protocol title
untitled h2

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 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  
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  
  
Statistician: Project **Manager:** Lorenzo Trippa Alexandra Savell Dana-Farber Cancer Institute Dana-Farber Cancer Institute ltrippa@partners.org AlexandraE_Savell@dfci.harvard.edu SCHEMA  
  
**Disease **Assessment:** Day 1 of each cycle  
| Table of Contents                           |                                                                                                                                                                            |                                                                                                                      |
|---------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------|
| LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS |                                                                                                                                                                            |                                                                                                                      |
| PROTOCOL SUMMARY .                          |                                                                                                                                                                            |                                                                                                                      |
| 1.                                          | OBJECTIVES                                                                                                                                                                 |                                                                                                                      |
| S S TUDY D ESIGN .                          |                                                                                                                                                                            |                                                                                                                      |
| 1.1                                         |                                                                                                                                                                            |                                                                                                                      |
| 1.2                                         | N N UMBER OF P ATIENTS .                                                                                                                                                   |                                                                                                                      |
| 1.3                                         | D DURATION OF STUDY                                                                                                                                                        |                                                                                                                      |
| 1.4                                         | PRIMARY OBJECTIVES                                                                                                                                                         |                                                                                                                      |
| 1.5                                         | S S ECONDARY  O BJECTIVES                                                                                                                                                  |                                                                                                                      |
| BACKGROUND                                  |                                                                                                                                                                            |                                                                                                                      |
| 2.                                          | 2.1                                                                                                                                                                        | M M ULTIPLE M YELOMA .                                                                                               |
| 2.2                                         | M MGUS AND SMM CONSISTENTLY PRECEDES MULTIPLE MYELOMA ......................................................16                                                             |                                                                                                                      |
| 2.3                                         | MOLECULAR STUDIES IN MGUS AND SMM                                                                                                                                          |                                                                                                                      |
| 2.4                                         | D DEFINITION OF SMM AND MM                                                                                                                                                 |                                                                                                                      |
| 2.5                                         | DEFINITIONS OF HIGH-RISK SMM .                                                                                                                                             |                                                                                                                      |
| 2.6                                         | T T REATMENT OF HIGH RISK SMM ......................................................................................................................................... 19 |                                                                                                                      |
| 2.7                                         | N NIVOLUMAB                                                                                                                                                                |                                                                                                                      |
| 2.8                                         | PHARMACOKINETICS AND DRUG METABOLISM                                                                                                                                       |                                                                                                                      |
| 2.9                                         | T RIAL R ATIONALE  .                                                                                                                                                       |                                                                                                                      |
| 2.10                                        | CORRELATIVE STUDIES BACKGROUND .                                                                                                                                           |                                                                                                                      |
| 3.                                          | PARTICIPANT  SELECTION .                                                                                                                                                   |                                                                                                                      |
| 3.1                                         | E ELIGIBILITY C RITERIA                                                                                                                                                    |                                                                                                                      |
| 3.2                                         | E E XCLUSION C RITERIA .                                                                                                                                                   |                                                                                                                      |
| 3.3                                         | I I NCLUSION OF W OMEN AND M INORITIES .                                                                                                                                   |                                                                                                                      |
| REGISTRATION  PROCEDURES                    |                                                                                                                                                                            |                                                                                                                      |
| 4.                                          | 4.1                                                                                                                                                                        | GENERAL GUIDELINES FOR DF/HCC AND DF/PCC I NSTITUTIONS .......................................................... 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                                                                                                                                                             |                                                                                                                      |
| 5.1                                         | T REATMENT R EGIMEN                                                                                                                                                        |                                                                                                                      |
| 5.2                                         | A A GENT A DMINISTRATION                                                                                                                                                   |                                                                                                                      |
| 5.3                                         | GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES .............................. 33                                                                            |                                                                                                                      |
| M MANAGEMENT OF C LINICAL E VENTS           |                                                                                                                                                                            |                                                                                                                      |
| 5.4                                         |                                                                                                                                                                            |                                                                                                                      |
| 5.5                                         | CRITERIA FOR TAKING A PARTICIPANT OFF PROTOCOL THERAPY ....................................................... 36                                                          |                                                                                                                      |
| 5.6                                         | D DURATION OF FOLLOW UP                                                                                                                                                    |                                                                                                                      |
| 5.7                                         | CRITERIA FOR TAKING A PARTICIPANT OFF STUDY  .                                                                                                                             |                                                                                                                      |
| DOSING DELAYS/DOSE MODIFICATIONS .          |                                                                                                                                                                            |                                                                                                                      |
| 6.                                          | 6.1                                                                                                                                                                        | RECOMMENDED CRITERIA FOR BEGINNING OR DELAYING A SUBSEQUENT TREATMENT CYCLE                                          |
| 38                                          |                                                                                                                                                                            |                                                                                                                      |
| N NIVOLUMAB                                 |                                                                                                                                                                            |                                                                                                                      |
| 6.2                                         |                                                                                                                                                                            |                                                                                                                      |
| 6.3                                         | L L ENALIDOMIDE                                                                                                                                                            |                                                                                                                      |
| 6.4                                         | D D EXAMETHASONE .                                                                                                                                                         |                                                                                                                      |
| 6.5                                         | D DOSE D ELAY G UIDELINES  .                                                                                                                                               |                                                                                                                      |
| CONFIDENTIAL                                |                                                                                                                                                                            |                                                                                                                      |  
| Local Protocol #: 16-242                                                                                                     |                                                                                                                  |                                      |
|------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------|--------------------------------------|
| Version Date: 23 January 2018                                                                                                |                                                                                                                  |                                      |
| ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .............................................48                             |                                                                                                                  |                                      |
| 7.1                                                                                                                          | DEFINITIONS                                                                                                      |                                      |
| 7.2                                                                                                                          | E E XPECTED T OXICITIES  .                                                                                       |                                      |
| 7.3                                                                                                                          | A A DVERSE E VENT C HARACTERISTICS                                                                               |                                      |
| 7.4                                                                                                                          | E E XPEDITED A DVERSE E VENT R EPORTING                                                                          |                                      |
| 7.5                                                                                                                          | DF/HCC EXPEDITED REPORTING GUIDELINES                                                                            |                                      |
| 7.6                                                                                                                          | E E XPEDITED R EPORTING TO THE F OOD AND D RUG A DMINISTRATION (FDA)  ....................................... 55 |                                      |
| E E XPEDITED R EPORTING TO B RISTOL - M YERS S QUIBB (BMS) .                                                                 |                                                                                                                  |                                      |
| 7.7                                                                                                                          |                                                                                                                  |                                      |
| 7.8                                                                                                                          | E E XPEDITED R EPORTING TO H OSPITAL R ISK M ANAGEMENT                                                           |                                      |
| 7.9                                                                                                                          | ROUTINE ADVERSE EVENT REPORTING                                                                                  |                                      |
| 8.                                                                                                                           | PHARMACEUTICAL INFORMATION                                                                                       |                                      |
| N NIVOLUMAB                                                                                                                  |                                                                                                                  |                                      |
| 8.1                                                                                                                          |                                                                                                                  |                                      |
| 8.2                                                                                                                          | L L ENALIDOMIDE                                                                                                  |                                      |
| 8.3                                                                                                                          | D EXAMETHASONE .                                                                                                 |                                      |
| 9.                                                                                                                           | BIOMARKER, CORRELATIVE, MRD ASSESSMENT AND SPECIAL STUDIES ...............61                                     |                                      |
| 9.1                                                                                                                          | MINIMAL RESIDUAL DISEASE ASSESSMENT (MRD)                                                                        |                                      |
| 9.2                                                                                                                          | BONE MARROW ASPIRATE SAMPLES .                                                                                   |                                      |
| 9.3                                                                                                                          | PERIPHERAL BLOOD SAMPLES .                                                                                       |                                      |
| 9.4                                                                                                                          | B B UCCAL S WAB S AMPLES                                                                                         |                                      |
| STUDY CALENDAR                                                                                                               |                                                                                                                  |                                      |
| 10.                                                                                                                          | ME A SUREMENT OF EFFECT                                                                                          |                                      |
| 1.                                                                                                                           | 11.1                                                                                                             | D DEVELOPMENT OF SYMPTOMATIC DISEASE |
| A A NTITUMOR E FFECT .                                                                                                       |                                                                                                                  |                                      |
| 11.2                                                                                                                         |                                                                                                                  |                                      |
| 12.                                                                                                                          | DATA REPORTING / REGULATORY REQUIREMENTS                                                                         |                                      |
| 12.1                                                                                                                         | D DATA R EPORTING                                                                                                |                                      |
| 12.2                                                                                                                         | D DATA S AFETY M ONITORING .                                                                                     |                                      |
| 13.                                                                                                                          | STATISTICAL CONSIDERATIONS                                                                                       |                                      |
| 13.1                                                                                                                         | S S TUDY D ESIGN / E NDPOINTS                                                                                    |                                      |
| 13.2                                                                                                                         | SAMPLE SIZE, ACCRUAL RATE AND STUDY DURATION .                                                                   |                                      |
| 13.3                                                                                                                         | STRATIFICATION FACTORS                                                                                           |                                      |
| 13.4                                                                                                                         | I I NTERIM M ONITORING P LAN .                                                                                   |                                      |
| 13.5                                                                                                                         | STOPPING R ULE FOR S AFETY .                                                                                     |                                      |
| 14.                                                                                                                          | PUBLICATION PLAN                                                                                                 |                                      |
| REFERENCES                                                                                                                   |                                                                                                                  |                                      |
| 15.                                                                                                                          |                                                                                                                  |                                      |
| APPENDIX A: PERFORMANCE STATUS CRITERIA ..................................................................................85 |                                                                                                                  |                                      |
| APPENDIX B: SPECIMEN COLLECTION SCHEDULE .............................................................................86     |                                                                                                                  |                                      |
| APPENDIX C: SPECIMEN REQUISITION .                                                                                           |                                                                                                                  |                                      |
| APPENDIX D: MANAGEMENT ALGORITHMS FOR ENDOCRINOPATHY,                                                                        |                                                                                                                  |                                      |
| GASTROINTESTINAL, HEPATIC, RENAL, SKIN, NEUROLOGICAL, AND PULMONARY                                                          |                                                                                                                  |                                      |
| A ADVERSE EVENTS DUE TO NIVOLUMAB                                                                                            |                                                                                                                  |                                      |
| APPENDIX E: DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER DATA AND                                                          |                                                                                                                  |                                      |
| SAFETY MONITORING PLAN .                                                                                                     |                                                                                                                  |                                      |
| INTRODUCTION .                                                                                                               |                                                                                                                  |                                      |
| 1.                                                                                                                           | 1.1                                                                                                              | P P URPOSE                           |  
Local Protocol \#: 16-242  
| Version Date: 23 January 2018        |                                                                                                                                        |                          |
|--------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------|--------------------------|
| 1.2                                  | MULTI-C ENTER D ATA AND S AFETY M ONITORING P LAN D EFINITIONS  .................................................... 96                |                          |
| GENERAL ROLES AND RESPONSIBILITIES . |                                                                                                                                        |                          |
| 2.                                   | 2.1                                                                                                                                    | DF/HCC Sponsor           |
| 2.2                                  | COORDINATING CENTER                                                                                                                    |                          |
| 2.3                                  | P P RTICIPATING  I NSTITUTION                                                                                                          |                          |
| 3.                                   | DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ............................................. 98                                        |                          |
| 3.1                                  | PROTOCOL DISTRIBUTION                                                                                                                  |                          |
| 3.2                                  | PROTOCOL REVISIONS AND CLOSURES                                                                                                        |                          |
| 3.3                                  | INFORMED CONSENT REQUIREMENTS                                                                                                          |                          |
| 3.4                                  | IRB DOCUMENTATION                                                                                                                      |                          |
| 3.5                                  | IRB RE-Approval                                                                                                                        |                          |
| 3.6                                  | PARTICIPANT CONFIDENTIALITY AND AUTHORIZATION STATEMENT................................................. 100                           |                          |
| 3.7                                  | DF/HCC M ULTI -C ENTER P ROTOCOL R EGISTRATION P OLICY .                                                                               |                          |
| 3.8                                  | DF/HCC PROTOCOL CASE NUMBER                                                                                                            |                          |
| 3.9                                  | S S AFETY A SSESSMENTS AND T OXICITY M ONITORING .                                                                                     |                          |
| 3.10                                 | D DATA M ANAGEMENT .                                                                                                                   |                          |
| REQUISITIONING INVESTIGATIONAL DRUG. |                                                                                                                                        |                          |
| 4.                                   |                                                                                                                                        |                          |
| 5.                                   | MONITORING: QUALITY CONTROL                                                                                                            |                          |
| 5.1                                  | ONGOING MONITORING OF PROTOCOL COMPLIANCE ........................................................................................ 104 |                          |
| 5.2                                  | MONITORING REPORTS .                                                                                                                   |                          |
| 5.3                                  | A A CCRUAL M ONITORING .                                                                                                               |                          |
| A AUDITING: QUALITY ASSURANCE        |                                                                                                                                        |                          |
| 6.                                   | 6.1                                                                                                                                    | DF/HCC I NTERNAL A UDITS |
| 6.2                                  | A A UDIT N OTIFICATIONS                                                                                                                |                          |
| 6.3                                  | A A UDIT R EPORTS                                                                                                                      |                          |
| 6.4                                  | PARTICIPATING INSTITUTION PERFORMANCE                                                                                                  |                          |
protocol title
list of abbreviations and glossary

| 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 systemCONFIDENTIAL                                           |  
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.*
CONFIDENTIAL
This document is confidential. Do not disclose or use except as authorized.  
6  
23  2018  
| 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                              |  
23  2018  
| 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                                                |  
23  2018  
| 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                                   |
protocol summary
list of abbreviations and glossary

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
protocol summary
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)
protocol summary
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.
protocol summary
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 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 DanaFarber 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)
protocol summary
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.
protocol summary
duration of study 5 years

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 19802and 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.
protocol summary
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.
protocol summary
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.
protocol summary
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.
protocol summary
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
protocol summary
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.
protocol summary
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 Mprotein ≥ 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. Ageadjusted 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 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  
| Model                               | No. of Risk                               | Time to Progression   |     |     |
|-------------------------------------|-------------------------------------------|-----------------------|-----|-----|
| Factors                             | 5-Year Progression %                      | (in years)            |     |     |
| Mayo Clinic Model                   | 1                                         | 25                    | 10  |     |
| Risk Factors: - M-protein ≥ 3.0g/dL | 2                                         | 51                    | 5.1 |     |
| -                                   | ≥10% plasma cells in the BM               |                       |     |     |
| -                                   | FLC ratio outside the range of 0.125 to 8 | 3                     | 76  | 1.9 |
protocol summary
2.2 mgus and smm consistently

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 kappalambda 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.
protocol summary
2.3 molecular studies in mgus

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 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.  
| 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% |
protocol summary
table 2 cytogenetic abnormalities in

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 evolutionary pressures with alternating dominance of various subclones at different time points3135. 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.
protocol summary
2.4 definition of smm and

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)
protocol summary
new mde criteria that indicates

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
protocol summary
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%   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
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
protocol summary
2.6 treatment of high risk

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).
protocol summary
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
protocol summary
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 PD1 with its ligands, PD-L1 and PD-L2, resulting in enhanced T-cell proliferation and interferongamma (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
protocol summary
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.
protocol summary
2.8 pharmacokinetics and drug metabolism

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.
protocol summary
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.
protocol summary
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.
protocol summary
2.9.1 dexamethasone effect on immune

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.
protocol summary
2.9.2 stem cell mobilization and

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.
protocol summary
2.10 correlative studies background

2.10.1 DNA and RNA sequencing of tumor cells 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.
protocol summary
2.10.2 exome sequencing of tumor

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 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.
protocol summary
2.10.3 rna sequencing of tumor

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.
protocol summary
2.10.4 immune cell characterization in

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.
protocol summary
2.10.5 rna sequencing of immune

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.
protocol summary
2.10.6 cell free dna to

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), 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.
protocol summary
3. participant selection 3.1 eligibility

3.1.1 Age  18 years.  
3.1.2 Must meet criteria of high risk smoldering MM based on the criteria described below:
protocol summary
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
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.  
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
protocol summary
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.  
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.
protocol summary
3.3 inclusion of women and

3.3.1 Both men and women of all races and ethnic groups are eligible for this trial.
protocol summary
4. registration procedures 4.1 general

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. 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.
protocol summary
4.2 registration process for df/hcc

DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject *Protocol* Registration (SOP \#: REGIST-101) must be followed.
protocol summary
4.3 general guidelines for other

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.
protocol summary
4.4 registration process for other

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
protocol summary
treatment may not begin without

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.
protocol summary
5. treatment plan 5.1 treatment

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.  
| 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 |         |
| Take with food;                                                                                                                          |                   |        |             |                          |         |
| Dexamethasone                                                                                                                            | Recommended to be | 40 mg  | Oral        | Days 1, 8, 15            |         |
| taken in the morning                                                                                                                     |                   |        |             |                          |         |
protocol summary
induction cycles 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 |         |  
CONFIDENTIAL
This document is confidential. Do not disclose or use except as authorized.  
30
* 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.
protocol summary
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.
protocol summary
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 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.
protocol summary
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.
protocol summary
5.3 general concomitant medication and

- 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.  
- 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.
protocol summary
- the following procedures are

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)
protocol summary
5.4 management of clinical events

- 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 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 lifethreatening 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.
protocol summary
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.
protocol summary
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).
protocol summary
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.  
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.
protocol summary
5.5 criteria for taking a

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
- 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.
protocol summary
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.
protocol summary
5.7 criteria for taking a

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). 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.
protocol summary
6. dosing delays/dose modifications 6.1

Patients must meet eligibility criteria on Cycle 1 Day 1 to begin treatment. There are no pretreatment 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.
protocol summary
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  
23  2018 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.  
| CTCAE 4.0 Category                                                     | CTCAE Grade                           | Nivolumab Action                      |
|------------------------------------------------------------------------|---------------------------------------|---------------------------------------|
| Grade 1                                                                | Continue to treat- Do NOT OMIT        |                                       |
| Pneumonitis                                                            |                                       |                                       |
| (See Section 6.2.1 for  management guidelines)                         | Grade 2                               | Hold dose until resolved to ≤ Grade 1 |
| ≥ Grade 3                                                              | Permanently discontinue nivolumab     |                                       |
| Grade 1                                                                | Continue to treat- Do NOT OMIT        |                                       |
| Colitis                                                                |                                       |                                       |
| (See Section 6.2.2 for  management guidelines)                         | Grade 2 or                            | Hold dose until resolved to ≤ Grade 1 |
| Grade 3 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     |                                       |
| Grade 1                                                                | Continue to treat- Do NOT OMIT        |                                       |
| Increase in  Creatinine                                                |                                       |                                       |
| (See Section 6.2.4 for  management guidelines)                         | Grade 2  or                           | Hold dose until resolved to ≤ Grade 1 |
| Grade 3 Grade 4                                                        | Permanently discontinue nivolumab     |                                       |
| Grade 1                                                                | Continue to treat- Do NOT OMIT        |                                       |
| All other related  toxicities not listed                               |                                       |                                       |
| previously in thistable (See Section 6.2.6 for  management guidelines) | Grade 2                               | Continue to treat- Do NOT OMIT        |
| Grade 3                                                                | Hold dose until resolved to ≤ Grade 1 |                                       |
| Recurrent Grade 3  or                                                  | Permanently discontinue nivolumab     |                                       |
| CONFIDENTIAL                                                           |                                       |                                       |
protocol summary
table 11 suggested guidelines for

CONFIDENTIAL
This document is confidential. Do not disclose or use except as authorized.  
39
protocol summary
if the patient discontinues nivolumab

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.
protocol summary
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 lifethreatening (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
protocol summary
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.
protocol summary
6.2.4 immune-mediated nephritis and renal

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.
protocol summary
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 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  
| Management/Next Dose for Nivolumab                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                  |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Cardiac * ≤ 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 Hold dose.** Admit to hospital. Cardiology consult. Rule out MI |
| Grade ≥2 with suspected myocarditis                                                                                                                                                                                                                                                    | 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 myocarditisis excluded or considered unlikely.                                                    |
| Grade ≥2 with confirmed                                                                                                                                                                                                                                                                | Off protocol therapy. Admit to CCU (consider transfer to nearest                                                                                                                                                                                                                                                                                                                                                                 |
| myocarditis                                                                                                                                                                                                                                                                            | 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. |                                                                                                                                                                                                                                                                                                                                                                                                                                  |
protocol summary
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 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.  
| CTCAE 4.0                                   | CTCAE Grade                                                                     | Lenalidomide Dose Modification                                                                                                                                                                                 |
|---------------------------------------------|---------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Category                                    | 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                     | Grade 3  or  Grade 4                                                            | Hold dose Administer Filgrastim Reduce dose one level when ANC≥1000                                                                                                                                            |
| ANC <1000 and temperature ≥38.5o C or 101ºF | Grade 1  or                                                                     | Continue to treat- Do NOT OMIT and DO NOT REDUCE therapy                                                                                                                                                       |
| Grade 2                                     |                                                                                 |                                                                                                                                                                                                                |
| Thrombocytopenia                            | CONFIDENTIAL                                                                    |                                                                                                                                                                                                                |
protocol summary
table 12 lenalidomide hematologic toxicities

| Provide platelet transfusion support  Redraw platelets                                                                                                                                                                |                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                              |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Aspirin prophylaxis  should be held if  platelets are ≤50,000                                                                                                                                                         | Grade 3  or  Grade 4                                                                                           | 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 |
| Grade 1 Grade 2 Grade 3                                                                                                                                                                                               | Continue to treat- Do NOT OMIT and DO NOT REDUCE therapy  Transfuse at the discretion of treating investigator |                                                                                                                                                                                                                                                                                                                                                                              |
| Anemia                                                                                                                                                                                                                | Hold treatment                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                              |
| Grade 4                                                                                                                                                                                                               | 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. |                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                              |
protocol summary
table 13 lenalidomide non hematologic

| CTCAE 4.0                                   | CTCAE Grade                                                                                                                            | Lenalidomide Dose Modification   |
|---------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------|----------------------------------|
| Category                                    | Day 1 of Cycle: Delay cycle until infection/viral  illness has resolved. Resume treatment at the same  dose level. Do not dose reduce. |                                  |
| Infection or Viral  Illness with ANC1 ≥1000 | Intracycle: Hold lenalidomide for a maximum of 21  days to allow for recovery. Resume treatment at same  dose level.                   |                                  |
| N/A                                         |                                                                                                                                        |                                  |
| Including herpes  zoster reactivation       | If patient has delay of greater than 21 days, the patient  must come off-study                                                         |                                  |  
| 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   |     |                                                                                                                                                                                                                                                                                                          |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Infection or Viral  Illness with ANC1 < 1000                                                                                                                                                          | N/A | 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 |  
| Grade 1                                                                                                                   | Continue to treat- Do NOT OMIT and DO NOT  REDUCE therapy                                                   |                                                                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Allergic reaction or  hypersensitivity to  Lenalidomide                                                                   | Grade 2                                                                                                     | Continue to treat- Do NOT OMIT and DO NOT  REDUCE therapy Hold lenalidomide  Follow at least weekly.                                                                            |
| Grade 3  or  Grade 4                                                                                                      |                                                                                                             |                                                                                                                                                                                 |
| Including Rash  related to  Lenalidomide                                                                                  | If toxicity resolves to ≤ grade 2, restart at next lower  dose level                                        |                                                                                                                                                                                 |
| Grade 1                                                                                                                   | Continue to treat- Do NOT OMIT and DO NOT  REDUCE therapy                                                   |                                                                                                                                                                                 |
| Renal/Metabolic                                                                                                           | Hold Lenalidomide until < grade 2 and resume  treatment at the same dose level                              |                                                                                                                                                                                 |
| For all grades,  provide hydration and  other supportive care  as needed at the  discretion of the  treating investigator | Grade 2                                                                                                     | If toxicity recurs, dose reduce one dose level at the  treating investigator's discretion Hold Lenalidomide until < grade 2 and resume  treatment with one dose level reduction |
| Grade 3  or  Grade 4                                                                                                      | If the toxicity remains ≥ grade 3, omit dose and restart  at subsequent scheduled visit with one dose level |                                                                                                                                                                                 |
| CONFIDENTIAL                                                                                                              |                                                                                                             |                                                                                                                                                                                 |  
| reduction If treatment-related toxicity occurs on day one of the  cycle, the cycle will be delayed.   |
|-------------------------------------------------------------------------------------------------------|  
| Grade 1                                                             | Continue to treat- Do NOT OMIT and DO NOT  REDUCE therapy Treat at the discretion of the investigator  Provide aggressive supportive care                 |
|---------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 2                                                             |                                                                                                                                                           |
| Diarrhea,  Constipation,  Nausea, or Vomiting                       | DO NOT REDUCE therapy Hold Lenalidomide until toxicity resolves to < grade 2                                                                              |
| Grade 3                                                             | If the patient has received maximum supportive care,  resume therapy with one dose level reduction Hold Lenalidomide until toxicity resolves to < grade 2 |
| Grade 4                                                             | Resume therapy with one dose level reduction                                                                                                              |
| Grade 1                                                             | Continue to treat- Do NOT OMIT and DO NOT  REDUCE therapy                                                                                                 |
| All other related  toxicities not listed  previously in this  table | Continue to treat- Do NOT OMIT and DO NOT  REDUCE therapy unless considered to be a clinically  significant finding                                       |
| Grade 2                                                             | Provide supportive care as needed                                                                                                                         |  
| Hold Lenalidomide until toxicity resolves to < grade 2   |                                                                                                                                                                                                                                                                                             |
|----------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 3                                                  | Resume therapy with one dose level reduction at the  discretion of the treating investigator 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. |
| Grade 4                                                  | 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                |
protocol summary
if lenalidomide is reduced for

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
protocol summary
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 |
| CONFIDENTIAL                                                                |               |                                           |
| This document is confidential. Do not disclose or use except as authorized. |               |                                           |  
| REDUCE therapy                                                                    |                                                                                                                                 |                                                                                 |
|-----------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------|
| Treat with oral  medication or  insulin at  discretion of  treating  investigator | Hold dexamethasone until < Grade 2 and resume at                                                                                |                                                                                 |
| Grade 2                                                                           | same dose level at the discretion of the treating  investigator Hold dexamethasone until < Grade 2                              |                                                                                 |
| Grade 3                                                                           | Resume therapy with one dose level reduction at the  discretion of the treating investigator Hold dexamethasone until < Grade 2 |                                                                                 |
| Grade 4                                                                           | Resume therapy with one dose level reduction                                                                                    |                                                                                 |
| Symptomatic  pancreatitis                                                         | Any Grade                                                                                                                       | Discontinue dexamethasone permanently                                           |
| Grade 1 or 2                                                                      | Continue to treat- Do NOT OMIT and DO NOT  REDUCE therapy                                                                       |                                                                                 |
| OTHER                                                                             | 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                |
protocol summary
if dexamethasone is reduced for

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
protocol summary
table 17 dose delay instructions

| To be resumed  within window?                                                                  | Lenalidomide                                                        | Dexamethasone                             | Nivolumab   |
|------------------------------------------------------------------------------------------------|---------------------------------------------------------------------|-------------------------------------------|-------------|
| Nivolumab                                                                                      | To be delayed                                                       |                                           |             |
| delayed on Day                                                                                 | N/A                                                                 | until Nivolumab is                        |             |
| 1 of Cycle                                                                                     | resumed                                                             | To be delayed until Nivolumab  is resumed | Resume      |
| dosing= new  Day 1 of Cycle Resume dose  any day within  window; dose  time point not  skipped |                                                                     |                                           |             |
| Nivolumab                                                                                      | No                                                                  | Dosing to continue                        |             |
| held on Day                                                                                    | as scheduled                                                        |                                           |             |
| 15of Cycle Nivolumab                                                                           | Yes                                                                 | Dosing to continue                        |             |
| held on Day 15                                                                                 | as scheduled                                                        |                                           |             |
| of Cycle                                                                                       | Dosing to  continue as  scheduled Dosing to  continue as  scheduled | Resume dosing  at next dosing  time point |             |
protocol summary
7. adverse events list and

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.
protocol summary
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).  
- 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).
protocol summary
- is a congenital anomaly/birth

- 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/mm3to 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.
protocol summary
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 . 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).
protocol summary
7.2.1.2 other immune mediated adverse

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.
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
protocol summary
7.2.1.3 adverse event list for

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 StevensJohnson 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.
protocol summary
7.2.1.4 adverse events list of

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 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.
protocol summary
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.
protocol summary
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.
protocol summary
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 Gr. 2 & 3  AE Expected Gr. 2 & 3  AE Unexpected   | Gr. 4  AE   |
|-----------------------------------------------------------------------------------|-------------|
| Expected                                                                          | Gr. 4  AE   |
| Unexpected                                                                        | Gr. 5 AE    |
| Expected or  Unexpected                                                           |             |
| Attribution                                                                       |             |  
CONFIDENTIAL
This document is confidential. Do not disclose or use except as authorized.  
52  
| Unrelated  Unlikely                                                                                                      | Not required   | Not required   | 5 calendar   | 5 calendar  days   | 24 hours*   |
|--------------------------------------------------------------------------------------------------------------------------|----------------|----------------|--------------|--------------------|-------------|
| days#                                                                                                                    |                |                |              |                    |             |
| Possible                                                                                                                 | Not required   | 5 calendar     | 5 calendar   | 5 calendar         |             |
| Probable                                                                                                                 | days           | 24 hours*      |              |                    |             |
| days#                                                                                                                    |                |                |              |                    |             |
| days                                                                                                                     |                |                |              |                    |             |
| Definite # If listed in protocol as expected and not requiring expedited reporting, event does not need to  be reported. |                |                |              |                    |             |  
\# 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.
protocol summary
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 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.
protocol summary
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.
protocol summary
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
protocol summary
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.  
7.5.1 Protocol-Specific Expedited Adverse Event Reporting Exclusions 7.5.1.1 There are no protocol specific exclusions.
protocol summary
7.6 expedited reporting to the

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.
protocol summary
7.7 expedited reporting to bristol-myers

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.
protocol summary
7.8 expedited reporting to hospital

Participating investigators will report to their local Risk Management office any participant safety reports or sentinel events that require reporting according to institutional policy.
protocol summary
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
irb fda etc.) must also
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.
irb fda etc.) must also
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 interferongamma (IFN-γ) release in vitro.
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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.
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8.1.3 storage and stability

The product does not contain a preservative. Vials of nivolumab injection must be stored at 28C (36-46F) 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.
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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.
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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
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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.
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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.
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8.1.9 ordering

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.
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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.)
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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-2yl) 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.
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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.
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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.
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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.  
CONFIDENTIAL
This document is confidential. Do not disclose or use except as authorized.  
59 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.