicities not listed 
previously in this 
table 
Grade 1 
Continue to treat- Do NOT OMIT and DO NOT 
REDUCE therapy 
Grade 2 
Continue to treat- Do NOT OMIT and DO NOT 
REDUCE therapy unless considered to be a clinically 
significant finding 
Provide supportive care as needed 


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Grade 3 
Hold Lenalidomide until toxicity resolves to < grade 2 
Resume therapy with one dose level reduction at the 
discretion of the treating investigator 
Grade 4 
Hold Lenalidomide until toxicity resolves to < grade 2 
Resume therapy with one dose level reduction 
If treatment-related toxicity occurs on day one of the 
cycle, the cycle will be delayed. 
If patient has a delay of less than or equal to 21 days, 
dose reduce to next dose level. If patient has delay of 
greater than 21 days, the patient must come off-study 
If the patient discontinues lenalidomide, he or she does is not required to come off protocol 
therapy. 
Table 14 Lenalidomide Dose Reduction 
Dose Level 
Lenalidomide Dose 
0 
25 mg 
-1 
20 mg 
-2 
15 mg 
-3 
10 mg 
-4 
5 mg 
If lenalidomide is reduced for any toxicity, the dose may not be re-escalated. 
6.4 Dexamethasone 
Dexamethasone Dose Modifications 
For adverse events that are considered to be possibly, probably or definitely related to 
dexamethasone, the following criteria for retreatment and dose modification should be followed 
unless discussed and approved first by the Overall Principal Investigator. The treating 
investigator should determine the clinical significance and attribution of the toxicity to 
dexamethasone. If toxicity is unlikely or not related to dexamethasone, do not omit or reduce 
therapy. Patients may continue on study if dexamethasone has been permanently discontinued 
Table 15 Dexamethasone Dose Modifications 
CTCAE 4.0 
Category 
CTCAE Grade 
Dexamethasone Dose Modification 
Hyperglycemia 
Grade 1 
Continue to treat- Do NOT OMIT and DO NOT 


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Treat with oral 
medication or 
insulin at 
discretion of 
treating 
investigator 
REDUCE therapy 
Grade 2 
Hold dexamethasone until < Grade 2 and resume at 
same dose level at the discretion of the treating 
investigator 
Grade 3 
Hold dexamethasone until < Grade 2 
Resume therapy with one dose level reduction at the 
discretion of the treating investigator 
Grade 4 
Hold dexamethasone until < Grade 2 
Resume therapy with one dose level reduction 
Symptomatic 
pancreatitis 
Any Grade 
Discontinue dexamethasone permanently 
OTHER 
Grade 1 or 2 
Continue to treat- Do NOT OMIT and DO NOT 
REDUCE therapy 
Grade 3 
Hold dexamethasone until ≤ Grade 2 
Resume therapy with one dose level reduction 
Grade 4 
Hold dexamethasone ≤ Grade 2 
Resume therapy with one dose level reduction 
If the patient discontinues dexamethasone prior to maintenance, he or she is not required to 
come off protocol therapy. 
Table 16 Dexamethasone Dose Reduction 
Dose Level 
Dexamethasone Dose 
0 
40 mg 
-1 
20 mg 
-2 
10 mg 
 If dexamethasone is reduced for any toxicity, the dose may not be re-escalated. 
6.5 Dose Delay Guidelines 
Required study schedule assessments should always correlate with the nivolumab dosing 
schedule. If lenalidomide and/or dexamethasone are held during a cycle, then study assessments 
should continue per the schedule of assessments in Section 10. If nivolumab is held at any 
timepoint, study calendar assessments for that day should be repeated prior to re-initiation of 


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nivolumab. 
Table 17 Dose Delay Instructions 
To be resumed 
within window? 
Lenalidomide 
Dexamethasone 
Nivolumab 
Nivolumab 
delayed on Day 
1 of Cycle 
N/A 
To be delayed 
until Nivolumab is 
resumed 
To be delayed 
until Nivolumab 
is resumed 
Resume 
dosing= new 
Day 1 of Cycle 
Nivolumab 
held on Day 15 
of Cycle 
Yes 
Dosing to continue 
as scheduled 
Dosing to 
continue as 
scheduled 
Resume dose 
any day within 
window; dose 
time point not 
skipped 
Nivolumab 
held on Day 
15of Cycle 
No 
Dosing to continue 
as scheduled 
Dosing to 
continue as 
scheduled 
Resume dosing 
at next dosing 
time point 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
7.1 Definitions 
7.1.1 
Adverse Event Definition 
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered 
a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product whether or not it is related to the medicinal product. 
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug. CTCAE version 4.03 will be used for this 
study. 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline. 
7.1.2 Serious Adverse Event Definition 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (refers to an AE in which the patient was at risk of death at the time of 
the event. It does not refer to an event which hypothetically might have caused death if it 
were more severe). 


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• Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph below on planned hospitalizations). 
• Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
• Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent one of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse; any 
organism, virus, or infectious particle (eg, prion protein transmitting Transmissible 
Spongiform Encephalopathy), pathogenic or nonpathogenic, is considered an infectious 
agent. 
Clarification should be made between a serious AE (SAE) and an AE that is considered severe in 
intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous. The 
general term severe is often used to describe the intensity (severity) of a specific event; the event 
itself, however, may be of relatively minor medical significance (such as a Grade 3 headache). 
This is NOT the same as the serious, which is based on patient/event outcome or action, criteria 
described above, and is usually associated with events that pose a threat to a patient’s life or 
ability to function. A severe AE (Grade 3 or 4) does not necessarily need to be considered 
serious. For example, a white blood cell count of 1000/mm3 to less than 2000 is considered 
Grade 3 (severe) but may not be considered serious. Seriousness (not intensity) serves as a guide 
for defining regulatory reporting obligations. 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of reported and/or potential AEs (Section 7.2) and the characteristics of an 
observed AE (Section 7.3) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
7.2 Expected Toxicities 
▪ Adverse Events List(s) 
7.2.1.1 
Adverse Event List of Nivolumab 
Events that are listed as very common (experienced in ≥10% of patients) according to the current 
IB ( Version 15 dated June 24 2016) include the following: diarrhea, nausea, fatigue, rash, and 
pruritis . 


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Events that are listed as common (experienced in ≥1% to <10% of patients )include: 
hypothyroidism, hyperthyroidism, hyperglycemia, colitis, stomatitis, mouth ulceration, vomiting, 
abdominal pain, constipation, dry mouth, pyrexia edema ( general and peripheral), hepatitis, 
infusion related reactions, upper respiratory infections, increased lipase, increased amylase, 
increased aspartate aminotrasferase, increase alanine aminotransferase, increased blood bilirubin, 
hyponatremia, decreased appetite, musculoskeletal pain, arthralgias, peripheral neuropathy, 
headache, dizziness, nephritis, pneumonitis, dyspnea, cough, vitiligo, dry skin, erythema, 
alopecia, and hypertension 
Events that are listed as uncommon ≥0.001% of patients to < 1% include the following: 
urticaria, vasculitis, rosacea, psoriasis, erythema multiforme, lung infiltration, tubulointerstitial 
nephritis, renal failure, acute kidney injury, encephalitis, autoimmune neuropathy, facial nerve 
paresis, myasthenic syndrome, demyelization, Guillain-Barre Syndrome, polymyalgia 
rheumatica, histiocytic necrotizing lympadenitis, bronchitis, hypersensitivity, anaphylactic 
reaction, duodenal ulcer, pancreatitis, uveitis, diabetes mellitus, diabetic ketoacidosis, thyroiditis, 
autoimmune hypophysitis, hypopituitarism, adrenal insufficiency, tachycardia, arrhythmias, 
Toxic epidermal necrolysis (including Stevens Johnson Syndrome) is included as a rare risk 
(experienced by ≥0.00001% to <0.001% of patients). 
7.2.1.2 
Other Immune Mediated Adverse Events 
For suspected immune-related adverse reactions, adequate evaluation should be performed to 
confirm etiology or exclude other causes. Based on the severity of the adverse reaction, 
nivolumab should be withheld or discontinued, and corticosteroids administered accordingly. 
Upon improvement, nivolumab may be resumed after corticosteroid taper. If there is recurrence 
of any Grade 3 or 4 immune-related adverse reactions or life-threatening immune-related adverse 
reactions, nivolumab must be permanently discontinued. Rare cases of myotoxicity (myositis, 
myocarditis, and rhabdomyolysis), some with fatal outcome, have been reported with nivolumab. 
If a patient develops signs and symptoms of myotoxicity, close monitoring should be 
implemented, and the patient referred to a specialist for assessment and treatment without delay. 
Based on the severity of myotoxicity, nivolumab should be withheld or discontinued, and 
appropriate treatment instituted. For Grade 3 myocarditis, nivolumab should be permanently 
discontinued. 
The following events have been identified during post approval use of nivolumab. Because 
reports are voluntary from a population of unknown size, an estimate of frequency cannot be 
made. 
• Solid organ and tissue transplant rejection has been reported in patients who have previously 
undergone transplantation and who were subsequently treated with programmed cell death 
1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors, including nivolumab. Treatment 
with nivolumab may increase the risk of rejection in solid organ or tissue transplant 
recipients. 
• Rapid-onset and severe GVHD, some with fatal outcome, has been reported in patients who 
had undergone prior allogeneic HSCT and subsequently received PD-1/PD-L1 inhibitors. 


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Subjects should be screened to determine whether they have undergone a prior allogeneic 
HSCT prior to participating in nivolumab clinical trials. 
• Complications of allogeneic HSCT after treatment with PD-1/PD-L1 inhibitors including 
nivolumab, administered before allogeneic HSCT, may be associated with an increased risk 
of transplant-related complications, including GVHD. Fatal cases have been reported in 
clinical studies. Patients should be monitored closely for early evidence of transplant-related 
complications 
7.2.1.3 
Adverse Event List for Lenalidomide 
Events that have occurred in >10% of individuals treated with lenalidomide include neutropenia, 
anemia, thrombocytopenia, fatigue, rash, diarrhea, constipation, nausea, loss of appetite, itching, 
dry skin, muscle cramps, lack or loss of strength, dizziness, insomnia, swelling of the 
extremities, headache, back and joint pain, fever, cough, upper respiratory infection, and 
dyspnea. 
Events that have occurred in >1% of individuals treated with lenalidomide include risk of DVT, 
PE, and blood clots that could lead to stroke, heart attack, or organ failure, febrile neutropenia, 
atrial fibrillation, pneumonia or lung infections, sepsis, dehydration and renal failure. 
Events that have occurred in <1% of individuals treated with lenalidomide include rare 
treatment-emergent adverse events of angioedema, serious skin reactions including Stevens- 
Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) or an allergic skin reaction 
similar to that seen with thalidomide, tumor lysis syndrome (TLS), tumor flare reaction (TFR), 
and rhabdomyolysis. In addition, lenalidomide has been shown to increase the level of digoxin in 
the blood in some patients. Patients will be instructed to inform their doctor if taking digoxin. 
There may be an increased risk of second cancers in patients who are on lenalidomide 
maintenance therapy after a bone marrow transplant. 
7.2.1.4 
Adverse events list of Dexamethasone 
Events that have occurred in 10-15% of individuals treated with dexamethasone include 
increased appetite, weight gain, sleep disturbance, hypertension, fluid retention, ankle swelling, 
bruising, infection, mood changes, slow wound healing, depression, and hyperglycemia, which 
may lead to fatigue, weight loss, excessive thirst and frequent urination. Events that have 
occurred in 1-9% of individuals treated with dexamethasone include loss of appetite, muscle 
twitching, increased thirst, frequent urination, increased perspiration, diarrhea, nausea, headache, 
bone thinning, spinal fracture or fracture of bones, tachycardia, fungal infections. Events that 
have occurred in <1% of individuals treated with dexamethasone include blurred vision, 
personality changes, stomach ulcers with bleeding that may cause hematemesis, blood in the 
stool and abdominal pain. Other, less frequent, events may include bowel perforation, irritation 
and bleeding of the esophagus, heart failure, allergic reaction that may lead to facial redness, 
shortness of breath, abdominal cramps and hypotension, convulsions, brain swelling, dizziness, 
cataracts, glaucoma and increased blood pressure in the eye, development of diabetes, pancreatic 
inflammation, abdominal swelling, hypokalemia, DVT or PE, malaise, swelling and/or redness 


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of skin, allergic skin reactions, itching, hirsutism, muscle weakness or loss of muscle mass, 
rupture of tendons, menstrual cycle disturbances, facial puffiness, leading to the appearance of a 
“moon face” hormonal disturbances, and hiccups. 
7.3 Adverse Event Characteristics 
• CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
7.4 Expedited Adverse Event Reporting 
▪ Investigators must report to the Overall PI any serious adverse event (SAE) that 
occurs after the initial dose of study treatment, during treatment, or within 30 
days of the last dose of treatment on the local institutional SAE form. 
For multi-institution studies where a DF/HCC investigator is serving as the Overall Principal 
Investigator, each participating institution must abide by the reporting requirements set by the 
DF/HCC. This applies to any medical event equivalent to an unexpected grade 2 or 3 with a 
possible, probable or definite attribution to nivolumab (the study medication), all grade 4 
toxicities, and grade 5 (death) regardless of study phase or attribution. 
7.5 DF/HCC Expedited Reporting Guidelines 
Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy. 
Other investigative sites will report SAEs to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events. A copy of the submitted institutional SAE 
form should be forwarded to the Overall PI within the timeframes detailed in the table below. 
Table 18- DF/HCC Reportable AEs 
Attribution 
Gr. 2 & 3 
AE 
Expected 
Gr. 2 & 3 
AE 
Unexpected 
Gr. 4 
AE 
Expected 
Gr. 4 
AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 


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Unrelated 
Unlikely 
Not required 
Not required 
5 calendar 
days# 
5 calendar 
days 
24 hours* 
Possible 
Probable 
Definite 
Not required 
5 calendar 
days 
5 calendar 
days# 
5 calendar 
days 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to 
be reported. 
* For participants enrolled and actively participating in the study or for AEs occurring within 
30 days of the last intervention, the AE should be reported within 1 business day of learning of 
the event. 
The Overall PI will submit SAE reports from outside institutions to the DFCI OHRS according 
to DFCI IRB policies and procedures in reporting adverse events. 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for 
subject safety). 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated. The investigator must immediately 
notify the BMS, Celgene (or designee) Medical Monitor of this event and complete and forward 
an SAE Form to BMS and Celgene (or designee) within 24 hours and in accordance with SAE 
reporting procedures described in this section. 
Pregnancy 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the Overall PI. Information on this pregnancy will be collected on the BMS Pregnancy 
Surveillance Form. Follow-up information regarding the course of the pregnancy, including 
perinatal and neonatal outcome and, where applicable, offspring information must be reported on 
the Pregnancy Surveillance Form. Please contact the Research Project Manager if you do not 
have this form in your regulatory files. 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on lenalidomide, or within 28 
days of the subject’s last dose of lenalidomide, are considered immediately reportable events. 
Lenalidomide is to be discontinued immediately. The pregnancy, suspected pregnancy, or 
positive pregnancy test must be reported to Celgene Drug Safety immediately by facsimile or 
email using the Pregnancy Initial Report Form. The female subject should be referred to an 
obstetrician-gynecologist, preferably one experienced in reproductive toxicity for further 
evaluation and counseling. 
The Investigator will follow the female subject until completion of the pregnancy, and must 


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54 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form. If the outcome of the 
pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the Investigator should 
report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety immediately by facsimile, or other 
appropriate method, within 24 hours of the Investigator’s knowledge of the event using the SAE 
Report Form. 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form. 
Male Subjects 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking lenalidomide should notify the Investigator, and the pregnant female partner 
should be advised to call their healthcare provider immediately. 
Celgene Drug Safety Contact Information: 
Celgene Corporation 
Global Drug Safety and Risk Management 
Connell Corporate Park 
300 Connell Dr. Suite 6000 
Berkeley Heights, NJ 07922 
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as SAEs. 
There is no specific experience in the management of lenalidomide overdose in patients with 
MM, MDS, or MCL. In dose-ranging studies in healthy subjects, some were exposed to up to 
200 mg (administered 100 mg BID) and in single-dose studies, some subjects were exposed to up 
to 400 mg. Pruritus, urticaria, rash, and elevated liver transaminases were the primary reported 
AEs. No clinically significant changes in ECGs, blood pressure, or pulse rate were observed. 
While no hematologic events were associated with an overdose, such events may be expected 
since in clinical trials; the dose-limiting toxicity was essentially hematologic. In the event of 
overdose, supportive care is advised. 
There is no available information concerning overdose with nivolumab. Depending on the 
symptoms and/or signs leading to the suspicion of overdose, supportive medical management 
should be provided. There is no specific antidote. 


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7.5.1 Protocol-Specific Expedited Adverse Event Reporting Exclusions 
7.5.1.1 
There are no protocol specific exclusions. 
7.6 Expedited Reporting to the Food and Drug Administration (FDA) 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
7.7 Expedited Reporting to Bristol-Myers Squibb (BMS) 
The Overall PI, as study sponsor, will be responsible for all communications with the BMS via 
the MedWatch 3500A form: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/ucm2007307.htm 
With the exception of any serious adverse event that meets the FDA’s criteria for expedited 
reporting, one should follow the reporting requirements and timelines set by the FDA. All SAEs 
and SUSARs should simultaneously be faxed or e-mailed to BMS by each participating site at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
The written report must be completed and supplied to BMS by facsimile or e-mail within 24 
hours. 
7.8 Expedited Reporting to Hospital Risk Management 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy. 
7.9 Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms. AEs reported through expedited processes (e.g., reported to the 


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IRB, FDA, etc.) must also be reported in routine study data submissions. 
8. PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the Nivolumab and lenalidomide 
administered in this study can be found in Section 7. 
8.1 Nivolumab 
8.1.1 Description 
Nivolumab is a fully human monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) 
that targets the PD-1 cell surface membrane receptor. Nivolumab inhibits the interaction of PD-1 
with its ligands, PD-L1 and PD-L2, resulting in enhanced T-cell proliferation and interferon- 
gamma (IFN-γ) release in vitro. 
8.1.2 Form 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) or 40 mg/4 mL (10 mg/mL), is a clear to 
opalescent, colorless to pale yellow liquid, which may contain light (few) particulates. The drug 
product is a sterile, nonpyrogenic, single-use, isotonic aqueous solution formulated at 10 mg/mL 
in sodium citrate, sodium chloride, mannitol, diethylenetriaminepentacetic acid (pentetic acid), 
and polysorbate 80, pH 6.0 and includes a 0.7 mL overfill to account for vial, needle, and syringe 
(VNS) holdup. It is supplied in 10-cc Type I flint glass vials, stoppered with butyl rubber 
stoppers and sealed with aluminum seals. The only difference between the two drug product 
presentations is the vial fill volume. 
8.1.3 Storage and Stability 
The product does not contain a preservative. Vials of nivolumab injection must be stored at 2- 
8C (36-46F) and protected from light, freezing, and shaking. 
After preparation, store the nivolumab infusion either: 
• At room temperature for no more than 4 hours from the time of preparation. This includes 
room temperature storage of the infusion in the IV container and time for administration 
of the infusion or 
• Under refrigeration at 2°C to 8°C (36°F-46°F) for no more than 24 hours from the time of 
infusion preparation. 
• Do not freeze. 
If a temperature excursion is noted at your site, the site must complete a temperature excursion 
form provided by the lead site. The lead site will then submit to Bristol- Myers Squibb to assess 
if the drug is appropriate for use, or should be destroyed. 


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8.1.4 Compatibility 
Do not co-administer other drugs through the same intravenous line. 
Flush the intravenous line at end of infusion. 
No incompatibilities between nivolumab and polyvinyl chloride (PVC), non PVC/non DEHP 
(di(2-ethylhexyl)phthalate) IV components, or glass bottles have been observed. 
8.1.5 Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 
8.1.6 Availability 
Nivolumab for injection will be supplied free of charge by BMS. The study team will provide all 
external sites with a study specific order form 
8.1.7 Preparation 
Visually inspect drug product solution for particulate matter and discoloration prior to 
administration. Nivolumab is a clear to opalescent, colorless to pale-yellow solution. Discard 
the vial if the solution is cloudy, is discolored, or contains extraneous particulate matter other 
than a few translucent-to-white, proteinaceous particles. Do not shake the vial. 
• Withdraw the required volume of nivolumab and transfer into an intravenous container. 
• Dilute nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
Injection, USP, to prepare an infusion with a final concentration ranging from 1 mg/mL 
to 10 mg/mL. 
o Mix diluted solution by gentle inversion. Do not shake. 
o Discard partially used vials or empty vials of nivolumab. 
8.1.8 Administration 
Administer the infusion over 60 minutes (+/- 10 minutes) through an intravenous line containing 
a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 
micrometer). 
Nivolumab will be administered at a flat dose of 240 mg as an intravenous infusion over 
60 minutes (+/- 10 minutes) every 2 weeks (Days 1 and 15 of each 28 day cycle). The 
administration of nivolumab infusion must be completed within 24 hours of preparation. 
8.1.9 Ordering 


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Each participating institution will order nivolumab directly from the supplier Bristol Myers 
Squibb Pharmaceuticals (BMS). A participating site may order the agent(s) only after the initial 
IRB approval for the site has been forwarded by the Coordinating Center. A study specific order 
form will be supplied by the lead site. 
8.1.10 Accountability 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form. (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
8.1.11 Destruction and Return. 
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible DFCI Study Monitor or designee unless study drug containers must be immediately 
destroyed as required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met: 
• On-site disposal practices must not expose humans to risks from the drug. 
• On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances. 
• Written procedures for on-site disposal are available and followed. The procedures must 
be filed with the site’s SOPs and a copy provided to BMS upon request. 
• Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification (ID) of the person disposing the 
containers. The method of disposal, (eg, incinerator, licensed sanitary landfill, or licensed 
waste disposal vendor) must be documented. 
• Accountability and disposal records are complete, up-to-date, and available for the 
Monitor to review throughout the clinical trial period. 
If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of study drug. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible Study Monitor. 


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8.2 Lenalidomide 
8.2.1 Description 
Lenalidomide (REVLIMID®), a thalidomide analogue, is an immunomodulatory agent with 
antiangiogenic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H- isoindol-2- 
yl) piperidine-2,6-dione and it has the following chemical structure: 
3-(4-amino-1-oxo  1,3-dihydro-2H-isoindol-2-yl)  piperidine-2,6-dione. 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 
259.3. 
8.2.2 Form 
Lenalidomide is off-white to pale-yellow solid powder. It is soluble in organic solvent/water 
mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and 
low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 
0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically 
active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of 
zero. 
Lenalidomide is available for this study as 5 and 25 mg capsules for oral administration. Each 
capsule contains lenalidomide as the active ingredient and the following inactive ingredients: 
lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. 
8.2.3 Storage and Stability 
At the study site, all investigational study drugs will be stored in a locked, safe area to prevent 
unauthorized access. Lenalidomide should be stored at room temperature away from direct 
sunlight and protected from excessive heat and cold. 
8.2.4 Handling 
Females of childbearing potential should not handle or administer lenalidomide unless they are 
wearing gloves. 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 
8.2.5 Availability 
Lenalidomide supply will be obtained through commercial supply. 
8.2.6 Preparation 
Lenalidomide is an oral drug, and does not require specific preparation details. 


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8.2.7 Administration 
Lenalidomide will be given daily on days 1-21 of each 28 day cycle. At all times when 
dispensing lenalidomide protocol therapy, study site personnel will review the instructions, 
printed on the packaging, with participants. 
8.2.8 Ordering 
Commercial supply of lenalidomide (Revlimid®) will be ordered through the participant’s 
insurance and will be filled through a retail pharmacy, and shipped on a per cycle basis to the 
patient’s home or to the treating institution’s outpatient pharmacy, whichever the study team 
prefers. Lenalidomide will be provided in accordance with the Celgene Corporation’s Revlimid 
REMS® program. Per standard Revlimid REMS® program requirements (as listed in section 
3.1.7), all physicians who prescribe lenalidomide for research subjects enrolled into this trial, 
and all research subjects enrolled into this trial, must be registered in, and must comply with, all 
requirements of the Revlimid REMS® program. 
8.2.9 Accountability 
As drug is from commercial supply, sites should keep records per their institutional policies. 
8.2.10 Destruction and Return 
Unused or returned supplies of lenalidomide should be destroyed and documented according to 
institutional policies. 
8.3 Dexamethasone 
8.3.1 Description 
Dexamethasone is a synthetic adrenocortical steroid. Corticosteroids are naturally occurring 
chemicals produced by the adrenal glands located above the kidneys. Corticosteroids affect the 
function of many cells within the body and suppress the immune system. Corticosteroids also 
block inflammation and are used in a wide variety of inflammatory diseases affecting many 
organs. 
The molecular weight for dexamethasone is 392.47. It is designated chemically as 9- fluoro- 
11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione. Dexamethasone is stable in air 
and almost insoluble in water. 
8.3.2 Form 
Dexamethasone is a white to practically white, odorless, crystalline powder. It is available in 2 or 
4 mg tablets (commercially) for oral administration. Each tablet contains dexamethasone as the 
active ingredient, and the following inactive ingredients: calcium phosphate, lactose, magnesium 
stearate, and starch. The tablet shell may contain the following: D&C Yellow 10, FD&C Yellow 


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6, and/or FD&C Blue 1. 
8.3.3 Storage and Stability 
At the study site, all investigational study drugs will be stored in a locked, safe area to prevent 
unauthorized access. Dexamethasone should be stored at controlled room temperature, 68-77◦F 
(20-25◦C) and not frozen, and according to label requirements. 
8.3.4 Handling 
Dexamethasone should be handled by trained pharmacy staff. The use of gloves and other 
appropriate protective clothing is recommended as necessary. 
8.3.5 Availability 
Dexamethasone supply will be obtained through commercial supply. 
8.3.6 Preparation 
Dexamethasone is an oral drug, and does not require specific preparation details. 
8.3.7 Administration 
During induction therapy, participants will receive dexamethasone as a single oral daily dose of 
40mg on Days 1, 8 and 15 of cycles 1-6. 
8.3.8 Ordering 
Dexamethasone will be ordered from retail pharmacy through commercial drug supply. 
8.3.9 Accountability 
As drug is from commercial supply, sites should keep records per their institutional policies. 
8.3.10 Destruction and Return 
Unused or returned supplies of dexamethasone should be destroyed and documented according 
to institutional policies. 
9. BIOMARKER, CORRELATIVE, MRD ASSESSMENT AND SPECIAL STUDIES 
The mandatory correlative studies will consider several potential predictive biomarkers. As 
discussed in the appropriate sections of the protocol, mutations such as N-RAS, K-RAS, MYC 
up-regulation, and gain or loss of chromosome 1q or 1p are hypothesized to correlate with 
disease progression. The sample size of this phase-2 study, 41 patients, will allow exploratory 
analyses on TTP correlation with biomarkers. The number of biomarkers and the associated 


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multiplicities will only allow us to provide empirical point estimates and confidence intervals 
for TTP-biomarker concordance indexes. 
Please refer to Appendix B for a full sample collection table. This trial will provide samples from 
consenting SMM patients treated with Nivolumab, lenalidomide and dexamethasone to 
comprehensively characterize the MM genome and immune cells function and define molecular 
events driving development and progression of MM. 
We will attempt to obtain samples on all patients at several time points during the study, 
including before therapy, at the end of cycle 6, at the time of response determination (CR),at 
disease relapse, and at the time of completion of the study. It is anticipated that approximately 
90% of samples collected will be adequate for sequencing studies proposed. 
The tumor cells will be collected as described below. From these samples, high quality DNA (for 
tumor cells) and RNA (for tumor cells and immune cells) for both exome sequencing and RNA 
sequencing will be obtained. Germline DNA will be also obtained from a buccal swab from all 
patients at any time point of the study. Samples collected for the purpose of research at Dana 
Farber Cancer Institute will be banked and retained for research use indefinitely. 
Peripheral blood and bone marrow derived mononuclear cells will undergo immunologic 
assessments to assess the impact of therapy on general measures of cellular immunity, MM 
reactive T cells, and antigen specific immunity. The percentage of circulating and bone marrow 
derived regulatory immune cells will be determined. 
9.1 Minimal residual disease assessment (MRD) 
MRD will be assessed using Adaptive’s LymphoSIGHT platform as part of normal clinical care. 
Bone marrow samples will be collected per the collection time described in the table of sample 
collection. The collection kits and shipping supplies will be provided to the sites by Adaptive 
Inc. These samples will be packaged whole, and shipped to Adaptive, Inc. the same day priority 
overnight. Using Adaptive’s LymphoSIGHT platform, rearranged immunoreceptor loci from 
genomic DNA will be extracted, amplified, and sequenced using V and J segment primers for 
each immunoreceptor gene. Tumor-specific clonotypes will be identified for each patient based 
on their high prevalence in peripheral blood. Sequences will be analyzed using standardized 
algorithms for clonotype determination. Adaptive MRD levels will be quantified using spiked-in 
reference sequences. 
Adaptive Inc. will hold samples for up to 6 months after they have been analyzed, and then will 
subsequently be destroyed. 
The processing of these samples will be billed to the patient’s insurance, and therefore, all 
information requested on the online test ordering portal must be filled out completely, and not 
de-identified. 
For Adaptive Inc. samples, use the packing supplies provided in each individual kit and follow 
the directions below to establish your account and order the required testing: 


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1. Create an online ordering profile for your physician and any staff who may order this test 
for your patients using the Physician Registration Form provided to you by the lead site. 
a. Enter all information under the “Ordering Physician” as the site 
responsible PI for the trial at your site 
b. “Online Access” should be checked off to enable online portal ordering of 
tests 
c. The “Designated Point of Contact” should be one non-physician member 
of the team as the contact for any and all study/order related questions 
d. The “Designated Point of Contact” should be the person ( along with the 
physician) who will have access to the patient’s results and be able to 
send them to the lead site 
e. Be sure to include your own practice as the Primary Institution 
f. Additional points of contact should list any other members of the study 
team who may place orders for the patients on the trial 
g. Submit the form to clinicalservices@adaptivebiotech.com to establish 
your site 
2. Order kits for your site by placing an order to clinicalservices@adaptivebiotech.com ; 
ensure that you identify yourself as being part of trial 16-242; Overall PI Irene Ghobrial, 
MD and provide the proper shipping address for the kits 
3. To order a ClonoSEQ ID test(also known as the B-Cell Clonality Test required at 
baseline/screening) or a Follow up Test (MRD or Tracking Test) for a patient: 
a. After logging into your account, click “New Order” 
b. Choose Ordering Physician associated with 16-242 
c. Under Trial/Study Code, enter 16-242 
d. Click Pick a Patient, and then Create New Patient ( for follow up/MRD 
samples, select established patient- Their information will populate the 
form) 
e. Enter patient complete demographics (new patients only) 
f. Under Diagnosis (es)/Clinical Indication ICD Codes, Multiple Myeloma 
C90.00 not having achieved a remission should be selected. 
g. Under clonoSEQ Assay, choose B Cell Clonality Test (Diagnostic ID test) 
if it is the baseline sample. For follow up samples, select Tracking Test 
( Minimal Residual Disease “MRD” test) 
h. Under Billing Information, select Insurance, and enter the patient’s 
complete insurance information (new patients only) 
i. Under patient status, select “outpatient” and enter your full institution 
name 
j. Enter any secondary insurance information for the patient if applicable 
(new patients only) 
k. Enter the patient’s complete billing address (new patients only) 
l. Under Specimen Information, select “ Shipping Specimen to Adaptive”, 
Specimen Type: fresh bone marrow and the collection date 


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m. The unique specimen ID should be chosen by the site and able to be 
connected to the patient later on ( you may use either letters or numbers or 
a combination of the two) 
n. Under special instructions, please enter Fed Ex tracking number of the 
package 
o. Print out a copy of the Test Requisition Form ( TRF) and have either the 
Point of Contact, Additional Contacts or the Physician listed on the 
Physician Registration Form sign the designated signature space, and 
include it in the shipment 
p. Retain retain a copy of the Fed Ex Waybill in the patient’s research folder 
attached to the copy of the TRF and file in the patient’s research chart 
q.  Please email Patrick Henrick (Phenrick@dfci.harvard.edu) and Alexandra 
Savell (asavell@dfci.harvard.edu) to notify of an outgoing shipment. 
Diagnostic Portal Log In: 
https://diagnostics.adaptivebiotech.com/account/login 
To order kits for your site: Please order via clinicalservices@adaptivebiotech.com and 
reference the study number, 16-242 , and include the address where the kits should be shipped 
Results: The results of these tests will be sent to the lead site in the form of a PDF/scanned 
document emailed to the study team listed abovein real time. The patient’s PHI should be 
redacted appropriately with only the patient’s date of birth, and study specific identifier (initials 
and assigned study number) visible. 
* External sites may choose to use an alternate method/source to bill for this test, if 
they so choose. This must first be discussed and approved by the lead site prior to ordering any 
test. 
9.2 Bone Marrow Aspirate Samples 
Collection of bone marrow aspirate specimens for exploratory analysis are requested at the times 
of all standard of care bone marrow collections. Specimens will be shipped (via traceable carrier) 
to and subsequently processed, analyzed, and stored at Dana-Farber Cancer Institute. 
9.2.1 Specimens Requested 
2 Purple Top Tubes (K2EDTA), 10mL each(3 tubes at baseline). Specimens must be 
collected on Mondays to Thursdays for same-day shipment. For complete sample 
collection table, please refer to Appendix B 
9.2.2 Processing Information 
Package tubes at room temperature and wrap in a liberal amount of paper towel 


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around the tubes to ensure adequate insulation of the specimen(s) and absorption in 
the event of a breakage. Place wrapped specimen in a biohazard labeled Ziploc bag 
with a fridge pack and zip close. Wrap bubble wrap around the bag and place in a 
cardboard box. If space remains in the box, stuff with extra paper towel to reduce 
shifting of samples. Complete the shipping requisition form using the address listed 
below. Prepare the package for shipping, applying packing tape as needed. Ship the 
package using FedEx First Priority Overnight delivery the same day the sample was 
collected. Please only ship Monday-Thursday. Please see Appendix B and C for 
Collection Schedule and Requisition Form 
9.2.3 Shipping Information for Bone Marrow Aspirate Specimens sent to DFCI 
Label all specimens with the following: Subject Initials, Subject study number (will 
include protocol number), Visit at which sample was drawn (screening, response, 
Cycle X, etc. or progression), Date sample drawn (mm/dd/yyyy), Time sample 
drawn (24 hour clock). 
Shipping Instructions 
Shipments must be sent on the day of collection and cannot be batched. 
1. Samples should be placed in a sealed biohazard bag and placed in a box with a fridge 
pack. 
2. An inventory sheet including a complete list of samples shipped (patient number, 
timepoint, study #) must accompany each shipment. Please sign and date the requisition 
form. 
3. An electronic copy (Word or Excel) of the sample requisition form must also be sent via 
email. The listing must also include a contact name, address and phone number of the 
person who is responsible for the shipment. 
4. Please email Patrick Henrick (Patrick_Henrick@dfci.harvard.edu) and Alexandra Savell 
(AlexandraE_Savell@dfci.harvard.edu) to notify of an incoming shipment. 
5. Please ship Monday to Thursday as shipments cannot be received on weekends and/or 
on holidays. 
6. Once drawn, samples may be shipped via overnight air to: 
Irene Ghobrial, MD, Dana-Farber Cancer Institute, 77 Avenue Louis Pasteur HIM 
Building room 240, MA551, Boston, MA 02215 Phone: (617) 582-9857 Fax: (617) 
632-8535. Please retain a copy for site record maintenance. Please see Appendix B 
and C for Collection Schedule and Requisition Form 


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9.3 
Peripheral Blood Samples 
Collection of peripheral blood specimens (including serum and plasma) for 
exploratory analysis are requested for all patients on this trial. Purple top tube 
collections will be requested at the same timepoints as bone marrow samples for 
correlative studies (see Section 10 and Appendix B for specific time points and 
instructions). These specimens should be taken at the time of routine blood 
collection required for this study. Specimens will be processed on site according to 
instructions below and shipped (via traceable carrier) to Dana-Farber Cancer 
Institute. Once the shipment is received, samples will be subsequently processed, 
analyzed, and stored at Dana-Farber indefinitely. Please see Appendix B and C for 
Collection Schedule and Requisition Form 
Specimens Required: 2 x 10mL purple top tubes (K2EDTA) and 1 x 10 mL Streck 
tube should be collected Mondays to Thursdays for same-day shipment. 
• Label all specimens with the following: 
o Subject Initials, Subject study number (will include protocol number), Visit at 
which sample was drawn (screening, response, Cycle X, progression etc.), Date 
sample drawn (mm/dd/yyyy), Time sample drawn (24 hour clock) 
9.3.1 Processing Information: 
Package tubes at room temperature and wrap in a liberal amount of paper towel around the tubes 
to ensure adequate insulation of the specimen(s) and absorption in the event of a breakage. Place 
wrapped specimen in a biohazard labeled Ziploc bag with a fridge pack and zip close. Wrap 
bubble wrap around the bag and place in a cardboard box. If space remains in the box, stuff with 
extra paper towel to reduce shifting of samples. Complete the shipping requisition form using the 
address listed below. Prepare the package for shipping, applying packing tape as needed. Ship 
the package using FedEx or UPS First Priority Overnight the same day the sample was collected. 
Only ship Monday-Thursday. 
With each shipment, please include the following: 
1. Samples should be placed in a sealed biohazard bag and placed in a box with a fridge 
pack. 
2. An inventory sheet including a complete list of samples shipped (patient number, 
timepoint, study #) must accompany each shipment. Please sign and date the form, and 
retain a copy for site record maintenance. See Appendix C for Sample Requisition 
Form 
3. An electronic copy (Word or Excel) of the sample list must also be sent via email and 
include the tracking number of the package. The listing must also include a contact name, 
address and phone number of the person who is responsible for the shipment. 


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4. Please email the lead site Project Manager to notify of an incoming shipment. 
5. Please ship Monday to Thursday as shipments cannot be received on weekends and/or on 
holidays. 
6. Once drawn, samples may be shipped via overnight air to: 
Irene Ghobrial, MD, Dana-Farber Cancer Institute, 77 Avenue Louis Pasteur HIM 
Building room 240, MA551, Boston, MA 02215 Phone: (617) 582-9857 Fax: (617) 632- 
8535. Please retain a copy for site record maintenance. 
9.4 Buccal Swab Samples 
9.4.1 Collection, Processing, and Shipping 
1. Ideally have the patient rinse mouth out with water immediately prior to sample 
collection at least one hour after eating, drinking, or brushing teeth 
2. Pull open the package from one end 
3. Remove the swab from the tube, taking care not to touch the white swab head with 
your fingers 
4. Insert the swab into your mouth and rub firmly against the inside of your cheek or 
underneath lower and upper lip. For standard DNA collection, rub for 1 minute and 
in all cases, for a minimum of 20 sections. Please use reasonable, firm, solid 
pressure 
5. Slide the plastic cap over the swab handle with the flat side of the cap facing 
upwards and the swab facing downwards 
6. Insert the swab into the clear plastic tube and push the cap into place- Next, hold the 
cap while pulling the swab handle outwards to release the swab material into the 
tube 
7. Close the cap by pushing the stopper fully into the cap ensuring the stopper is flush 
with the cap- The tube is now completely sealed 
8. Mail same day, ambient to the lead site for processing. The caps can be placed in an 
envelope or other container with the trial number, patient study number (if 
registered), date of birth, site name, collection date and time 
9. Two swabs should be used for each patient to ensure adequate sample for analysis 


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10. STUDY CALENDAR 
Screening evaluations are to be conducted within 28 days of registration. Imaging assessments that are completed within 6 
weeks of registration need not be repeated at screening. If a patient had a bone marrow core biopsy done within 6 weeks of 
registration, a bone marrow aspirate sample need only be collected for baseline and research purposes. Baseline 
assessments are to be conducted on C1D1 of initial therapy and should be considered separate from screening evaluations. 
If screening assessments are performed within 7 days of C1D1, disease assessments (SPEP, UPEP, Immunofixation, Free 
light chain assay, quantitative immunoglobulins) do not need to be repeated. Lab values that are used to prove eligibility 
for patients with progressive (evolving) smoldering myeloma do not need to be within the 21 day window, but screening 
values will need to be established in window. All assessments must be performed prior to administration of any study 
medication. See below for detailed scheduled of assessments. Study medications will be administered according to the 
schedule and guidelines outlined in Section 5. 
Pre-registration 
Cycles 1-12 (28 days) 3 
Follow-Up 
 
 
Tests and procedures 
 28 
days 
prior to 
registrat 
ion 
 21 
days 
prior to 
registrat 
ion 
Day 1 of 
cycles 1- 
61 
Day 1 of 
cycles 7-12 
Cycle 7 
Day 1 
and to 
confirm 
CR8 
End of 
Treatment18 
Every 3 
Months11 
History and exam, height, weight. 
Performance Status 
X 
X 
X 
X 
X 
Response Assessment17 
X 
X 
X 
X 
Toxicity Notation 
X 
X 
X 
Hematology group (WBC w/ diff, 
PLT, Hgb, ANC) 
X 
X 
X 
X 
X 
Chemistry4 
X 
X 
X 
X 
X 
Direct & total bilirubin2 
X 
X 
X 
X 
Free light chain assay 
X 
X 
X 
X 
X 
Serum and Urine Immunofixation 
(SPEP and UPEP) with quantitative 
immunoglobulins9 
X 
X 
X 
X 
X 
2M, CRP, LDH16 
X 
X 
X 
X 
TSH, Free T4, Free T3 
X 
X 
X 
X 
Metastatic Bone Survey and Spine 
MRI OR PET/CT only10 
X 
X 
EKG15 
X 
X 
Serum pregnancy test12 
X 
Unilateral bone marrow aspirate and 
biopsy5 
X 
X 
X 
Research bone marrow aspirate6 
X5 
X6 
X6 
Research Blood7 
X7 
X7 
X7 
X7 
X7 
Buccal Swab13 
X 
1- Cycle 1, Day 1 laboratory values need to meet eligibility criteria 
2- Direct bilirubin to be obtained if total bilirubin is abnormal. 
3- Scheduling allows for +/- 7 days all cycles. 
4- Chemistry includes sodium, potassium, chloride, bicarbonate, bun, creatinine, calcium, glucose, albumin, ALT (SGPT), total protein, AST (SGOT), total bilirubin, 
magnesium, and phosphorus. 
5- A bone marrow biopsy is required within 6 weeks of registration. A bone marrow aspirate for clinical and research purposes is required pre-treatment and may be 
performed up to 28 days prior to registration. Both core and aspirate are required any time during the course of the study to confirm CR, and is also required at C7D1 
6- Research bone marrow aspirate and biopsy at the same time as clinically indicated bone marrow biopsy and to confirm response. 


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7- Peripheral blood samples for correlative studies may be done at any time pre-treatment, though baseline and C1D1 samples should be considered separate time 
points. 
8- If C7D1 or confirmation of response BM aspirate and core biopsy was performed within 3 weeks of either timepoint, the procedure need not be repeated. At 
minimum, an aspirate sample is required 
9- Disease assessment/response assessment is required each Day 1 starting with C2-If the participant’s disease response is not followed primarily via a UPEP (24 hour 
urine collection) and Urine immunofixation, these tests may be done only at screening, end of treatment, and every 3 months during treatment. 
10-A CD of scans at screening and end of treatment is required to be sent to the lead site for central review. Screening scans should be sent with the eligibility packet to 
the lead site- This requirement includes a full body skeletal survey in addition to spinal MRI OR the patient may have only a low dose PET CT 
11- Follow-up should occur every 3 months (+/- 14 days) for up to 3 years after end of treatment. 
12- Women of child-bearing potential must abide by revlimid REMS procedures and may require additional pregnancy testing as described in section 3.1.7. 
13- Buccal swab may be collected at any time throughout the study but should be collected pre treatment on C1D1 
14- Thyroid labs are required at screening, C3D1, C6D1 and every 3 cycles thereafter, at end of treatment, and at any time that it is clinically indicated 
15- Alert Overall PI immediately if there is concern for cardiac toxicity (At minimum, the following should be performed: cardiology consult, EKG, echocardiogram, 
and labs CPK and troponin; refer to section 6.2.7 for more details 
16- B2M, CRP, and LDH are required at screening, C3D1, C6D1 and every 3 cycles thereafter, at end of treatment, and at any time that it is clinically indicated 
17- A disease response assessment will be required at every Day 1 starting with Cycle 2, end of treatment, and every follow up visit ( q3 months) until completion, 
withdrawal, disease progression, subsequent therapy or death 
18- All end of treatment assessments will be performed within 14 days from the date that the decision to end treatment was made by the study team 
11. MEASUREMENT OF EFFECT 
11.1 Development of symptomatic disease 
In this study, the final endpoint is development of symptomatic MM that requires therapy. 
This is defined as one of the following criteria (≥1 CRAB Criterion and Myeloma Defining Events ≥1 MDE): 
• Increased calcium levels (corrected serum calcium >0.25 mmol/dL above the upper limit of normal 
or >2.75 mmol/dL) due to myeloma 
• Renal insufficiency (attributable to myeloma); 
• Anemia (Hb 2g/dL below the lower limit of normal or <10g/dL) due to myeloma 
• Bone lesions (lytic lesions or generalized osteoporosis with compression fractures) 
• Myeloma Defining Events (MDE) as follows: 
o Clonal bone marrow plasma cell percentage ≥ 60%7 
o An abnormal FLC-ratio ≥100 (involved kappa) or <0.01 (involved lambda)8 
o 2 or more focal lesions on MRI or PET-CT studies9,10 
For measurement of response: 
The disease response will be assessed using criteria based on the International Myeloma Working Group 
Uniform Response Criteria in Section 11.2.2.1 or FreeLite™ Disease Response Criteria in Section 11.2.2.2. 
Disease response by the Modified EBMT Response Criteria in Section 11.3.2.3 will also be collected on 
participants as a secondary measure. 
The same method of assessment and technique should be used for disease measurement at baseline and 
during follow-up. Disease response should be confirmed by two consecutive assessments. 
11.2 Antitumor Effect 
11.2.1 Methods for Evaluation of Disease 
All baseline evaluations should be performed on Cycle 1, Day 1 of initial therapy. Response will be assessed 


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70 
every cycle for the first 6 cycles and then every 3 months in the maintenance phase. Response will be assessed 
by M-protein quantification, protein electrophoresis and immunofixation from serum and a 24-hour urine 
collection. A serum sample for FreeLiteTM testing will be obtained. In addition, bone marrow aspiration and 
biopsy, as well as skeletal survey will be performed to determine overall response or confirm response. 
The same method of assessment and technique should be used for disease measurement at 
baseline and during follow-up. 
11.2.2 Response Criteria 
A confirmation measurement for disease response assessments is required in this protocol. 
11.2.2.1 
International Myeloma Working Group Response Criteria 
Response criteria for all categories and subcategories of response except CR are applicable only to 
patients who have ‘measurable’ disease, as defined in Section 11.1.1 All 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. 
Response 
Criteria for Response 
 
 
 
 
Stringent CR 
(sCR) 
CR as defined below plus normal free light chain ratio and absence of 
clonal cells in bone marrow* by immunohistochemistry or 
immunofluorescence.** 
*Confirmation with repeat bone marrow biopsy is not needed. 
**Presence/absence of clonal cells is based upon the k/λ ratio. An abnormal 
k/l ratio by immunohistochemistry and/or immunofluorescence requires a 
minimum of 100 plasma cells for analysis. An abnormal ratio reflecting 
presence of an abnormal clone is k/λ of > 4:1 or < 1:2. 
 
Complete 
Response (CR) 
Negative immunofixation on the serum and urine and disappearance of 
any soft tissue plasmacytomas and <5% plasma cells in bone marrow. 
*Confirmation with repeat bone marrow biopsy is not needed. 
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 <100mg per 24 hours. 
Partial Response 
(PR) 
> 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by > 
90% or to < 200mg per 24 hours. If the serum and urine M-protein are 


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71 
 
unmeasurable, a > 50% decrease in the difference between involved and 
uninvolved free light chain levels is required in place of the M-protein criteria 
(definition of measurable disease in Section 10.2.3). If serum and urine M-protein 
are unmeasurable, and serum free light assay is also unmeasurable, > 50% 
reduction in plasma cells is required in place of M-protein, provided baseline bone 
marrow plasma cell percentage was > 30%. In addition to the above listed criteria, 
if present at baseline, a > 50% reduction in the size of soft tissue plasmacytomas is 
also required. 
Stable Disease 
(SD) 
Not meeting criteria for CR, VGPR, PR or progressive disease. This 
is not recommended as an indicator of response; stability of disease is 
best described by providing the time to progression estimates. 
 
 
 
 
Progressive 
Disease (PD) 
> 25% increase of serum M-protein (which must also be an absolute increase of > 
0.5 g/dL) and/or urine M-protein (which must also be an absolute increase of > 200 
mg/24hr). If serum and urine M-protein are unmeasurable, there must be an 
absolute increase of > 10 mg/dL between involved and uninvolved FLC levels. PD 
is also measured by an absolute increase in bone marrow plasma cells > 10%. In 
addition to the above listed criteria, progression may also be measured by a definite 
development of new bone lesions or soft tissue plasmacytomas or definite increase 
in the size of existing bone lesions or soft tissue plasmacytomas or 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. 
11.2.2.2 
FreeLite™ Disease Response Criteria 
Response 
Criteria for Response 
 
 
 
 
 
Complete Response (CR) 
For those patients being followed by serum free light 
chain (and NO measurable serum or urine M-spike), 
which were immunofixation negative at enrollment, 
normalization of serum free light chain ratio. 
Normalization is defined as the serum free light 
chain ratio being within the normal range. If the 
serum free light chain ratio is not within the normal 
range, but the individual kappa and lambda light 
chain values are within normal range, this may be 
considered CR. 
 
Partial Response (PR) 
If only measurable parameter is serum 
immunoglobulins free light chain (FLC), EITHER 


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Criteria for Responsea 
Response 
 
of the following changes qualify as partial response: 
• ≥50% decrease in the difference between 
involved and uninvolved FLC levels from the 
lowest response level, which must also be an 
absolute increase of at least 10 mg/dL 
OR 
• ≥50% decrease in the level of involved FLC 
AND a ≥50% decrease in the ratio of 
involved/uninvolved FLC from the lowest 
response level. 
 
 
 
 
 
 
Progressive Disease (PD) 
If only measurable parameter is serum 
immunoglobulins free light (FLC), EITHER of 
the following qualify as progression: 
• ≥50% increase in the difference between 
involved and uninvolved FLC levels from the 
lowest response level, which must also be an 
absolute increase of at least 10 mg/dL 
OR 
• ≥50% increase in the level of involved FLC 
AND a ≥50% increase in the ratio of 
involved/uninvolved FLC from the lowest 
response level. 
11.2.2.3 
Modified EBMT Response Criteria 


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Complete Response 
(CR) 
Requires all of the following: 
Disappearance of the original monoclonal protein from the blood and urine on at 
least two determinations for a minimum of six weeks by immunofixation studies. 
<5% plasma cells in the bone marrow on at least two determinations for a 
minimum of six weeks. b 
No increase in the size or number of lytic bone lesions (development of a 
compression fracture does not exclude response).c 
Disappearance of soft tissue plasmacytomas for at least six weeks. 
 
Near Complete Response 
(nCR) 
Requires the following: 
Same as CR, but immunofixation studies continue to show presence of the 
monoclonal protein 
Very Good Partial 
Response 
(VGPR) 
Requires the following: 
> 90% reduction in serum M-protein plus urine M-protein level <100mg per 24 
hours on at least two determinations for a minimum of six weeks. 
 
 
 
 
 
 
 
Partial response (PR) 
PR includes participants in whom some, but not all, criteria for CR are fulfilled 
providing the remaining criteria satisfy the requirements for PR. Required all of 
the following: 
≥50% reduction in the level of serum monoclonal protein for at least two 
determinations six weeks apart. 
If present, reduction in 24-hour urinary light chain excretion by either ≥90% or to < 
200 mg for at least two determinations six weeks apart. 
≥50% reduction in the size of soft tissue plasmacytomas (by clinical or 
radiographic examination) for at least six weeks. 
No increase in size or number of lytic bone lesions (development of compression 
fracture does not exclude response).c 


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Minimal response (MR) 
MR included participants in whom some, but not all, criteria for PR were 
fulfilled, providing the remaining criteria satisfied the requirements for MR. 
Required all of the following: 
≥25% to 49% reduction in the level of serum monoclonal protein for at least two 
determinations six weeks apart. 
If present, a ≥50 to 89% reduction in 24-hour light chain excretion, which still 
exceeds 200 mg/24 h, for at least two determinations six weeks apart. 
≥25-49% reduction in the size of plasmacytomas (by clinical or radiographic 
examination) for at least six weeks. 
No increase in size or number of lytic bone lesions (development of compression 
fracture does not exclude response).c 
No change (NC) 
Not meeting the criteria for MR or PD. 
 
 
 
 
 
 
 
 
Progressive disease 
(PD) 
(for participants not in 
CR) 
Requires one or more of the following: 
>25% increased in the level of serum monoclonal paraprotein, which must also be 
an absolute increase of at least 5 g/L and confirmed on a repeat investigation. 
>25% increased in 24-hour urinary light chain excretion, which must also be an 
absolute increase of at least 200 mg/24 h and confirmed on a repeat investigation. 
>25% increased in plasma cells in a bone marrow aspirate or on trephine biopsy, 
which must also be an absolute increase of at least 10%. 
Definite increase in the size of existing lytic bone lesions or soft tissue 
plasmacytomas. 
Development of new bone lesions or soft tissue plasmacytomas (not including 
compression fracture). 
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8 
mmol/L not attributable to any other cause). 


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a Based on the criteria reported by Blade et al., 1998. 
b Per Blade et al., 1998, if absence of the monoclonal protein is sustained for 6 weeks it is not necessary to repeat the bone marrow except in participants with 
nonsecretory myeloma where the marrow examination must be repeated after an interval of at least 6 weeks to confirm CR. 
c Per Blade et al., 1998, skeletal X-Rays are not required for the definition of response, but if performed there must be no evidence of progression of bone disease 
(no increase in size or number of lytic bone lesions). 
d It is suggested that the reference point for calculating any increase should be the lowest value of the preceding confirmed response (MR, PR or CR) or the 
baseline value if there is no previous confirmed response. 
e Other clinical data may be requested by the IRC, as necessary, to assess the cause of the hypercalcemia. 
11.2.3 Criteria for Molecular CR and Minimal Residual Disease (MRD) measurement 
We will measure MRD in patients who achieve CR to determine the number of patients who are MRD negative 
vs MRD positive. 
11.2.3.1 
MRD by LymphoSIGHT (Adaptive Inc.) 
MRD will be carried out according to the LymphoSIGHTTM method (Adaptive Inc, Seattle, WA) 61. Prior 
studies have compared this technique to the traditional MRD immunofluorescence technique, as previously 
reported 62 and showed that MRD by LymphoSight is a sensitive method that can be used in future clinical 
practice. 
For MM diagnostic samples, genomic DNA will be amplified using locus-specific primer sets for the 
immunoglobulin heavy-chain locus (IGH) complete (IGH-VDJH), IGH incomplete (IGH-DJH), and 
immunoglobulin κ locus (IGK). The amplified product will be subjected to sequencing, and the sequences and 
frequencies of the different clonotypes in the sample will be obtained. Myeloma gene rearrangements will be 
identified. Patients in whom a high-frequency myeloma clone (>5%) is not identified will be excluded from the 
MRD analysis. MRD will be assessed in patients with a high-frequency myeloma clone using the IGH-VDJH 
and IGK or IGH-VDJH, IGH-DJH, and IGK assays. Once the absolute amount of total cancer-derived 
molecules present in a sample will be determined, a final MRD measurement will be calculated, providing the 
number of cancer-derived molecules per 1 million cell equivalents. In cases in which 2 or more tumor clones 
existed, the clone with the highest MRD value will be reported. Molecular CR will be defined according to the 
International Myeloma Working Group (IMWG) consensus recommendations63. 
Required at least one of the following: 
Reappearance of serum or urinary paraprotein on immunofixation or routine 
electrophoresis confirmed by at least one follow-up and excluding oligoclonal 
immune reconstitution. 
≥5% plasma cells in the bone marrow aspirate or biopsy. 
Development of new lytic bone lesions or soft tissue plasmacytomas or definite 
increase in the size of residual bone lesions (not including compression fracture). 
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8 
mmol/L not attributable to any other cause)e. 
 
 
 
 
 
 
 
Relapse from CR 


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11.2.4 Duration of Response and Endpoint Definitions 
11.2.4.1 
Duration of overall response 
The duration of overall response is measured as the time from initiation of first 
response to first documentation of disease progression or death. Patients who have not 
progressed or died are censored at the date last known progression-free. 
11.2.4.2 
Duration of overall complete response 
The duration of overall CR is progression or death. Patients who have not progressed or 
died are censored at the date last known progression-free. 
11.2.4.3 
Time to progression 
Time to progression is defined as the time of randomization until progression. Patients 
who have died without evidence of progression are censored in the TTP analysis at the time 
of death and patients who are alive without progression are censored at the last disease 
assessment. 
11.2.5 Progression-Free Survival 
The secondary endpoint in this study, PFS is defined as the time from randomization to the 
disease progression or death from any cause. Patients who have not progressed or died are 
censored at the date last known progression-free. 
11.2.6 Response Review 
Central review of disease response assessments is not planned. 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse Events: 
List and Reporting Requirements). 
12.1 Data Reporting 
12.1.1 Method 
The DFCI Office of Data Quality will collect, manage, and perform quality checks on the data for this study. 
12.1.2 Responsibility for Data Submission 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data forms to the Data 
Safety Monitoring Committee According to the schedule set by the Office of Data Quality. 
Data should be entered within 14 business days of the corresponding visit and within 14 business days of 
the end of a cycle for any forms to be completed per cycle. 


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12.2 Data Safety Monitoring 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual 
data from this study. The committee is composed of clinical specialists with experience in oncology and who 
have no direct relationship with the study. Information that raises any questions about participant safety will be 
addressed with the Overall PI and study team. 
The DSMC will review each protocol up to four times a year or more often if required to review toxicity and 
accrual data. Information to be provided to the committee may include: up-to-date participant accrual; current 
dose level information; DLT information; all grade 2 or higher unexpected adverse events that have been 
reported; summary of all deaths occurring with 30 days of intervention for Phase I or II protocols; for gene 
therapy protocols, summary of all deaths while being treated and during active follow-up; any response 
information; audit results, and a summary provided by the study team. Other information (e.g. scans, laboratory 
values) will be provided upon request. 
13. STATISTICAL CONSIDERATIONS 
13.1 Study Design/Endpoints 
The proportion of patients who achieve progression free at 2 years will be compared to the rate published for 
the high risk SMM. By the Mayo Clinic model for risk factors, the median time to progression for patients with 
high risk SMM was only 1.9 years. Therefore, we assume that, a 2-years progression-free rate of 50% will not 
be considered promising and a true progression free rate of 70% or higher will be considered promising. A 
single-stage design will be employed with 39 eligible patients entered. If 24 or more of the 39 eligible patients 
are progression free at 2 years (observed rate of 62%), we will conclude that this treatment warrants further 
study. The probability of concluding that the treatment is effective if the true rate is 50% is 0.10 and is >0.9 if 
the true rate is 70%. Assuming a dropout rate of 5%, we will accrue 41 patients to the trial in order to have 39 
eligible patients. The Type I and II error probabilities have been derived using exact binomial 
probabilities. 
13.1.1 Analysis of Primary Endpoint 
The primary endpoint will be the 2-year progression-free rate and will be analyzed using binomial probability 
and corresponding 90% confidence interval. All patients who have received one dose of study treatment will be 
included for the TTP analysis, including those who die or are lost to follow-up within 2 years. 
13.1.2 Analysis of Secondary Endpoints 
The objective response rate (partial response or better according to the modified IMWG criteria) and the 
proportion of patients with a MRD, CR, PR or MR will be reported with 90% exact binominal confidence 
interval (CI). The exact 90% CI around response rate will be no wider than 28% with 39 eligible patients 
Time to progression (TTP) is defined as the time from protocol therapy initiation until documented progression, 
censored at date last known progression-free for those who have not progressed. 
To estimate the duration of response (time from objective response to disease progression or death, or date last 
known progression-free and alive for those who have not progressed or died), progression-free survival (time 


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from protocol therapy initiation to the disease progression or death from any cause, censored at date last known 
progression free for those who have not progressed or died), and overall survival (time from protocol therapy 
initiation to death or date last known alive), the Kaplan-Meier method will be used. 
It is expected that approximately 20% of the patients will receive cyclophosphamide (CTX) for mobilization 
and this may influence the PFS. Therefore, in a secondary analysis the 2 year PFS rate will be evaluated among 
those patients who did not receive CTX. Assuming that among the 39 eligible patients between 5-20% of the 
patients receive CTX for mobilization, the treatment will be considered promising if the observed response rate 
is at least 62%. With this rule, there is at least 80% probability of concluding the treatment is effective, when 
the true rate is 70% and less than 10% if true rate is 50%. 
Safety analysis will be conducted using the Safety Population defined as any patient receiving one dose of study 
treatment. For toxicity reporting, all adverse events and laboratory abnormalities will be graded and analyzed 
using CTCAE version 4 as appropriate. 
13.2 Sample Size, Accrual Rate and Study Duration 
A total of 41 patients will be enrolled. We expect 1.5 years of active accrual (approximately 2 patients per 
month) and 3 years of follow-up of patients. 
The final analyses of progression-based endpoints, such as estimating the 2-year progression-free rate and 
estimating the TTP distribution, will be conducted at the end of the study, which will occur after either all 
subjects have progressed or died or 2-years after the initiation of therapy of the last subject enrolled, whichever 
occurs first. 
13.3 Stratification Factors 
There are no stratification factors. 
13.4 Interim Monitoring Plan 
The study will be monitored by the DFCI Data Safety Monitoring Committee (DSMC). The DSMC will meet at 
least four times a year and more often if needed (e.g., for safety review). For each meeting, the study will be 
reviewed for safety and progress toward completion. Copies of the toxicity reports prepared by the DSMC 
meetings will be distributed to the Principal Investigator. The Principal Investigator will then distribute to sub- 
investigators. Any DSMC recommendations for changes to the study will be distributed to the Principal 
Investigator and then circulated to sub- investigators by the Principal Investigator. No interim analysis of the 
outcome data is planned. 
13.5 Stopping Rule for Safety 
All participants will be evaluable for treatment-related toxicity from the time of therapy initiation. The serious 
adverse event (SAE) for this purpose is defined as any grade 4 or higher unexpected, adverse event that is 
assessed as being related to the study intervention. 
The following table provides the probabilities of observing 3 or more SAEs after the 20th patient and before the 
40th patient. For example, with 20 participants, there is 0.60 probability of observing 3 or more SAEs if a true 


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rate is 15% and the probability is 0.021 if a true rate is 3%. 
True SAE rate 
1% 
3% 
5% 
10% 
15% 
20% 
30% 
Probability 
(≥SAEs) 
0.001 
0.021 
0.075 
0.32 
0.60 
0.79 
0.96 
14. PUBLICATION PLAN 
The results should be made public within 24 months of reaching the end of the study. The end of the study is the 
time point at which the last data items are to be reported, or after the outcome data are sufficiently mature for 
analysis, as defined in the section on Sample Size, Accrual Rate and Study Duration. If a report is planned to be 
published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of 
the International Committee of Medical Journal Editors. A full report of the outcomes should be made public no 
later than three (3) years after the end of the study. 


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33. Walker BA, Wardell CP, Melchor L, et al: Intraclonal heterogeneity and distinct molecular mechanisms 
characterize the development of t(4;14) and t(11;14) myeloma. Blood 120:1077-86, 2012 
34. Bahlis NJ: Darwinian evolution and tiding clones in multiple myeloma. Blood 120:927-8, 2012 
35. Greaves M, Maley CC: Clonal evolution in cancer. Nature 481:306-13, 2012 
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46. Chng WJ, Huang GF, Chung TH, et al: Clinical and biological implications of MYC activation: a common 
difference between MGUS and newly diagnosed multiple myeloma. Leukemia 25:1026-35, 2011 
47. Lopez-Corral L, Sarasquete ME, Bea S, et al: SNP-based mapping arrays reveal high genomic complexity in 
monoclonal gammopathies, from MGUS to myeloma status. Leukemia 26:2521-9, 2012 
48. Paiva B, Gutierrez NC, Rosinol L, et al: High-risk cytogenetics and persistent minimal residual disease by 
multiparameter flow cytometry predict unsustained complete response after autologous stem cell 
transplantation in multiple myeloma. Blood 119:687-91, 2012 
49. Lohr JG, Stojanov P, Lawrence MS, et al: Discovery and prioritization of somatic mutations in diffuse large 
B-cell lymphoma (DLBCL) by whole-exome sequencing. Proceedings of the National Academy of 
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50. Cibulskis K, Lawrence MS, Carter SL, et al: Sensitive detection of somatic point mutations in impure and 
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51. Hammerman PS, Hayes DN, Wilkerson MD, et al: Comprehensive genomic characterization of squamous 
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52. Chen CL, Rappailles A, Duquenne L, et al: Impact of replication timing on non-CpG and CpG substitution 
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53. Lieberman-Aiden E, van Berkum NL, Williams L, et al: Comprehensive mapping of long-range interactions 
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54. Beroukhim R, Getz G, Nghiemphu L, et al: Assessing the significance of chromosomal aberrations in 
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56. Kothari V, Wei I, Shankar S, et al: Outlier kinase expression by RNA sequencing as targets for precision 
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58. Griffith M, Griffith OL, Mwenifumbo J, et al: Alternative expression analysis by RNA sequencing. Nat 
Methods 7:843-7, 2010 
59. Rosenblatt J, Glotzbecker B, Mills H, et al: PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex 
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60. Azzi J, Moore RF, Elyaman W, et al: The novel therapeutic effect of phosphoinositide 3-kinase-gamma 
inhibitor AS605240 in autoimmune diabetes. Diabetes 61:1509-18, 2012 
61. Martinez-Lopez J, Lahuerta JJ, Pepin F, et al: Prognostic value of deep sequencing method for minimal 
residual disease detection in multiple myeloma. Blood 123:3073-9, 2014 
62. Paiva B, Gutierrez NC, Rosinol L, et al: High-risk cytogenetics and persistent minimal residual disease by 
multiparameter flow cytometry predict unsustained complete response after autologous stem cell 
transplantation in multiple myeloma. Blood 119:687-91, 2012 
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2011 


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APPENDIX A: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, 
but 
ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In 
bed 
<50% 
of 
the 
time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% 
bedridden. 
Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 


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APPENDIX B: SPECIMEN COLLECTION SCHEDULE 
Sample Time Point 
Recipient 
Sample Type 
Shipping Method 
Container1,2,4 
Baseline 
DFCI 
Peripheral Blood 
Fridge pack same day 
3x10mL Purple Top 
1x10mL Streck Tube 
Bone Marrow Aspirate 
2x10mL Purple Top 
Oragene Kit or Buccal 
Swab2 
Ambient same day 
2x Buccal Swabs or 1 
Oragene Kit 
Adaptive 
Bone Marrow Aspirate 
Same day – Use kit 
provided 
1x3ml Purple Top 
Cycle 1 Day 1 
(Pre Dose) 
DFCI 
Peripheral Blood 
Fridge pack same day 
2x10mL Purple Top 
1x10mL Streck Tube 
Cycle 2-6 Day 1 
(Predose) 
DFCI 
Peripheral Blood 
Fridge pack same day 
2x10mL Purple Top 
1x10mL Streck Tube 
End of Cycle 6 
(Cycle 7 Day 1) 
DFCI 
Peripheral Blood 
Fridge pack same day 
2x 10mL Purple Top 
1x10mL Streck Tube 
Bone Marrow Aspirate 
2x10mL Purple Top 
Cycle 8-12 Day 1 
(Predose) 
DFCI 
Peripheral Blood 
Fridge pack same day 
2x10mL Purple Top 
1x10mL Streck Tube 
Confirm Complete 
Response 3 
DFCI 
Peripheral Blood 
Fridge pack same day 
2x 10mL Purple Top 
1x10mL Streck Tube 
Bone Marrow Aspirate 
2x10mL Purple Top 
Adaptive 
Bone Marrow Aspirate 
Same day – Use kit 
provided 
1x3ml Purple Top 
End of Treatment 
and/or Disease 
Progression 
DFCI 
Peripheral Blood 
Fridge pack same day 
2x 10mL Purple Top 
1x10mL Streck Tube 
Bone Marrow Aspirate 
2x10mL Purple Top 
Clinically Indicated 
DFCI 
Bone Marrow Aspirate 
Fridge pack same day 
2x10mL Purple Top 
1 Purple Top= K2EDTA Tube; Streck Tube–Cell Free DNA collection tube-Please ensure you alert the lead site with enough notice if you need 
additional Streck tubes for your site.- All shipping materials are to be purchased and obtained by the external sites except for the buccal swabs and 
the Streck tubes, which will be provided by the lead site. 
2 Buccal swabs and or Oragene kits will be provided by the lead site, and can be taken/sent at any time point during the trial 
3 For definition of Complete Response, please refer to section 11.2.2 
4 Streck Tubes should be drawn before any heparinized tubes if applicable 


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APPENDIX C: SPECIMEN REQUISITION 
 
Complete this form and include with the specimen shipment. Label all materials with DFCI participant study ID, collection time point and collection 
date and time. Email Patrick Henrick (Patrick_Henrick@dfci.harvard.edu) and Alexandra Savell (AlexandraE_Savell@dfci.harvard.edu) to alert 
study team of shipment and include tracking number. 
 
Ship specimen(s) to:  Irene Ghobrial, MD 
Dana Farber Cancer Institute 
77 Louis Pasteur Avenue 
HIM 240; MA551 
Boston, MA 02115 
 
Specimen Information 
DFCI Participant Study ID Number:  
 
 
Date specimen(s) shipped:  
 
 
Correlative Sample Time Points 
(indicate inclusion in shipment by checking box) 
Sample Type 
Quantity of Tubes 
(6ml) 
Collection Date 
Collection Time 
Pre-treatment/Baseline 
Blood 
Saliva 
Aspirate 
 
Streck Top 
 
Purple Top 
Buccal Swab 
Cycle 1-12 Day 1  Specify Cycle 
 
Blood 
 
Streck Top 
 
Purple Top 
Confirm Response 
Blood 
Aspirate 
 
Streck Top 
 
Purple Top 
Cycle 7 Day 1 (end of Cycle 6) 
Blood 
Aspirate 
 
Streack Top 
 
Purple Top 
End of Treatment 
Disease Progression 
Blood 
Aspirate 
 
Streck Top 
 
Purple Top 
Clinically Indicated/ Standard of Care 
Aspirate 
Blood 
 
Purple Top 
 
Streck Top 
 
 
Responsible Contact:  
 
Email:  
 
 
Site:  
 
Phone number:  
 
 
Note: All samples are to be shipped with a fridge pack Fed-Ex priority overnight- Please retain a copy of the waybill, and reference the tracking number in the 
email and paper correspondence. Ship only Monday- Thursday, as shipments cannot be received over the weekend. 


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APPENDIX D: MANAGEMENT ALGORITHMS FOR ENDOCRINOPATHY, 
GASTROINTESTINAL, HEPATIC, RENAL, SKIN, NEUROLOGICAL, AND PULMONARY 
ADVERSE EVENTS DUE TO NIVOLUMAB 


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APPENDIX E: DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER DATA AND 
SAFETY MONITORING PLAN 


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TABLE OF CONTENTS 
1. INTRODUCTION 
96 
1.1 PURPOSE 
96 
1.2 MULTI-CENTER DATA AND SAFETY MONITORING PLAN DEFINITIONS 
96 
2. GENERAL ROLES AND RESPONSIBILITIES 
97 
2.1 DF/HCC SPONSOR 
97 
2.2 COORDINATING CENTER 
97 
2.3 PARTICIPATING INSTITUTION 
98 
3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
98 
3.1 PROTOCOL DISTRIBUTION 
99 
3.2 PROTOCOL REVISIONS AND CLOSURES 
99 
3.3 INFORMED CONSENT REQUIREMENTS 
99 
3.4 IRB DOCUMENTATION 
100 
3.5 IRB RE-APPROVAL 
100 
3.6 PARTICIPANT CONFIDENTIALITY AND AUTHORIZATION STATEMENT 
100 
3.7 DF/HCC MULTI-CENTER PROTOCOL REGISTRATION POLICY 
100 
3.8 DF/HCC PROTOCOL CASE NUMBER 
101 
3.9 SAFETY ASSESSMENTS AND TOXICITY MONITORING 
103 
3.10 DATA MANAGEMENT 
103 
4. REQUISITIONING INVESTIGATIONAL DRUG 
104 
5. MONITORING: QUALITY CONTROL 
104 
5.1 ONGOING MONITORING OF PROTOCOL COMPLIANCE 
104 
5.2 MONITORING REPORTS 
105 
5.3 ACCRUAL MONITORING 
105 
6. AUDITING: QUALITY ASSURANCE 
105 
6.1 AUDIT PLAN: 
101 
6.2 AUDIT PLAN: DF/HCC SPONSORED TRIALS 
106 
6.3 AUDIT NOTIFICATION 
106 
6.4 AUDIT REPORTS 
106 
6.5 PARTICIPATING INSTITUTION PERFORMANCE 
106 


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1. INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC DSMP) 
outlines the procedures for conducting a DF/HCC Multi-Center research protocol. The DF/HCC DSMP serves 
as a reference for any sites external to DF/HCC that are participating in a DF/HCC clinical trial. 
 
1.1 
Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center protocol will 
comply with Federal Regulations, Health Insurance Portability and Accountability Act (HIPAA) requirements 
and applicable DF/HCC Standard Operating Procedures. 
 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-Center Protocol: A research protocol in which one or more outside institutions are 
collaborating with Dana-Farber/Harvard Cancer Center where a DF/HCC investigator is the sponsor. DF/HCC 
includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial Affiliates. 
 
Lead Institution: One of the Dana-Farber/Harvard Cancer Center consortium members (Dana-Farber Cancer 
Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess Medical Center (BIDMC), 
Boston Children’s Hospital (BCH), Brigham and Women’s Hospital (BWH) responsible for the coordination, 
development, submission, and approval of a protocol as well as its subsequent amendments per the DFCI IRB 
and applicable regulatory guidelines (CTEP, Food and Drug Administration (FDA), Office of Biotechnology 
Activities (OBA) etc.). The Lead Institution is typically the home of the DF/HCC Sponsor. The Lead 
Institution also typically serves as the Coordinating Center for the DF/HCC Multi-Center Protocol. 
 
DF/HCC Sponsor: The person sponsoring the submitted Multi-Center protocol who takes responsibility for 
initiation, management and conduct of the protocol at all research locations. In applicable protocols, the 
DF/HCC Sponsor will serve as the single liaison with any regulatory agencies. The DF/HCC Sponsor has 
ultimate authority over the protocol and is responsible for the conduct of the study at DF/HCC and all 
Participating Institutions. In most cases the DF/HCC Sponsor is the same person as the DF/HCC Overall 
Principal Investigator; however, both roles can be filled by two different people. 
 
Participating Institution: An institution that is outside the DF/HCC and DF/PCC consortium that is 
collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator. The Participating 
Institution acknowledges the DF/HCC Sponsor as having the ultimate authority and responsibility for the 
overall conduct of the study. 
 
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract Research Organization 
(CRO), etc) that provides administrative support to the DF/HCC Sponsor in order that he/she may fulfill the 
responsibilities outlined in the protocol document and DSMP, and as specified in applicable regulatory 
guidelines (i.e. CTEP Multi-Center Guidelines). In general, the Lead Institution is the Coordinating Center for 
the DF/HCC Multi-Center Protocol. 
 
DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible ensuring high-quality standards 
are used for data collection and the ongoing management of clinical trials, auditing, and data and safety 
monitoring. ODQ also coordinates quality assurance efforts related to multi-center clinical research. 


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DF/HCC Clinical Trials Research Informatics Office (CTRIO): A group within DF/HCC responsible for 
providing a comprehensive data management platform for managing clinical trial data. 
 
2. GENERAL ROLES AND RESPONSIBILITIES 
 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the Participating 
Institutions are expected to adhere to the following general responsibilities: 
 
2.1 
DF/HCC Sponsor 
 
The DF/HCC Sponsor, Irene Ghobrial, MD will accept responsibility for all aspects of conducting a DF/HCC 
Multi-Center protocol which includes but is not limited to: 
• Oversee the coordination, development, submission, and approval of the protocol as well as 
subsequent amendments. 
• Ensure that the investigators, study team members, and Participating Institutions are qualified and 
appropriately resourced to conduct the protocol. 
• Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the protocol. 
• Ensure all Participating Institutions are using the correct version of the protocol. 
• Ensure that each participating investigator and study team member receives adequate protocol training 
(and/or a Site Initiation Visit prior to enrolling participants) and throughout trial’s conduct as needed. 
• Ensure the protocol will be provided to each participating site in a language understandable to all 
applicable site personnel when English is not the primary language. 
• Monitor progress and overall conduct of the study at all Participating Institutions. 
• Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable reporting 
requirements are met. 
• Review data and maintain timely submission of data for study analysis. 
• Act as the single liaison with the FDA 
• Ensure compliance with all requirements as set forth in the Code of Federal Regulations, applicable 
DF/HCC requirements, HIPAA requirements, and the approved protocol. 
• Commit to the provision that the protocol will not be rewritten or modified by anyone other than the 
DF/HCC Sponsor. 
• Identify and qualify Participating Institutions and obtain accrual commitments prior to extending the 
protocol to that site. 
• Monitor accrual and address Participating Institutions that are not meeting their accrual requirements. 
 
2.2 
Coordinating Center 
 
The general responsibilities of the Coordinating Center may include but are not limited to: 
• Assist in protocol development. 
• Maintain FDA correspondence, as applicable. 
• Review registration materials for eligibility and register participants from Participating Institutions in 
the DF/HCC clinical trial management system (CTMS). 
• Distribute protocol and informed consent document updates to Participating Institutions as needed. 
• Oversee the data collection process from Participating Institutions. 


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• Maintain documentation of Serious Adverse Event (SAE) reports and deviations/violation submitted 
by Participating Institutions and provide to the DF/HCC Sponsor for timely review and submission to 
the DFCI IRB, as necessary. 
• Distribute serious adverse events reported to the DF/HCC Sponsor that fall under the DFCI IRB 
Adverse Event Reporting Policy to all Participating Institutions. 
• Provide Participating Institutions with information regarding DF/HCC requirements that they will be 
expected to comply with. 
• Carry out plan to monitor Participating Institutions either by on-site or remote monitoring. 
• Maintain Regulatory documents of all Participating Institutions which includes but is not limited to the 
following: local IRB approvals/notifications from all Participating Institutions, confirmation of 
Federalwide Assurances (FWAs) for all sites, all SAE submissions, Screening Logs for all sites, IRB 
approved consents for all sites 
• Conduct regular communications with all Participating Institutions (conference calls, emails, etc) and 
maintain documentation all relevant communications. 
 
2.3 
Participating Institution 
 
Each Participating Institution is expected to comply with all applicable federal regulations and DF/HCC 
requirements, the protocol and HIPAA requirements. 
 
The general responsibilities for each Participating Institution may include but are not limited to: 
 
• Document the delegation of research specific activities to study personnel. 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Maintain regulatory files as per sponsor requirements. 
• Provide the Coordinating Center with regulatory documents or source documents as requested. 
• Participate in protocol training prior to enrolling participants and throughout the trial as required (i.e. 
teleconferences). 
• Update Coordinating Center with research staff changes on a timely basis. 
• Register participants through the Coordinating Center prior to beginning research related activities. 
• Submit Serious Adverse Event (SAE) reports to local IRB per institutional requirements and to the 
Coordinating Center, in accordance with DF/HCC requirements. 
• Submit protocol deviations and violations to local IRB per institutional requirements and to the 
DF/HCC Sponsor in accordance with DF/HCC requirements. 
• Order, store and dispense investigational agents and/or other protocol mandated drugs per federal 
guidelines and protocol requirements. 
• Have office space, office equipment, and internet access that meet HIPAA standards. 
• Participate in any quality assurance activities and meet with monitors or auditors at the conclusion of a 
visit to review findings. 
• Promptly provide follow-up and/or corrective action plans for any monitoring queries or audit 
findings. 
 
3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 


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The following section will clarify DF/HCC Requirements and further detail the expectations for participating in 
a DF/HCC Multi-Center protocol. 
 
3.1 
Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any subsequent amended 
protocols to all Participating Institutions. 
 
3.2 
Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures from the Coordinating 
Center. It is the individual Participating Institution’s responsibility to notify its IRB of these revisions. 
 
• Non life-threatening revisions: Participating Institutions will receive written notification of protocol 
revisions regarding non life-threatening events from the Coordinating Center. Non-life-threatening 
protocol revisions must be IRB approved and implemented within 90 days from receipt of the 
notification. 
 
• Revisions for life-threatening causes: Participating Institutions will receive immediate notification 
from the Coordinating Center concerning protocol revisions required to protect lives with follow-up by 
fax, mail, e-mail, etc. Life-threatening protocol revisions will be implemented immediately followed 
by IRB request for approval. 
 
• Protocol closures and temporary holds: Participating Institutions will receive notification of 
protocol closures and temporary holds from the Coordinating Center. Closures and holds will be 
effective immediately. In addition, the Coordinating Center, will update the Participating Institutions 
on an ongoing basis about protocol accrual data so that they will be aware of imminent protocol 
closures. 
 
3.3 
Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the informed consent for 
Participating Institutions. The Participating Institution consent form must follow the consent template as closely 
as possible and should adhere to specifications outlined in the DF/HCC Guidance Document on Model Consent 
Language for PI-Initiated Multi-Center Protocols. This document will be provided separately to each 
Participating Institution upon request. 
 
Participating Institutions are to send their version of the informed consent document and HIPAA authorization, 
if a separate document, to the Coordinating Center for review and approval prior to submission to their local 
IRB. The approved consent form must also be submitted to the Coordinating Center after approval by the local 
IRB for all consent versions. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician members of the study 
team who will be obtaining consent and signing the consent form for therapeutic protocols. Participating 
institutions must follow the DF/HCC requirement that only attending physicians obtain informed consent and 
re-consent for all interventional drug, biologic, or device research. 


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3.4 
IRB Documentation 
 
The following must be on file with the Coordinating Center: 
 
• Initial approval letter of the Participating Institution's IRB. 
• Copy of the Informed Consent Form(s) approved by the Participating Institution’s IRB. 
• Participating Institution’s IRB approval for all amendments. 
• Annual approval letters by the Participating Institution's IRB. 
 
3.5 
IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to continue research 
activities. There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received from the 
Participating Institution on or before the anniversary of the previous approval date. 
 
3.6 
Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information known as the Health 
Insurance Portability and Accountability Act (HIPPA). Any information, related to the physical or mental health 
of an individual is called Protected Health Information (PHI). HIPAA outlines how and under what 
circumstances PHI can be used or disclosed. 
 
In order for covered entities to use or disclose protected health information during the course of a study, the 
study participant must sign an authorization statement. This authorization statement may or may not be 
separate from the informed consent document. The Coordinating Center, with the approval from the DFCI IRB, 
will provide a consent template, with information regarding authorization for the disclosure of protected health 
information. 
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its trials. However, 
because of the nature of these trials, certain protected health information must be collected. DF/HCC has chosen 
to use authorizations, signed by the participant in the trial, rather than limited data sets with data use 
agreements. 
3.6.1 
DF/HCC Multi-Center Protocol Confidentiality 
All documents, investigative reports, or information relating to the participant are strictly confidential. 
Whenever reasonably feasible, any participant specific reports (i.e. Pathology Reports, MRI Reports, Operative 
Reports, etc.) submitted to the Coordinating Center should be de-identified. It is recommended that the assigned 
protocol case number (as described below) be used for all participant specific documents. Participant initials 
may be included or retained for cross verification of identification. 
3.7 
DF/HCC Multi-Center Protocol Registration Policy 
 
See section 4.4 of the protocol document for specific registration details and logistics. 


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3.7.1 
Participant Registration 
 
To register a participant, the following documents should be completed by the Participating Institution and 
faxed or e-mailed to the Research Project Manager at the lead site 
 
• Copy of required laboratory tests including labs that satisfy inclusion criteria 
• Signed informed consent document 
• HIPAA authorization form (if separate from the informed consent document) 
• Completed Eligibility Checklist complete with appropriate signatures 
• Study specific cover sheet 
The Coordinating Center will review the submitted documents in order to verify eligibility and consent. To 
complete the registration process, the Coordinating Center will: 
 
• Register the participant on the study with the DF/HCC Clinical Trial Management System (CTMS). 
• Upon receiving confirmation of registration, the Coordinating Center will inform the Participating 
Institution and provide the study specific participant case number. 
 
Treatment may not begin without confirmation from the Coordinating Center that the participant 
has been registered. 
 
Enrollment can only occur during normal business hours, Monday through Friday from 8:00 AM to 5:00 PM 
Eastern Standard Time unless given ample notice to the lead site. 
 
3.7.2 
Initiation of Therapy 
 
Participants must be registered with the DF/HCC CTMS before the initiation of treatment or other protocol- 
specific interventions. Treatment and other protocol-specific interventions may not be initiated until the 
Participating Institution receives confirmation of the participant’s registration from the Coordinating Center. 
The DF/HCC Sponsor and DFCI IRB must be notified of any violations to this policy. 
 
3.7.3 
Eligibility Exceptions 
 
No exceptions to the eligibility requirements for a protocol without DFCI IRB approval will be permitted. All 
Participating Institutions are required to fully comply with this requirement. The lead site will provide the 
appropriate paperwork to submit an eligibility exception request at the time of study start up. 
 
 
3.8 
DF/HCC Protocol Case Number 
 
At the time of registration, the following identifiers are required for all subjects: initials, date of birth, gender, 
race and ethnicity. Once eligibility has been established and the participant successfully registered, the 
participant is assigned a unique protocol case number. Participating Institutions should submit all de-identified 
subsequent communication and documents to the Coordinating Center, using this case number to identify the 
subject. 


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3.8.1 
Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research activity to ensure that researchers 
do not initiate changes in approved research without IRB review and approval, except when necessary to 
eliminate apparent immediate hazards to the participant. DF/HCC requires all departures from the defined 
procedures set forth in the IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn is 
responsible for reporting to the DFCI IRB. 
 
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” to describe departures 
from a protocol. All Participating Institutions must adhere to these requirements for reporting to the DF/HCC 
Sponsor and will follow their institutional policy for reporting to their local IRB. 
 
3.8.2 
Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved protocol which is 
prospectively approved prior to its implementation. 
 
Protocol Exception: Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
 
Protocol Violation: Any protocol departure that was not prospectively approved by the IRB prior to its initiation 
or implementation. 
 
3.8.3 
Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the medical record and/or 
regulatory documents to describe all protocol exceptions, deviations and violations. The DF/HCC Sponsor will 
also be responsible for ensuring that all protocol violations/deviations are promptly reported per DFCI IRB 
guidelines. 
 
Participating Institutions: Protocol deviations require prospective approval from the DFCI IRB. The 
Participating Institution must submit the deviation request to the Coordinating Center who will then submit the 
deviation request to the DFCI IRB. Upon DFCI IRB approval the deviation is submitted to the Participating 
Institution IRB, per institutional policy. A copy of the Participating Institution’s IRB report and determination 
will be forwarded to the Coordinating Center within 10 business days after the original submission. The 
deviation may not be implemented without all required approvals. 
 
All protocol violations must be sent to the Coordinating Center in a timely manner. The Coordinating Center 
will provide training for the requirements for the reporting of violations. 
 
Coordinating Center: Upon receipt of the violation/deviation report from the Participating Institution, the 
Coordinating Center will submit the report to the DF/HCC Sponsor for review. Subsequently, the Participating 
Institution’s IRB violation/deviation report will be submitted to the DFCI IRB for review per DFCI IRB 
reporting guidelines. DF/HCC will forward all violation reports to CTEP via an internal DF/HCC process, as 
applicable. 


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3.9 
Safety Assessments and Toxicity Monitoring 
 
The study teams at all participating institutions are responsible for protecting the safety, rights and well-being of 
study participants. Recording and reporting of adverse events that occur during the course of a study help ensure 
the continuing safety of study participants. 
 
All participants receiving investigational agents and/or other protocol mandated therapy will be evaluated for 
safety. The safety parameters include all laboratory tests and hematological abnormalities, physical examination 
findings, and spontaneous reports of adverse events reported by participants. All toxicities encountered during 
the study will be evaluated according to the NCI criteria specified in the protocol. Life-threatening toxicities 
must be reported immediately to the DF/HCC Sponsor via the Coordinating Center. 
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
3.9.1 
Guidelines for Reporting Serious Adverse Events 
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are detailed in protocol 
section 7 of the protocol. 
 
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the Coordinating Center following 
the DFCI IRB Adverse Event Reporting Policy. 
 
The Coordinating Center will maintain documentation of all Participating Institution Adverse Event reports and 
be responsible for communicating to all participating investigators, any observations reportable under the DFCI 
IRB Reporting Requirements. Participating Institutions will review and submit to their IRB according to their 
institutional policies and procedures 
 
3.9.2 
Guidelines for Processing IND Safety Reports 
 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety Reports are distributed 
to the Participating Institutions. Participating Institutions will review/submit to their IRB according to their 
institutional policies and procedures. 
 
 
 
3.10 
Data Management 
 
DF/HCC CTRIO develops case report forms (CRF/eCRFs), for use with the protocol. These forms are designed 
to collect data for each study. DF/HCC CTRIO provides a web based training for all eCRF users. 
 
3.10.1 
Data Forms Review 
 
Data submissions are monitored for timeliness and completeness of submission. If study forms are received 
with missing or questionable data, the submitting institution will receive a written or electronic query from the 
DF/HCC Office of Data Quality, Coordinating Center, or designee. 


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Responses to all queries should be completed and submitted within 14 calendar days. 
 
Responses may be returned on the written query or on an amended paper case report form, or in the case of 
electronic queries, within the electronic data capture (eDC) system. In the case of a written query for data 
submitted on a paper case report form, the query must be attached to the specific data being re-submitted in 
response. 
 
If study forms are not submitted on schedule, the Participating Institution will periodically receive a Missing 
Form Report from the Coordinating Center noting the missing forms. 
 
4. REQUISITIONING INVESTIGATIONAL DRUG 
 
The ordering of investigational agent is specified in the protocol section 8 of the protocol. 
Participating Institutions should order their own agent regardless of the supplier. 
If the agent is commercially available, check with the local Director of Pharmacy and/or the Research Pharmacy 
to ensure that the agent is in stock. If the agent is not stocked, ensure that the agent can be ordered once the 
protocol is approved by the local IRB. 
 
If the agent is investigational, ensure that the pharmacy will be able to receive and store the agent according to 
state and federal requirements. The local IRB should be kept informed of who will supply the agent so that any 
regulatory responsibilities can be met in a timely fashion 
 
5. MONITORING: QUALITY CONTROL 
 
The quality control process for a clinical trial requires verification of protocol compliance and data accuracy. 
The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, provides quality control oversight 
for the protocol. 
 
5.1 
Ongoing Monitoring of Protocol Compliance 
 
The Participating Institutions may be required to submit participant source documents to the Coordinating 
Center for monitoring. Participating Institution may also be subject to on-site monitoring conducted by the 
Coordinating Center. 
 
The DF/HCC lead site will implement ongoing monitoring activities to ensure that Participating Institutions are 
complying with regulatory and protocol requirements, data quality, and participant safety. Monitoring practices 
may include but are not limited to source data verification, and review and analysis of eligibility requirements, 
informed consent procedures, adverse events and all associated documentation, review of study drug 
administration/treatment, regulatory files, protocol departures reporting, pharmacy records, response 
assessments, and data management. 
 
Monitoring practices may include but are not limited to; source verification, review and analysis of the 
following: eligibility requirements of all participants, informed consent procedures, adverse events and all 
associated documentation, study drug administration / treatment, regulatory records and site trial master files, 
protocol deviations, pharmacy records, response assessments, and data management. Additionally, regular and 


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ongoing communication with Participating Institutions will be accomplished by holding all site teleconferences 
at least monthly. The Lead Institution will keep in close touch with the Participating Institutions via email and 
phone. Source documents from Participating Institutions, will be collected at specific data points that support 
the primary and or secondary endpoints 
 
Remote/ Virtual Monitoring 
 
The Coordinating Center will request source documentation from Participating Institutions as needed to 
complete monitoring activities. Participating Institutions will be asked to forward de-identified copies of 
participants’ medical record and source documents to the Coordinating Center to aid in source documentation 
verification. 
 
On-Site Monitoring 
 
On-Site Monitoring: On-site monitoring will occur at least once per year depending on a site’s accrual. 
Participating Institutions will be required to provide access to participants’ complete medical record and source 
documents for source documentation verification during the on-site visit. In addition, upon request from a 
monitor or auditor, Participating Institutions should provide access to regulatory documents, pharmacy records, 
local policies related to the conduct of research, and any other trial-related documentation maintained by the 
participating site. If there are concerns for protocol compliance, issues that impact subject safety or the integrity 
of the study are found, or trends identified based on areas of need, additional monitoring visits may be 
scheduled. On site monitoring visits can be supplemented with virtual monitoring assessments, provided that the 
minimum monitoring frequencies are adhered to. 
5.2 
Monitoring Reports 
 
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. The DF/HCC Sponsor 
may increase the monitoring activities at Participating Institutions that are unable to comply with the protocol, 
DF/HCC Sponsor requirements or federal and local regulations. 
 
5.3 
Accrual Monitoring 
 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual requirements for 
each participating institution. Accrual will be monitored for each participating institution by the DF/HCC 
Sponsor or designee. Sites that are not meeting their accrual expectations may be subject to a formal letter 
regarding accrual expectations, or termination. Due to the small patient population of this trial, the accrual 
minimum requirement is at least one patient every year. 
 
 
6. AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance and involves the systematic and independent examination of all trial 
related activities and documents. Audits determine if evaluated activities were appropriately conducted and 
whether data was generated, recorded and analyzed, and accurately reported per the protocol, applicable 
Standard Operating Procedures (SOPs), and the Code of Federal Regulations (CFR). 


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6.1 DF/HCC Internal Audits 
 
All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality (ODQ). Typically, 
approximately 3-4 participants would be audited at the site over a 2 day period. If violations which impact 
participant safety or the integrity of the study are found, more participant records may be audited. 
 
6.2 
Audit Notifications 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all scheduled audit dates 
(internal or NCI) and re-audit dates (if applicable), which involve this protocol. All institutions will forward a 
copy of final audit and/or re-audit reports and corrective action plans (if applicable) to the Coordinating Center, 
within 12 weeks after the audit date. 
 
6.3 
Audit Reports 
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if applicable. The 
Coordinating Center, must forward any reports to the DF/HCC ODQ per DF/HCC policy for review by the 
DF/HCC Audit Committee. For unacceptable audits, the DF/HCC Audit Committee would forward the final 
audit report and corrective action plan to the DFCI IRB as applicable. 
 
6.4 
Participating Institution Performance 
 
The DF/HCC Sponsor, DFCI IRB, is charged with considering the totality of an institution’s performance in 
considering institutional participation in the protocol. 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of timely and accurate 
data, adherence to protocol requirements, and compliance with state and federal regulations, may be 
recommended for a six-month probation period. Such institutions must respond with a corrective action plan 
and must demonstrate during the probation period that deficiencies have been corrected, as evidenced by the 
improved performance measures. Participating Institutions that fail to demonstrate significant improvement will 
be considered by the DF/HCC Sponsor for revocation of participation. A DF/HCC Sponsor and/or the DFCI 
IRB may terminate a site’s participation if it is determined that a site is not fulfilling its responsibilities as 
described above. 


CA204185 USA Richardson Pregnancy Information Sheet 1.0 (Draft 0.2) 30Jun2016 
 
 
 
 
 
Pregnancy Risk – All Patients: 
 
You must never share lenalidomide (or other study drugs) with someone else. You must 
never donate blood while you are participating in this study and for at least 28 days after 
you have been discontinued from the study. You must receive counseling and complete 
phone surveys as required by the Revlimid REMS® program. Females of childbearing 
potential that might be caring for you should not touch the lenalidomide capsules or 
bottles unless they are wearing gloves. Any unused lenalidomide should be returned to 
the study staff. 
 
 
Pregnancy Risk – Females: 
 
If you are a female of childbearing potential, you will be required to have a negative 
pregnancy test prior to receiving lenalidomide. 
 
• For the purposes of this study, a female of childbearing potential is a sexually 
mature female who: 
o Has not undergone a hysterectomy (the surgical removal of the uterus) or 
bilateral oophorectomy (the surgical removal of both ovaries) 
o Has not been naturally postmenopausal for at least 24 consecutive months 
(i.e., has had menses at any time during the preceding 24 consecutive 
months) 
 
You will be required to use TWO reliable forms of birth control, one highly effective 
method and one additional effective method at the same time or practice complete 
abstinence from heterosexual intercourse during the following time periods related to 
this study: 1) throughout lenalidomide therapy, including interruptions in therapy; and 2) 
for at least 28 days after discontinuation of lenalidomide. The use of birth control is 
required for 120 days following the last dose of nivolumab. 
Protocol Number: 16-242 
Principal Investigator: Irene Ghobrial, M.D. 
Protocol Title: Phase II Trial of the PD-1 Antibody Nivolumab in Combination with 
Lenalidomide and Low Dose Dexamethasone in Patients with High-Risk 
Smoldering Multiple Myeloma 
Instruction Sheet for Participants Regarding Reproductive Risks 


CA204185 USA Richardson Pregnancy Information Sheet 1.0 (Draft 0.2) 30Jun2016 
 
 
Pregnancy Risk – Males: 
 
Lenalidomide is present at very low levels in human semen of healthy men for three 
days after stopping the drug according to a study. For some men, such as men with 
kidney problems, lenalidomide may be present in semen for more than three days. For 
these reasons, to be safe, all male patients receiving lenalidomide must use a latex 
condom during any sexual contact with a pregnant female or with a female of 
childbearing potential while you are participating in this study, including during times 
when lenalidomide is temporarily stopped, and for at least 28 days after permanently 
stopping therapy, even if you have had a successful vasectomy. You must never donate 
blood, sperm, or semen while you are participating in this study and for at least 28 days 
after you have stopped therapy. In addition, men are required to continue to use birth 
control for 154 days following the last dose of nivolumab. 


 
Institutional Conflict of Interest Information Sheet 
 
Phase II Trial of the PD‐1 Antibody Nivolumab in Combination with Lenalidomide and Low Dose 
Dexamethasone in Patients with High‐Risk Smoldering Multiple Myeloma 
 
Protocol #16‐242 
 
You are invited to take part in a clinical trial, a type of research. For purposes of this research, you will 
be referred to as a “participant”. This research study is studying a targeted immunotherapy as a 
possible treatment for this diagnosis. Bristol‐Myers Squibb is supporting this research study by 
providing the study drug, Nivolumab. You are receiving this Information Sheet because Dana‐Farber 
Cancer Institute has a financial interest in Nivolumab, which may be affected by the outcome of this 
research. This is known as a potential “institutional conflict of interest.” 
 
Nivolumab is an investigational drug, which means that the intervention is being studied and has not 
been approved for your type of cancer by the FDA (U.S. Food and Drug Administration). It is possible 
that, as the result of this clinical trial and other clinical trials involving this drug that may follow, this 
investigational drug could be approved by the FDA, and become widely available for sale. Specifically, 
the drug being investigated involves a technology that was discovered through research conducted at 
DFCI. As a result, a concern exists that DFCI could be biased because it stands to benefit financially from 
the outcome of clinical trials involving this drug. 
 
Dana‐Farber Cancer Institute (“DFCI”) is committed to ensuring that all of its research and clinical 
activities are conducted with integrity. As part of this commitment, DFCI fully discloses the existence of 
all actual or potential conflicts of interest to research participants, sponsors, and regulatory bodies. Also, 
we have made sure that appropriate steps have been taken to ensure the safety of research participants 
and the reliability of research results. 
 
First, DFCI will disclose the existence and nature of its financial interest to all research participants. 
 
Second, DFCI will disclose the existence and nature of its financial interest to all research collaborators 
and in all public presentations and publications of data related to this research. 
 
Finally, and most importantly, we want to be certain that all research participants are fully informed 
about the financial interest, and are able to consider this information in deciding whether to participate 
in this trial. To that end, if you have additional questions about DFCI’s financial interests and their 
potential impact upon this clinical trial, or any of the steps taken by DFCI to safeguard the integrity of 
this research, please contact: 
 
Roberta Driscoll, JD 
Director, Office of Research Integrity 
Dana‐Farber Cancer Institute 
450 Brookline Avenue, BP333 
Boston, MA 02215‐5450 
617‐632‐4557 
Roberta_Driscoll@dfci.harvard.edu 


Version 3.0 
 
 
16-242: PHASE II TRIAL OF THE PD-1 ANTIBODY NIVOLUMAB IN COMBINATION WITH LENALIDOMIDE AND 
LOW DOSE DEXAMETHASONE IN PATIENTS WITH HIGH-RISK SMOLDERING MULTIPLE MYELOMA 
 
PARTICIPANT SELF-ADMINISTERED DRUG DIARY 
PATIENT INSTRUCTIONS: 
Take your medications exactly as prescribed by your doctor. See the next page for specific doses for each medication that you are taking on this 
study. 
• Keep capsules in the bottle(s) provided and do not transfer them to any other container. Store at room temperature. 
• Lenalidomide should be taken by mouth once per day for 21 days. Capsules must be swallowed whole with water at the same time each day. 
• Dexamethasone should be taken by the mouth. The days you will take dexamethasone will vary depending on your cycle. Please refer to 
the next page for a list of the appropriate days. Tablets must be swallowed whole and taken with food at the same time each day. 
• If you vomit after taking lenalidomide or dexamethasone, do NOT take another dose. Please note any vomiting in the Comments section 
of the diary on the next page. 
• If you miss a dose of lenalidomide and it has been less than 12 hours since the missed dose, take it as soon as you remember on the same day. 
If it has been more than 12 hours since missing a lenalidomide dose, you should not take the dose on that day, but take the next dose at the 
normal time on the following day. 
• If you miss a dose of dexamethasone, take it as soon as you remember on the same day. If you miss taking dexamethasone for the entire day, 
take your regular dose the next scheduled day (do NOT take double your regular dose to make up for the missed dose). 
• If you miss a dose please record “0” for Number Taken on the next page. 
• If you accidentally take an extra dose of lenalidomide in one day skip the next day’s dose and record the extra dose on the next page and 
contact your study team immediately and seek emergency medical care. 
• Please bring any unused lenalidomide and all empty containers and diary to your next visit. 
 
FOR CLINIC USE ONLY: 
• Give patient all 2 pages of Drug Diary stapled 
together. Provide one diary per cycle (28 days). 
• Enter the appropriate dose for the current cycle. 
• Complete patient identifiers and medical team 
contact information on page 2. 
• When patient returns pill bottles and diary perform a 
Lenalidomide pill count and record adherence 
information in the box to the right. 
Staff Initials: 
Date Returned: 
# Lenalidomide capsules returned: 
# Lenalidomide capsules that should have been taken: 
Discrepancy Notes: 


Version 3.0 
 
 
 
STUDY PARTICIPANT SELF-ADMINISTERED DIARY 
CYCLES 1-6 
Participant Identifier:  
 Cycle #:  
 
 
Your MD  
 
 
Phone  
 
Your RN  
 
  
Phone  
 
STUDY DRUG INSTRUCTIONS: 
Take the following medications as indicated below. 
Record the dose of each medication on the chart to 
the right after taking each day. 
 
Lenalidomide: 
Cycles 1-6:  
 mg by mouth on Days 1-21 
 
 
Dexamethasone: 
Cycles 1-6:  
 mg by mouth on Days 1, 8, 15 
 
 
Patient Signature: 
Date: 
 
 
 
Delegated Study Staff Signature: 
Date: 
 
Date 
Number Taken 
Comments 
Lenalidomide 
Dexamethasone 
Ex: 
6/1/2009 
1 
1 
vomited hour 
later 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 


STUDY PARTICIPANT SELF-ADMINISTERED DIARY CYCLES 7-12 
Version 3.0 
 
 
 
 
 
 
Participant Identifier:  
 Cycle #:  
 
 
Your MD  
 
 
Phone  
 
Your RN  
 
  
Phone  
 
STUDY DRUG INSTRUCTIONS: 
Take the following medications as indicated below. 
Record the dose of each medication on the chart to 
the right after taking each day. 
 
Lenalidomide: 
Cycles 7-12:  
 mg by mouth on Days 1-21 
 
 
Patient Signature: 
Date: 
 
 
 
Delegated Study Staff Signature: 
Date: 
 
Date 
Number Taken 
Comments 
Lenalidomide 
Ex: 
6/1/2009 
1 
vomited hour 
later 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 


STUDY PARTICIPANT SELF-ADMINISTERED DIARY 
Version 3.0 
 
 
 
 
 
CYCLES 7-12 FOR USE ONLY IF RECEIVING 
DEXAMETHASONE IN MAINTENANCE 
Participant Identifier:  
 Cycle #:  
 
 
Your MD  
 
 
Phone  
 
Your RN  
 
  
Phone  
 
STUDY DRUG INSTRUCTIONS: 
Take the following medications as indicated below. 
Record the dose of each medication on the chart to 
the right after taking each day. 
 
Lenalidomide: 
Cycles 7-12:  
 mg by mouth on Days 1-21 
 
 
Dexamethasone: 
Cycles 7-12:  
 mg by mouth on Days 1, 8, 15 
 
 
Patient Signature: 
Date: 
 
 
 
Delegated Study Staff Signature: 
Date: 
 
Date 
Number Taken 
Comments 
Lenalidomide 
Dexamethasone 
Ex: 
6/1/2009 
1 
1 
vomited hour 
later 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 


Protocol #16-242: Drafted (9/7/16)(KAR)/Approved (12/20/16)(EMR) 
 
 
DANA-FARBER CANCER INSTITUTE 
Nursing Protocol Education Sheet 
Protocol Number: 
16-242 
Protocol Name: 
Phase II Trial of the PD-1 Antibody Nivolumab in Combination with Lenalidomide and Low 
Dose Dexamethasone in Patients with High-Risk Smoldering Multiple Myeloma 
DFCI Site PI: 
Irene Ghobrial, MD 
DFCI Research Nurse: 
Kaitlen Reyes, DNP; John Harran, Eileen Regan Laura Amweg, Kathleen Colson, Kristen 
Cummings, Heidi DiPietro, Meghan Leahy Ray 
Page the DFCI research nurse or DFCI site PI if there are any questions/concerns about the protocol. 
Please also refer to ONC 15: Oncology Nursing Protocol Education Policy 
*** Remember to check the ALERT PAGE*** 
SPECIAL NURSING CONSIDERATIONS UNIQUE TO THIS PROTOCOL 
Study Design 
Nivolumab is a fully human monoclonal antibody that targets the PD-1 cell surface membrane receptor. 
Nivolumab inhibits the interaction of PD-1 with its ligands, PD-L1 and PD-L2, resulting in enhanced T-cell 
proliferation and interferon-gamma (IFN-γ) release in vitro. Lenalidomide (REVLIMID) is a thalidomide analogue, is 
an immunomodulatory agent with antiangiogenic properties. Dexamethasone is a synthetic adrenocortical steroid. 
• 
The Study Design is in Section 1.1 
• 
The Study Rationale is in Section 2.9 
• 
A cycle is defined as 28 days in Section 5.1 
Dose 
Calc. 
• 
Nivolumab is dosed in fixed dosing, 240 mg IV 
• 
Lenalidomide is dosed in fixed dosing, between 5-25 mg (increments of 5 mg for dose reductions) 
• 
Dexamethasone is dosed in fixed dosing, 40 mg or 20 mg or 10 mg for dose reductions 
Study Drug 
Administration 
Agent Administration Guidelines are found in Section 5.2 
• 
Nivolumab is given IV every other week on Days 1&15; Lenalidomide is PO Days 1-21; Dexamethasone is 
PO Days 1, 8, 15 for Cycles 1-6 ONLY 
• 
Nivolumab is given IV over 60 minutes (+/- 10 minutes); No standard premeds required, unless history of 
infusion reaction. A 60 min post-infusion observation period is suggested, especially during first 2 cycles, but 
not mandatory per protocol. 
• 
The drugs may be administered in any order. 
• 
Criteria to treat DAY 1: ANC>1,000; PLT>50; Other drug related, non-heme tox <Grade 1 or baseline. 
• 
Criteria to treat DAY 15: 
For Lenalidomide: ANC>1,000; PLT>30; Hgb>8 Other drug related less than Grade 3 or baseline. 
For Nivolumab: AST<90; ALT<156; Bilirubin<1.8; Creatinine<1.95 or <1.5 x baseline 
• 
Fasting is not required. 
• 
Lenalidomide capsules and Dexamethasone tablets should be swallowed whole, and should not be broken, 
chewed or opened. Administration should be at approximately the same time each day. If a dose is missed and 
less than 12 hours has elapsed since the missed dose, the patient may take the dose for that day. If more than 
12 hours has elapsed since missing a dose at the normal time, the patient should not take the dose, but take 
the next dose at the normal time on the following day. If a dose is missed, it should be taken as soon as 
possible on the same day. If a dose is vomited, the dose should not be made up and the participant should 
continue with the regular schedule of the drug at the next dose. 
Dose 
Mods & 
Toxicity 
Dose Modifications/Dosing Delay for Toxicity are outlined in Section 
• 
This protocol uses NCI CTCAE criteria, version 4.03 
• 
There are no dose modifications for Nivolumab, there are dose reductions per protocol for Lenalidomide and 
Dexamethasone. 
Con 
Meds 
Concomitant Therapy Guidelines are in Section 5.3.1 
• 
Stem cell mobilization and collection may be performed at time of best response or after 6 cycles of therapy. 
• 
Filgrastim is allowed, pegfilgrastim is NOT. 
• 
Transfusions and supportive care are allowed; bisphosphonate therapy included. 
Required 
Data 
Study Calendar and Assessment Required data are outlined in Section 10 
• 
The study calendar is in Section 10 
• 
Vital signs: Before any infusion. 
• 
ECGs: One at screening and one at EOT. 
• 
NO PK’s or biomarkers. 


Protocol #16-242: Drafted (9/7/16)(KAR)/Approved (12/20/16)(EMR) 
 
 
Charting Tips 
All study drugs require documentation of exact administration time. 
Please be sure to DOCUMENT study medication actual UP/DOWN times in medical record (e.g. LMR, eMAR, 
nursing notes). Edit eMAR as needed to match the exact time given. 
• If there is a discrepancy in the infusion time, delay in administration, or the infusion takes longer than is 
permitted by the guidelines of the protocol, please document the reason for the discrepancy in the medical 
record. 
Please be sure to also DOCUMENT any required observation periods, any additional vital signs, routes of 
administration, injection sites, etc. 


 
450 Brookline Ave. 
Boston, Massachusetts 02215 
617-632-3000 
617-632-5330 TDD 
 
 
November XX, 2017 
 
XXXXXXX 
XXXXXXXX 
XXXXXXXXX 
XXXXXXXXX 
 
 
Re: 16-242 A Phase II Trial of the PD-1 Antibody Nivolumab in Combination with 
Lenalidomide and Low Dose Dexamethasone in Patients with High-Risk Smoldering 
Multiple Myeloma 
 
ClinicalTrials.gov Identifier: NCT02903381 
Dear XXXXXXXX, 
We are reaching out to you to follow up on the recent closure of the clinical trial by 
the Food and Drug Administration that you had been enrolled on. 
 
On August 31st, 2017, the FDA requested that the company that makes this drug (Bristol- 
Myers Squibb) notify patients of safety concerns that were seen on two clinical trials using 
the drugs pembrolizumab (a similar drug to nivolumab), revlimid and dexamethasone. 
 
It was reported that there was an increased risk of death on those trials. This risk may also be 
associated with nivolumab. Although nivolumab is not the same drug, it works in a similar 
way and these findings may be relevant to your safety. 
 
We are formally requesting that you contact us immediately if you experience any new side 
effects. If you never received nivolumab, revlimid, or dexamethasone on this clinical trial, 
please retain this letter for reference. 
 
Please contact me at (617) 632-4198 or at Irene_Ghobrial@DFCI.HARVARD.EDU if you 
have any questions regarding the clinical hold, the future of the trial, or your safety as it 
relates to these findings. 
 
 
Sincerely, 
 
 
 
Irene M. Ghobrial, MD 
Sponsor-Investigator 

ICF_001.pdf: 
 
 
Research Consent Form 
  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
Page 1 of 27 
DFCI Protocol Number:     16-242 
Approved Date (DFCI IRB Approval):  
05/07/2019 
Date Posted for Use:  
05/10/2019  
  
 
 
 
Protocol Title:   
Phase II Trial of the PD-1 Antibody Nivolumab in Combination with Lenalidomide and 
Low Dose Dexamethasone in Patients with High-Risk Smoldering Multiple Myeloma 
 
DF/HCC Principal Research Doctor / Institution:   
Irene Ghobrial, MD/ Dana-Farber Cancer Institute 
 
 
A. INTRODUCTION 
 
You are invited to take part in a clinical trial, a type of research study because 
you have smoldering multiple myeloma (SMM). Patients with smoldering multiple 
myeloma do not have symptoms but are at risk for progressing to active multiple 
myeloma. Multiple myeloma is a cancer of the plasma cell, which is an important 
part of the immune system. Patients with active multiple myeloma generally 
require treatment. There are currently no approved therapies for smoldering 
multiple myeloma. This research study is evaluating a new drug called 
“nivolumab” as a possible treatment for smoldering multiple myeloma in order to 
prevent or postpone development of active multiple myeloma. 
 
For purposes of this research, you will be referred to as a “participant”.  
 
It is expected that about 41 people will take part in this research study.  
 
Dana-Farber Cancer Institute has a financial interest in the investigational agent 
used in this trial (Nivolumab) which may be affected by the outcome of this 
research. The Institute has taken steps to manage any actual or potential conflict 
of interest created by this financial interest, which are more fully described in the 
Information Sheet available to all participants 
 
Bristol Myers-Squibb, a pharmaceutical company, is supporting this research 
study by providing funding for the research study and the study drug. 
 
This research consent form explains why this research study is being done, what 
is involved in participating in the research study, the possible risks and benefits 
of participation, alternatives to participation, and your rights as a research 
participant.  The decision to participate is yours.  If you decide to participate, 
please sign and date at the end of this form. We will give you a copy so that you 
3/26/2020 1:27 pm


 
 
Research Consent Form 
  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
Page 2 of 27 
DFCI Protocol Number:     16-242 
Approved Date (DFCI IRB Approval):  
05/07/2019 
Date Posted for Use:  
05/10/2019  
  
 
 
 
can refer to it while you are involved in this research study. If you choose not to 
participate in this research study, the research doctors will discuss other 
treatment options with you and/or refer you back to your primary doctor.  
We encourage you to take some time to think this over, to discuss it with other 
people and your primary doctor, and to ask questions now and at any time in the 
future. 
  
B. WHY IS THIS RESEARCH STUDY BEING DONE?  
 
This research study is a Phase II clinical trial, which tests the effectiveness of an 
investigational drug(s). The investigational drugs used in this research study are 
nivolumab, lenalidomide, and dexamethasone. Preliminary experience suggests 
that the combination of lenalidomide and dexamethasone may prevent or 
postpone SMM from becoming active multiple myeloma. The purpose of this 
research study is to determine if the addition of nivolumab may improve the rate 
of prevention in combination with lenalidomide and dexamethasone.  
 
“Investigational” means that the FDA (the U.S. Food and Drug Administration) 
has not approved the combination of nivolumab, lenalidomide and 
dexamethasone as a treatment regimen for your specific disease. 
 
Lenalidomide is an immunomodulatory drug derived from thalidomide. 
Lenalidomide works by stopping blood flow to your cancer cells and signaling 
your cancer cells to die off. The FDA has approved lenalidomide for the 
treatment of many types of cancer including multiple myeloma, and 
myelodysplastic syndromes.  
 
Dexamethasone, also FDA approved, is a type of steroid and is usually 
combined with other chemotherapy for the treatment of blood cancers, such as 
myeloma and leukemias.  
 
Nivolumab is approved by the FDA for some lung cancers, some skin cancers, 
some kidney cancers, and Hodgkin lymphoma. It is currently being evaluated for 
use in the treatment of several other types of cancers. Nivolumab may kill or stop 
cancer cells from growing by blocking a signal in your cells allowing your immune 
system to fight your cancer. This drug is a human monoclonal antibody, which is 
a molecule that is made in a laboratory that is designed to act identically to cells 
in your immune system.  
3/26/2020 1:27 pm


 
 
Research Consent Form 
  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
Page 3 of 27 
DFCI Protocol Number:     16-242 
Approved Date (DFCI IRB Approval):  
05/07/2019 
Date Posted for Use:  
05/10/2019  
  
 
 
 
C. WHAT OTHER OPTIONS ARE THERE? 
 
Taking part in this research study is voluntary. Instead of being in this research 
study, you have other options which may include the following: 
 
• Take part in another research study.  
• Observation, meaning no therapy at this time specific to your 
smoldering Multiple Myeloma 
 
Please talk to the research doctor about your options before you decide whether 
you will take part in this research study. 
  
D. WHAT IS INVOLVED IN THE RESEARCH STUDY? 
 
Sometimes it is hard to keep track of all of the details and procedures that are 
part of a research study.  We will describe them in this consent form and you can 
refer to this at any time during the research study. 
 
If you take part in this research study you will be given a drug diary. You will be 
asked to document information in the drug diary about the study treatment you 
are being asked to take. 
 
Before the research starts (screening):   
 
After signing this consent form, you will be asked to undergo some screening 
tests or procedures to find out if you can be in the research study.  Many of these 
tests and procedures are likely to be part of regular cancer care and may be 
done even if it turns out that you do not take part in the research study.  If you 
have had some of these tests or procedures recently, they may or may not have 
to be repeated.   
 
• Medical History and Physical Exam will be performed and you will be 
asked questions about your general health and specific questions about 
any problems that you might be having and any medication changes. 
• Performance status, which evaluates how you are able to carry on with 
your usual activities.  
• Blood Tests will be done to check your overall health (1-2 tablespoons). 
• 24 hour Urine Sample will be done to test for signs of disease that 
sometimes does not show in blood or marrow   
3/26/2020 1:27 pm


 
 
Research Consent Form 
  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
Page 4 of 27 
DFCI Protocol Number:     16-242 
Approved Date (DFCI IRB Approval):  
05/07/2019 
Date Posted for Use:  
05/10/2019  
  
 
 
 
• Scans (or Imaging Tests) will assess your tumor by X-Ray, MRI or 
PET/CT 
• Electrocardiogram (ECG) will be conducted to measure the electrical 
activity and health of the heart (Only required at screening, at end of 
treatment or if clinically indicated). 
• Blood Pregnancy Test is required if you are a woman who is able to 
get pregnant. The test will need to be negative prior to starting Cycle 1.   
• Bone Marrow Aspirate and Biopsy will be done to evaluate your 
disease. For the bone marrow aspirate, a sample of bone marrow cells is 
taken by a needle and inserted into a bone in your body. For the biopsy, a 
small piece of bone is removed. These tests are done under local 
anesthesia. Your physician may require this procedure more often to 
assess your disease. 
 
If these tests show that you are eligible to participate in the research study, you 
will begin the study treatment.  If you do not meet the eligibility criteria, you will 
not be able to participate in this research study. 
 
Additional research procedures to be performed at the time of screening 
but not required to determine eligibility:   
 
• Blood Sample: Approximately 2 tablespoons of blood will be drawn for 
research to assess your disease status by looking at your DNA and RNA 
(the information in your cells that makes you unique) 
• Bone Marrow Aspirate Sample: For bone marrow procedures that are 
done as standard of care, a small amount of extra bone marrow cells will 
be taken for research tests. This additional sample will be taken at the 
same time as the other sample; you will not need an additional procedure. 
The research tests will help determine how nivolumab affects your 
disease. 
• Buccal Swab will be collected when you are in clinic at the beginning of 
the study (or at any time during the trial). The purpose is to harvest your 
normal DNA. You will not be provided with results about the genetic tests, 
nor will the information be placed in your medical record. 
 
 
Study Drug Dosing Table: 
 
Each cycle is 28 days in length.  
 
3/26/2020 1:27 pm


 
 
Research Consent Form 
  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
Page 5 of 27 
DFCI Protocol Number:     16-242 
Approved Date (DFCI IRB Approval):  
05/07/2019 
Date Posted for Use:  
05/10/2019  
  
 
 
 
Cycles 1-6 
 
Drug 
Route 
Schedule 
Nivolumab 
Intravenous 
Days 1 and 15 
Lenalidomide 
Oral 
Days 1-21 
Dexamethasone 
Oral 
Days 1, 8, and 15 
 
Cycles 7-12 (Maintenance)* 
 
Drug 
Route 
Schedule 
Nivolumab 
Intravenous 
Days 1 and 15 
Lenalidomide 
Oral 
Days 1-21 
 
*Depending on your disease, your doctor may want you to continue to take dexamethasone 
during the maintenance portion of the trial. If you do continue to take dexamethasone, you will 
take it on day 1, 8, and 15 of a 28 day cycle 
 
Nivolumab Administration: This drug will be given as a single dose that will be 
given to you through a vein in your arm (intravenously) over a 60 minute period 
once daily on the days instructed.  
 
Lenalidomide Administration: This drug will be given as a single dose that you 
will take orally once daily on the days instructed. You must record all 
administrations of this drug at home and in clinic in the study drug diary provided 
to you. 
 
Dexamethasone Administration: This drug will be given as a single dose that 
you will take orally once daily on the days instructed. You must record all 
administrations of this drug at home and in clinic in the study drug diary provided 
to you. 
 
 
 
 
 
On Study Visits:  
Please see the research study plan below for a full list of tests required at each 
timepoint on the study. If specified, visits will involve the following: 
 
3/26/2020 1:27 pm


 
 
Research Consent Form 
  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
Page 6 of 27 
DFCI Protocol Number:     16-242 
Approved Date (DFCI IRB Approval):  
05/07/2019 
Date Posted for Use:  
05/10/2019  
  
 
 
 
• Medical History and Physical Exam will be performed and you will be 
asked questions about your general health and specific questions about 
any problems that you might be having and any medication changes. 
• Performance status, which evaluates how you are able to carry on with 
your usual activities.  
• Blood Tests will be done to check your overall health (1-2 tablespoons). 
• 24 hour Urine Sample will be required, which you will return to clinic on 
Day 1 of each cycle for some patients whose disease is assessed by their 
urine result. This is to perform a specific test that shows signs of disease 
that sometimes does not show in blood or marrow. 
• Scans (or Imaging Tests) will assess your tumor by X-Ray, MRI or 
PET/CT at the end of your treatment. 
• Electrocardiogram (ECG) will be done to measure the electrical activity 
and health of the heart (Only required at screening, at end of treatment or 
if your doctor thinks that it is necessary). 
• Blood Pregnancy Test is required if you are a woman who is able to get 
pregnant. The test will need to be negative within 24 hours of starting 
Cycle 1 and then again every cycle thereafter on Day 1. 
• Bone Marrow Aspirate and Biopsy will be done to look more closely at 
your disease. For the bone marrow aspirate, a thin needle is inserted into 
a bone in your body and a sample of your bone marrow cells is taken out. 
For the biopsy, a small piece of bone is removed during the same 
procedure. These tests are done under local anesthesia. Your physician 
may require this procedure more often to assess your disease. 
• Side Effects will be assessed by your research doctor  
 
 
 
 
 
 
 
 
 
Research Study Plan: 
 
Tests and Procedures 
Screening 
Cycles 1-12 
Day 1 
Cycle 7 Day 1 
or 
to Confirm CR 
End of 
Treatment 
Follow-Up  
Every 3 Months 
3/26/2020 1:27 pm


 
 
Research Consent Form 
  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
Page 7 of 27 
DFCI Protocol Number:     16-242 
Approved Date (DFCI IRB Approval):  
05/07/2019 
Date Posted for Use:  
05/10/2019  
  
 
 
 
Medical History and 
Physical Exam 
X 
X 
 
X 
X 
Blood Tests 
X 
X 
 
X 
X 
Urine Test 
X 
X 
 
X 
X 
X-Ray/ PET-CT/ 
MRI3 
X 
 
 
X 
 
EKG 
X 
 
 
X 
 
Pregnancy Test 
(if applicable) 
X 
X 
 
 
 
Bone Marrow 
Aspirate and Biopsy 
X 
 
X 
X 
 
Research Bone 
Marrow Aspirate2 
X 
 
X 
X 
 
Research Blood 
Sample2 
X 
X 
X 
X 
 
Research Buccal 
Swab1 
X 
 
 
 
 
1 Can be obtained at any time during the study 
2 Research samples are mandatory on this trial 
3 You will be required to either get an X-Ray and an MRI of your spine, or a PET/CT for this trial 
 
Planned Follow-up:  
 
We would like to keep track of your medical condition every three months for up 
to three years after you have completed the research study. We would like to do 
this by seeing you and completing routine blood and urine tests.  Keeping in 
touch with you and checking your condition every three months helps us look at 
the long-term effects of the research study. 
  
E. HOW LONG WILL I BE IN THIS RESEARCH STUDY? 
 
You will be in this research study for about 14 months and be followed for an 
additional 3 years.  
 
 
The research doctor may decide to take you off the research study for many 
reasons including if: 
• It is considered to be in your best interest 
• The study treatment or procedures are found to be unsafe or ineffective 
• There is any problem with following study treatments and procedures 
• Your condition worsens 
3/26/2020 1:27 pm


 
 
Research Consent Form 
  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
Page 8 of 27 
DFCI Protocol Number:     16-242 
Approved Date (DFCI IRB Approval):  
05/07/2019 
Date Posted for Use:  
05/10/2019  
  
 
 
 
• A decision is made to close the study 
• Or for other unforeseen reasons that make it necessary to stop your 
participation in the research study 
 
If you are removed from the research study, the research doctor will explain to 
you why you were removed.   
 
In addition, you can stop participating in the research study at any time, however, 
the FDA requires that any information collected up to the point of your withdrawal 
cannot be removed from the study.  If you decide to stop participating in this 
research study, we encourage you to talk to the research doctor and your 
primary doctor first. 
  
F. WHAT ARE THE RISKS OR DISCOMFORTS OF THE RESEARCH STUDY? 
 
There are risks to taking part in any research study. One risk is that you may get 
a study drug that does not help treat your disease or that makes your condition or 
disease worse. Another risk is that there may be side effects.   
 
All cancer treatments can have side effects, which can range from mild and 
reversible to severe, long lasting and possibly life-threatening.  There is a great 
deal of variability among side effects of different cancer treatments and between 
individuals.  In a research study, all of the risks or side effects may not be known 
before you start the study. You need to tell your doctor or a member of the 
study team immediately if you experience any side effects.  
 
Everyone in the research study will be watched carefully for side effects.  You will 
be monitored during the administration of study drugs to keep track of your blood 
counts and organ function, particularly your kidney and liver function.  If you 
experience side effects, they may go away after you stop taking the study drug.  
Some side effects can be mild; but others can be long lasting and may never go 
away.  Some may be life-threatening or fatal.  
Since the effect of the study drug(s) taken with other medications may not be 
known, it is important that you tell the research doctor about all prescription and 
non-prescription drugs, herbal preparations and nutritional supplements that you 
are taking or planning to take. There may also be some foods that you should 
avoid while on this research study and your research doctor will review this 
information with you. 
 
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Research Consent Form 
  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
Page 9 of 27 
DFCI Protocol Number:     16-242 
Approved Date (DFCI IRB Approval):  
05/07/2019 
Date Posted for Use:  
05/10/2019  
  
 
 
 
During the research study, you will be notified of newly discovered side effects or 
significant findings, which may affect your health or willingness to participate.  
You may be asked to sign a new consent form that shows that you have been 
informed of new information relating to this research study. 
  
Additional Safety Information from the Food and Drug Administration and 
Bristol-Myers Squibb: 
 
In two clinical trials, patients with multiple myeloma were recently stopped from 
taking pembrolizumab (a drug which destroys cancer cells by working with the 
immune system) if they were also being treated with lenalidomide (or 
pomalidomide) and dexamethasone. The treatment was stopped because a 
higher number of deaths were seen when patients were treated with 
pembrolizumab together with lenalidomide (or pomalidomide) and 
dexamethasone. 
 
• Keynote-183 was a randomized trial which evaluated pomalidomide 
and low-dose dexamethasone with or without pembrolizumab in 
patients with relapsed and refractory multiple myeloma. This trial 
showed an overall survival hazard ratio of 1.61 (95% CI: 0.91, 2.85) in 
the pembrolizumab-containing arm compared to the control arm, which 
did not contain pembrolizumab. With the current information, on an 
average it is estimated that the risk of death in the pembrolizumab 
treated arm is 1.6 times that of the control arm which did not contain 
pembrolizumab. 
 
• Keynote-185 was a randomized trial which evaluated lenalidomide and 
low-dose dexamethasone with or without pembrolizumab in patients 
with newly diagnosed multiple myeloma. This trial showed an overall 
survival hazard ratio of 2.06 (95% CI: 0.93, 4.55) in the 
pembrolizumab-containing arm compared to the control arm, which did 
not contain pembrolizumab. With the current information, on an 
average it is estimated that pembrolizumab doubles the risk of death 
compared to the control arm which did not contain pembrolizumab 
 
Some patients in these studies developed fatal, serious side effects, including 
inflammation of the heart (myocarditis), rash with peeling of skin and/or 
mucous membranes, heart attack, cardiac arrest, cardiac failure, bleeding of 
the heart lining, respiratory tract infection, respiratory failure, blood clots in the 
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for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
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DFCI Protocol Number:     16-242 
Approved Date (DFCI IRB Approval):  
05/07/2019 
Date Posted for Use:  
05/10/2019  
  
 
 
 
lungs, sepsis, multiple organ failure, suicide, and sudden death. Some of the 
causes of death are unknown at this time. 
 
Although nivolumab is not the same drug, it works in a similar way and these 
findings may be relevant for your treatment in this study.  
 
Your study doctor may recommend that you stop treatment if he/she thinks the 
study treatment does not result in benefit or could be unsafe for you. 
 
If your treatment is stopped, you will be asked to return for safety follow-up visits 
at 28 days after the end of treatment visit and at 90 days after your last dose of 
nivolumab. 
  
Risks Associated with Nivolumab 
 
Most Common (More than a 50% chance that this will happen) 
• 
Fatigue  
• 
Skin reactions: including rash, itching, hives, redness, and dry skin.  
• 
Diarrhea 
• 
Vomiting 
• 
Nausea 
• 
Decrease in the number of white blood cells that fight infection, which can 
lead to infections which may be serious or life threatening (neutropenia and 
eosinophilia) 
  
Less Common (Chance of 1-10% that this will happen) 
• 
Underactive thyroid gland which may be associated with weight gain, heart 
failure, and or constipation  
• 
Overactive thyroid gland which may cause weight loss, fast heartbeat, and 
or sweating  
• 
High blood sugar which if severe, may require urgent treatment  
• 
Inflammation of the intestines and colon which could cause fever, abdominal 
pain, diarrhea, and sometimes blood in the stool (colitis) 
• 
Mouth blisters or sores (stomatitis) 
• 
Abdominal pain 
• 
Weight loss 
• 
Constipation 
• 
Dry mouth 
• 
High body temperature or fever 
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for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
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DFCI Protocol Number:     16-242 
Approved Date (DFCI IRB Approval):  
05/07/2019 
Date Posted for Use:  
05/10/2019  
  
 
 
 
• 
Buildup of fluid in the body just under the skin in the limbs or face (fluid 
retention) 
• 
Infusion reaction which may include fever, dizziness, change in blood 
pressure, shortness of breath, or pain at the site of the infusion 
• 
Lung and upper respiratory infections (like pneumonia and bronchitis) that 
can be serious or life threatening. If uncontrolled, it can lead to an infection 
of the blood stream (sepsis) which can be fatal. 
• 
Other infections of the body including skin infections.  
• 
Liver function abnormalities, which is when there are abnormally high levels 
of enzymes produced by the liver in your blood, meaning that your liver is 
not functioning properly and can cause fatigue, and jaundice (yellowing of 
the skin and eyes). Although this is usually mild and reversible, this can be 
serious or life threatening. This can be a sign of liver damage due to 
inflammation (hepatitis) which could lead to fatigue, jaundice, and mild to 
severe side effects which could require hospitalization and or surgery. 
• 
Low level of sodium in the blood which may cause confusion, dizziness, or 
fatigue which may require intervention (hyponatremia) 
• 
Decreased appetite 
• 
Muscle and joint pain 
• 
Inflammation of the joints which can be accompanied by swelling and 
stiffness (arthritis) 
• 
Inflammation of the joints due to an immune response that can cause tissue 
and joint damage (rheumatoid arthritis)  
• 
Nerve damage to the arms and feet which may result in numbness, pain 
and or loss of motor function which can be permanent (peripheral 
neuropathy) 
• 
Headache  
• 
Dizziness  
• 
Decreased kidney function due to inflammation which could cause a buildup 
of waste in your blood, and in severe cases, require dialysis 
• 
Shortness of breath (hypoxia) 
• 
Cough 
• 
Condition where patches of your skin turn lighter than the surrounding skin 
(vitiligo) 
• 
Hair loss 
• 
High blood pressure  
 
Rare (Chance of less than 2% that this will happen) 
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for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
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DFCI Protocol Number:     16-242 
Approved Date (DFCI IRB Approval):  
05/07/2019 
Date Posted for Use:  
05/10/2019  
  
 
 
 
• 
Inflammation of the blood vessels that can damage different organs 
(vasculitis) 
• 
Rash-like bumps on the face (rosacea) 
• 
Red dry scaly patches on the skin (psoriasis)  
• 
Damage to the kidneys causing organ failure which may require dialysis 
(nephritis and renal failure) 
• 
Damage to nerves due to a problem with your immune system which can 
cause muscle weakness, pain and numbness (Guillain-Barre Syndrome) 
• 
Weakness in the muscles of your face and other parts of your body 
• 
Muscle pain 
• 
A condition where the lymph nodes swell, and sometimes have a fever and 
a decrease in white blood cells (histiocytic necrotizing lymphadenitis) 
• 
Lung Inflammation (pneumonitis):  It is possible that nivolumab may cause 
inflammation of the tissues of the lung.  Signs and symptoms of lung 
inflammation may include difficulty breathing, pain or discomfort while 
breathing, chest pain, cough, shortness of breath, increased rate of 
breathing, fever, low blood oxygen levels, or fatigue. 
• 
Allergic reaction to nivolumab or components of nivolumab which could be 
life threatening   
• 
Intestinal ulcer 
• 
Diabetes mellitus 
• 
Severe high blood sugar caused by uncontrolled diabetes (ketoacidosis) 
• 
Inflammation of the thyroid gland which could cause tenderness in the neck  
• 
Inflammation of the pituitary gland which may cause headaches, changes in 
eyesight, affect the menstrual cycle of women, increase in thirst, and an 
increase in urination  
• 
Adrenal insufficiency which results in decrease of hormones in your blood 
and may cause fatigue, weakness, confusion, weight loss, dizziness, loss of 
appetite, low blood pressure, nausea or vomiting  
• 
Fast heartbeat (tachycardia) 
• 
Autoimmune disorders, including Guillain-Barre syndrome (associated with 
progressive muscle weakness or paralysis)  
• 
Problems with the heart, including palpitations, atrial fibrillation, and 
ventricular arrhythmia and an inflammation of the heart wall (myocarditis) 
• 
Dehydration 
• 
Inflammation of the pancreas that can cause severe stomach pain, nausea, 
vomiting, and may be life threatening (pancreatitis) 
• 
Inflammation of the optic nerve which can cause pain and temporary vision 
loss, which usually returns (uveitis) 
3/26/2020 1:27 pm


 
 
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for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
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DFCI Protocol Number:     16-242 
Approved Date (DFCI IRB Approval):  
05/07/2019 
Date Posted for Use:  
05/10/2019  
  
 
 
 
• 
Inflammation or loss of the lining of the brain and spinal cord 
(demyelination) which can cause headaches, fever, nausea, weakness, 
nerve damage and sometimes paralysis 
•  Abnormal brain function due to brain inflammation (encephalitis), potentially   
life-threatening or fatal 
 
Very Rare (Chance of less than 0.1% that this will happen) 
• Severe reaction of the skin and gut lining that may include rash and 
shedding or death of tissue. This can include conditions in which the death 
is skin tissue causes the outer layer of the skin to separate from the 
middle layer and be serious and life threatening. (Stevens-Johnsons 
syndrome) 
 
•  Toxic epidermal necrolysis:   a potentially fatal disease characterized by 
blistering and peeling of the top layer of skin resembling a severe sun burn 
 
Other Risks Associated with Nivolumab 
• Solid organ rejection in patients who have previously undergone allogeneic 
stem cell transplantation and then were treated with nivolumab.  Treatment 
with nivolumab may increase the risk of organ rejection in patients who have 
received a solid organ or tissue transplant. 
 
• Severe or fatal Graft-Versus-Host Disease, a condition in which immune 
cells from a tissue transplant donor attacks the organs of its recipient, have 
been reported in patients who have had a type of bone marrow or stem cell 
transplant called an allogeneic stem cell transplant that were then treated 
with nivolumab.  
 
• Patients who have received nivolumab may be at an increased risk of 
transplant related complications including Graft –Versus-Host Disease, 
which may be severe or life threatening.  
  
Risks Associated with Lenalidomide 
 
Most Common (More than a 50% chance that this will happen) 
• Low number of red blood cells (anemia) which can cause tiredness, 
shortness of breath, and may require a blood transfusion 
• Constipation or difficult bowel movements 
• Diarrhea or loose/frequent bowel movements 
• Fatigue 
3/26/2020 1:27 pm


 
 
Research Consent Form 
  
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
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DFCI Protocol Number:     16-242 
Approved Date (DFCI IRB Approval):  
05/07/2019 
Date Posted for Use:  
05/10/2019  
  
 
 
 
• A serious or life threatening decrease in the number of a type of white 
blood cell (neutrophil/ granulocyte) that helps to protect against infection 
which causes an increased risk of infection 
• Decreased number of a type of blood cell that help to clot blood (platelet). 
This may result in bleeding. 
 
Somewhat Common (Chance of 10-50% that this will happen) 
• Abnormally low level of thyroid hormones. This may cause fatigue, weight 
gain, fluid retention, sensitivity to cold and mental apathy. Can be serious 
or life threatening. 
• Nausea or the urge to vomit 
• Vomiting 
• Chills 
• Swelling or tingling of the arms and legs 
• Fever 
• Infection, which may be serious and life threatening 
• A decrease in the number of a type of white blood cell (lymphocyte) and 
decrease in the total number of white blood cells (leukocytes) which may 
increase the risk of infection. 
• Weight loss 
• Loss of appetite 
• Back, joint and muscle pain 
• Muscle cramps/spasms 
• Dizziness (or sensation of lightheadedness, unsteadiness, giddiness, 
spinning or rocking) 
• Headache or head pain 
• Difficulty sleeping or falling asleep 
• Cough 
• Shortness of breath 
• Itching 
• Skin rashes that may be flat (macular), raised (papular) or red and 
irritated. 
• Excess sweating 
• Formation of a blood clot that may break loose and be carried by the blood 
stream to plug another blood vessel. May be serious and life threatening. 
(thromboembolism)  
 
Rare (Chance of less than 1% that this will happen) 
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Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
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DFCI Protocol Number:     16-242 
Approved Date (DFCI IRB Approval):  
05/07/2019 
Date Posted for Use:  
05/10/2019  
  
 
 
 
• Inflammation of the pancreas. This may cause abdominal pain and require 
hospitalization and intravenous treatment. It may be accompanied by 
increased blood levels of a fat-digesting enzyme called lipase. 
• Serious life-threatening allergic reaction requiring immediate medical 
treatment. The reaction may include extremely low blood pressure, 
swelling of the throat, difficulty breathing, and loss of consciousness. 
• Tumor Lysis Syndrome, which is the result of rapid destruction of cancer 
cells that can occur after treatment of cancer has started and may cause 
an electrolyte imbalance, increased uric acid buildup (gout), and kidney 
damage 
• Decreased production of blood cells by the bone marrow (marrow aplasia) 
including cells that fight infection, clot the blood, and carry oxygen to 
tissue 
• Temporary growth in tumor or worsening of tumor-related problems 
• Tissue death of a part of the brain without inflammation that may affect 
different functions of the brain including speech or movement and may be 
severe or life threatening 
• Sudden decrease of kidney function. When the kidneys do not work 
properly, wastes can build up in your blood, leading to swelling in the arms 
and legs, tiredness and weakness. This could become severe, requiring 
hospitalization and dialysis to clean the wastes out of your blood. If the 
wastes are not removed from your blood, this could cause seizures and be 
life threatening. 
• Severe reaction of the skin and gut lining that may include rash and 
shedding or death of tissue. This can include conditions in which the death 
is skin tissue causes the outer layer of the skin to separate from the 
middle layer and be serious and life threatening. 
• Development of a second cancer including leukemia. 
 
Risks Associated with Dexamethasone 
 
Less Common (Between a 1-10% chance that this will happen): 
• Increased blood sugar. If you have diabetes, this may lead to a need to 
adjust your medications used to treat the diabetes. 
• Increased appetite. 
• Weight gain. 
• Fluid retention (edema), which can cause a buildup of fluid in the body or 
extremities causing swelling. 
• Elevation of blood pressure 
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for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
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DFCI Protocol Number:     16-242 
Approved Date (DFCI IRB Approval):  
05/07/2019 
Date Posted for Use:  
05/10/2019  
  
 
 
 
• Mood changes (depression, or abnormal feelings of well-being and 
excitement) 
• Difficulty sleeping 
• Skin changes leading to thinning and easy bruising 
• Gradual changes to bones that may increase their risk of breaking 
• Muscle weakness 
• Stomach irritation/ulcer 
• Increased risk of infection 
• Acne 
 
Rare (Less than 1% chance that this will happen): 
• Loss of potassium, which may lead to weakness and abnormal heart 
beats. 
• Increased eye pressure in patients with glaucoma which may cause 
damage to the optic nerve and vision loss 
• Gradual development of cataracts, or a clouding of the lens of the eye 
causing hazy or blurry vision  
• If used for a long time, dexamethasone can suppress the function of the 
normal glands that make steroids. This may cause weakness, confusion, 
fatigue, listlessness, low blood pressure, dizziness, weight loss, and loss 
of appetite. May also cause abdominal cramps, nausea, vomiting and 
diarrhea and changes in electrolytes (body salts). Symptoms may be 
worse at times of stress, such as high fevers, infection, surgery or a 
serious accident. If your adrenal glands do not produce enough hormones, 
you will need to take oral medications to replace the hormones  
• Glaucoma, or optic nerve and vision damage which can be caused by an 
increase in pressure within the eye 
• Pancreatitis or an inflammation of the pancreas causing pain in the upper 
abdomen that can become severe and cause nausea, vomiting, and could 
require hospitalization and may be life threatening.  
 
Special Considerations  
 
Lenalidomide is a member of a class of drug that causes damage to a fetus 
(teratogen). It is important that mandatory contraceptive measures be used 
while taking lenalidomide. It also requires special prescription forms (RevAssist) 
and frequent counseling. Your physician will discuss this with you. 
 
Lenalidomide has been shown to increase the level of digoxin in the blood in 
some patients. Please tell your doctor immediately if you are taking digoxin. 
3/26/2020 1:27 pm


 
 
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for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
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DFCI Protocol Number:     16-242 
Approved Date (DFCI IRB Approval):  
05/07/2019 
Date Posted for Use:  
05/10/2019  
  
 
 
 
 
The use of lenalidomide therapy has been known to hinder the collection of your 
own stem cells in patients with multiple myeloma. If your disease progresses to 
multiple myeloma and you are deemed a candidate for autologous (using your 
own cells) stem cell transplant, it is unknown if the long term use of lenalidomide 
therapy will rule out stem cell collection from your peripheral blood. 
 
Cancer research often includes biopsies, scans, x-rays that are also provided as 
routine care.  The following describes the side effects of procedures done only 
for the purposes of research.  
 
Risks Associated with Bone Marrow Aspiration: 
 
For this procedure, a numbing drug is injected into the skin over one of your 
hipbones. A needle is then inserted into the hipbone and a sample of bone 
marrow fluid is removed. Risks of this procedure are small, but may include: 
• Pain from the needle sticks 
• Pain from aspirating the bone marrow with a syringe 
• Bleeding 
• Infection 
• Local nerve damage 
Risks Associated with Bone Marrow Biopsies: 
 
For this procedure, a numbing drug is injected into the skin over the same 
hipbone. A needle is then inserted into the hipbones and a small piece of bone is 
removed. The risks may include: 
• Moderate pain and discomfort 
• Bleeding at the biopsy site 
• Scarring at the biopsy site 
• Rarely, an infection at the biopsy site 
• Rarely, nerve injury at the biopsy site 
 
Radiation Risks Associated with Scans and X-Rays:  
 
While you are in this research study, PET/CT scans, Bone Scans, and/or x-rays 
utilizing radioactivity may be used to evaluate your disease. In the long term, 
over many years, there is a very low risk of developing a new cancer as a result 
of the radiological evaluation and treatment for your cancer.   
 
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for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
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DFCI Protocol Number:     16-242 
Approved Date (DFCI IRB Approval):  
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Date Posted for Use:  
05/10/2019  
  
 
 
 
Risks Associated with MRI Scans:  
 
When having an MRI (Magnetic Resonance Imaging) scan, you will lie still on a 
table that slides into a tunnel slightly wider than your body. People who feel 
uncomfortable in confined spaces (claustrophobia) may feel uncomfortable in the 
narrow cylinder. If you feel uncomfortable in confined spaces, please tell your 
research doctor. Your doctor may give you a medication to make you feel more 
comfortable. As images are taken, a loud banging noise will be produced.  
Earplugs or headphones will be available if needed. The MRI can be stopped at 
any time at your request, but the scan may not be complete. 
Uncommonly, some people have allergic reactions (such as hives and itching) to 
the contrast agent.  Serious reactions (for example, drop in blood pressure, 
difficulty breathing or severe allergic reaction and death) are rare.   
 
Reproductive Risks:  
 
The drugs used in this research study may affect a fetus.  While participating in 
this research study, you should not become pregnant or father a baby and should 
not nurse a baby.  We can provide counseling about preventing pregnancy for 
either male or female study participants. Let your doctor know immediately if you 
become pregnant or find out that you are going to be the father of a child. 
 
In the event that your partner becomes pregnant, it may be critical to share 
information regarding your participation in this research study with that person.  
Your research doctor should also be told if this happens.  The study sponsor may 
want to collect data on your partner’s pregnancy.   
 
Lenalidomide is related to thalidomide. Thalidomide is known to cause severe 
life-threatening human birth defects. Findings from a laboratory study indicate 
that lenalidomide caused birth defects in the offspring of females who received 
the drug during pregnancy. If lenalidomide is taken during pregnancy, it may 
cause birth defects or death to any unborn baby. Females should not become 
pregnant while taking lenalidomide. You have been informed that the risk of birth 
defects is unknown. If you are female, you agree not to become pregnant while 
taking lenalidomide 
 
Patients with blood cancers who take lenalidomide and dexamethasone have a 
greater chance of having blood clots. Because of this, it is recommended patients 
discuss the use of birth control pills or hormone replacement therapy with the 
study doctor to better understand the risks and benefits of these choices 
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Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
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Non-Physical Risks:  
 
Because of side effects or the time required for tests and clinic visits while you 
are on this research study, you may be unable to keep up with your normal daily 
activities.  
  
G. WHAT ARE THE BENEFITS OF THE RESEARCH STUDY? 
 
This study may or may not help you. Taking part in this research study may help 
researchers learn things that may help people in the future  
  
H. CAN I STOP BEING IN THE RESEARCH STUDY AND WHAT ARE MY RIGHTS? 
 
You have the right to choose not to sign this form.  If you decide not to sign this 
form, you cannot participate in this research study.  
 
You can stop being in the research study at any time.  Tell the research doctor if 
you are thinking about stopping or decide to stop.  He or she will tell you how to 
stop.  Leaving the research study will not affect your medical care outside of the 
research study.   
 
If you choose not to participate, are not eligible to participate, or withdraw from 
this research study, this will not affect your present or future care and will not 
cause any penalty or loss of benefits to which you are otherwise entitled.  
 
It is important to tell the research doctor if you are thinking about stopping so 
your research doctor can evaluate the risks from stopping the nivolumab/ 
lenalidomide/ dexamethasone. Another reason to tell your research doctor that 
you are thinking about stopping is to discuss what follow-up care and testing 
could be most helpful for you. 
  
I. WILL I BE PAID TO TAKE PART IN THIS RESEARCH STUDY? 
 
We may use your samples and information to develop a new product or medical 
test to be sold.  The sponsor (DFCI) and hospital may benefit if this happens. 
There are no plans to pay you if your samples are used for this purpose.  
 
Your participation in this research study may contribute to the development of 
commercial products from which Bristol-Myers Squibb, Inc or others, may derive 
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Dana-Farber/ Harvard Cancer Center 
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an economic benefit. You will have no rights to any patents or discoveries arising 
from this research, and you will receive no economic benefit. 
 
You will not be paid to take part in this research study.  
  
J. WHAT ARE THE COSTS? 
 
Taking part in this research study might lead to added costs to you or your 
insurance company. 
 
You will not be charged for nivolumab. You or your insurance company will be 
charged for portions of your care during this research study that are considered 
standard care, including the study drugs lenalidomide and dexamethasone. You 
may be responsible for co-payments and deductibles that are typical for your 
insurance coverage. 
Lenalidomide and dexamethasone are commercially available which means that 
the FDA has approved them for use in patients with another type of cancer.  
Because there is evidence that supports using this drug in patients with your type 
of cancer, you or your insurance company will be billed for the cost of both 
lenalidomide and dexamethasone. 
 
If you have questions about your insurance coverage, or the items you might be 
required to pay for, please call financial services for information.  The contact 
information for financial services is:   
 
• Dana-Farber Cancer Institute: (617) 632-3455 
 
The National Cancer Institute provides an online resource to help people 
participating in cancer clinical trials understand which services their insurance 
company is required by law to pay.  This can be found at the website below or 
can be provided by the study team: 
 
www.cancer.gov or 1-800-4-CANCER (1-800-422-6237) 
 
 
K. WHAT HAPPENS IF I AM INJURED OR SICK BECAUSE I TOOK PART IN THIS 
RESEARCH STUDY? 
 
If you think you have been injured as a result of taking part in this research study, 
tell the person in charge of this research study as soon as possible.  The 
research doctor’s name and phone number are listed in this consent form. 
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Dana-Farber/ Harvard Cancer Center 
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The treating hospital will offer you the care needed to treat injuries directly 
resulting from taking part in this research.  The treating hospital may bill your 
insurance company or other third parties, if appropriate, for the costs of the care 
you get for the injury, but you may also be responsible for some of them. 
 
There are no plans for any of the sponsors of this study to pay you or give you 
other compensation for the injury.  You do not give up your legal rights by signing 
this form. 
 
 
L. WHAT ABOUT CONFIDENTIALITY? 
 
We will take measures to protect the privacy and security of all your personal 
information, but we cannot guarantee complete confidentiality of study data.  
 
Medical information created by this research study may become part of your 
hospital medical record and may be forwarded to your primary doctor. 
Information that does not become part of your medical record will be stored in 
your study file. It may also become part of a DF/HCC research database.   
 
The results of this research study may be published. You will not be identified in 
publications without your permission. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law.  This web site will not include information that can 
identify you.  At most, the web site will include a summary of the results.  You 
can search this Web site at any time. 
  
M. WHOM DO I CONTACT IF I HAVE QUESTIONS ABOUT THE RESEARCH STUDY? 
 
If you have questions about the study, please contact the research doctor or 
study staff as listed below: 
 
Dana-Farber Cancer Institute: 
 
• Irene Ghobrial, MD: Irene_Ghobrial@dfci.harvard.edu; 617-632-
4198 
 
If you are experiencing an urgent medical issue, please go to the nearest 
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for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
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emergency medical facility, or contact our site to have your physician paged. 
 
24-hour contact: DFCI: Irene Ghobrial, MD (617) 632-3352 and ask for your 
physician to be paged at beeper 41651 
 
For questions about your rights as a research participant, please contact a 
representative of the Office for Human Research Studies at DFCI (617) 632-
3029. This can include questions about your participation in the study, concerns 
about the study, a research related injury, or if you feel/felt under pressure to 
enroll in this research study or to continue to participate in this research study.  
 
N. PRIVACY OF PROTECTED HEALTH INFORMATION 
 
Federal law requires Dana-Farber/Harvard Cancer Center (DF/HCC) and its 
affiliated research doctors, health care providers, and physician network to 
protect the privacy of information that identifies you and relates to your past, 
present, and future physical and mental health conditions (“protected health 
information”).  If you enroll in this research study, your “protected health 
information” will be used and shared with others as explained below. 
 
1. What protected health information about me will be used or shared with 
others during this research? 
 
• Existing medical records, including mental health records. 
• New health information created from study-related tests, procedures, 
visits, and/or questionnaires 
 
2. Why will protected information about me be used or shared with others? 
 
The main reasons include the following: 
• To conduct and oversee the research described earlier in this form; 
• To ensure the research meets legal, institutional, and accreditation 
requirements;  
• To conduct public health activities (including reporting of adverse events 
or situations where you or others may be at risk of harm); and 
• To provide the study sponsor with information arising from an adverse 
event or other event that relates to the safety or toxicity of the drug for the 
purpose of this or other research relating the study drug and its use in 
cancer; and, 
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• Other reasons may include for treatment, payment, or health care 
operations.  For example, some medical information produced by this 
research study may become part of your hospital medical record because 
the information may be necessary for your medical care. (You will also be 
given a notice for use and sharing of protected health information.) 
 
3. Who will use or share protected health information about me? 
 
• DF/HCC and its affiliated research doctors and entities participating in the 
research will use and share your protected health information.  In addition, 
other DF/HCC offices that deal with research oversight, billing or quality 
assurance will be able to use and share your protected health information. 
 
4. With whom outside of DF/HCC may my protected health information be 
shared? 
 
While all reasonable efforts will be made to protect the confidentiality of your 
protected health information, it may also be shared with the following entities: 
 
• Outside individuals or entities that have a need to access this information 
to perform functions relating to the conduct of this research such as 
analysis by outside laboratories on behalf of DF/HCC and its affiliates (for 
example, data storage companies, insurers, or legal advisors). 
• Adaptive, Inc. in Seattle, WA will receive bone marrow samples that 
directly identify you. However, your identifiers will only be shared with 
Adaptive, Inc and will not be shared with Dana Farber. The results of 
these tests will be shared with Dana Farber in aggregate, meaning; the 
results will not be linked to any information that identifies you. Your 
samples and related medical information will not be retained for more than 
6 months after your samples have been analyzed.  
• Bristol-Myers Squibb, who is supporting this research study by providing 
funding for the research study and the study drug 
• Other research doctors and medical centers participating in this research, 
if applicable 
• Federal and state agencies (for example, the Department of Health and 
Human Services, the Food and Drug Administration, the National 
Institutes of Health, and/or the Office for Human Research Protections), or 
other domestic or foreign government bodies if required by law and/or 
necessary for oversight purposes. A qualified representative of the FDA 
and the National Cancer Institute may review your medical records. 
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• Hospital accrediting agencies 
• A data safety monitoring board organized to oversee this research, if 
applicable 
 
Some who may receive your protected health information may not have to 
satisfy the privacy rules and requirements.  They, in fact, may share your 
information with others without your permission.  
 
5. For how long will protected health information about me be used or 
shared with others? 
 
• There is no scheduled date at which your protected health information that 
is being used or shared for this research will be destroyed, because 
research is an ongoing process.   
 
6. Statement of privacy rights: 
 
• You have the right to withdraw your permission for the research doctors 
and participating DF/HCC entities to use or share your protected health 
information.  We will not be able to withdraw all the information that 
already has been used or shared with others to carry out related activities 
such as oversight, or that is needed to ensure quality of the study. To 
withdraw your permission, you must do so in writing by contacting the 
researcher listed above in the section: “Whom do I contact if I have 
questions about the research study?” 
• You have the right to request access to your protected health information 
that is used or shared during this research and that is related to your 
treatment or payment for your treatment, but you may access this 
information only after the study is completed.  To request this information, 
please contact the researcher listed above in the section: “Whom do I 
contact if I have questions about the research study?” 
 
 
 
 
 
 
 
 
 
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OHRS 07.17.15 
 
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O.  Safeguards of Confidentiality in Studies Involving Genes 
     (Genetic Studies) 
 
A federal law (Genetic Information Non-Discrimination Act, GINA) will help 
lower the risk from health insurance or employment discrimination on the 
basis of genetic information. The federal law does not include other types 
of misuse by life insurance, long term care or disability insurance. If you 
want to learn more about the GINA Law, which went into effect in 2009, 
you can find information about it on the internet or ask the study staff. In 
addition to the federal law, some states have laws that also help to protect 
against genetic discrimination. While we believe that the risks to you and 
your family are very low, we cannot tell you exactly what all of the risks are 
from taking part in genetic research studies. Your privacy and 
confidentiality will be protected to the fullest extent possible. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 07.17.15 
 
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Approved Date (DFCI IRB Approval):  
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P. DOCUMENTATION OF CONSENT 
 
My signature below indicates: 
• I have had enough time to read the consent and think about 
participating in this study; 
• I have had all of my questions answered to my satisfaction; 
• I am willing to participate in this study; 
• I have been told that my participation is voluntary and I can withdraw at 
any time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Participant 
 
 
 
Date 
or Legally Authorized Representative   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relationship of Legally Authorized Representative to Participant   
 
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Adult Participants 
To be completed by person obtaining consent: 
 
The consent discussion was initiated on   
 (date). 
 
Signature of individual obtaining consent:  
 
 
Printed name of above:   
 
 
Date:  
 
 
 A copy of this signed consent form will be given to the participant or legally authorized 
representative, or, where the participant is a minor, the participant’s parent or legal guardian. 
For Adult Participants 
 1)  The participant is an adult and provided consent to participate. 
 
 1a)  Participant (or legally authorized representative) is a non-English speaker and 
 
signed the translated Short Form in lieu of English consent document: 
 
As someone who understands both English and the language spoken by the participant, I 
interpreted and/or witnessed, in the participant’s language, the researcher’s presentation 
of the English consent form.  The participant was given the opportunity to ask questions.  
Signature of Interpreter/Witness:  
 
Printed Name of Interpreter/Witness:  
 
Date:  
 
 
 
 1b)  Participant is illiterate 
 
The consent form was read to the participant who was given the opportunity  
 
to ask questions.  
Signature of Witness:  
 
Printed Name of Witness:  
 
Date:  
 
 2)  The participant is an adult who lacks capacity to provide consent and his/her legally 
authorized representative: 
 2a) gave permission for the adult participant to participate  
 2b) did not give permission for the adult participant to participate  
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