Conditions: Smoldering Myeloma Smoldering Multiple Myeloma
Keywords: Smoldering myeloma Smoldering Multiple Myeloma
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 51
Healthy volunteers: no

Brief summary:
This research study is aimed to determine the proportion of high risk smoldering multiple myeloma patients who are progression free at 2 years after receiving elotuzumab, lenalidomide and dexamethasone combination therapy.

Detailed description:
This research study is a Phase II clinical trial, which tests the effectiveness of the investigational drugs elotuzumab, lenalidomide and dexamethasone in smoldering multiple myeloma. Recent research studies have shown that early treatment of smoldering multiple myeloma may delay or prevent the progression to active multiple myeloma. The purpose of this research study is to learn whether the combination of elotuzumab, lenalidomide and dexamethasone works in treating smoldering multiple myeloma.

Arms:
arm 1: •Drug: Elotuzumab 10 mg/kg IV; Days 1, 8,15, 22 Cycles 1-2 10 mg/kg IV; Days 1 \& 15 Cycles 3-8

Other Name: HuLuc63

•Drug: Lenalidomide 25 mg Oral; Days 1-21 days Cycles 1-24

Other Name: REVLIMID

•Drug: Dexamethasone 40 mg Oral; Days 1, 8, 15, 22 Cycles 1-2 40 mg Oral; Days 1, 8, 15 Cycles 3-8

Other Name: Decadron arm 2: •Drug: Elotuzumab 10 mg/kg IV; Days 1, 8,15, 22 Cycles 1-2 10 mg/kg IV; Days 1 \& 15 Cycles 3-8

Other Name: HuLuc63

•Drug: Lenalidomide 25 mg Oral; Days 1-21 days Cycles 1-24

Other Name: REVLIMID

Interventions: intervention 1: Elotuzumab intervention 2: Lenalidomide intervention 3: Dexamethasone
Intervention descriptions: intervention 1: 10 mg/kg IV; Days 1, 8,15, 22 Cycles 1-2 10 mg/kg IV; Days 1 \& 15 Cycles 3-8 intervention 2: 25 mg Oral; Days 1-21 days Cycles 1-24 intervention 3: 40 mg Oral; Days 1, 8, 15, 22 Cycles 1-2 40 mg Oral; Days 1, 8, 15 Cycles 3-8

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
Protocol Title 
E- PRISM (Precision Intervention Smoldering Myeloma): A Phase II Trial of Combination of 
Elotuzumab, Lenalidomide and Dexamethasone in High-Risk Smoldering Multiple Myeloma 
 
NCT #: NCT02279394 
 
IRB Approval Date: 04/09/2021 
 
 


Protocol #: 14-338 
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Local Protocol #: 14-338 
Bristol-Myers Squibb Protocol #: CA 204-119 
Celgene Protocol #: RV-CL-MM-PI-004473 
 
TITLE: E- PRISM (Precision Intervention Smoldering Myeloma): A Phase II Trial of 
Combination of Elotuzumab, Lenalidomide and Dexamethasone in High-Risk 
Smoldering Multiple Myeloma 
 
Coordinating Center: 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02115 
Phone: 617-632-4198 
Fax: 617-582-8608 
 
 
Principal Investigator (PI):  
Irene M. Ghobrial, MD 
Dana-Farber Cancer Institute 
Irene_Ghobrial@dfci.harvard.edu 
 
Statistician: 
Project Manager: 
Lorenzo Trippa 
Alexandra Savell 
Dana-Farber Cancer Institute 
Dana-Farber Cancer Institute 
Ltrippa@jimmy.harvard.edu 
Asavell@partners.org 
 
 
 
Agent(s): Elotuzumab, Bristol-Myers Squibb 
Lenalidomide, Celgene 
Dexamethasone, commercial 
 
 
IND #: 122322 
 
 
Amendment 10/ 10.0/ April 9th, 2021 


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CYCLES 1-2 
• 
• 
• 
Elotuzumab days 1, 8, 15, 22 
Lenalidomide days 1-21 
Dexamethasone days 1, 8, 15, 22 
Cycle Length: 28 days 
CYCLES 3-8 
• 
• 
• 
Elotuzumab days 1, 15 
Lenalidomide days 1-21 
Dexamethasone days 1, 8, 15 
Cycle Length: 28 days 
MAINTENANCE (CYCLES 9-24) 
• 
Elotuzumab Day 1 
• 
Lenalidomide Days 1-21 
• 
Dexamethasone Day 1 
Cycle Length: 28 days 
Stop 
Therapy 
**At any time 
• 
Progression to Active Myeloma 
• 
Unacceptable Toxicity 
• 
Refusal 
• 
Alternative Therapy 
REGISTRATION* 
Event 
Monitoring 
up to 3 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
**Disease Assessment: Day 1 of each cycle 
*Stratify based on age and cytogenetics: 
• Age ≥65 years 
• High Risk Cytogenetics based on t(4:14), 
t(14:16), 17p deletion, or p53 mutation, 
and 1q amplification 


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TABLE OF CONTENTS 
SCHEMA ......................................................................................................................................... 2 
SYNOPSIS ....................................................................................................................................... 6 
1. 
OBJECTIVES ...................................................................................................................... 9 
1.1 
Study Design ............................................................................................................ 9 
1.2 
Primary Objectives ................................................................................................. 10 
1.3 
Secondary Objectives ............................................................................................. 10 
2. 
BACKGROUND ................................................................................................................ 10 
2.1 
Multiple Myeloma .................................................................................................. 10 
2.2 
MGUS and SMM consistently precedes multiple myeloma .................................. 11 
2.3 
Molecular studies in MGUS and SMM .................................................................. 11 
2.4 
Definition of SMM ................................................................................................. 13 
2.5 
Definitions of high-risk SMM ................................................................................ 14 
2.6 
Treatment of high risk SMM .................................................................................. 14 
2.7 
Elotuzumab............................................................................................................. 15 
2.8 
Rationale for Elotuzumab in SMM ........................................................................ 15 
2.9 
Rationale for dose and schedule of Elotuzumab .................................................... 16 
2.10 
Trial Rationale ........................................................................................................ 21 
2.11 
Correlative Studies Background ............................................................................. 22 
3. 
PARTICIPANT SELECTION ........................................................................................... 23 
3.1 
Eligibility Criteria .................................................................................................. 23 
3.2 
Exclusion Criteria ................................................................................................... 25 
3.3 
Inclusion of Women and Minorities ....................................................................... 26 
4. 
REGISTRATION PROCEDURES .................................................................................... 26 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions .................................... 26 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions .................................. 26 
4.3 
General Guidelines for Other Investigative Sites ................................................... 27 
4.4 
Registration Process for Other Investigative Sites ................................................. 27 
5. 
TREATMENT PLAN ........................................................................................................ 27 
5.1 
Treatment Regimen ................................................................................................ 27 
5.2 
Pre-Treatment Criteria ............................................................................................ 30 
5.3 
Agent Administration ............................................................................................. 31 
5.4 
General Concomitant Medication and Supportive Care Guidelines ...................... 33 
5.5 
Criteria for Taking a Participant Off Protocol Therapy ......................................... 34 
5.6 
Duration of Follow Up ........................................................................................... 35 
5.7 
Criteria for Taking a Participant Off Study ............................................................ 36 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ................................................................ 36 
6.1 
Elotuzumab............................................................................................................. 36 


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6.2 
Lenalidomide .......................................................................................................... 36 
6.3 
Dexamethasone ...................................................................................................... 40 
6.4 
Guidelines for Elotuzumab Infusion in Subjects with Infusion Reactions ............. 42 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ............................. 44 
7.1 
Expected Toxicities ................................................................................................ 44 
7.2 
Adverse Event Characteristics ................................................................................ 46 
7.3 
Expedited Adverse Event Reporting ...................................................................... 46 
7.4 
DF/HCC Expedited Reporting Guidelines ............................................................. 46 
Overdose of Lenalidomide ................................................................................................. 49 
7.5 
Expedited Reporting to the Food and Drug Administration (FDA) ....................... 49 
7.6 
Expedited Reporting to Bristol-Myers Squibb (BMS) ........................................... 49 
7.7 
Expedited Reporting to Celgene ............................................................................ 49 
7.8 
Expedited Reporting to Hospital Risk Management .............................................. 50 
7.9 
Routine Adverse Event Reporting .......................................................................... 50 
8. 
PHARMACEUTICAL INFORMATION .......................................................................... 50 
8.1 
Elotuzumab............................................................................................................. 50 
8.2 
Lenalidomide .......................................................................................................... 52 
8.3 
Dexamethasone ...................................................................................................... 54 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ......................................... 56 
9.1 
Bone Marrow Aspirate Samples ............................................................................. 57 
9.2 
Peripheral Blood Samples ...................................................................................... 58 
10. 
STUDY CALENDAR ........................................................................................................ 61 
11. 
MEASUREMENT OF EFFECT ......................................................................................... 62 
11.1 
Development of symptomatic disease .................................................................... 62 
11.2 
Antitumor Effect .................................................................................................... 63 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ........................................... 70 
12.1 
Data Reporting ....................................................................................................... 70 
12.2 
Data Safety Monitoring ........................................................................................... 70 
13. 
STATISTICAL CONSIDERATIONS. .............................................................................. 70 
13.1 
Study Design/Endpoints ......................................................................................... 70 
13.2 
Sample Size, Accrual Rate and Study Duration ..................................................... 72 
13.3 
Stratification Factors .............................................................................................. 72 
13.4 
Interim Monitoring Plan ......................................................................................... 72 
13.5 
Stopping Rule for Safety ........................................................................................ 72 
14. 
PUBLICATION PLAN ...................................................................................................... 73 
15. 
REFERENCES ................................................................................................................... 74 
APPENDIX A: PERFORMANCE STATUS CRITERIA ............................................................. 78 


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APPENDIX B: PREPARATION AND ADMINISTRATION OF ELOTUZUMAB ................... 79 
APPENDIX C: 14-338 SPECIMEN COLLECTION SCHEDULE .............................................. 82 
APPENDIX D: 14-338 SPECIMEN REQUISITION .................................................................... 84 
APPENDIX E: DF/HCC MULTI-CENTER DATA AND SAFETY MONITORING PLAN ...... 85 
1. 
INTRODUCTION .............................................................................................................. 89 
1.1 
Purpose ................................................................................................................... 89 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions ................................... 89 
2. 
GENERAL ROLES AND RESPONSIBILITIES ................................................................ 90 
2.1 
DF/HCC Sponsor ................................................................................................... 90 
2.2 
Coordinating Center ............................................................................................... 91 
2.3 
Participating Institution .......................................................................................... 91 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS .............................. 92 
3.1 
Protocol Distribution .............................................................................................. 92 
3.2 
Protocol Revisions and Closures ............................................................................ 92 
3.3 
Informed Consent Requirements ............................................................................ 93 
3.4 
IRB Documentation ................................................................................................ 93 
3.5 
IRB Re-Approval ................................................................................................... 93 
3.6 
Participant Confidentiality and Authorization Statement....................................... 94 
3.7 
DF/HCC Multi-Center Protocol Registration Policy ............................................. 94 
3.8 
DF/HCC Protocol Case Number ............................................................................ 95 
3.9 
Safety Assessments and Toxicity Monitoring ........................................................ 96 
3.10 
Data Management .................................................................................................. 97 
4. 
REQUISITIONING INVESTIGATIONAL DRUG .......................................................... 97 
5. 
MONITORING: QUALITY CONTROL .......................................................................... 98 
5.1 
Ongoing Monitoring of Protocol Compliance ........................................................ 98 
5.2 
Monitoring Reports ................................................................................................ 99 
5.3 
Accrual Monitoring ................................................................................................ 99 
6. 
AUDITING: QUALITY ASSURANCE ............................................................................ 99 
6.1 
Audit Plan: DF/HCC Sponsored Trials .................................................................. 99 
6.2 
Audit Notification ................................................................................................... 99 
6.3 
Audit Reports ........................................................................................................ 100 
6.4 
Participating Institution Performance ................................................................... 100 


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SYNOPSIS 
Study Rationale 
Early therapeutic interventions in patients with smoldering MM will 
prevent/delay progression to overt MM. Recent studies of a phase III trial of 
lenalidomide and dexamethasone vs. placebo showed improved response, 
progression free survival and overall survival in patients with high risk 
SMM compared to placebo control. Therefore, there is a need to examine 
novel therapeutic combinations in patients with high risk smoldering MM. 
Based on the activity of lenalidomide and dexamethasone in patients with 
high risk SMM and based on the safety and activity profile of elotuzumab 
and lenalidomide in patients with relapsed MM, we propose to examine the 
activity of elotuzumab and lenalidomide in patients with high risk SMM. We 
will identify the role of early intervention on prevention of progression in 
patients with high-risk SMM who have a 50% rate of progression at 2 years. 
Products 
Elotuzumab is a humanized recombinant monoclonal IgG1 antibody 
product directed to human SLAMF7 (CD2-subset-1, also known as 
CRACC), a cell surface glycoprotein that is highly expressed in MM cells. 
Lenalidomide (REVLIMID®), a thalidomide analogue, is an 
immunomodulatory agent with antiangiogenic properties. 
Dexamethasone is a synthetic adrenocortical steroid. 
Study 
Objectives 
Primary Objectives 
• To determine the proportion of high risk smoldering multiple 
myeloma patients who are progression free at 2 years after receiving 
elotuzumab, lenalidomide and dexamethasone combination therapy 
Secondary Objectives 
• To assess the response rate of the combination in these patients 
• To assess time to progression 
• To assess duration of response 
• To assess overall survival 
• To assess 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) 
Efficacy 
Endpoints 
Response will be assessed using the IMWG criteria for response in Multiple 
Myeloma. 
Safety 
Endpoints 
AEs will be evaluated during the treatment period using CTCAE v4.03. 
Study Design 
This is a phase II study using the combination of elotuzumab, lenalidomide 
and dexamethasone in patients with high-risk smoldering multiple myeloma. 
Dosing Regimen 
Each Cycle = 28 days 
Cycle 1 & 2 
• Elotuzumab (IV): Days 1, 8, 15 ,22 
• Lenalidomide (oral): Day 1-21 


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• Dexamethasone: (oral and IV): Days 1, 8, 15, 22 
Cycles 3-8 
• Elotuzumab (IV): Days 1 and 15 
• Lenalidomide (oral): Day 1-21 
• Dexamethasone: (oral and IV): Days 1, 8, 15 
Cycles 9-24 (maintenance) 
• Elotuzumab (IV): Days 1 
• Lenalidomide (oral): Day 1-21 
Select Inclusion 
Criteria 
• Age  18 years. 
• Must have smoldering myeloma with high risk markers based on the 
Mayo OR the Spanish criteria and including the new criteria for SMM as 
described below: 
o Monoclonal protein in the serum of  3gm/dL and >10% plasma 
cells in the bone marrow with a free light chain ratio outside the 
range of 0.125 to 8 
OR 
o Ratio or abnormal to normal bone marrow plasma cells greater 
than or equal to 95 percent or at least one immunoglobulin level 
lower than the normal range 
• No evidence of CRAB criteria or new criteria of overt MM which 
includes the following: 
o Increased calcium levels (corrected serum calcium >0.25 mmol/L 
(>1mg/dL) above the upper limit of normal OR >2.75 mmol/L 
(>11mg/dL) 
o Renal insufficiency (attributable to myeloma); 
o Anemia (Hgb 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 (>5mm) 
• ECOG Performance Status (PS) 0, 1, or 2. (Appendix A) 
• The following laboratory values obtained  21days prior to registration: 
o ANC  1000/L 
o PLT  50,000/L 
o Total bilirubin ≤ 2.0 mg/dL (If total is elevated check direct and 
if normal patient is eligible.) 
o AST  3 x institutional upper limit of normal (ULN) 


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o ALT  3 x institutional upper limit of normal (ULN) 
• Estimated creatinine clearance  60mL/min or a creatinine  2.2 mg/dL 
Select Exclusion 
Criteria 
• Symptomatic Multiple Myeloma or any evidence of CRAB criteria. Any 
prior therapy for active Myeloma should also be excluded. Prior therapy 
for smoldering myeloma is not an exclusion criteria. Concurrent therapy 
with bisphosphonates are not excluded. 
• 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. Prior clinical trials for smoldering MM or 
MGUS are allowed as long as the last therapy was at least 2 months prior 
and there was no improvement in M spike. 
Study Duration 
60 months 


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1. OBJECTIVES 
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)1-3. 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 control4. Therefore, 
there is a need to examine novel therapeutic combinations in patients with high risk smoldering 
MM. Based on the activity of lenalidomide and dexamethasone in patients with high risk SMM 
and based on the safety and activity profile of elotuzumab and lenalidomide in patients with 
relapsed MM5-8, we propose to examine the activity of elotuzumab and lenalidomide in patients 
with high risk SMM. 
 
Pretreatment of MM cells with lenalidomide in-vitro enhances elotuzumab-induced antibody- 
dependent cell-mediated cytotoxicity (ADCC) against MM cells and this has also been 
demonstrated in in vivo xenograft MM models6. The mechanism of synergism between these two 
agents has not been fully explored, however, recent discoveries into the precise mechanism of 
action of lenalidomide in MM has provided some insight9; lenalidomide-enhanced production of 
the cytokine interleukin-2 (IL-2), which spurs T cell production and stimulation of NK cells. 
The importance of the T cell mediated effect of lenalidomide has recently been elegantly 
demonstrated by two studies9,10, uncovering previously unknown mechanisms of action for this 
drug in MM. Lenalidomide induced IL-2 production in T cells was found to be due to the 
depletion of two proteins, IKZF1 and IKZF3. These proteins normally function to bind the IL-2 
promoter and repress IL-2 transcription in T cells, treatment with lenalidomide markedly 
depletes IKZF1 and IKZF3 in T cells inducing IL-2 production and T cell activation. IL-2 is 
known to exert anti-myeloma activity through activation of NK cells. Treatment with 
lenalidomide could therefore prime NK-cells for Elotuzumab-mediated ADCC, which may 
explain the synergistic anti-myeloma effect of these therapies. Additionally, Elotuzumab itself 
may activate a subset of CD8+ T cells which express EAT-2, and has been shown to bind to 
CD3+CD8+ T cells in blood and bone marrow from MM patients. Interestingly, both EAT-2 and 
CS-1 are located on chromosome 1q, this region is amplified in 30-50% of MM patients and is 
associated with poor prognosis and lack of response to lenalidomide plus dexamethasone. 1q 
amplification is known to be an early event in myelomagenesis and has been associated with an 
increased risk of conversion from SMM to overt 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 elotuzumab and lenalidomide in patients with high-risk SMM. We 
will identify the role of early intervention on prevention of progression in patients with high-risk 
SMM who have a 50% rate of progression at 2 years. This will be performed in a phase II study 
to determine progression-free survival (PFS) in this patient population. Secondary endpoints 
include response rate, safety of this combination in patients with high-risk SMM. 
 
1.1 Study Design 
 
This is a phase II study using the combination of elotuzumab, lenalidomide and dexamethasone 
in patients with high-risk smoldering multiple myeloma. 


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1.2 Primary Objectives 
 
• To determine the proportion of high risk smoldering multiple myeloma patients who are 
progression free at 2 years after receiving elotuzumab, lenalidomide and dexamethasone 
combination therapy 
 
1.3 Secondary Objectives 
• To assess the response rate of the combination in these patients 
• To assess time to progression 
• To assess duration of response 
• To assess overall survival 
• To assess safety of the combination 
• To examine molecular evolution of the tumor cells obtained 
• To determine the role of immune cells in the progression of smoldering MM 
• To determine minimal residual disease (MRD) 
 
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 11. 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 12. Smoldering multiple myeloma was defined by the presence of serum M- 
protein ≥ 3 g/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 13. They identified MGUS in 
694 of 21,463 patients tested (3.2%). While the overall prevalence was noted to be 3.2% (95 % 
CI, 3.0 to 3.5), there was a significant age dependent increase in both sexes with the prevalence 
among persons 80 years of age or older 4 times as high as among those 50-59 years of age. Age- 
adjusted rates were higher in men (4.0 %, 95% C.I., 3.5 to 4.4) than in women (2.7%, 95% C.I., 
2.4 to 3.0). In a subsequent study on a majority of the same patients from Olmsted County, 
Dispenzieri, et al., used the free light chain assay (FREELITE) and showed that 0.8% of people 
older than 50 years had light chain-MGUS. The total MGUS prevalence including the light 
chain-MGUS cases was noted at 4.2% (95% C.I., 3.9 to 4.5%) 14. 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 15,16. The 5-year 


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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 
17. 
Table 1: Mayo Clinic model for risk factors and % risk of progression for smoldering MM 
 
Model 
No. of risk factors 
5-year progression % 
Time to progression 
in years 
Mayo Clinic model 
1 
25 
10 
Risk factors: M- 
2 
51 
5.1 
protein ≥ 3.0g/dL, 
≥10% plasma cells in 
the BM, FLC ratio 
outside the range of 
3 
76 
1.9 
0.125 to 8 
 
2.2 MGUS and SMM consistently precedes multiple myeloma 
 
Since the early description of monoclonal gammopathy of undermined significance it was known 
that some cases of MGUS progressed to symptomatic myeloma, but it was not clear whether all 
cases of myeloma are preceded by MGUS. In a study of more than 77,000 individuals, 55 to 74 
years of age, from a cancer screening trial, Landgren et al. found 71 patients who developed 
multiple myeloma18. They performed serum protein electrophoresis, immunofixation and kappa- 
lambda free light chain assay on prediagnostic samples in these patients. The study showed that 
patients who eventually developed multiple myeloma consistently had MGUS in the years 
preceding development of multiple myeloma. Interestingly, in half the patients, there was a 
steady increase in the M-protein before the development of symptomatic myeloma, while in the 
other half the M-protein stayed fairly stable. A second study by Weiss et al. found a monoclonal 
gammopathy in 27 of 30 patients (90%) in sera 2 or more years before the diagnosis of myeloma 
19. 
 
2.3 Molecular studies in MGUS and SMM 
 
A recent study using SNP-based arrays compared MGUS, SMM and MM samples 20. 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. 


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Table 2: Cytogenetic abnormalities in MGUS, SMM and MM 
 
Cytogenetic 
abnormality 
Involved oncogene 
MGUS% 
SMM% 
MM% 
IgH translocations 
See below 
40-50% 
40-50% 
50-70% 
t(11;14)(q13;q32) 
CCND1 (cyclin D1) 
10-25% 
10-25% 
15% 
t(4;14)(p16;q32) 
FGFR3 and 
MMSET 
2-9% 
3-13% 
10-15% 
t(14;16)(q32;q23) 
C-MAF 
2-5% 
2-5% 
2-5% 
Other IgH 
translocations- 
t(6;14)(p21;q32), 
t(14;20)(q32;q11) etc. 
CCND3 (cyclin D3), 
MAFB, etc. 
6-10% 
1-10% 
10% 
13q deletion 
Unknown 
25-50% 
35-50% 
40-50% 
Hyperdiploidy 
Unknown 
40-50% 
40-50% 
40-50% 
 
Other molecular studies in MGUS and SMM included microRNA studies. MicroRNAs are single 
stranded RNA molecules that regulate gene expression posttranscriptionally and are being 
implicated in a large number of cancers 21. 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 22. 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 21,22. The mir17 cluster has been shown to upregulated by the transcription 
factor c-Myc, which is considered a late event in myeloma progression 23-25. 
 
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 26. 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 points27- 
31. 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 patients20,32,33. 


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2.4 Definition of SMM 
 
The diagnosis of smoldering (asymptomatic) multiple myeloma (SMM) is based on the 
demonstration of M-protein in serum (>3 gm/dL) or urine and/or the presence of 10-60% 
clonal bone marrow plasma cells (BMPC). 1-3 The risk of progression of SMM to overt 
MM is approximately 10 percent per year in the first five years after diagnosis, with 
decreasing progression rates in later years. 
 
 
But with no evidence of the following CRAB* criteria or other Myeloma defining events 
(MDE): 
 
• Increased calcium levels: Corrected serum calcium >0.25 mmol/L(>1mg/dL) above the 
upper limit of normal or >2.75 mmol/L ( >11mg/dL) 
• Renal insufficiency (attributable to myeloma) 
• Anemia (Hgb 2g/dL below the lower limit of normal or <10g/dL) 
• Bone lesions (lytic lesions or generalized osteoporosis with compression fractures) 
• Other (symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (>2 
episodes in 12 months). 
 
*Participants with CRAB criteria that are attributable to conditions other than the disease 
under study may be eligible 
 
New MDE criteria that indicates overt MM and not SMM 
 
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 clonal plasma cells >60% on bone marrow examination 
• Serum involved/uninvolved FLC ratio ≥100, provided the level of the involved free light 
chain is at least 100mg/L (a patient’s “involved” free light chain- either kappa or lambda- 
is the one that is above the normal reference range; the uninvolved light chain is the one 
that typically is in, or below the normal range)* 
• More than one focal lesion on MRI that is at least 5mm or greater in size 
*If serum free light chain ratio is stable ( not increasing) for greater or equal to six 
months, the patient may be eligible after discussion with the overall PI 


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2.5 Definitions of high-risk SMM 
 
Based on the new defined high risk criteria for smoldering myeloma2,3 as described below: 
 
Bone marrow clonal plasma cells ≥10% and any one or more of the following: 
Serum M protein ≥3.0gm/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 (≥5mm) 
PET-CT with one focal lesion (≥5mm) 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 multiple myeloma61 
 
2.6 Treatment of high risk SMM 
 
In a randomized open-label phase 3 trial, 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). 


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2.7 Elotuzumab 
 
Elotuzumab (HuLuc63/BMS-901608) is a humanized monoclonal IgG1 antibody product 
directed to human SLAMF7 (CD2 subset-1, also known as CRACC ), a cell surface glycoprotein 
with homology to the CD2 family of cell surface proteins34,35. Originally, SLAMF7 was 
identified as a natural killer cell (NK) marker and was shown to be expressed in a subset of 
circulating leukocytes.10 Blood analysis confirmed expression of SLAMF7 on the cell surface of 
NK, NK-like T-cells (NKT), activated monocytes, CD8 positive T cells and on tissue plasma 
cells.11 High SLAMF7 expression was seen in plasma cells obtained from normal healthy 
donors and from patients with MGUS, SMM, and active MM. More than 90% of MM bone 
marrow samples, irrespective of cytogenetic abnormalities, express SLAMF7.. In addition 
SLAMF7 expression is maintained in MM subjects after relapse from therapy. A paired analysis 
of a subset of subjects with MM showed that SLAMF7 gene expression is detectable in subjects 
both at diagnosis and at relapse. 
 
In agreement with the gene chip data, flow cytometry analysis demonstrated that CD138+ 
plasma cells from MM bone marrow stained strongly positive for elotuzumab binding. In 
addition, immunohistochemistry (IHC) using anti SLAMF7 antibodies showed strong staining of 
MM cells in 9/9 plasmacytoma tissue samples and in 20/20 myeloma bone marrow cores 
tested36,37. 
 
The proposed mechanism of action of elotuzumab involves natural killer (NK) cell mediated 
antibody dependent cell-mediated cytotoxicity (ADCC). Elotuzumab monotherapy can kill MM 
cell lines and primary myeloma cells in vitro in the presence of peripheral blood mononuclear 
cells (PBMCs) or purified NK cells. In addition, elotuzumab exhibits significant in vivo 
monotherapy anti-tumor activity against human myeloma xenograft models grown in severe 
combined immunodeficient (SCID) mice36-38. This in vivo anti-tumor activity of elotuzumab 
appears to be largely dependent on the presence of active NK cells. Experiments using an in vivo 
mouse xenograft model suggest that maximal antitumor activity is reached at elotuzumab serum 
levels of 70 to 430 mcg/mL. 
 
2.8 Rationale for Elotuzumab in SMM 
 
Although several non-clinical models demonstrated elotuzumab monotherapy activity, no 
objective responses were observed in subjects in Study HuLuc63-1701 (Study 1701), a Phase 1 
elotuzumab monotherapy trial in humans. This is in contrast to the high response rates observed 
in studies of elotuzumab in combination with lenalidomide/dexamethasone (Study HuLuc-1703 
(Study 1703); or bortezomib (Study HuLuc-1702 (Study 1702). The best response in Study 1701 
was stable disease (SD) seen in 27% of all subjects. However, elotuzumab may have slowed 
disease progression in some subjects since SD was also observed in 3 subjects whose best 
response to prior therapy was progressive disease and some of the subjects had prolonged SD 
(median time to progression of 4.2 months in subjects with SD at study Day 52) suggesting 
possible maintenance or disease control. 
 
Study 1701 did not completely rule out monotherapy activity for elotuzumab. Subjects in Study 
1701 may have had a lower likelihood of responding to elotuzumab monotherapy due to their 
prior therapies, inadequate elotuzumab dosing, and host immune status. These subjects had 


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advanced, heavily pretreated myeloma, having received a median of 4.5 prior lines of therapy 
and may have been less likely to respond to any subsequent therapy. In addition, this was a Phase 
1 multiple ascending dose escalation study, in which subjects were treated with potentially 
inadequate doses of elotuzumab. Half of the subjects received doses below the threshold required 
to consistently saturate bone marrow plasma cell SLAMF7and the percentage of subjects 
achieving SD was higher (35%) at doses adequate to saturate SLAMF7binding sites (10 and 20 
mg/kg). 
 
A primary mechanism of action of elotuzumab is NK cell mediated ADCC. In vitro, elotuzumab 
has no direct anti-tumor effects and requires the presence of active PBMCs or NK cells. In Study 
1701, heavily pretreated subjects with advanced myeloma likely had impaired immune systems, 
which may also have contributed to the lack of objective responses. Host immune status is a 
function of both the number and intrinsic activity of specific immune cells and advanced cancers 
and other hematologic diseases have impaired NK cell activity. Reduced NK cell function has 
been reported in advanced myelodysplastic syndrome. Subjects with active myeloma have lower 
levels of a protein (DNAM-1) required for NK-mediated ADCC than control subjects or 
myeloma patients in complete response. In Study 1701, the total lymphocyte and NK cell counts 
in all study subjects were below the mean for healthy patients. 
 
Subjects with earlier stages of myeloma have better NK activity and more cytotoxic NK cells. 
Therefore, elotuzumab may demonstrate monotherapy activity in untreated subjects in earlier 
stages of myeloma (e.g., prior to development of symptoms) and who are likely to have a better 
immune function. SMM is an appropriate patient population to test this hypothesis. Limiting 
enrollment to high risk SMM narrows the population to subjects in whom the risk of progression 
to active myeloma is higher (median time to progression of two years) and for whom 
chemoprevention trials are recommended. 
 
2.9 Rationale for dose and schedule of Elotuzumab 
 
In this current study, elotuzumab will be administered at 10 mg/kg per cycle. This dose intensity 
was chosen because it matches the dose intensity in the cohort with the higher response rate in 
the phase 2 portion of study 1703. 
 
2.9.1 Non-clinical Toxicology 
 
The expression of the elotuzumab target, SLAMF7, is restricted to malignant myeloma cells and 
subsets of normal leukocytes in humans (NK, NK-like T cells [NKT], activated monocytes, a 
subset of CD8+ T cells, and tissue plasma cells). High SLAMF7 expression was seen in plasma 
cells obtained from normal healthy donors and from patients with MGUS, SMM, and active 
MM.11 No significant expression was detected in resting CD4+ T cells, B cells, resting 
monocytes, neutrophils, and granulocytes. Elotuzumab binding was not observed on epithelia, 
vessels, or smooth muscle cells of any of the organs examined. 
 
Elotuzumab only recognizes human SLAMF7 protein and does not appear to bind SLAMF7 
from other species, including chimpanzee, cynomolgus monkey, dog, mini-pig, mouse, rabbit, 
rat, and rhesus monkey. Due to the lack of species-specific cross-reactivity, there are no relevant 
animal species in which to conduct toxicological studies. Therefore, the nonclinical studies 


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consisted primarily of in vitro safety assessments and in vivo biological activity assessment to 
address the selectivity of elotuzumab and potential toxicities. 
 
Elotuzumab (100 and 200 mcg/mL) in vitro had no effect on lymphocytes, CD3+, CD4+, CD8+, 
and B cell counts in blood samples from healthy donors. NK cell counts were decreased on 
average by 20% at both doses of elotuzumab. The observed decline was variable between donors 
and ranged between 0% and 45%. 
 
Elotuzumab at concentrations up to500 mcg/mL did not adversely affect the ability of bone 
marrow-derived hematopoietic stem cells to differentiate down the erythroid and myeloid 
pathways. 
 
2.9.2 Clinical Experience with Elotuzumab in Multiple Myeloma 
 
As of March 2011, the elotuzumab clinical development program has consisted of three studies 
in active myeloma: Study 1701, a Phase 1 elotuzumab monotherapy study; Study 1702, a Phase 
1 study of elotuzumab + bortezomib; and Study 1703, a Phase 1/2 study of elotuzumab + 
lenalidomide/low-dose dexamethasone. 
 
2.9.3 HuLuc63-1701, a Phase 1 Elotuzumab Monotherapy Study 
 
In this Phase 1 study, escalating doses (0.5 - 20 mg/kg) of elotuzumab monotherapy were 
administered intravenously (IV) every 2 weeks for a total of 4 doses in subjects with advanced 
MM. Subjects with stable disease or better had the option to receive additional doses of 
elotuzumab. As of 03-Jul-2009, the study is complete. A total of 35 subjects were enrolled: 3 in 
the 0.5 mg/kg cohort, 4 in the 1.0 mg/kg cohort, 6 in the 2.5 mg/kg cohort, 4 in the 5.0 mg/kg 
cohort, 4 in the 10 mg/kg cohort, and 14 in the 20 mg/kg cohort. One (1) subject in the 10 mg/kg 
cohort did not receive study drug. The primary objective of this study was to determine the 
MTD. 
 
In the 2.5 mg/kg cohort, 1 out of the first 3 subjects dosed experienced a dose-limiting toxicity of 
(DLT) Grade 3 increase in blood creatinine levels leading to Grade 4 acute renal failure and that 
cohort was then expanded to include another 3 subjects. No further DLTs occurred in the 2.5 
mg/kg cohort and dosing continued up to the 20 mg/kg cohort. In the 20-mg/kg cohort, 1 out of 
14 subjects experienced a DLT of Grade 3 hypersensitivity. Therefore, the MTD was not reached 
in this study. A total of 31 SAEs were reported in 15 subjects. Six (6) of the SAEs were assessed 
as related to elotuzumab which included Grade 4 acute renal failure, Grade 2 chills, Grade 2 
pyrexia, Grade 3 hypersensitivity, Grade 2 bradycardia, and Grade 2 chest discomfort. The most 
common treatment emergent AEs (TEAE) overall during the study were chills (13 [38.2%] 
subjects), fatigue (13 [38.2%] subjects), pyrexia (13 [38.2%] subjects), cough (10 [29.4%] 
subjects), headache (10 [29.4%] subjects), and anemia (9 [26.5%] subjects). The most common 
treatment-related AEs were chills (11 [32.4% subjects), pyrexia (6 [17.6%] subjects), and 
flushing (4 [11.8% subjects). There was no apparent dose response relationship with respect to 
the incidence of AEs overall or treatment related TEAEs. Most TEAEs and treatment-related 
TEAEs were Grade 1 or Grade 2. 
 
A secondary objective of this study was assessment for preliminary activity. Nine (9) subjects 


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had a best response of stable disease. Although no subject had a confirmed response, this study 
was 1) conducted in heavily pre-treated subjects with likely compromised immune systems (for 
example compromised NK cell function), and 2) did not include immune activating myeloma 
therapies such as lenalidomide or bortezomib. 
 
2.9.4 HuLuc63-1702, a Phase 1 Elotuzumab + Bortezomib Study 
 
This is a Phase 1 study of elotuzumab in combination with bortezomib (plus dexamethasone if 
applicable) in subjects with MM who have had 1 to 3 prior therapies. Escalating doses (2.5- 
20mg/kg) of elotuzumab (dosed Days 1, 11) are administered in combination with 1.3 mg/m2 
bortezomib (dosed Days 1, 4, 8, 11) in a 21-day cycle. Subjects with disease progression at the 
end of Cycle 2 or 3 also received an oral dose of 20 mg dexamethasone on Days 1, 2, 4, 5, 8, 9, 
11, and 12 of each cycle thereafter. 
 
Data are preliminary as of 25-Mar-2011, 8 subjects with relapsed and relapsed and refractory 
MM have been treated; 3 each at 2.5, 5, and 10 mg/kg and 19 at 20 mg/kg of elotuzumab 
respectively. Twenty-eight (28) subjects in the intent-to-treat (ITT) population received at least 1 
dose of elotuzumab and all 28 subjects (100%) experienced at least 1 AE. No DLT was observed 
in the study and MTD was not established up to the planned highest dose of 20 mg/kg. There 
were 23 (82.1%) subjects with an elotuzumab related AE. The most common AEs (in 45% or 
higher, regardless of causality) include Grade 1 to 3 fatigue, diarrhea, anemia, thrombocytopenia, 
nausea, hyperglycemia, lymphopenia, leukopenia, neutropenia, constipation, and peripheral 
neuropathy. 
 
Grade 3 or higher AEs occurred in 22 (78.6%) subjects of whom 7 (25%) subjects experienced 
Grade 3 or higher AEs assessed as related to elotuzumab (lymphopenia, thrombocytopenia, 
gastroenteritis, chest pain, fatigue, and hypersensitivity). SAEs occurred in 10 (35.7%) subjects. 
 
Additionally, 6 (21.4%) subjects, 2 in the 5.0 mg/kg and 4 in the 20.0 mg/kg cohorts, withdrew 
from treatment due to an AE (neuropathy peripheral (2 subjects), acute myocardial infarction, 
gastroenteritis, sepsis and pain in extremity). No deaths have been reported due to AEs. Overall 
there does not appear to be a dose relationship with the incidence of AEs. 
 
As of 25-Mar-2011, the best clinical response (minimal (minor) response (MR)) and the best 
response rate (partial response (PR)) by the combined European Group for Blood and Marrow 
Transplantation and uniform criteria33 in 27 response evaluable subjects compare favorably to 
the historical, Phase 3 clinical trial of bortezomib monotherapy (APEX) in a similar 
population.34 The clinical response rate was 63% in Study 1702 compared to 46% in APEX and 
the objective response rate was 48% in Study 1702 compared to 38% in APEX. Finally, the 
median time to progression (TTP) was 9.5 months compared to 6.2 months in APEX. 
 
2.9.5 HuLuc63-1703, a Phase 1/2 Lenalidomide/dexamethasone + Elotuzumab (LdE) Study 
 
2.9.5.1 Phase 1 
 
This is a Phase 1/2 study of elotuzumab with lenalidomide and low dose dexamethasone (Ld) in 
subjects with MM who have had 1 or more prior therapies. Data are preliminary as of 25-Mar- 


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2011. Escalating doses (5-20 mg/kg) of elotuzumab (dosed weekly in the first 2 cycles) are 
administered with 25 mg lenalidomide (dosed orally Days 1 - 21) and 40 mg dexamethasone 
(dosed orally on Days 1, 8, 15, and 22) in a 28 day cycle. 
 
A total of 28 subjects received elotuzumab. One (1) subject was withdrawn from the study prior 
to receiving study drug due to investigator decision. Subjects had a median of 3 prior MM 
treatments. Three (3) subjects each received 5 mg/kg and 10 mg/kg and 22 subjects received 20 
mg/kg of elotuzumab. 
 
No DLT was observed during dose-escalation and an MTD was not established. The interim 
safety analysis revealed a key safety signal of elotuzumab-associated infusion reactions. These 
AEs included mostly Grade 1 and 2 nausea, dyspnea, chills, and headache. Two (2) subjects in 
the 20 mg/kg cohort discontinued due to infusion reactions, one Grade 4 SAE of anaphylaxis 
(related to elotuzumab) and one Grade 3 SAE of stridor (related to elotuzumab/dexamethasone). 
Subsequent to these events, a new elotuzumab premedication regimen for the whole program has 
been instituted to minimize infusion reactions. 
 
The final data of this trial was published in 2012 36. Three cohorts were enrolled and treated with 
elotuzumab (5.0, 10, or 20 mg/kg intravenously) on days 1, 8, 15, and 22 of a 28-day cycle in the 
first two cycles, and days 1 and 15 of each subsequent cycle; lenalidomide 25 mg orally [PO] on 
days 1 to 21; and dexamethasone 40 mg PO weekly. Dose-limiting toxicities (DLTs) were 
assessed during cycle 1 of each cohort, and clinical responses were evaluated during each cycle. 
The first five patients received up to six cycles of therapy; subsequent patients were treated until 
disease progression. 
 
Twenty-nine patients with advanced MM and a median of three prior MM therapies were 
enrolled; 28 patients were treated, three each in the 5.0-mg/kg and 10-mg/kg cohorts and 22 in 
the 20-mg/kg cohort. No DLTs were observed up to the maximum proposed dose of 20 mg/kg. 
The most frequent grade 3 to 4 toxicities were neutropenia (36%) and thrombocytopenia (21%). 
Two patients experienced a serious infusion reaction (one grade 4 anaphylactic reaction and one 
grade 3 stridor) during the first treatment cycle. Objective responses were obtained in 82% (23 of 
28) of treated patients. After a median of 16.4 months follow-up, the median time to progression 
was not reached for patients in the 20-mg/kg cohort who were treated until disease progression. 
 
2.9.5.2 Phase 2 
 
Study 1703 is continuing in Phase 2 where subjects who have not been previously exposed to 
lenalidomide are randomized to 10 vs 20 mg/kg elotuzumab + Ld. Data are preliminary as of 25- 
Mar-2011. A total of 73 subjects with a median age of 63 years were enrolled in the Phase 2 
portion; 36 subjects received 10 mg/kg elotuzumab and 37 received 20 mg/kg. In all subjects, the 
median number of cycles of therapy to date is 10. At least 1 AE was experienced by 100% of 
subjects across both dose groups, with largely similar AE rates; there were some exceptions 
based on preferred terms, but are not considered statistically significant or clinically meaningful. 
 
Grade 3/4 AEs, regardless of causality occurred in 68% of subjects, which were also similar 
between the 2 arms (Table 1.4.2.3-1), and comparable to historical AE data for LD with 
lymphopenia (16%), neutropenia (14%), thrombocytopenia (15%), and anemia (10%) being most 


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common overall. SAEs were reported in 41% of all subjects of which 6 (8.2%) were assessed as 
drug related. Related SAEs included 1 subject with Grade 3 febrile neutropenia and Grade 4 
neutropenia; 1 subject with Grade 3 visceral leishmaniasis, Grade 4 leukopenia, and Grade 4 
thrombocytopenia; 1 subject with Grade 3 bronchitis; 1 subject with Grade 4 increased C - 
reactive protein and Grade 3 hyperuricemia; 1 subject with Grade 4 H1N1 influenza; and 1 
subject with Grade 3 nausea. A total of 25 subjects have discontinued treatment as of the cutoff 
date: 9 for adverse events, 9 for disease progression, 4 for subject’s decision, 2 for investigators 
decision, and 1 to start a new therapy. 
 
As with prior elotuzumab studies, the interim safety analysis revealed a key safety signal of 
elotuzumab-associated infusion reactions defined for the purposes of these studies to include a 
pre-specified set of AEs that occurred on the day of, or the day after, elotuzumab infusion. Rates 
of infusion reactions were similar between arms with 56.2% subjects experiencing at least one 
infusion associated AE. All subjects have received a premedication regimen instituted at the end 
of Phase 1. Common infusion-associated AEs in Phase 2 included mostly Grade 1 and 2 nausea 
(16.4%), dizziness (11%), headache (12.3%), pyrexia (13.7%), and cough (8.2%). There was 
only Grade 3 infusion associated reaction: rash in a subject at 10 mg/kg. 
 
Of the 73 treated subjects in the Phase 2 portion of this study, as of this data cut, all were 
randomized 12 weeks months prior to the cutoff date and are considered evaluable for response 
assessment by IMWG criteria. The ORR ( PR) in these 73 subjects was 82.2%. This ORR 
compares favorably with other Ld clinical trials in relapsed/refractory myeloma (60% ORR for 
LD in MM-009/010 and previously untreated myeloma (70% ORR for Ld in E4A03). 
 
Although the study is not complete, the interim data analysis demonstrates 91.7% ORR at 10 
mg/kg arm and 73.0% ORR at 20 mg/kg arm. This ORR is based on a median of 10 cycles. 
 
Responses were rapid, with a median time to response of approximately 1 month in evaluable 
subjects. 
 
2.9.5.3 Infusion Reactions 
 
Treatment with therapeutic monoclonal antibodies is associated with infusion reactions with 
variable time of onset and varying levels of incidence and severity. As of March 2011 the key 
safety signal with elotuzumab is infusion reactions. As stated above, the definition of an infusion 
reaction for this analysis includes relevant signs and symptoms reported the day of or the day 
after elotuzumab infusion. The most frequent elotuzumab infusion reaction AEs regardless of 
causality across all Phase 1 studies included nausea, vomiting, chills, fever, flushing, dyspnea, 
cough, headache, dizziness, and rash. The majority of infusion reaction AEs were Grade 1 or 2 
and resolved with little or no treatment. There was no apparent dose relationship for infusion 
reaction. 
 
To minimize infusion reactions, all ongoing elotuzumab studies were amended in 2010, after the 
Grade 3 infusion AEs in the Phase 1 program (1701, 1702, and 1703Ph1), to ensure that all 
subjects receive premedication with IV corticosteroids, oral or IV diphenhydramine and oral 
acetaminophen prior to each elotuzumab infusion. As of 25-Mar-2011 all subjects treated in the 
Phase 2 expansion of Study 1703 have received this amended premedication regimen. Of the 73 


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treated subjects, 56% of subjects experienced at least 1 Grade 1/2 infusion associated AE either 
the day of or the day after elotuzumab infusion. In contrast, 89% of subjects in the Phase 1 of 
Study 1703 (prior to new pre-medication regimen) experienced at least 1 infusion associated AE 
regardless of causality. Most infusion reactions occurred during the first cycle of therapy. 
 
In summary, elotuzumab infusions have been associated with predominantly Grade 1 or 2 
infusion reactions. All infusion reactions were managed by infusion rate changes and/or 
medications and almost all resolved the same day or within 24 hours. In most cases, subjects 
have been able to continue on study. Only 1 subject premedicated with diphenhydramine, 
acetaminophen, and IV corticosteroids prior to all doses of elotuzumab developed a Grade 3 
infusion reaction related to elotuzumab and discontinued. 
 
2.9.5.4 Clinical Pharmacokinetics 
 
Blood samples were collected for estimation of serum elotuzumab concentrations following 
single and multiple dose administration in Studies 1701, 1702, and 1703. Preliminary 
pharmacokinetic (PK) analysis results limited to Cmin and Cmax have been reported for all 3 of 
these studies. 
 
Following single dose administration (Study 1701) of escalating doses of elotuzumab alone, Cmax 
increased with increasing dose over the dose range of 0.5 to 20 mg/kg. Following multiple dose 
administration of escalating doses of elotuzumab on Days 1 and 11 of a 21-day cycle in 
combination with bortezomib (Study 1702), the observed steady-state Cmin values consistently 
remained above 70 µg/mL, the minimum maximally efficacious trough concentration, following 
administration of the 10 mg/kg dose (296 to 698 µg/mL) and the 20 mg/kg dose (572 to 1092 
µg/mL). Following administration of elotuzumab every 7 days for the first 2 cycles, and every 14 
days for all subsequent cycles in combination with lenalidomide and dexamethasone (Study 
1703), the steady state Cmin concentrations associated with the 10 mg/kg dose ranged from 163 to 
301 µg/mL, which was above the minimum maximally efficacious trough concentration. 
 
2.9.5.5 Overall Risk/Benefit Assessment 
 
Elotuzumab is a humanized monoclonal IgG1 antibody directed to human SLAMF7, a cell 
surface glycoprotein. SLAMF7 is expressed on plasma cells and a subset of circulating 
leukocytes. Since elotuzumab does not recognize non-human SLAMF7, minimal animal 
toxicology has been performed. Non-clinical activity as monotherapy as well as in combination 
led to human trials. Although as monotherapy in heavily pretreated subject the best responses 
were SD, elotuzumab showed high response rates in combination with bortezomib or 
lenalidomide. 
 
Elotuzumab as monotherapy or with bortezomib or lenalidomide is well tolerated. As of March 
2011 the key elotuzumab related serious AEs have been infusion-related AEs. 
 
2.10 Trial Rationale 
 
Pretreatment of MM cells with lenalidomide in-vitro enhances elotuzumab induced ADCC 
against MM cells, and this has also been demonstrated in in vivo xenograft MM models,37. The 


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22 
 
 
mechanism of synergism between these two agents has not been fully explored, however, recent 
discoveries into the precise mechanism of action of lenalidomide in MM has provided some 
insight; lenalidomide enhanced production of the cytokine interleukin-2 (IL-2), which spurs T 
cell production and stimulation of NK cells. The importance of the T cell mediated effect of 
lenalidomide has recently been elegantly demonstrated by two studies10,39, uncovering previously 
unknown mechanisms of action for this drug in MM. Lenalidomide induced IL-2 production in T 
cells was found to be due to the depletion of two proteins, IKZF1 and IKZF3. These proteins 
normally function to bind the IL-2 promotor and repress IL-2 transcription in T cells, treatment 
with lenalidomide markedly depletes IKZF1 and IKZF3 in T cells inducing IL-2 production and 
T cell activation. IL-2 is known to exert anti-myeloma activity through activation of NK cells. 
Treatment with lenalidomide could therefore prime NK-cells for Elotuzumab-mediated ADCC, 
which may explain the synergistic anti-myeloma effect of these therapies. The evidence for 
elotuzumab activation of immune system is based on SLAMF7 on NK cells (where EAT-2 is 
expressed). Interestingly, both EAT-2 and SLAMF7 are located on chromosome 1q, this region 
is amplified in 30-50% of MM patients and is associated with poor prognosis and lack of 
response to lenalidomide plus dexamethasone. 1q amplification is known to be an early event in 
myelomagenesis and has been associated with an increased risk of conversion from SMM to 
overt MM. 
 
We will be using lenalidomide for only two years and not for longer time periods. In addition, 
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. If we observe any problems with stem cell collection, we will follow the current 
standard guidelines of using cyclophosphamide or plerixafor mobilization. Based on data using 
combination therapies for induction, there has been no major concerns regarding stem cell 
collections after treatment with those agents. 
 
 
2.11 Correlative Studies Background 
 
2.11.1 Clonal evolution in MM 
 
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 heterogeneity40,41. The genomic complexity in 
MM was recently corroborated by massive parallel-sequencing studies displaying the lack of a 
universal driving mutation26. Recent studies have shown intraclonal heterogeneity that occurs at 
different stages of progression in MM27,28. 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 progression42,43. Point mutations such as N-RAS, 
K-RAS, MYC up-regulation44, and gain or loss of chromosome 1q or 1p seem to correlate with 
disease progression from MGUS and SMM25. A progressive increase in the incidence of copy 
number abnormalities from MGUS to SMM and to MM has been recently observed45. 


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2.11.2 Immune cells and MM 
 
An important step in the progression of tumors is evasion and suppression of the host immune 
system46,47. Several numerical and functional T cell abnormalities have been reported in MM48. 
Studies have shown an increase of functional T-regs in MM patients and MM mouse models, 
which may lead to suppression of immune effector cells49,50. It was also reported that T-regs 
increase during progression in MM, and increased number of T-regs are associated with survival. 
Since, there are some conflicting data8 and lack of good murine myeloma models for analyzing 
immune cells, the significance of T-regs and other immune cells in MM pathogenesis is not fully 
understood. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous, immature myeloid 
cell population with the ability to suppress immune responses. Recent studies have shown that 
MDSCs induce MM growth while suppressing T-cell-mediated immune responses. SLAMF7 is 
highly expressed on NK cells. Accumulating evidence indicates that EAT-2 mediates its 
activating effect on NK cells via tyrosine 127 which is believed to undergo phosphorylation on 
engagement of SLAMF7. Elotuzumab may interfere with the ability of myeloid derived 
suppressor cells (MDSC’s) to suppress anti-myeloma immune responses by T cells or other 
immune cells, In mice it has been demonstrated that engagement of SLAMF7 on T helper cells 
inhibited antigen induced T cell proliferation and cytokine production51, indicating that 
SLAMF7 may be inhibitory in T-cells however this would depend on the presence or absence of 
EAT2. Therefore the characterization of SLAMF7, EAT2 and elotuzumab treatment on T cell 
subsets remains an unanswered question in MM and may help to unravel the mechanism of 
synergy between elotuzumab and lenalidomide. Based on these studies and based on the 
SLAMF7 role in these cells, we will focus our studies of immune regulation on 3 types of cells: 
NK cells, T-regs and MDSCS. 
 
3. PARTICIPANT SELECTION 
 
3.1 Eligibility Criteria 
 
3.1.1 Age  18 years. 
 
3.1.2 Must meet criteria of high risk smoldering MM as described with one of the below 
criteria: 
• Bone marrow clonal plasma cells ≥10% and any one or more of the following: 
o Serum M protein ≥3.0 gm/dL 
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)† 
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 


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24 
 
 
immunoglobulin isotypes 
* All patients should have four or six color flow cytometry performed on the 
baseline bone marrow sample, as feasible. Patients evaluated for eligibility by 
Spanish Criteria must have their result confirmed by four color flow cytometry. If 
four or six color flow cytometry is not available at the site, the baseline bone 
marrow must be sent to Dana-Farber Cancer Institute to confirm eligibility prior 
to enrollment. 
o t (4;14) or del 17p or 1q gain 
o Increased circulating plasma cells 
o MRI with diffuse abnormalities or 1 focal lesion (≥5mm) 
o PET-CT with one focal lesion (≥5mm) with increased uptake without 
underlying osteolytic bone destruction 
† Increase in serum monoclonal protein by ≥10% on two successive 
evaluations within a 6 month period 
 
3.1.3 No evidence of CRAB criteria* or new criteria of active MM which including the 
following: 
• Increased calcium levels: Corrected serum calcium >0.25 mmol/L 
(>1mg/dL) above the upper limit of normal or >2.75 mmol/L (>11mg/dL); 
• Renal insufficiency (attributable to myeloma); 
• Anemia (Hgb 2g/dL below the lower limit of normal or <10g/dL); 
• Bone lesions (lytic lesions or generalized osteoporosis with compression 
fractures) 
• 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 
* Participants with CRAB criteria that are attributable to conditions other than 
the disease under study may be eligible 
 
3.1.4 ECOG Performance Status (PS) 0, 1, or 2 (Appendix A) 
 
3.1.5 The following laboratory values obtained  21 days prior to registration: 
• 
ANC  1000/L 
• 
PLT  50,000/L 
• 
Total bilirubin ≤ 2.0 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) 
• 
Estimated creatinine clearance  60mL/min or a creatinine  2.2 mg/dL 
 
3.1.6 Voluntary written informed consent before performance of any study-related procedure 
not part of normal medical care, with the understanding that consent may be withdrawn 
by the subject at any time without prejudice to future medical care. 


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25 
 
 
3.1.7 Females of childbearing potential* must have a negative serum or urine pregnancy test 
with a sensitivity of at least 50 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. 
 
* 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) 
 
3.1.8 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. 
 
3.1.9 Females of reproductive potential must adhere to the scheduled pregnancy testing as 
required in the Revlimid REMS® program. 
 
3.1.10 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. 
 
3.1.11 Ability to understand and the willingness to sign a written informed consent. 
 
3.2 Exclusion Criteria 
 
3.2.1 Symptomatic Multiple Myeloma or any evidence of CRAB criteria including the new 
criteria for overt myeloma. Any prior therapy for active Myeloma should also be 
excluded. Prior therapy for smoldering myeloma is not an exclusion criterion. 
Bisphosphonates are not excluded 
 
3.2.2 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. Prior clinical trials or therapy 
for smoldering MM or MGUS are allowed but should be discussed with the Principal 
Investigator. 
 
3.2.3 Serious medical or psychiatric illness likely to interfere with participation in this 
clinical study. 


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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 Pregnant or nursing women will be excluded from the study because lenalidomide is an 
agent with the potential for teratogenic or abortifacient effects. 
 
3.2.7 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to elotuzumab or lenalidomide. 
 
3.2.8 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. Patients who are positive 
for hepatitis B core antibody or hepatitis B surface antigen must have a negative 
polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive 
will be excluded. 
 
 
3.3 Inclusion of Women and Minorities 
 
3.3.1 Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1 General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible 
 
 
4.2 Registration Process for DF/HCC and DF/PCC Institutions 


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DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed. 
 
 
4.3 General Guidelines for Other Investigative Sites 
 
Eligible participants will be entered on study centrally at DFCI by the Study Coordinator. All 
sites should call the Research Project Manager, at the lead site. 
 
Following registration, participants should begin protocol therapy as soon as possible. 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 lead study team should be notified of cancellations as soon as possible. 
 
4.4 Registration Process for Other Investigative Sites 
 
To register a participant, the following documents should be completed by the research nurse or 
data manager and e-mailed to the Research Project Manager: 
• Copy of labs and clinical information that satisfy inclusion criteria 
• Signed participant consent form 
• HIPAA authorization form 
• Registration Form 
• Completed eligibility checklist 
 
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 lead site will then fax or email the participant study number to confirm registration. 
 
Treatment may not begin without confirmation from the Coordinating Center that the 
participant has been registered. 
 
NOTE: Registration and randomization 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 DF/HCC. 
 
5. TREATMENT PLAN 
 
5.1 Treatment Regimen 
 
All patients will be treated with elotuzumab, lenalidomide and dexamethasone. Patients will also 
by stratified by age>65 years or older and high risk cytogenetics based on t(4:14), t(14:16), 17p 
deletion or p53 mutation, +1q amplification. 
 
A treatment cycle is defined as 28 consecutive days. 


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28 
 
 
 
Elotuzumab will be administered Cycles 1 and 2 on days 1, 8, 15, 22 and cycles 3-8 on days 1 
and 15. Lenalidomide will be administered days 1-21 every 28 days. Dexamethasone will be 
administered on days 1, 8, 15 and 22 on cycles 1-2 then on days 1, 8 and 15 on cycles 3-8. 
Patients on maintenance treatment will be administered elotuzumab on day 1, and lenalidomide 
on days 1-21. For treatment cycles 1 and 2, a +/- 3 day window is allowed. 
 
For treatment cycle 3-24, a +/-7 day window is allowed. Treatment will be administered on an 
outpatient basis. 
 
Reported adverse events and potential risks are described in Section 7. Appropriate dose 
modifications are described in Section 6. No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the participant's 
malignancy. 
 
The participant will be requested to maintain a medication diary of each dose of lenalidomide 
and dexamethasone. The medication diary should be returned to clinic staff at the end of each 
cycle. 
 
Elotuzumab and Lenalidomide Dexamethasone Combination (Cycles 1-2) 
Agent 
Premedication and 
Precautions 
Schedule 
Dose 
Route 
Cycle Length 
Elotuzumab 
Premedications are 
described below 
Days 1, 8, 
15, 22 
10 mg/kg 
Intravenous-See 
appendix B for 
more details 
28 days 
(4 weeks) 
Lenalidomide 
None 
Days 1-21 
of each 
cycle 
25 mg 
Oral 
Dexamethasone 
Take with food; 
recommended to be 
taken in the 
morning 
Days 1, 8, 
15, 22 
8 mg 
IV 
32 mg 
Oral 


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Elotuzumab and Lenalidomide Dexamethasone Combination (Cycles 3-8) 
Agent 
Premedication and 
Precautions 
Schedule 
Dose 
Route 
Cycle Length 
Elotuzumab 
Premedications are 
described below 
Days 1 and 
15 
10 mg/kg 
Intravenous- See 
appendix B for 
more details 
28 days 
(4 weeks) 
Lenalidomide 
None 
Days 1-21 
of each 
cycle 
25 mg 
Oral 
Dexamethasone 
Take with food; 
recommended to be 
taken in the 
morning 
Days 1, 15 
8 mg 
IV 
32 mg 
Oral 
Day 8 
40mg 
Oral 
 
Elotuzumab and Lenalidomide Maintenance Therapy (Cycles 9-24) 
Agent 
Premedication and 
Precautions 
Schedule 
Dose 
Route 
Cycle Length 
Elotuzumab 
Premedications are 
described below 
Days 1 of 
each cycle 
20 mg/kg 
Intravenous-See 
appendix B for 
more details 
28 days 
(4 weeks) 
Lenalidomide 
None 
Days 1-21 
of each 
cycle 
15 mg 
Oral 
Dexamethasone* 
Take with food; 
recommended to be 
taken in the 
morning 
Day 1 of 
each cycle 
8 mg 
IV 
28 mg 
Oral 
* After discussion with the overall PI, high-dose dexamethasone may be re-added during 
maintenance due to biochemical progression (progressive increase in SPEP [25% and an absolute 
increase of 0.5g/d] or UPEP [25% and an absolute increase of 200mg/24hours] on 2 successive 
evaluations as determined by the IMWG response criteria or documented progression by the 
FreeLiteTM progressive disease criteria in the absence of serum or urine involvement). 
Dexamethasone should be given as follows after overall PI approval: 
 
Day 
Dose 
Route 
1 
8 mg 
IV 
32 mg 
Oral 
8 
40 mg 
Oral 
15 
40 mg 
Oral 


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5.2 Pre-Treatment Criteria 
 
There are no pretreatment criteria for elotuzumab dosing. Refer to section 6.2 for Lenalidomide 
pretreatment criteria and 6.3 for Dexamethasone pre treatment criteria. 
 
5.2.1 Premedication Regimen in Subjects without a Prior Infusion Reaction 
 
• Premedication is required prior to all Elotuzumab infusions. Refer to table 3 for the 
guidelines for premedication. 
 
5.2.2 Premedication Regimen in Subjects With a Prior Infusion Reaction 
 
To be re-treated with elotuzumab, subjects with a prior infusion reaction must receive 
H1, H2 blockers and acetaminophen at maximum doses specified (e.g., 50 mg diphenhydramine, 
50 mg ranitidine [or equivalent], and 1000 mg acetaminophen) 90-45 minutes before initiating 
the elotuzumab. 
 
Doses of intravenous dexamethasone above 10 mg require a decrease in the oral dexamethasone. 
Recommended dexamethasone dosing is summarized below and in Table 3. 
 
For subjects with prior Grade 2 infusion reaction, administer 10 mg IV dexamethasone (instead 
of 8 mg IV) as the premedication steroid 90-45 minutes before elotuzumab. Subjects should take 
30 mg oral dexamethasone 24-3 hours before elotuzumab administration. 
 
For subjects with Grade 3 or recurrent Grade 2 elotuzumab infusion reactions, consultation with 
the Principal Investigator is recommended. Administer 18 mg IV dexamethasone as the 
premedication steroid at least 45 minutes before elotuzumab. These patients should receive 8mg 
of oral dexamethasone 24-12 hours the day prior to elotuzumab administration. Then, administer 
14 mg oral dexamethasone at most 3 hours prior to elotuzumab administration. 
 
If a subject with a prior Grade 2 (recurrent) or 3 infusion reaction also requires dose reduction of 
oral dexamethasone, the dexamethasone dose on the days of elotuzumab infusion should be no 
less than 18 mg IV (on the day of elotuzumab infusion at least 45 minutes before elotuzumab). 
 
Subjects with a Grade 4 infusion reaction are not eligible to receive additional elotuzumab. 
These subjects may continue to receive lenalidomide and dexamethasone. Subjects who 
experience an infusion reaction of any grade should be administered the recommended 
premedication for that reaction severity for the duration of the trial. 
 
Subjects with prior infusion reactions may receive more aggressive pre-medications after 
discussion with the Overall Principal Investigator 


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Table 3: Recommended Corticosteroid Premedication 
 
None or 
24-3 hours prior to 
32 mg PO Dexamethasone 
Grade 1 
Elotuzumab Infusion 
Prior 
90-45 min prior to 
8mg IV Dexamethasone 
Infusion 
Elotuzumab Infusion 
Diphenhydramine 25-50 mg IV or PO or equivalent 
Reaction 
H1 blocker 
Ranitidine 50mg IV or equivalent H2 blocker 
Acetaminophen 650-1000mg PO 
 
Prior 
24-3 hours prior to 
30mg PO Dexamethasone 
Grade 2 
Elotuzumab Infusion 
Infusion 
90-45 min prior to 
10mg IV Dexamethasone 
Reaction 
Elotuzumab 
Diphenhydramine 50 mg IV or PO or equivalent H1 
blocker 
Ranitidine 50mg IV or equivalent H2 blocker 
Acetaminophen 1000mg PO 
 
Prior 
Grade 3 
Infusion 
Reaction or 
recurrent 
Grade 2 
24-12 hours prior to 
Elotuzumab Infusion 
8mg PO Dexamethasone 
No more than 3 hours prior 
to Elotuzumab Infusion 
14mg PO Dexamethasone 
90-45min prior to 
Elotuzumab 
18mg IV Dexamethasone 
Diphenhydramine 50 mg IV or PO or equivalent H1 
blocker 
Ranitidine 50mg IV or equivalent H2 blocker 
Acetaminophen 1000mg PO 
5.3 Agent Administration 
 
The order in which elotuzumab and lenalidomide are administered does not matter. 
 
5.3.1 Elotuzumab 
 
Elotuzumab will be administered intravenously at a dose of 10 mg/kg on Days 1, 8, 15 and 22 for 
the first 2 cycles (a cycle =28 days). During cycles 3 through 8, elotuzumab will be given on 
days 1 and 15. Elotuzumab will be administered intravenously at a dose of 20 mg/kg only on 
Day 1 for cycles 9-24. The patient should be observed for 60 minutes after the infusion is 
complete for cycle 1 and should be observed for 30 minutes after the infusion for subsequent 
cycles. All patients should have their vital signs checked before and after elotuzumab infusion or 
per institutional standard. If an infusion reaction occurs, reference section 6.4.2 for guidelines on 
additional vital monitoring. 
 
Cycle 1 and Cycle 2 treatment may be administered +/- 3 days. For subsequent cycles +/- 7 days 
is allowed. 


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5.3.1.1 Guidelines for Elotuzumab infusion in subjects with infusion reactions 
Please refer to section 6.4 of the protocol. 
5.3.1.2 Dose Delay or Interruption 
Please refer to section 6.4.3 of the protocol. 
5.3.2 Lenalidomide 
 
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 cycles 1-8 and 15 mg per day on days 1-21 for cycles 9-24. Cycle 1 
and Cycle 2 treatment may be administered +/- 3 days. For subsequent cycles +/- 7 days is 
allowed. Dose modification guidelines are described in Section 6.2 (Dose Modifications/Delays). 
 
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 can 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 
will 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 6.2). 
 
Lenalidomide related resources will 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. 
 
5.3.2.1 Dose Delay or Interruption 
 
Dose modification and delay guidelines are described in Section 6.2 (Dose 
Modifications/Delays) 
 
5.3.3 Dexamethasone 
 
Dexamethasone will be obtained by commercial supply in this study. This may lead to added 
costs for the participant or the participant’s insurance company. It will be given as an oral dose. 
Dexamethasone should be taken at approximately the same time each day. Doses of oral 
dexamethasone should be taken with food and administered per the recommended guidelines in 
Table 3. It is recommended that dexamethasone be taken in the morning to reduce insomnia. A 
drug diary will be provided to participants to record oral administration of doses. 


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Please refer to Section 5.1 for instructions on dexamethasone dosing. 
 
5.3.3.1 Dose Delay or Interruption 
 
Dose modification and delay guidelines are described in Section 6.3 (Dose 
Modifications/Delays). 
 
5.4 General Concomitant Medication and Supportive Care Guidelines 
 
5.4.1 Medications permitted at Investigator’s Discretion 
 
• Steroids, diphenhydramine, or hydroxyzine, acetaminophen/ paracetamol, H2 
inhibitors (e.g., cimetidine), leukotriene inhibitors (montelukast sodium) for the 
management of elotuzumab infusion reactions. Additional supportive measures 
should be provided as indicated including oxygen inhalation, epinephrine, and 
bronchodilators. 
 
• At the discretion of the treating investigator, patients will receive Pneumocystis 
jiroveci pneumonia (PJP) prophylaxis during treatment (Bactrim or acceptable 
alternative). This may be discontinued at the start of maintenance therapy, or at 
the investigator’s discretion. 
 
• Stem cell mobilization will be allowed at the time of best response or at the end 
of 8 cycles for patients who are eligible for stem cell transplant. Stem cell 
collection may be done sooner after discussion with overall PI. Standard 
mobilization treatment (with GCSF or with cyclophosphamide or plerixafor, 
etc) will be used based on Institutional guidelines. Patients may delay treatment 
for up to 3 weeks after stem cell collection is complete. 
 
• Use of white cell growth factors [G-CSF (Filgrastim or acceptable equivalent)] 
is allowed for management of treatment induced neutropenia at physician 
discretion. Daily use of Filgrastim is not allowed, and participants may receive a 
maximum of 3 doses per week. Filgrastim should be given according to the 
ASCO guidelines. Pegfilgrastim is not to be used in replace of filgrastim. 
 
• Patients will receive bisphosphonates per recommendations of myeloma 
therapy. A note should be placed about patients who are not receiving 
bisphosphonates for clinical reasons such as osteonecrosis of the jaw. 
 
• Nausea/Vomiting: If nausea and/or vomiting is noted at any point in time, 
premedication with prochlorperazine or other antiemetics may be used before 
future doses. If nausea persists in spite of the use of standard antiemetics 
additional symptom management should be as per standard antiemetic 
guidelines. 
 
• Thromboprophylaxis is required for all participants. Participants may receive 


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34 
 
 
daily aspirin administration (81 or 325 mg), daily enoxaparin (40 mgs), or low 
molecular weight heparin (type Innohep® 4500 UI anti-Xa as needed) or 
equivalent to decrease the risk of thromboembolic complications. Aspirin 
prophylaxis will be the preferred first choice unless contraindicated. It is 
recommended that if the platelet count falls below 50,000/mm3, 
thromboprophylaxis be held to minimize the risk of bleeding and then resumed 
when platelet counts are equal to or above this level. 
 
o For patients at high risk for thromboembolic events, full 
anticoagulation is recommended. 
 
5.5 Criteria for Taking a Participant Off Protocol Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 24 cycles 
or until one of the following criteria applies: 
 
• Disease progression 
o Participants who have developed symptoms similar to CRAB criteria 
or MDE (see section 2.4), but are not attributable to active, 
symptomatic myeloma may remain on study after discussion with the 
Overall PI. 
 
• 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 QACT Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the QACT website or obtained from the QACT 
registration staff. 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 # 617-632-4198. 


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5.6 Duration of Follow Up 
 
Participants will be followed for up to 3 years after removal from protocol therapy or until 
progression to active symptomatic MM, whichever occurs first. Assessments will be performed 
every 3 to 6 months ( +/- 28 days ) for up to 3 years. Patients who have undergone stem cell 
mobilization will also be followed for 3 years after removal from protocol therapy or until 
progression to active symptomatic myeloma, whichever occurs first. Participants removed from 
protocol therapy for unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event. 
 
 
Participants unable to participate in follow up every 3 months may follow up every 6 months at 
PI discretion in accordance with standard of care follow-up frequency and COVID precautions. 
Physical exams and correlative blood draws that are not done due to virtual visits will not be 
considered violations. Local myeloma labs must be provided to the participating site for data 
entry purposes. Bone marrow biopsy and scans are strongly recommended yearly after EOT, but 
not require however, scans and bone marrow biopsy and research samples are required at time of 
suspected disease progression 
 
The following is required during the Active Follow Up period (for up to 3 years): 
1. Physical exams are voluntary during this period 
a. Virtual visits/telehealth visits are acceptable 
2. SPEP and Immunofixation 
3. Serum Free Light Chains (SFLC) 
4. UPEP and Immunofixation only for those where disease is tracked by 
the urine 
5. Serum Immunoglobulin test 
6. PET/CT assessments are strongly recommended yearly and is required 
at the time of suspected progression 
a. The same assessment modality should be used consistently 
across the duration of the trial 
7. Bone marrow biopsies are and strongly recommended yearly after 
EOT and is required at the time of suspected progression 
8. Research bone marrow samples will be collected at the time of any 
bone marrow biopsy/aspirate procedure 
9. Research blood will be collected whenever an in person visit to the site 
occurs. Research blood samples that are not collected at time points in 
the collection calendar due to COVID precautions or q6 month follow 
up will not be considered violations unless it is missed at the time of 
suspected progression. 
10. Response 
11. CRAB/MDE Assessment 
12. Bone marrow biopsy/aspirate results and cytogenetics/FISH if ordered 
13. Scan results and modality 


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Participants who come off active follow up when they pursue other SMM or MM 
directed therapy will be followed for survival indefinitely which will capture survival 
stats, and subsequent therapy information. 
 
5.7 Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
 
• Lost to follow-up 
• Completion of 3 years of follow up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 Elotuzumab 
 
No dose reductions for elotuzumab are allowed. If Elotuzumab is held on Day 1 of a new cycle, 
treatment with Lenalidomide/Dexamethasone will also be delayed. If Elotuzumab is held during 
any cycle on days 8, 15, or 22, the treating investigator will decide if Lenalidomide will be held 
using recommended guidance for retreatment below. Dexamethasone should always be given 
with Elotuzumab. The dose of dexamethasone may be modified per guidance below. Treatment 
may be delayed for a maximum of 21 days. If a patient must discontinue treatment with 
lenalidomide, they may continue to receive elotuzumab on study after discussion with the overall 
principal investigator. 
 
If a patient must discontinue elotuzumab for unacceptable toxicity, they may continue to receive 
lenalidomide and dexamethasone on study after discussion and approval of the overall principal 
investigator. 
 
6.2 Lenalidomide 
 
Patients may hold treatment of lenalidomide for up to 21 if the toxicity is considered either 
possibly, probably or definitely related to the drug. Patients may hold lenalidomide for greater 
than 21 days only after discussion and subsequent approval of the overall principal investigator. 
 
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. Treatment may be held for a maximum of 21 days. Refer to 
Table 4 for dose reduction levels for Lenalidomide. 


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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. 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. Treatment may be held for a maximum of 21 
days. Refer to Table 4 for dose reduction levels for Lenalidomide. 
 
Dose delays and modifications will be made as indicated in the following table(s). 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. 
 
 
Hematologic Toxicities 
 
CTCAE 4.0 Category 
CTCAE 
Grade 
Lenalidomide Dose Modification 
Absolute Neutrophil Count 
(ANC)1 
Grade 1 
or 
Grade 2 
Continue to treat- Do NOT OMIT and DO NOT REDUCE 
therapy 
Grade 3 
Hold dose 
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 
Grade 4 
Hold dose 
Administer Filgrastim 
Resume therapy at one dose level lower when ANC is ≥ 
1000 
Neutropenia with Fever 
ANC <1000 and temperature 
≥38.5o C or 101ºF 
Grade 3 
or 
Grade 4 
Hold dose 
Administer Filgrastim 
Reduce dose one level when ANC≥1000 
Thrombocytopenia 
Aspirin prophylaxis should be 
held if platelets are ≤50,000 
Grade 1 
or 
Grade 2 
Continue to treat- Do NOT OMIT and DO NOT REDUCE 
therapy 
Grade 3 
or 
Grade 4 
Provide platelet transfusion support 
Redraw platelets 
If redrawn platelet value ≥ 50,000 -> Do NOT OMIT and 
DO NOT REDUCE therapy 
If redrawn platelet value <50,000 continue to transfuse at 
the discretion of the investigator and hold therapy until 
platelets are ≥ 50,000 on Day 1 or ≥ 30,000 intracycle 


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Resume therapy at one dose level lower when the patient’s 
platelets are ≥ 50,000 on Day 1 or ≥ 30,000 intracycle 
Anemia 
Grade 1 
Grade 2 
Grade 3 
Continue to treat- Do NOT OMIT and DO NOT REDUCE 
therapy 
Transfuse at the discretion of treating investigator 
Grade 4 
Hold treatment 
Transfuse 
Resume treatment when hemoglobin ≥ 8.0 g/dL 
DO NOT REDUCE therapy 
1 ANC can be calculated two ways: From the percentage of neutrophils: White Blood Count (WBC) x total 
neutrophils (polys% + bands%) x 10. From the absolute number of cells: (Absolute polys + Absolute bands) x 10. 
 
 
Non Hematologic Toxicities 
 
CTCAE 4.0 
Category 
CTCAE 
Grade 
Lenalidomide Dose Modification 
Infection or Viral 
Ilness with ANC1 
≥1000 
Including herpes 
zoster reactivation 
N/A 
Day 1 of Cycle: Delay cycle until infection/viral 
illness has resolved. Resume treatment at the same 
dose level. Do not dose reduce. 
Intracycle: Hold lenalidomide for a maximum of 21 
days to allow for recovery. Resume treatment at same 
dose level. 
If patient has delay of greater than 21 days, the patient 
must come off-study 
Infection or Viral 
Illness with ANC1 
< 1000 
N/A 
Day 1 of Cycle: Delay cycle until infection/viral 
illness has resolved. Administer filgrastim or 
equivalent as indicated. 
Reduce one dose level when infection/virus has 
resolved, and ANC ≥1000 
Intracycle: Hold lenalidomide for a maximum of 21 
days. Reduce one dose level when infection/virus has 
resolved and ANC ≥ 500 
If patient has a delay of less than or equal to 21 days, 
dose reduce to next dose level. If patient has delay of 
greater than 21 days, the patient must come off-study 
Allergic reaction or 
hypersensitivity to 
Grade 1 
Continue to treat- Do NOT OMIT and DO NOT 
REDUCE therapy 


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Lenalidomide 
Including Rash 
related to 
Lenalidomide 
Grade 2 
Continue to treat- Do NOT OMIT and DO NOT 
REDUCE therapy 
Grade 3 
or 
Grade 4 
Hold lenalidomide 
Follow at least weekly. 
If toxicity resolves to ≤ grade 2, restart at next lower 
dose level 
 
Renal/Metabolic 
For all grades, 
provide hydration and 
other supportive care 
as needed at the 
discretion of the 
treating investigator 
Grade 1 
Continue to treat- Do NOT OMIT and DO NOT 
REDUCE therapy 
Grade 2 
Hold Lenalidomide until < grade 2 and resume 
treatment at the same dose level 
If toxicity recurs, dose reduce one dose level at the 
treating investigator’s discretion 
Grade 3 
or 
Grade 4 
Hold Lenalidomide until < grade 2 and resume 
treatment with one dose level reduction 
If the toxicity remains ≥ grade 3, omit dose and restart 
at subsequent scheduled visit with one dose level 
reduction 
If treatment-related toxicity occurs on day one of the 
cycle, the cycle will be delayed. 
Diarrhea, 
Constipation, 
Nausea, or Vomiting 
Grade 1 
Continue to treat- Do NOT OMIT and DO NOT 
REDUCE therapy 
Grade 2 
Treat at the discretion of the investigator 
Provide aggressive supportive care 
DO NOT REDUCE therapy 
Grade 3 
Hold Lenalidomide until toxicity resolves to < grade 2 
If the patient has received maximum supportive care, 
resume therapy with one dose level reduction 
Grade 4 
Hold Lenalidomide until toxicity resolves to < grade 2 
Resume therapy with one dose level reduction 


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40 
 
 
 
 
All other related 
toxicities not listed 
previously in this 
table 
Grade 1 
Continue to treat- Do NOT OMIT and DO NOT 
REDUCE therapy 
Grade 2 
Continue to treat- Do NOT OMIT and DO NOT 
REDUCE therapy unless considered to be a clinically 
significant finding 
Provide supportive care as needed 
Grade 3 
Hold Lenalidomide until toxicity resolves to < grade 2 
Resume therapy with one dose level reduction at the 
discretion of the treating investigator 
Grade 4 
Hold Lenalidomide until toxicity resolves to < grade 2 
Resume therapy with one dose level reduction 
If treatment-related toxicity occurs on day one of the 
cycle, the cycle will be delayed. 
If patient has a delay of less than or equal to 21 days, 
dose reduce to next dose level. If patient has delay of 
greater than 21 days, the patient must come off-study 
1 ANC can be calculated two ways: From the percentage of neutrophils: White Blood Count (WBC) x total 
neutrophils (polys% + bands%) x 10. From the absolute number of cells: (Absolute polys + Absolute bands) x 10 
 
 
Table 4 Lenalidomide Dose Reduction 
 
Dose Level 
Lenalidomide Dose 
Starting Dose Level 
25 mg 
First Dose Reduction 
20 mg 
Second Dose Reduction 
15 mg 
Third Dose Reduction 
10 mg 
Fourth Dose Reduction 
5 mg 
 
6.3 Dexamethasone 
Dexamethasone Dose Modifications 


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Premedication with dexamethasone is required prior to all elotuzumab infusions. If there are 
clinically significant, intolerable ≥Grade 3 adverse events attributed to dexamethasone (given as 
a premedication) treatment may be delayed until recovery to ≤ Grade 2 at the discretion of 
treating investigator. 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. 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 oral dexamethasone has been 
permanently discontinued 
 
Patients who have not experienced an infusion reaction related to elotuzmab and have 
experienced an adverse event attributable to dexamethasone may have their premedication of 
dexamethasone decreased after completion of cycle 1 at the discretion of the treating investigator 
and after discussion with the overall PI. 
 
 
CTCAE 4.0 
Category 
CTCAE Grade 
Dexamethasone Dose Modification 
Grade 1 
Continue to treat- Do NOT OMIT and DO NOT 
REDUCE therapy 
Hyperglycemia 
Grade 2 
Hold dexamethasone until < Grade 2 and resume at 
same dose level at the discretion of the treating 
investigator 
Treat with oral 
medication or 
insulin at 
discretion of 
treating 
investigator 
Grade 3 
Hold dexamethasone until < Grade 2 
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 
OTHER 
Grade 1 or 2 
Continue to treat- Do NOT OMIT and DO NOT 
REDUCE therapy 
Grade 3 
Hold dexamethasone until ≤ Grade 2 
Resume therapy with one dose level reduction 
Grade 4 
Hold dexamethasone ≤ Grade 2 
Resume therapy with one dose level reduction 


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42 
 
 
 
 
 
 
 
Table 5 Dexamethasone dose reduction 
 
Total Dexamethasone Dose Administration for Patients with none or Prior Grade 1 
Infusion Reaction 
Dose Levels 
Week with Elotuzumab 
Week Without Elotuzumab* 
PO 
IV 
PO 
IV 
Starting Dose Level 
32 
8 
40 
0 
First Dose Reduction 
28 
8 
20 
0 
Second Dose Reduction 
28 
8 
10 
0 
* During Maintenance, patients only receive dexamethasone on Day 1 
 
Total Dexamethasone Dose Administration for Patients with Prior Grade 2 
Infusion Reaction 
Dose Levels 
Week with Elotuzumab 
Week Without Elotuzumab* 
PO 
IV 
PO 
IV 
Starting Dose Level 
30 
10 
40 
0 
First Dose Reduction 
28 
10 
20 
0 
Second Dose Reduction 
28 
10 
10 
0 
* During Maintenance, patients only receive dexamethasone on Day 1 
 
 
Total Dexamethasone Dose Administration for Patients Prior Grade 3 or recurrent Grade 
2 Infusion Reaction 
Dose Levels 
Week with Elotuzumab 
Week Without Elotuzumab* 
PO 
IV 
PO 
IV 
Starting Dose Level 
22 
18 
40 
0 
First Dose Reduction 
16 
18 
20 
0 
Second Dose Reduction 
16 
18 
10 
0 
* During Maintenance, patients only receive dexamethasone on Day 1 
 
** If patient is intolerant of dexamethasone, after discussion with overall PI, oral 
dexamethasone may be omitted at any dose level. 
 
6.4 Guidelines for Elotuzumab Infusion in Subjects with Infusion Reactions 
 
6.4.1 Grade 1 Infusion Reaction 
 
Grade 1 elotuzumab infusion-related reactions by definition do not require intervention; 
however, increased monitoring is recommended. 


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6.4.2 Grade 2 Infusion Reaction 
 
Infusion reactions during the elotuzumab infusion: For a Grade  2 elotuzumab infusion- related 
reaction, the infusion must be interrupted. The subject should be treated as clinically indicated 
with one or more of the following medications or interventions: antiemetics, antihistamines, 
analgesics, corticosteroids, leukotriene inhibitors, oxygen inhalation, epinephrine, 
bronchodilators, or other supportive measures as indicated. 
 
Subjects with a Grade 3 infusion reaction may be discontinued from study drug at the discretion 
of the investigator, but must be discontinued if the Grade 3 infusion reaction recurs. Subjects 
with any Grade 4 infusion reaction are not eligible to receive additional elotuzumab. 
 
If a patient’s elotuzumab regimen is discontinued before the completion of cycle 2, he or she 
must come off protocol therapy. If elotuzumab is discontinued after completion of cycle 2, he or 
she can remain on protocol therapy. 
 
Once the elotuzumab infusion-related reaction has resolved to  Grade 1, the infusion can be 
restarted at 0.5 mL/minute. If symptoms do not recur after 30 minutes, the infusion rate may be 
increased in a stepwise fashion (0.5 mL/minute every 30 minutes) to a maximum of 2 mL/minute 
or the rate at which the infusion reaction occurred, whichever is lower. Subjects who experience 
an infusion reaction require vital signs to be monitored approximately every 30 minutes for up to 
2 hours after the end of the elotuzumab infusion. If the elotuzumab infusion reaction recurs, the 
infusion must be stopped and not restarted on that day. Appropriate therapy should be 
administered to address the subject’s signs and symptoms. The infusion can be reattempted at the 
next protocol defined infusion time point at the investigator’s discretion with additional 
premedication as described previously. 
 
Infusion reactions after the completion of elotuzumab infusion: Should a Grade 2 infusion 
reaction occur following completion of an elotuzumab infusion, the subject should be treated as 
clinically indicated with 1 or more of the following medications or interventions: 
diphenhydramine, acetaminophen, hydrocortisone, H2 inhibitor, leukotriene inhibitor, oxygen 
inhalation, epinephrine, bronchodilators, or other supportive measures as indicated. 
 
Elotuzumab infusions on subsequent weeks after a prior Grade 2 infusion reaction: Subjects 
with prior Grade 2 or higher infusion reactions should have future infusions started at 0.5 
mL/min and then escalated in a stepwise fashion (0.5 mL/minute every 30 minutes). If no Grade 
 2 infusion reaction recurs, the escalation regimen may be resumed and the next infusion may 
be initiated as planned per the regimen. 
 
If a patient experiences an infusion reaction of less than or equal to Grade 2, and the infusion 
reaction does not recur, the patient can resume elotuzumab administration at the rate at which the 
reaction occurred at the start of the next cycle at the investigator’s discretion 
 
6.4.3 Dose Delay or Interruption 
 
If a patient’s elotuzumab administration is delayed on day 1 of a cycle, both lenalidomide and 
dexamethasone will also be delayed until the elotuzumab is resumed, which would then become 


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the new day 1 of that cycle. 
 
If a patient’s elotuzumab is held in the middle of a cycle, lenalidomide dosing will continue as 
scheduled. If the patient’s elotuzumab is delayed during the cycle and is resumed within the 
designated window, (+/-3 days Cycles 1 and 2; +/-7 days Cycles 3 and beyond) the patient may 
receive that scheduled dose. If the elotuzumab is not resumed within the given window (+/-3 
days Cycles 1 and 2; +/-7 days Cycles 3 and beyond), the patient is to omit that dose, and resume 
dosing at the next dosing time point. Dexamethasone should be held and resumed when 
Elotuzumab is held and subsequently resumed. 
 
Patients may delay treatment for up to 3 weeks for elective surgeries and other non toxicity 
related events. 
 
 
Table 6: Dose Delay Instructions 
 
To be resumed 
within window? 
Lenalidomide 
Dexamethasone 
Elotuzumab 
Elotuzumab 
delayed on Day 
1 of Cycle 
N/A 
To be delayed 
until Elotuzumab 
is resumed 
To be delayed 
until Elotuzumab 
is resumed 
Resume 
dosing= new 
Day 1 of Cycle 
Elotuzumab 
held on Day 
8,15,or 22 of 
Cycle 
Yes 
Dosing to continue 
as scheduled 
To be delayed 
until Elotuzumab 
is resumed 
Resume dose 
any day within 
window; dose 
time point not 
skipped 
Elotuzumab 
held on Day 
8,15, or 22 of 
Cycle 
No 
Dosing to continue 
as scheduled 
To be delayed 
until Elotuzumab 
is resumed 
Resume dosing 
at next dosing 
time point 
(skip dose) 
 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
7.1 Expected Toxicities 
 
7.1.1 Adverse Events List(s) 
 
7.1.1.1 Adverse Event List of Elotuzumab 
 
Treatment with therapeutic monoclonal antibodies is associated with infusion reactions with 
variable time of onset and varying levels of incidence and severity. The key safety signal with 


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elotuzumab is infusion reactions. As stated above, the definition of an infusion reaction for this 
analysis includes relevant signs and symptoms reported the day of or the day after elotuzumab 
infusion. The most frequent elotuzumab infusion reaction AEs regardless of causality across all 
Phase 1 studies included nausea, vomiting, chills, fever, flushing, dyspnea, cough, headache, 
dizziness, and rash. The majority of infusion reaction AEs were Grade 1 or 2 and resolved with 
little or no treatment. There was no apparent dose relationship for infusion reaction. 
 
7.1.1.2 Adverse Event List for Lenalidomide 
 
Events that have occurred in >10% of individuals treated with lenalidomide include neutropenia, 
anemia, thrombocytopenia, fatigue, rash, diarrhea, constipation, nausea, loss of appetite, itching, 
dry skin, muscle cramps, lack or loss of strength, dizziness, insomnia, swelling of the 
extremities, headache, back and joint pain, fever, cough, upper respiratory infection, and 
dyspnea. 
 
Events that have occurred in >1% of individuals treated with lenalidomide include risk of DVT, 
PE, and blood clots that could lead to stroke, heart attack, or organ failure, febrile neutropenia, 
atrial fibrillation, pneumonia or lung infections, sepsis, dehydration and renal failure. 
 
Events that have occurred in <1% of individuals treated with lenalidomide include rare 
treatment-emergent adverse events of angioedema, serious skin reactions including Stevens- 
Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) or an allergic skin reaction 
similar to that seen with thalidomide, tumor lysis syndrome (TLS), tumor flare reaction (TFR), 
and rhabdomyolysis. In addition, lenalidomide has been shown to increase the level of digoxin in 
the blood in some patients. Patients will be instructed to inform their doctor if taking digoxin. 
 
There may be an increased risk of second cancers in patients who are on lenalidomide 
maintenance therapy after a bone marrow transplant. 
 
7.1.1.3 Adverse events list of Dexamethasone 
 
Events that have occurred in 10-15% of individuals treated with dexamethasone include 
increased appetite, weight gain, sleep disturbance, hypertension, fluid retention, ankle swelling, 
bruising, infection, mood changes, slow wound healing, depression, and hyperglycemia, which 
may lead to fatigue, weight loss, excessive thirst and frequent urination. Events that have 
occurred in 1-9% of individuals treated with dexamethasone include loss of appetite, muscle 
twitching, increased thirst, frequent urination, increased perspiration, diarrhea, nausea, headache, 
bone thinning, spinal fracture or fracture of bones, tachycardia, fungal infections. Events that 
have occurred in <1% of individuals treated with dexamethasone include blurred vision, 
personality changes, stomach ulcers with bleeding that may cause hematemesis, blood in the 
stool and abdominal pain. Other, less frequent, events may include bowel perforation, irritation 
and bleeding of the esophagus, heart failure, allergic reaction that may lead to facial redness, 
shortness of breath, abdominal cramps and hypotension, convulsions, brain swelling, dizziness, 
cataracts, glaucoma and increased blood pressure in the eye, development of diabetes, pancreatic 
inflammation, abdominal swelling, hypokalemia, DVT or PE, malaise, swelling and/or redness 
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 


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“moon face” hormonal disturbances, and hiccups. 
 
7.2 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. 
 
• For expedited reporting purposes only: 
o AEs for the agent(s) that are listed above should be reported only if the 
adverse event varies in nature, intensity or frequency from the 
expected toxicity information which is provided. 
o Other AEs for the protocol that do not require expedited reporting are 
outlined in the next section (Expedited Adverse Event Reporting) 
under the sub-heading of Protocol-Specific Expedited Adverse Event 
Reporting Exclusions. 
 
• Attribution of the AE: 
o Definite – The AE is clearly related to the study treatment. 
o Probable – The AE is likely related to the study treatment. 
o Possible – The AE may be related to the study treatment. 
o Unlikely – The AE is doubtfully related to the study treatment. 
o Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 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, all grade 4 toxicities, and grade 5 (death) regardless of 
study phase or attribution. 
 
7.4 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 


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form should be forwarded to the Overall PI within the timeframes detailed in the table below. 
 
DF/HCC Reportable AEs 
Attribution 
Gr. 2 & 3 
AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE 
Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar 
days# 
5 calendar 
days 
24 hours* 
Possible 
Probable 
Definite 
Not required 
5 calendar 
days 
5 calendar 
days# 
5 calendar 
days 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to 
be reported. 
* For participants enrolled and actively participating in the study or for AEs occurring within 
30 days of the last intervention, the AE should be reported within 1 business day of learning of 
the event. 
 
The Overall PI will submit SAE reports from outside institutions to the DFCI OHRS according 
to DFCI IRB policies and procedures in reporting adverse events. 
 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for 
subject safety). 
 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated. The investigator must immediately 
notify the BMS, Celgene (or designee) Medical Monitor of this event and complete and forward 
an SAE Form to BMS and Celgene (or designee) within 24 hours and in accordance with SAE 
reporting procedures described in this section. 
 
Pregnancy 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the Overall PI. Information on this pregnancy will be collected on the BMS Pregnancy 
Surveillance Form. Follow-up information regarding the course of the pregnancy, including 
perinatal and neonatal outcome and, where applicable, offspring information must be reported on 
the Pregnancy Surveillance Form. Please contact the Research Project Manager if you do not 
have this form in your regulatory files. 
 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on lenalidomide, or within 28 


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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. 
 
Male Subjects 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking lenalidomide should notify the Investigator, and the pregnant female partner 
should be advised to call their healthcare provider immediately. 
 
Celgene Drug Safety Contact Information: 
 
Celgene Corporation 
Global Drug Safety and Risk Management 
Connell Corporate Park 
300 Connell Dr. Suite 6000 
Berkeley Heights, NJ 07922 
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 
 
Overdose 
 
Include any product-specific definition of overdose in addition to the following mandatory 
statement as the last sentence. 
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. 


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Overdose of Lenalidomide 
 
Overdose, as defined for this protocol, refers to Revlimid dosing only. 
 
On a per dose basis, an overdose is defined as the following amount over the protocol-specified 
dose of Revlimid assigned to a given patient, regardless of any associated adverse events or 
sequelae. 
• PO 
any amount over the protocol-specified dose 
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency. 
 
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the case report form. 
 
 
7.4.1 Protocol-Specific Expedited Adverse Event Reporting Exclusions 
There are no protocol specific exclusions. 
7.5 Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
7.6 Expedited Reporting to Bristol-Myers Squibb (BMS) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the BMS. With 
the exception of any serious adverse event that meets the FDA’s criteria for expedited reporting 
following 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 3 
business days.. The report should also include the BMS trial number, which is CA204-119. 
 
7.7 Expedited Reporting to Celgene 
 
Serious adverse events (SAE) are defined above. The investigator must inform Celgene in 
writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 hours of 


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being aware of the event. The written report must be completed and supplied to Celgene by 
facsimile within 24 hours. The initial report must be as complete as possible, including an 
assessment of the causal relationship between the event and the investigational product(s). 
Information not available at the time of the initial report (e.g., an end date for the adverse event 
or laboratory values received after the report) must be documented on a follow-up report. A 
final report to document resolution of the SAE is required. The Celgene tracking number (RV- 
CL-MM-PI-004473) and the institutional protocol number should be included on SAE reports (or 
on the fax cover letter) sent to Celgene. A copy of the fax transmission confirmation of the SAE 
report to Celgene should be attached to the SAE and retained with the patient records. 
 
7.8 Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy. 
 
7.9 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms. AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the Elotuzumab and lenalidomide 
administered in this study can be found in Section 7. 
 
8.1 Elotuzumab 
 
8.1.1 Description 
 
Elotuzumab (BMS- 901608; formerly known as HuLuc63) is a humanized recombinant 
monoclonal IgG1 antibody product directed to human SLAMF7 (CD2-subset-1, also known as 
CRACC), a cell surface glycoprotein that is highly expressed in MM cells. 
 
8.1.2 Form 
 
Elotuzumab for injection has been developed to be used as an intravenous (IV) infusion for the 
clinical studies. Drug product is a non-pyrogenic lyophilized powder which is white to off-white 
contained in 20-cc Type I glass vials, closed with 20-mm stoppers and sealed with aluminum 
seals. Each vial of drug product contains the labeled amount of BMS-901608 drug substance, 
sucrose, sodium citrate dihydrate, citric acid, and polysorbate 80. A 10% overfill is included in 
each vial to account for vial, needle, syringe (VNS) holdup. The drug product will be 
reconstituted prior to administration. 
 
Table 7 
 
Product 
Potency 
Primary 
Secondary 
Appearance 
Storage 


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Description and 
Dosage Form 
Packaging 
(Volume)/ 
Label Type 
Packaging 
(Qty) /Label 
Type 
Conditions 
(per label) 
Elotuzumab 
Powder for 
Solution for 
Infusion 
400mg/vial 
20 ml vial/ 
open Label 
10 vials per 
kit/open 
Label 
Sterile, white 
to off-white, 
preservative- 
free, 
lyophilized 
cake 
Store at 2°C - 
8°C 
 
8.1.3 Storage and Stability 
 
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the sponsor. If 
concerns regarding the quality or appearance of the study drug arise, do not dispense the study 
drug and contact the sponsor immediately. 
 
The lyophilized elotuzumab drug product should be stored at 2° to 8° C. Prior to administration 
the drug product must be reconstituted with Sterile Water for Injection, USP, and then further 
diluted in 0.9% sodium chloride normal saline, USP, as per the instructions in Appendix B. After 
the dose is diluted in normal saline, it must be administered within 8 hours if stored at room 
temperature. If a delay is anticipated, the prepared dose may be refrigerated at 2° to 8° C for up 
to 24 hours. If stored under refrigerated conditions, the prepared study drug solution should be 
equilibrated to room temperature (process takes 2 - 2.5 hours) and the container must be gently 
inverted to mix well before administration. Do not use the accelerated warming method. If 
administration is delayed beyond the specified time, the prepared dose solution must be 
discarded, and the reason documented by the pharmacist in study drug accountability records. 
The dose of elotuzumab to be administered to a subject will be calculated by multiplying the 
subject’s weight (kg) by 10 mg/kg. The subject’s predose weight on Day 1 of each cycle or 
predose weight at each visit, whichever is institutional policy, will be used to calculate the dose 
for each cycle. Each dose should be infused as per instructions in Appendix B. 
 
8.1.4 Handling 
 
The lyophilized elotuzumab drug product should be stored at 2° to 8°C. Prior to administration 
the drug product must be reconstituted with Sterile Water for Injection, USP, and then further 
diluted in 0.9% sodium chloride normal saline, USP, as per the instructions in Appendix B. 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 
 
8.1.5 Availability 
 
Bristol-Myers Squibb will supply elotuzumab. Elotuzumab is an investigational agent and will 
be supplied free-of- charge. Drug will be shipped to the pharmacy at the study site. 


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8.1.6 Preparation 
 
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the sponsor. If 
concerns regarding the quality or appearance of the study drug arise, do not dispense the study 
drug and contact the sponsor immediately. 
 
After the dose is diluted in normal saline, it must be administered within 8 hours if stored at 
room temperature. If a delay is anticipated, the prepared dose may be refrigerated at 2° to 8°C for 
up to 24 hours. If stored under refrigerated conditions, the prepared study drug solution should 
be equilibrated to room temperature (process takes 2 - 2.5 hours) and the container must be 
gently inverted to mix well before administration. Do not use the accelerated warming method. If 
administration is delayed beyond the specified time, the prepared dose solution must be 
discarded, and the reason documented by the pharmacist in study drug accountability records. 
 
8.1.7 Administration 
 
Elotuzumab will be given cycle 1 & 2 at 10 mg/kg IV once a week (days, 1, 8, 15, and 22). 
Elotuzumab will be given cycle 3 to 8 at 10mg/kg IV days 1 and 15 every cycle. 
Maintenance elotuzumab will be given at 20 mg/kg IV day 1 every cycle up to cycle 24 (total of 
2 years). 
 
8.1.8 Ordering 
 
The investigator or designee will order drug from Bristol-Myers Squibb, according to the 
ordering instructions provided by company. A study specific order form will be provided by the 
lead site. 
 
8.1.9 Accountability 
 
The investigator, or designee, is responsible for taking an inventory of each shipment of 
elotuzumab received, and comparing it with the accompanying accountability form. The 
Investigator, or designee, will verify the accuracy of the information on the form, sign and date 
it, retain a copy in the study fill. Accurate records will be kept in the source documentation of all 
drug administration (including dispensing and dosing). 
 
8.1.10 Destruction and Return 
 
If study drugs (those supplied by the sponsor or sourced by the investigator) are to be destroyed 
on site, it is the investigator’s responsibility to ensure that arrangements have been made for the 
disposal, procedures for proper disposal have been established according to applicable 
regulations, guidelines and institutional procedures, and appropriate records of the disposal have 
been documented. 
 
8.2 Lenalidomide 


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8.2.1 Description 
 
Lenalidomide (REVLIMID®), a thalidomide analogue, is an immunomodulatory agent with 
antiangiogenic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H- isoindol-2- 
yl) piperidine-2,6-dione and it has the following chemical structure: 
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione. The empirical formula for 
lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3. 
 
8.2.2 Form 
 
Lenalidomide is off-white to pale-yellow solid powder. It is soluble in organic solvent/water 
mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and 
low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 
0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically 
active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of 
zero. 
 
Lenalidomide is available for this study as 5 and 25 mg capsules for oral administration. Each 
capsule contains lenalidomide as the active ingredient and the following inactive ingredients: 
lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. 
 
8.2.3 Storage and Stability 
 
At the study site, all investigational study drugs will be stored in a locked, safe area to prevent 
unauthorized access. Lenalidomide should be stored at room temperature away from direct 
sunlight and protected from excessive heat and cold. 
 
8.2.4 Handling 
 
Females of childbearing potential should not handle or administer lenalidomide unless they are 
wearing gloves. 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 
 
8.2.5 Availability 
 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no charge 
through Celgene’s Revlimid Risk Evaluation and Mitigation Strategy™ (REMS) (formerly 
known as RevAssist® Program, Research). Each patient’s individual drug supply will be 
delivered to the site by the drug courier Biologics and be distributed to the patient through the 
research side of the pharmacy of that site. 
 
8.2.6 Preparation 


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Lenalidomide is an oral drug, and does not require specific preparation details. 
 
8.2.7 Administration 
 
Lenalidomide will be given daily at 25 mg days 1-21 on a 28 day cycle, cycles 1-8. Maintenance 
therapy can be given until cycle 24 (total of 2 years). During maintenance, lenalidomide will be 
given 15 mg daily days 1-21 every cycle. 
 
At all times when dispensing lenalidomide protocol therapy, study site personnel will review the 
instructions, printed on the packaging, with participants. 
 
8.2.8 Ordering 
 
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers. Lenalidomide will be 
provided in accordance with the Celgene Corporation’s Revlimid REMS® program. Per 
standard Revlimid REMS® program requirements, all physicians who prescribe lenalidomide 
for research subjects enrolled into this trial, and all research subjects enrolled into this trial, must 
be registered in, and must comply with, all requirements of the Revlimid REMS® program. 
Drug will be shipped on a per patient basis by the contract pharmacy to the clinic site. Only 
enough lenalidomide for one cycle of therapy will be supplied to the patient each cycle. 
 
Lenalidomide will be shipped directly to the clinic site. Bottles will contain a sufficient number 
of capsules for one cycle of dosing. A study specific order form will be provided by the lead 
site. 
 
8.2.9 Accountability 
 
The Investigator or designee is responsible for taking an inventory of each shipment of study 
drug received, and comparing it with the accompanying study drug accountability form. 
 
8.2.10 Destruction and Return 
 
If study drugs (those supplied by the sponsor or sourced by the investigator) are to be destroyed 
on site, it is the investigator’s responsibility to ensure that arrangements have been made for the 
disposal, procedures for proper disposal have been established according to applicable 
regulations, guidelines and institutional procedures, and appropriate records of the disposal have 
been documented. The unused study drugs should be destroyed per institutional policies after the 
drug returns have been reconciled by the monitor, or when the lead site instructs the site to do so. 
 
If any study drug is lost or damaged, its disposition should be documented in the source 
documents. Patients will be instructed to return empty bottles or unused capsules to the clinic 
site. 
 
8.3 Dexamethasone 


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8.3.1 Description 
 
Dexamethasone is a synthetic adrenocortical steroid. Corticosteroids are naturally occurring 
chemicals produced by the adrenal glands located above the kidneys. Corticosteroids affect the 
function of many cells within the body and suppress the immune system. Corticosteroids also 
block inflammation and are used in a wide variety of inflammatory diseases affecting many 
organs. 
 
The molecular weight for dexamethasone is 392.47. It is designated chemically as 9- fluoro- 
11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione. Dexamethasone is stable in air 
and almost insoluble in water. 
 
8.3.2 Form 
 
Dexamethasone is a white to practically white, odorless, crystalline powder. It is available in 2 or 
4 mg tablets (commercially) for oral administration. Each tablet contains dexamethasone as the 
active ingredient, and the following inactive ingredients: calcium phosphate, lactose, magnesium 
stearate, and starch. The tablet shell may contain the following: D&C Yellow 10, FD&C Yellow 
6, and/or FD&C Blue 1. 
 
8.3.3 Storage and Stability 
 
At the study site, all investigational study drugs will be stored in a locked, safe area to prevent 
unauthorized access. Dexamethasone should be stored at controlled room temperature, 68-77◦F 
(20-25◦C) and not frozen, and according to label requirements. 
 
8.3.4 Handling 
 
Dexamethasone should be handled by trained pharmacy staff. The use of gloves and other 
appropriate protective clothing is recommended as necessary. 
 
8.3.5 Availability 
 
Dexamethasone supply will be obtained through commercial supply. 
 
8.3.6 Preparation 
 
Dexamethasone is an oral drug, and does not require specific preparation details. 
 
8.3.7 Administration 
 
, Participants will receive dexamethasone Days 1, 8 15 and 22 during cycles 1-2 and then days 
1, 8, 15 on cycles 3-8 and on day 1 of cycles 9-24 of maintenance . 
 
8.3.8 Ordering 
 
The investigator or designee will order drug supply from commercial supply. 


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8.3.9 Accountability 
 
As drug is from commercial supply, sites should keep records per their institutional policies. 
 
8.3.10 Destruction and Return 
 
At the end of the study, unused supplies of dexamethasone should be destroyed and documented 
according to institutional policies. 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
This trial will provide samples high-risk SMM patients treated with elotuzumab and 
lenalidomide to comprehensively characterize the MM genome and immune cells function and 
define molecular events driving development and progression of MM. 
 
We will attempt to obtain samples on all patients at the following time points: before therapy, at 
the end of cycle 8, at the time of response determination (CR) , at disease relapse, and at several 
more time points over the course of the study. It is anticipated that approximately 90% of 
samples collected will be adequate for sequencing studies proposed. 
 
The tumor cells will be collected as described below. From these samples, high quality DNA (for 
tumor cells) and RNA (for tumor cells and immune cells) for both exome sequencing and RNA 
sequencing will be obtained. Germline DNA will be also obtained from a buccal swab from all 
patients at any time point of the study. 
 
Peripheral blood and bone marrow derived mononuclear cells will undergo immunologic 
assessments to assess the impact of therapy on general measures of cellular immunity, MM 
reactive T cells, and antigen specific immunity. The percentage of circulating and bone marrow 
derived regulatory T cells, NK cells and MDSCs will be determined. The percent of PD-1 and 
other checkpoint regulators on immune cells will also be measured. Levels of naïve, effector and 
central memory cells will be quantified. T cell proliferative response to tetanus toxoid and PHA 
mitogen will be determined. NK cell mediated cytotoxicity will be measured. 
 
We will also determine the level of SLAMF7 on these cells. 
 
In addition, we will examine the level of soluble SLAMF7 pre-treatment and monthly on Day 1 
of each cycle. 


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Peripheral blood and bone marrow samples will be collected at the screening time and for 
analysis in order to confirm response as well as at C9D1. The collection kits and shipping 
supplies will be provided to the sites by Sequenta. These samples will be packaged whole, and 
shipped to Sequenta, Inc. in South San Francisco, CA same day priority overnight.. Using 
Sequenta’s LymphoSIGHT platform, rearranged immunoreceptor loci from genomic DNA will 
be extracted, amplified, and sequenced using V and J segment primers for each immunoreceptor 
gene. Tumor-specific clonotypes will be identified for each patient based on their high 
prevalence in peripheral blood. Sequences will be analyzed using standardized algorithms for 
clonotype determination. Sequenta MRD levels will be quantified using spiked-in reference 
sequences. 
 
9.1 Bone Marrow Aspirate Samples 
 
Collection of bone marrow aspirate specimens for exploratory analysis will be requested for this 
trial. Collections that are requested will be obtained at screening, C9D1, confirmation of CR and 
at end of study treatment. At any time a bone marrow aspirate procedure is performed, an 
additional sample for exploratory analysis is requested. This will not require extra access for 
participants. Specimens will be shipped (via traceable carrier) to and subsequently processed, 
analyzed, and stored at Dana-Farber Cancer Institute. 
 
Specimens Requested: 2 Purple Top Tubes (K2EDTA), 10mL each. Specimens must be 
collected on Mondays to Thursdays for same-day shipment. 
 
Processing Information: There is no required processing for bone marrow samples at each 
participating site prior to shipment. 
 
Shipping Information for Bone Marrow Aspirate Specimens: Label all specimens with the 
following: Subject Initials, Subject study number (will include protocol number), Visit at which 
sample was drawn (screening, response or relapse/progression), Date sample drawn 
(mm/dd/yyyy), Time sample drawn (24 hour clock) 
 
9.1.1 Shipping Instructions: 
 
Shipments must be sent on the day of collection and cannot be batched. 
 
1. An inventory sheet including a complete list of samples shipped (patient number, 
timepoint, study #) must accompany each shipment. Please sign and date the requisition 
form. 
 
2. An electronic copy (Word or Excel) of the sample list must also be sent via email. The 
listing must also include a contact name, address and phone number of the person who is 
responsible for the shipment. 
 
3. Please email the lead site contact to notify of an incoming shipment. 
 
4. Please ship ONLY Monday to Thursday as shipments cannot be received on weekends 
and/or on holidays. 


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5. Once drawn, samples may be shipped via overnight air to: 
 
Dana Farber Cancer Institute 
Ghobrial Lab 
360 Longwood Avenue LC8116 
Boston, MA 02215 
Email: GhobrialLab@dfci.harvard.edu 
 
Please retain a copy for site record maintenance. Please see Appendix C and D for 
Collection Schedule and Requisition Form 
 
9.2 
Peripheral Blood Samples 
 
Collection of peripheral blood specimens (including serum and plasma) for exploratory analysis 
are requested for this trial. Purple top tube collections should be obtained at the same timepoints 
as bone marrow samples for correlative studies (see Section 10 for list of required timepoints, 
and Appendix C for specific instructions). These collections will be taken at the time of routine 
blood collection timepoints required for this study. Specimens will be processed on site 
according to instructions below and shipped (via traceable carrier) to Dana-Farber Cancer 
Institute. Once the shipment is received, samples will be subsequently processed, analyzed, and 
stored at Dana-Farber. 
 
9.2.1 Specimens Required: 2 x 10ml Purple Top Tubes (K2EDTA), and 1x 6ml Red Top (no 
additive) tube, must be collected Mondays to Thursdays for same-day shipment. 
 
9.2.2 Shipping Information: Label all specimens with the following: 
 
• Subject Initials 
• Subject study number (will include protocol number) 
• Visit at which sample was drawn (screening, response or relapse/progression) 
• Date sample drawn (mm/dd/yyyy) 
• Time sample drawn (24 hour clock) 
9.2.3 Processing Information: Once collected, the vacutainers will be refrigerated and stored 
according to instructions below. There is no required processing for purple top tubes at 
each participating site prior to shipment. 
 
9.2.4 Shipping Instructions: Shipments must be sent on the day of collection and cannot be 
batched. 
 
Processing Information: 
 
Invert each tube 5 times at blood collection to ensure adequate mixing of anticoagulant with 
blood immediately after the blood collection. Package tubes at room temperature and wrap in a 
liberal amount of paper towel around the tubes to ensure adequate insulation of the specimen(s) 
and absorption in the event of a breakage. Place wrapped specimen in a biohazard labeled Ziploc 


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bag with a fridge pack and zip close. Wrap bubble wrap around the bag and place in a cardboard 
box. If space remains in the box, stuff with extra paper towel to reduce shifting of samples. 
Complete the shipping requisition form using the address listed below. Prepare the package for 
shipping, applying packing tape as needed. Ship the package using FedEx or UPS next day or 
overnight delivery the same day the sample was collected. Please only ship Monday-Thursday, 
as the lab is only able to accept Saturday shipments with 1 week advance notice. With each 
shipment, please include the following: 
 
1. An inventory sheet including a complete list of samples shipped (patient number, 
timepoint, study #) must accompany each shipment. Please sign and date the form, and 
retain a copy for site record maintenance. See Appendix D for Sample Requisition 
Form 
 
2. An electronic copy (Word or Excel) of the sample list must also be sent via email and 
include the tracking number of the package. The listing must also include a contact name, 
address and phone number of the person who is responsible for the shipment. 
 
3. Please email the Dana-Farber/lead site contact to notify of an incoming shipment. 
 
4. Please ship Monday to Thursday as shipments cannot be received on weekends and/or on 
holidays. 
 
5. Once drawn, samples may be shipped via overnight air to: 
 
Dana Farber Cancer Institute 
Ghobrial Lab 
360 Longwood Avenue LC8116 
Boston, MA 02215 
 
Email: GhobrialLab@dfci.harvard.edu 
 
For Sequenta samples, use the packing supplies provided in each individual kit and follow the 
directions below: 
 
1. Label each tube with date of collection, patient’s study specific number, initials, and date 
of birth 
 
2. Store collected tubes at room temperature until same day shipment. 
 
3. On the ClonoSEQtest requisition form, fill out requisition with patient first and last name, 
date of birth, and gender. Ordering physician should be listed as Irene Ghobrial, MD. 
Please ensure that the sample tubes are labeled, and reference patient specific study 
number, the treating site, and the treating physician name at the top of the requisition 
form. 
 
4. Under ICD-10, Other: Multiple Myeloma C90.00 should be entered 


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5. Under specimen information, enter collection date under fresh specimens, and mark 
which samples have been provide ( blood and bone marrow ) 
 
6. For baseline samples, ClonoSIGHT ID Test should be checked. For confirmation of 
response time point, ClonoSIGHT MRD Test should be checked. 
 
7. Under billing, please provide insurance information for the patient 
 
8. Complete pathology, physician signature, and billing information sections 
 
9.  Please make a copy of the requisition to retain for your records along with the Fed-Ex 
tracking number in the event that the package is lost. 
 
10. Follow the sample packing instructions included in the kit, and send out same day. 
Shipping on Friday is ok for Saturday processing for these samples. 
 
11. An electronic notification must be sent via email and include the tracking number of the 
package, and all relevant sample information and patient identifiers to the study team 
The listing must also include a contact name, address and phone number of the person 
who is responsible for the shipment. 
 
a) Please email the lead site contact to notify of an incoming shipment. 


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10. STUDY CALENDAR 
Screening evaluations are to be conducted within 28 days prior to initiation of registration. 
Protocol therapy should start as soon after registration as feasible. Baseline assessments are to be 
conducted on C1D1 of initial therapy and should be considered separate from screening 
evaluations. Evaluations need not be repeated for C1D1 if screening evaluations are performed 
within 7 days of registration. Scans and bone marrow assessments do not need to be repeated if 
performed within 6 weeks of registration. All assessments must be performed prior to 
administration of any study medication.. See below for detailed scheduled of assessments. Study 
medications will be administered according to the schedule and guidelines outlined in Section 5. 
 
Pre-registration 
Cycles 1-24 (28 days) 3 
Follow Up11 
 
 
Tests and procedures 
≤ 28 days 
prior to 
registration 
≤ 21 days 
prior to 
registration 
Day 1 
of all 
cycles1 
Days 8, 15 
and 22 of 
cycles 1 & 2 
Cycle 9 
Day 1/ Or 
to confirm 
CR9 
End of 
Tx 
Every 3 or 
6 Months 
(+/- 28 
days) 
Days 1 &15 
from cycle 
3-8 
History and exam, height, 
weight. Performance Status 
X 
X 
X 
(X) 
Toxicity Notation 
X 
X 
Hematology group (WBC 
w/ diff, PLT, Hgb, ANC) 
X 
X 
X 
X 
X 
Chemistry4 
X 
X 
X 
X 
X 
Direct & total bilirubin2 
X 
X 
X 
Free light chain assay 
X 
X 
X 
X 
Serum and Urine 
Immunofixation (SPEP and 
UPEP) with quantitative 
immunoglobulins10 
X 
X 
X 
X 
2M, CRP, LDH 
X 
X 
Metastatic Bone Survey/ 
Spine MRI or PET/CT12 
X 
X 
(X) 
EKG 
X 
X 
Serum pregnancy test 
X 
Unilateral bone marrow 
aspirate and biopsy5 
X 
X 
X 
(X) 
Research bone marrow 
aspirate6 
X5 
X6 
X6 
(X) 
Research Blood7 
X8 
X 
X 
X 
(X) 
1- Cycle 1, Day 1 laboratory values need to meet eligibility criteria 
2- Direct bilirubin to be obtained if total bilirubin is abnormal. 
3- Scheduling allows for +/- 3 days cycles 1-2 and +/- 7 days for cycle 3 and beyond. 
4- Chemistry includes sodium, potassium, chloride, bicarbonate, bun, creatinine, calcium, glucose, albumin, ALT (SGPT), total protein, AST (SGOT), 
total bilirubin, magnesium, and phosphorus. 
5- These procedures should also be done at any time during the course of the study to confirm CR. 
6- Research bone marrow aspirate and biopsy at the same time of clinically indicated bone marrow biopsy and to confirm response. 
7- Peripheral blood samples for correlative studies including serum SLAMF7 levels. 
8- Oragene kit for germline DNA will be acquired once at any time point from patients enrolled on this study. 
9- If C9D1 or confirmation of response BM biopsy was performed within 3 weeks of subsequent time point listed; do not need to repeat BM biopsy. 


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10- Patients who are not followed for disease response in their urine per IMWG criteria need only bring urine every third cycle and at end of 
treatment after baseline 
11- Follow up will occur approximately every 3 to 6 months (+/- 28days) for up to 3 years after discontinuation of therapy (EOT). Participants unable to 
participate in follow up every 3 months may follow up every 6 months at PI discretion in accordance with standard of care follow-up frequency and 
COVID precautions. Physical exams and correlative blood draws that are not done due to virtual visits will not be considered violations. Local myeloma 
labs must be provided to the participating site for data entry purposes. Bone marrow biopsy and scans are strongly recommended yearly after EOT but are 
required when there is suspicion of clinical progression. These assessments can be waived due to extenuating circumstances or for insurance coverage 
reasons. Scans and bone marrow biopsy and research samples are required at time of suspected disease progression if one is performed as part of standard 
of care procedures. 
12- A CD of scans at screening and end of treatment is requested to be sent to the lead site for central review. Screening scans should be sent with the 
eligibility packet to the lead site 
 
(X)- Indicates this assessment may not be required 
Note: Research blood and bone marrow studies are voluntary and do not exclude patients from participating 
 
11. MEASUREMENT OF EFFECT 
 
11.1 Development of symptomatic disease 
 
In this study, the final endpoint is development of symptomatic MM that requires therapy. 
This is defined as one of the following criteria (CRAB* and Myeloma defining events< MDE): 
 
• Increased calcium levels (corrected serum calcium >0.25 mmol/dL above the 
upper limit of normal or >.275 mmol/dL); 
• Renal insufficiency (attributable to myeloma); 
• Anemia (Hgb 2g/dL below the lower limit of normal or <10g/dL); 
• Bone lesions (lytic lesions or generalized osteoporosis with compression 
fractures) 
• Or any MYELOMA DEFINING EVENTS (MDE) as follows: 
o Clonal bone marrow plasma cell percentage*> 60%2 
o An abnormal FLC-ratio ≥100 (involved kappa) or ≤0.01 (involved 
lambda)52 
o 2 or more focal lesions on MRI or PET-CT studies53,54 
 
* Participants with CRAB criteria that are attributable to conditions other than the disease 
under study may be eligible 
 
For measurement of response: 
 
In this study, patients must have measurable disease. The disease response will be assessed using 
criteria based on the International Working Group Uniform Response Criteria in Section 11.2.4. 
If the only measurable parameter is serum immunoglobulins free light chain (FLC), the 
participant will be followed by FreeLite™ Disease Response Criteria provided in Section 11.2.5. 
 
Disease response by the Modified EBMT Response Criteria in Section 11.2.6.2 will also be 
collected on participants as a secondary measure. 
 
The same method of assessment and technique should be used for disease measurement at 
baseline and during follow-up. Disease response should be confirmed by two consecutive 


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assessments. 
 
 
 
 
 
 
 
 
11.2 Antitumor Effect 
 
11.2.1 Disease Parameters 
 
Measurable disease: Measurable disease is disease that can be measured either by serum or 
urinary evaluation of the monoclonal component or by serum assay of 
FLC and is defined by at least one of the following three measurements: 
 
• Serum M-protein > 0.5 g/dl 
 
• Urine M-protein > 200 mg/24 h 
 
• Serum FLC assay: Involved FLC level > 10 mg/dl (> 100 mg/l) provided 
serum FLC ratio is abnormal. 
 
If a patient has measurable disease, but not by IMWG standards listed above, the patient may 
be eligible after discussion with the Overall Principal Investigator. 
 
11.2.2 Methods for Evaluation of Measurable Disease 
 
All baseline evaluations should be performed on Cycle 1, Day 1 of initial therapy. Response will 
be assessed by M-protein quantification, protein electrophoresis and immunofixation from 
serum and a 24-hour urine collection. A serum sample for FreeLiteTM testing will be obtained. 
In addition, bone marrow aspiration and biopsy, as well as skeletal survey will be performed to 
determine overall response or confirm response. 
The same method of assessment and technique should be used for disease 
measurement at baseline and during follow-up. 
 
11.2.3 Response Criteria 
 
A confirmation measurement for disease response assessments is required in this 
protocol. 
 
11.2.4 International Myeloma Working Group Response Criteria 
 
Response criteria for all categories and subcategories of response except CR are applicable 


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only to patients who have ‘measurable’ disease, as defined in Section 11.2 All response 
categories require two consecutive assessments made at any time before the institution of 
any new therapy; all categories also require no known evidence of progressive or new bone 
lesions if radiographic studies were performed. Radiographic studies are not required to 
satisfy these response requirements. 
 
Stringent CR: CR as defined below plus normal free light chain ratio and absence of 
clonal cells in bone marrow* by immunohistochemistry or immunofluorescence.** 
*Confirmation with repeat bone marrow biopsy is not needed. 
**Presence/absence of clonal cells is based upon the k/λ ratio. An abnormal k/ λ ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma 
cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is k/λ of > 
4:1 or < 1:2. 
 
CR: Negative immunofixation on the serum and urine and disappearance of any soft 
tissue plasmacytomas and <5% plasma cells in bone marrow. 
*Confirmation with repeat bone marrow biopsy is not needed. 
 
VGPR: Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein 
level <100mg per 24 hours. 
 
PR: > 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by > 90% or 
to < 200mg per 24 hours. If the serum and urine M-protein are unmeasurable, a > 50% decrease 
in the difference between involved and uninvolved free light chain levels is required in place of 
the M-protein criteria (definition of measurable disease in Section 10.2.3). If serum and urine M- 
protein are unmeasurable, and serum free light assay is also unmeasurable, > 
50% reduction in plasma cells is required in place of M-protein, provided baseline bone 
marrow plasma cell percentage was > 30%. In addition to the above listed criteria, if present at 
baseline, a > 50% reduction in the size of soft tissue plasmacytomas is also required. 
 
SD: Not meeting criteria for CR, VGPR, PR or progressive disease. This is not 
recommended as an indicator of response; stability of disease is best described by 
providing the time to progression estimates. 
 
PD: > 25% increase of serum M-protein (which must also be an absolute increase of > 0.5 g/dL) 
and/or urine M-protein (which must also be an absolute increase of > 200 mg/24hr). If serum and 
urine M-protein are unmeasurable, there must be an absolute increase of > 10 mg/dL between 
involved and uninvolved FLC levels. PD is also measured by an absolute increase in bone 
marrow plasma cells > 10%. In addition to the above listed criteria, progression may also be 
measured by a definite development of new bone lesions or soft tissue plasmacytomas or definite 
increase in the size of existing bone lesions or soft tissue plasmacytomas or development of 
hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) that can be attributed 
solely to the plasma cell proliferative disorder. 


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11.2.5 FreeLite™ Disease Response Criteria 
 
Complete Response: For those patients being followed by serum free light chain (and NO 
measurable serum or urine M-spike), which were immunofixation negative at enrollment, 
normalization of serum free light chain ratio. 
 
- Normalization is defined as the serum free light chain ratio being within the normal range. 
If the serum free light chain ratio is not within the normal range, but the individual kappa and 
lambda light chain values are within normal range, this may be considered CR. 
 
 
Partial Response: If only measurable parameter is serum immunoglobulins free light chain 
(FLC), EITHER of the following changes qualify as partial response: 
 
- A 50% decrease in the difference between involved and uninvolved FLC levels; OR 
 
- A 50% decrease in the level of involved FLC AND a 50% decrease (or 
normalization) in the ratio of involved/uninvolved FLC 
 
Progressive Disease: If only measurable parameter is serum immunoglobulins free light 
(FLC), either of the following qualify as progression: 
 
- 50% increase in the difference between involved and uninvolved FLC levels from the lowest 
response level, which must also be an absolute increase of at least 
10 mg/dL; OR 
 
- 50% increase in the level of involved FLC AND a 50% increase in the ratio of 
involved/uninvolved FLC from the lowest response level. 
 
11.2.6 Criteria for Molecular CR and Minimal Residual Disease (MRD) measurement 
We will measure MRD in patients who achieve CR to determine the number of patients who are 
MRD negative vs MRD positive. 
 
11.2.6.1 
MRD by LymphoSIGHT 
MRD will be carried out according to the LymphoSIGHTTM method (Sequenta, Inc., San 
Francisco, CA)55. Prior studies have compared this technique to the traditional MRD 
immunofluorescence technique, as previously reported 60 and showed that MRD by 
LymphoSight is a sensitive method that can be used in future clinical practice. 
For MM diagnostic samples, genomic DNA will be amplified using locus-specific primer sets for 
the immunoglobulin heavy-chain locus (IGH) complete (IGH-VDJH), IGH incomplete (IGH- 
DJH), and immunoglobulin κ locus (IGK). The amplified product will be subjected to 


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sequencing, and the sequences and frequencies of the different clonotypes in the sample will be 
obtained. Myeloma gene rearrangements will be identified. Patients in whom a high-frequency 
myeloma clone (>5%) is not identified will be excluded from the MRD analysis. MRD will be 
assessed in patients with a high-frequency myeloma clone using the IGH-VDJH and IGK or 
IGH-VDJH, IGH-DJH, and IGK assays. Once the absolute amount of total cancer-derived 
molecules present in a sample will be determined, a final MRD measurement will be calculated, 
providing the number of cancer-derived molecules per 1 million cell equivalents. In cases in 
which 2 or more tumor clones existed, the clone with the highest MRD value will be reported. 
Molecular CR will be defined according to the International Myeloma Working Group (IMWG) 
consensus recommendations.56 
11.2.6.2 
Modified EBMT Response Criteria 
 
Response 
Criteria for Responsea 
Complete response 
(CR) 
Requires all of the following: 
Disappearance of the original monoclonal protein from the blood and 
urine on at least two determinations for a minimum of six weeks by 
immunofixation studies. 
<5% plasma cells in the bone marrow on at least two 
determinations for a minimum of six weeks. b 
No increase in the size or number of lytic bone lesions 
(development of a compression fracture does not exclude 
response).c 
Disappearance of soft tissue plasmacytomas for at least six weeks. 
Near Complete 
Response 
(nCR) 
Requires the following: 
Same as CR, but immunofixation studies continue to show presence 
of the monoclonal protein 
Very Good Partial 
Response 
(VGPR) 
Requires the following: 
> 90% reduction in serum M-protein plus urine M-protein level <100mg 
per 24 hours on at least two determinations for a minimum of six weeks. 


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Partial response 
(PR) 
PR includes participants in whom some, but not all, criteria for CR are 
fulfilled providing the remaining criteria satisfy the requirements for PR. 
Required all of the following: 
50% reduction in the level of serum monoclonal protein for at 
least two determinations six weeks apart. 
If present, reduction in 24-hour urinary light chain excretion by either 
90% or to 
<200 mg for at least two determinations six weeks apart. 
50% reduction in the size of soft tissue plasmacytomas (by 
clinical or radiographic examination) for at least six weeks. 
No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response).c 
Minimal response 
(MR) 
MR included participants in whom some, but not all, criteria for PR 
were fulfilled, providing the remaining criteria satisfied the 
requirements for MR. Required all of the following: 
25% to  49% reduction in the level of serum monoclonal protein for 
at least two determinations six weeks apart. 
If present, a 50 to 89% reduction in 24-hour light chain excretion, 
which still exceeds 200 mg/24 h, for at least two determinations six 
weeks apart. 
25-49% reduction in the size of plasmacytomas (by clinical or 
radiographic examination) for at least six weeks. 
No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response).c 
No change (NC) 
Not meeting the criteria for MR or PD. 


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Response 
Criteria for Responsea 
Requires one or more of the following: 
>25% increased in the level of serum monoclonal paraprotein, which 
must also be an absolute increase of at least 5 g/L and confirmed on a 
repeat investigation. 
Progressive 
disease (PD) (for 
participants not 
in CR) 
>25% increased in 24-hour urinary light chain excretion, which must 
also be an absolute increase of at least 200 mg/24 h and confirmed on a 
repeat investigation. 
>25% increased in plasma cells in a bone marrow aspirate or on trephine 
biopsy, which must also be an absolute increase of at least 10%. 
Definite increase in the size of existing lytic bone lesions or soft 
tissue plasmacytomas. 
Development of new bone lesions or soft tissue plasmacytomas (not 
including compression fracture). 
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL 
or 2.8 mmol/L not attributable to any other cause). 


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Relapse from CR 
Required at least one of the following: 
Reappearance of serum or urinary paraprotein on immunofixation or 
routine electrophoresis confirmed by at least one follow-up and 
excluding oligoclonal immune reconstitution. 
5% plasma cells in the bone marrow aspirate or biopsy. 
Development of new lytic bone lesions or soft tissue plasmacytomas or 
definite increase in the size of residual bone lesions (not including 
compression fracture). 
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL 
or 2.8 mmol/L not attributable to any other cause).e 
a Based on the criteria reported by Blade et al., 1998. 
b Per Blade et al., 1998, if absence of the monoclonal protein is sustained for 6 weeks it is not necessary to 
repeat the bone marrow except in participants with nonsecretory myeloma where the marrow examination 
must be repeated after an interval of at least 6 weeks to confirm CR. 
c Per Blade et al., 1998, skeletal X-Rays are not required for the definition of response, but if performed there 
must be no evidence of progression of bone disease (no increase in size or number of lytic bone lesions). 
d It is suggested that the reference point for calculating any increase should be the lowest value of the 
preceding confirmed response (MR, PR or CR) or the baseline value if there is no previous confirmed 
response. 
e Other clinical data may be requested by the IRC, as necessary, to assess the cause of the hypercalcemia. 
 
 
11.2.7 Duration of Response and Endpoint Definitions 
 
Duration of overall response: The duration of overall response is measured as the time from 
initiation of first response to first documentation of disease progression or death. Patients 
who have not progressed or died are censored at the date last known progression-free. 
 
Duration of overall complete response: The duration of overall CR is progression 
or death. Patients who have not progressed or died are censored at the date last 
known progression-free. 
Time to progression: Time to progression is defined as the time of randomization until 
progression. Patients who have died without evidence of progression are censored in the TTP 
analysis at the time of death and patients who are alive without progression are censored at the 
last disease assessment. 
Overall survival (OS): OS is defined as the time from randomization to death. Alive patients 
are censored at the date last known alive. 
11.2.8 Progression-Free Survival 
Progression-Free Survival (PFS): the primary endpoint in this study. PFS is defined as the time 
from randomization to the disease progression or death from any cause. Patients who have not 


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progressed or died are censored at the date last known progression-free. 
11.2.9 Response Review 
Central review of disease response assessments is not planned. 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 Data Reporting 
 
12.1.1 Method 
 
The QACT will collect, manage, and perform quality checks on the data for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms to the QACT according to the schedule set by the QACT. Data should be entered within 
14 business days of the corresponding visit and within 14 business days of the end of a cycle for 
any forms to be completed per cycle. 
 
12.2 Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 Study Design/Endpoints 
 
The primary endpoint of this phase II study is to determine the proportion of high risk 


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smoldering multiple myeloma (SMM) patients who are progressive free at 2 years after receiving 
treatment (Elotuzumab + lenalidomide+ Dexamethasone). The secondary objectives include 
toxicities, objective response rate, time to progression, duration of response, and overall survival. 
In addition, we will examine the molecular evolution of the tumor cells, the role of circulating 
tumor cells and immune cells, and the role of NK cells and other immune cells present in the 
bone marrow in the progression of smoldering MM. 
 
The proportion of patients who achieve progression free at 2 years will be compared to the rate 
published for the high risk SMM. By the Mayo Clinic model for risk factors, the median time to 
progression for patients with high risk SMM was only 1.9 years. Therefore, we assume that for 
this study, a 2-years progression-free rate of 50% will not be considered promising and a true 
progression free rate of 70% or higher will be considered promising. A single-stage design will 
be employed with 39 eligible patients entered. If 24 or more of the 39 eligible patients are 
progression free at 2 years (observed rate of 62%), we will conclude that this treatment warrants 
further study. The probability of concluding that the treatment is effective if the true rate is 50% 
is 0.10 and is >0.9 if the true rate is 70%. Assuming an ineligibility rate of 5%, we will accrue 41 
patients/per Arm to the trial in order to have 39 eligible patients. A total of 55 patients will be 
enrolled. 
 
 
13.1.1 Analysis of Primary Endpoint 
 
Time to progression (TTP) is defined as the time from protocol therapy initiation until 
documented progression, censored at date last known progression-free for those who have not 
progressed. At time of final analysis, the 2-year progression-free rate will be estimated using the 
Kaplan-Meier method with 90% confidence interval per Arm. All patients who have received 
one dose of study treatment will be included for the TTP analysis, including those who die or are 
lost to follow-up within 2 years. 
 
The percent of patients who undergo stem cell mobilization and the modality of mobilization will 
be noted in the study. These patients will not be censored. 
 
13.1.2 Analysis of Secondary Endpoints 
 
The objective response rate (partial response or better according to the modified IMWG criteria) 
and the proportion of patients with a MRD, CR, PR or MR will be reported by Arm with 90% 
exact binominal confidence interval (CI). The exact 90% CI around response rate will be no 
wider than 28% with 39 eligible patients. 
 
To estimate the duration of response (time from objective response to disease progression or 
death, or date last known progression-free and alive for those who have not progressed or died), 
progression-free survival (time from protocol therapy initiation to the disease progression or 
death from any cause, censored at date last known progression free for those who have not 
progressed or died), and overall survival (time from protocol therapy initiation to death or date 
last known alive), the Kaplan-Meier method will be used. The results will be reported separately 
for each Arm. 


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Safety analysis will be conducted using the Safety Population defined as any patient receiving 
one dose of study treatment. For toxicity reporting, all adverse events and laboratory 
abnormalities will be graded and analyzed using CTCAE version 4 as appropriate. 
 
13.2 Sample Size, Accrual Rate and Study Duration 
 
A total of 55 patients will be enrolled. We expect 3.5 years of active accrual (approximately 2 
patients per month) and 3 years of follow-up of patients. 
 
The final analyses of progression-based endpoints, such as estimating the 2-year progression-free 
rate and estimating the TTP distribution, will be conducted at the end of the study, which will 
occur after either all subjects have progressed or died or 2-years after the initiation of therapy of 
the last subject enrolled, whichever occurs first. 
 
13.3 Stratification Factors 
 
The patients will be stratified based on age and cytogenetics. 
• 
Age 65 years or older 
• 
High risk cytogenetics based on t(4:14), t(14:16), 17p deletion or p53 mutation, 
+1q amplification (3 groups: high risk, low risk or Fish failure) 
 
13.4 Interim Monitoring Plan 
 
The study will be monitored by the DFCI Data Safety Monitoring Committee (DSMC). The 
DSMC will meet at least four times a year and more often if needed (e.g., for safety review). For 
each meeting, the study will be reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of the outcome data. Copies of the 
toxicity reports prepared by the DSMC meetings will be distributed to the Principal Investigator. 
The Principal Investigator will then distribute to sub-investigators. Any DSMC 
recommendations for changes to the study will be distributed to the Principal Investigator and 
then circulated to sub- investigators by the Principal Investigator. 
 
13.5 Stopping Rule for Safety 
 
All participants will be evaluable for treatment-related toxicity from the time of therapy 
initiation. The severe adverse event (SAE) is defined as any grade 3 adverse events that affect 
organ function (cardiac, hepatic, thromboembolic) or grade 4/5 non hematologic AEs. We 
anticipate that the rate of SAE is low in this study population. However, if 2 or more SAEs are 
observed at any time in the first 20 treated patients in any study cohort, further patient enrollment 
will be paused for that cohort. 
 
The following table provides the probabilities of observing 2 or more SAEs with 20 treated 
participants in each cohort. For example, with 20 participants, there is 0.82 probability of 
observing 2 or more SAEs if a true rate is 15% and the probability is 0.12 if a true rate is 3%. 


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73 
 
 
 
True SAE Rate 
1% 
3% 
5% 
10% 
15% 
20% 
30% 
Probability (≥2 SAEs) 
0.017 
0.120 
0.264 
0.608 
0.824 
0.931 
0.992 
 
 
 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study. Data sets from other relevant studies such as 17-212, 16-313, 
or data sets from other collaborators may be used and/or analyzed for the purposes of the 
publication. 


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74 
 
 
15. REFERENCES 
 
1. 
Ghobrial IM, Landgren O. How I treat smoldering multiple myeloma. 
Blood. 2014 Nov 27;124(23):3380-8. doi: 10.1182/blood-2014-08-551549. Epub 2014 
Oct 8. 
2. 
Rajkumar SV, Dimopoulos MA, Palumbo A, et.al. International 
Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. 
Lancet Oncol. 2014 Nov;15(12):e538-48. doi: 10.1016/S1470-2045(14)70442-5. Epub 
2014 Oct 26. Review. PubMed PMID: 25439696. 
3. 
Rajkumar SV, Landgren O, Mateos MV. Smoldering Multiple Myeloma. Blood. 2015 
Apr 2. pii: blood-2014-09-568899 
4. 
Mateos, M.V., et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple 
myeloma. The New England journal of medicine 369, 438-447 (2013). 
5. 
Lonial, S., Kaufman, J., Laubach, J. & Richardson, P. Elotuzumab: a novel anti-CS1 
monoclonal antibody for the treatment of multiple myeloma. Expert Opin Biol Ther 13, 
1731-1740 (2013). 
6. 
Collins, S.M., et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma 
via CS1 ligation: evidence for augmented NK cell function complementing ADCC. 
Cancer immunology, immunotherapy : CII 62, 1841-1849 (2013). 
7. 
Kuroda, J., Nagoshi, H., Shimura, Y. & Taniwaki, M. Elotuzumab and daratumumab: 
emerging new monoclonal antibodies for multiple myeloma. Expert Rev Anticancer Ther 
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Lonial, S., et al. Elotuzumab in combination with lenalidomide and low-dose 
dexamethasone in relapsed or refractory multiple myeloma. Journal of clinical oncology : 
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9. 
Kronke, J., et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in 
multiple myeloma cells. Science 343, 301-305 (2014). 
10. 
Lu, G., et al. The myeloma drug lenalidomide promotes the cereblon-dependent 
destruction of Ikaros proteins. Science 343, 305-309 (2014). 
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Anderson, K.C. & Carrasco, R.D. Pathogenesis of myeloma. Annu Rev Pathol 6, 249-274 
(2011). 
12. 
Kyle, R.A., et al. Monoclonal gammopathy of undetermined significance (MGUS) and 
smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk 
factors for progression and guidelines for monitoring and management. Leukemia 24, 
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13. 
Kyle, R.A., et al. Prevalence of monoclonal gammopathy of undetermined significance. 
N Engl J Med 354, 1362-1369 (2006). 
14. 
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gammopathy of undetermined significance: a retrospective population-based cohort 
study. Lancet 375, 1721-1728 (2010). 
15. 
Kyle, R.A., et al. Clinical course and prognosis of smoldering (asymptomatic) multiple 
myeloma. The New England journal of medicine 356, 2582-2590 (2007). 
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Engl J Med 365, 474-475 (2011). 
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Landgren, O., et al. Monoclonal gammopathy of undetermined significance (MGUS) 
consistently precedes multiple myeloma: a prospective study. Blood 113, 5412-5417 
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19. 
Weiss, B.M., Abadie, J., Verma, P., Howard, R.S. & Kuehl, W.M. A monoclonal 
gammopathy precedes multiple myeloma in most patients. Blood 113, 5418-5422 (2009). 
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Lopez-Corral, L., et al. SNP-based mapping arrays reveal high genomic complexity in 
monoclonal gammopathies, from MGUS to myeloma status. Leukemia (2012). 
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Visone, R. & Croce, C.M. MiRNAs and cancer. Am J Pathol 174, 1131-1138 (2009). 
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Pichiorri, F., et al. MicroRNAs regulate critical genes associated with multiple myeloma 
pathogenesis. Proc Natl Acad Sci U S A 105, 12885-12890 (2008). 
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regulated microRNAs modulate E2F1 expression. Nature 435, 839-843 (2005). 
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Chesi, M., et al. AID-dependent activation of a MYC transgene induces multiple 
myeloma in a conditional mouse model of post-germinal center malignancies. Cancer 
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Chiecchio, L., et al. Loss of 1p and rearrangement of MYC are associated with 
progression of smouldering myeloma to myeloma: sequential analysis of a single case. 
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26. 
Chapman, M.A., et al. Initial genome sequencing and analysis of multiple myeloma. 
Nature 471, 467-472 (2011). 
27. 
Egan, J.B., et al. Whole-genome sequencing of multiple myeloma from diagnosis to 
plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood 
120, 1060-1066 (2012). 
28. 
Keats, J.J., et al. Clonal competition with alternating dominance in multiple myeloma. 
Blood 120, 1067-1076 (2012). 
29. 
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characterize the development of t(4;14) and t(11;14) myeloma. Blood 120, 1077-1086 
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928 (2012). 
31. 
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32. 
Rasillo, A., et al. Fluorescence in situ hybridization analysis of aneuploidization patterns 
in monoclonal gammopathy of undetermined significance versus multiple myeloma and 
plasma cell leukemia. Cancer 97, 601-609 (2003). 
33. 
Bergsagel, P.L. & Kuehl, W.M. Molecular pathogenesis and a consequent classification 
of multiple myeloma. Journal of clinical oncology : official journal of the American 
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activates the PI3K and phospholipase Cgamma signaling pathways in human NK cells. J 
Immunol 175, 7996-8002 (2005). 
35. 
Boles, K.S. & Mathew, P.A. Molecular cloning of CS1, a novel human natural killer cell 
receptor belonging to the CD2 subset of the immunoglobulin superfamily. 
Immunogenetics 52, 302-307 (2001). 
36. 
Tai, Y.T., et al. CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and 
tumorigenicity via c-maf-mediated interactions with bone marrow stromal cells. Blood 


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113, 4309-4318 (2009). 
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Hsi, E.D., et al. CS1, a potential new therapeutic antibody target for the treatment of 
multiple myeloma. Clinical cancer research : an official journal of the American 
Association for Cancer Research 14, 2775-2784 (2008). 
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Tai, Y.T., et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma 
cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow 
milieu. Blood 112, 1329-1337 (2008). 
39. 
Ebert, B.L., et al. An erythroid differentiation signature predicts response to lenalidomide 
in myelodysplastic syndrome. PLoS Med 5, e35 (2008). 
40. 
Anderson, K., et al. Genetic variegation of clonal architecture and propagating cells in 
leukaemia. Nature 469, 356-361 (2011). 
41. 
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Genet 22, 106-109 (1999). 
42. 
Morgan, G.J., Walker, B.A. & Davies, F.E. The genetic architecture of multiple 
myeloma. Nat Rev Cancer 12, 335-348 (2012). 
43. 
Walker, B.A., et al. Intraclonal heterogeneity is a critical early event in the development 
of myeloma and precedes the development of clinical symptoms. Leukemia (2013). 
44. 
Chng, W.J., et al. Clinical and biological implications of MYC activation: a common 
difference between MGUS and newly diagnosed multiple myeloma. Leukemia 25, 1026- 
1035 (2011). 
45. 
Lopez-Corral, L., et al. SNP-based mapping arrays reveal high genomic complexity in 
monoclonal gammopathies, from MGUS to myeloma status. Leukemia 26, 2521-2529 
(2012). 
46. 
Quail, D.F. & Joyce, J.A. Microenvironmental regulation of tumor progression and 
metastasis. Nature medicine 19, 1423-1437 (2013). 
47. 
Swann, J.B. & Smyth, M.J. Immune surveillance of tumors. J Clin Invest 117, 1137-1146 
(2007). 
48. 
Dhodapkar, M.V. Immune response to premalignancy: insights from patients with 
monoclonal gammopathy. Ann N Y Acad Sci 1062, 22-28 (2005). 
49. 
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50. 
Feyler, S., et al. CD4(+)CD25(+)FoxP3(+) regulatory T cells are increased whilst 
CD3(+)CD4(-)CD8(-)alphabetaTCR(+) Double Negative T cells are decreased in the 
peripheral blood of patients with multiple myeloma which correlates with disease burden. 
British journal of haematology 144, 686-695 (2009). 
51. 
Cruz-Munoz, M.E., Dong, Z., Shi, X., Zhang, S. & Veillette, A. Influence of CRACC, a 
SLAM family receptor coupled to the adaptor EAT-2, on natural killer cell function. Nat 
Immunol 10, 297-305 (2009). 
52. 
Larsen, J.T., et al. Serum free light chain ratio as a biomarker for high-risk smoldering 
multiple myeloma. Leukemia 27, 941-946 (2013). 
53. 
Hillengass, J., et al. Prognostic significance of focal lesions in whole-body magnetic 
resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 28, 
1606-1610 (2010). 
54. 
Hillengass, J. & Landgren, O. Challenges and opportunities of novel imaging techniques 
in monoclonal plasma cell disorders: imaging "early myeloma". Leuk Lymphoma (2013). 
55. 
Martinez-Lopez, J., et al. Prognostic value of deep sequencing method for minimal 
residual disease detection in multiple myeloma. Blood 123, 3073-3079 (2014). 


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56. 
Rajkumar, S.V., et al. Consensus recommendations for the uniform reporting of clinical 
trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 117, 
4691-4695 (2011). 
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Durie, B.G., et al. International uniform response criteria for multiple myeloma. 
Leukemia 20, 1467-1473 (2006). 
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Cavo, M., et al. International Myeloma Working Group consensus approach to the 
treatment of multiple myeloma patients who are candidates for autologous stem cell 
transplantation. Blood 117, 6063-6073 (2011). 
59. 
Ludwig, H., et al. International Myeloma Working Group recommendations for global 
myeloma care. Leukemia 28, 981-992 (2014). 
60. 
Paiva, B., et al. High-risk cytogenetics and persistent minimal residual disease by 
multiparameter flow cytometry predict unsustained complete response after autologous 
stem cell transplantation in multiple myeloma. Blood 119, 687-691 (2012). 
61. 
Rajkumar, S.V., et, al. Clinical course of light chain smouldering multiple myeloma 
(idiopathic Bence Jones proteinuria): a retrospective cohort study. Lancet 1, 28-36 
(2014). 


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


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APPENDIX B: PREPARATION AND ADMINISTRATION OF ELOTUZUMAB 
 
Dose Preparation Instructions 
 
After dilution in normal saline, elotuzumab must be administered within 8 hours if kept at room 
temperature (25°C). If a delay is anticipated after the dose has been diluted in normal saline, the 
prepared dose (properly identified) may be refrigerated at 2°C to 8°C for up to 24 hours. If stored 
under refrigerated conditions, the study drug solution should be equilibrated to room temperature 
(takes about 2 to 2.5 hours), and the container must be gently inverted to thoroughly mix the 
contents before administration. If the storage time limit is exceeded, the prepared dose solution 
must be discarded and the reason documented by the pharmacist in the study drug accountability 
records. 
 
Elotuzumab will be administered to each subject as an IV infusion, using an automated infusion 
pump set at the appropriate rate according to the dose administration section (see Administration 
Instruction section below) discussed below. The dose of elotuzumab will be calculated using the 
subject’s predose weight on Day 1 of each cycle or predose weight at each visit, whichever 
institutional policy is, and then added to 0.9% saline for infusion. Do not round up or down. 
 
Reconstitute elotuzumab lyophilized study drug, as described in Steps 1 to 5. Each 400 mg vial 
contains 10% overfill for a total of 440 mg of study drug but is intended to deliver 400 mg of 
elotuzumab. Standard aseptic technique should be utilized. 
 
Step 1: Remove the flip-top from elotuzumab and Sterile Water for Injection (SWFI) vials. 
 
Step 2: Withdraw 17 mL of SWFI using an 18-gauge or smaller needle. Place the elotuzumab 
vial upright on a flat surface and insert the syringe needle into the vial through the center of the 
rubber stopper. Slowly inject the SWFI along the side of the vial to help prevent bubbling or 
foaming. Slowly remove the syringe needle out of the vial. 
 
Step 3: DO NOT SHAKE. Avoid prolonged or vigorous agitation. Hold the vial upright and 
gently swirl the solution by rotating the vial to dissolve the lyophilized cake. Then gently invert 
the vial a few times in order to dissolve any powder that may be present on top of the vial or the 
stopper. Finally, hold the vial upright again and gently swirl the solution a few more times to 
dissolve any remaining particles. 
 
Step 4: After the remaining solids are completely dissolved, allow the reconstituted solution to 
stand for 5 to 10 minutes. The final volume of the reconstituted solution is approximately 17.6 
mL, for an approximate concentration of 25 mg/mL. 
 
It is acceptable to have small bubbles and/or foam around the edge of the vial. The reconstituted 
preparation results in a colorless to slightly yellow, clear to slightly opalescent solution. 
 
Step 5: Once the reconstitution is completed and prior to IV administration, the reconstituted 
solution is further diluted with 230-340 ml of 0.9% sodium chloride injection (NS), USP, 
resulting in elotuzumab concentrations between 2 mg/mL and 6.6 mg/mL. The infusion is to be 
administered through a sterile, non-pyrogenic, low protein binding in-line filter. Additionally, 


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care must be taken to ensure the sterility of the prepared solution, as the drug product does not 
contain anti-microbial preservatives or bacteriostatic agents. A sufficient excess of drug product 
is included in each vial to account for withdrawal losses. 
 
The first dose of elotuzumab will be administered following pre-medications to each subject as 
an IV infusion, using an automated infusion pump set at an initial rate of 0.5 mL per minute (30 
mL/hour). If the subject does not have an infusion reaction within 30 minutes, escalate the 
infusion rate by 0.5 mL per minute. If the subject still does not have an infusion reaction within 
30 minutes, escalate the infusion rate to a maximum of 2 mL per minute (120 mL/hour). If a 
subject experiences a Grade 2 infusion reaction, the infusion must be interrupted. 
 
The second dose of elotuzumab should be initiated at an infusion rate of 3 mL per minute if no 
infusion reactions were reported with the first elotuzumab infusion. If the subject does not 
experience an infusion reaction during the first 30 minutes of the second dose of elotuzumab, 
escalate the infusion rate by 1.0 mL per minute to a maximum infusion rate of 4 mL per minute. 
 
If no infusion reactions were observed during the first two doses cycle of elotuzumab, the third 
dose can commence at a rate of 5 mL per minute. 
 
If a patient experiences an infusion reaction of less than or equal to Grade 2, and the infusion 
reaction does not recur, the patient can resume elotuzumab administration at the rate at which the 
reaction occurred at the start of the next cycle at the investigator’s discretion. 
 
If a subject experiences a Grade 2 infusion reaction, the infusion must be interrupted. Please 
refer to Section 6.4.2 for detailed information on the management of infusion reaction and re- 
initiation of infusion. If a subject experiences a Grade 3 elotuzumab infusion reaction that has 
resolved to Grade 1, subsequent infusion rate of elotuzumab should be escalated in a stepwise 
fashion (0.5 mL every 30 minutes). 
 
1) Administer through a low-protein-binding 0.22-micrometer in-line filter (placed as 
proximal to the subject as is practical). Prime the infusion line with study drug before 
starting the infusion. 
 
2) Set the IV pump to deliver the infusion at the rate of 0.5mL per minute (including the 
drug in the line). The total time of infusion will vary depending upon the maximum 
tolerated mL/min infusion rate as discussed above. 
 
3) Record every time the infusion is started and stopped and the reason why the start and 
stop occurred. 
 
4) Monitor the IV setup and the subject’s IV site frequently during infusion, checking for 
the correct infusion rate and IV site infiltration. 
 
5) Ensure that the full volume of elotuzumab is infused. 
 
After elotuzumab has been infused from the line, discontinue the infusion, disconnect the IV 
tubing, and dispose of materials appropriately according to the facility’s standard procedure. 


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81 
 
 
Note: Subjects must be premedicated as described previously prior to elotuzumab infusion. 
 
 
The elotuzumab infusion rate will be increased gradually to a maximum of 5 mL/min as 
presented in the table below. The schedule below will be permitted only if no infusion reactions 
are encountered. For guidance related to elotuzumab infusion reactions, refer to section 6.4. 
 
 
Cycle/Day 
Infusion Rate 
Duration of 
Infusion 
Approximate 
Total Infusion 
Time 
Cycle 1 Day 1 
(10mg/kg) 
0.5 mL/min 
30 minutes 
2 hours and 50 
minutes 
1 mL/min 
30 minutes 
2mL/min 
110 minutes 
Cycle 1 Day 8 
(10mg/kg) 
3 mL/min 
30 minutes 
1 hour and 13 
minutes 
4 mL/min 
43 minutes 
Cycle 1 Day 15 and 22 
And 
Cycle 2-8 
(10mg/kg) 
5mL/min 
53 minutes 
53 minutes 
Cycle 9-24 
(20mg/kg) 
5mL/min 
81 minutes 
81 minutes 


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APPENDIX C: 14-338 SPECIMEN COLLECTION SCHEDULE 
 
Sample Time Point 
Recipient 
Sample Type 
Shipping Method 
Container1,2 
Baseline 
DFCI 
Peripheral Blood 
Fridge pack same day 
3x 10mL Purple Top 
1x6ml Red Top 
Bone Marrow Aspirate 
2x10mL Purple Top 
Buccal Swab2 
Ambient same day 
1x Buccal Swab Kit 
Sequenta 
Bone Marrow Aspirate 
Same day – Use kit 
provided 
1x3ml Purple 
Cycle1 Day 1 
(Pre Dose) 
DFCI 
Peripheral Blood 
Fridge pack same day 
2x10mL Purple Top 
1x6ml Red Top 
Cycle 2-8 Day 1 
(Predose) 
DFCI 
Peripheral Blood 
Fridge pack same day 
2x10mL Purple Top3 
1x6ml Red Top 
End of Cycle 8 
(Cycle 9 Day 1) 
DFCI 
Peripheral Blood 
Fridge pack same day 
2x 10mL Purple Top3 
1x6ml Red Top 
Bone Marrow Aspirate 
2x10mL Purple Top3 
Cycle 10-24 Day 1 
(Predose) 
DFCI 
Peripheral Blood 
Fridge pack same day 
2x10mL Purple Top 
1x6ml Red Top 
Confirm Complete 
Response 4 
DFCI 
Peripheral Blood 
Fridge pack same day 
2x 10mL Purple Top 
1x6ml Red Top 
Bone Marrow Aspirate 
2x10mL Purple Top 
Sequenta 
Bone Marrow Aspirate 
Same day – Use kit 
provided 
1x3ml Purple Top 
End of Treatment 
and/or Disease 
Progression 
DFCI 
Peripheral Blood 
Fridge pack same day 
2x 10mL Purple Top 
1x6ml Red Top 
Bone Marrow Aspirate 
2x10mL Purple Top 
Clinically Indicated/ 
and/or Yearly Bone 
Marrow 
Biopsy/Aspirate 
DFCI 
Bone Marrow Aspirate 
Fridge pack same day 
2x10mL Purple Top3 
Peripheral Blood 
1 Purple Top= K2EDTA Tube; Red Top= No Additive; Sequenta Tubes= Provided by Sequenta/Lead Site 
2 Buccal Swabs will be provided by the lead site, and can be sent at any time point during the trial 
3 Samples at these time points are voluntary, and do not exclude patients from treatment 
4 For definition of Complete Response, please refer to section 11.2.3. 


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Protocol #: 14-338 
Version Date: 4.9.2021 
 
APPENDIX D: 14-338 SPECIMEN REQUISITION 
Complete this form and include with the specimen shipment. Label all materials with DFCI participant study ID, collection time point and collection 
date and time. Email GhobrialLab@dfci.harvard.edu to alert study team of shipment and include tracking number. 
 
Ship specimen(s) to:  
Dana Farber Cancer Institute 
Ghobrial Lab 
360 Longwood Avenue LC8116 
Boston, MA 02215 
 
Specimen Information 
DFCI Participant Study ID Number:  
 
 
Date specimen(s) shipped:  
 
 
Correlative Sample Time Points 
(indicate inclusion in shipment by checking box) 
Sample Type 
Quantity of Tubes 
(6ml or 10ml) 
Collection Date 
Collection Time 
Pre-treatment/Baseline 
Blood 
Swabs 
Aspirate 
 
Red Top 
Purple Top 
Cycle 1-24 Day 1 
Specify Cycle 
 
Blood 
 
Red Top 
Purple Top 
Confirm Response 
Blood 
Aspirate 
 
Red Top 
Purple Top 
Cycle 9 Day 1 (end of Cycle 8) 
Blood 
Aspirate 
 
Red Top 
Purple Top 
End of Treatment 
Disease Progression 
Blood 
Aspirate 
 
Red Top 
Purple Top 
Clinical Necessity/ Standard of Care 
Aspirate 
 
Purple Top 
 
Responsible Contact:  
 
Site:  
 
Email:  
  
Phone number:  
 
Note: All samples are to be shipped with a fridge pack Fed-Ex priority overnight- Please retain a copy of the waybill, and reference the tracking 
number in the email and paper correspondence. Ship only Monday- Thursday, as shipments cannot be received over the weekend 
 
 
 
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84 


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DFCI IRB Protocol #: 14-338 
 
 
 
 
APPENDIX E: DF/HCC MULTI-CENTER DATA AND SAFETY MONITORING PLAN 


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TABLE OF CONTENTS 
SCHEMA ......................................................................................................................................... 2 
SYNOPSIS ....................................................................................................................................... 6 
1. 
OBJECTIVES ...................................................................................................................... 9 
1.1 
Study Design ............................................................................................................ 9 
1.2 
Primary Objectives ................................................................................................. 10 
1.3 
Secondary Objectives ............................................................................................. 10 
2. 
BACKGROUND ................................................................................................................ 10 
2.1 
Multiple Myeloma .................................................................................................. 10 
2.2 
MGUS and SMM consistently precedes multiple myeloma .................................. 11 
2.3 
Molecular studies in MGUS and SMM .................................................................. 11 
2.4 
Definition of SMM ................................................................................................. 13 
2.5 
Definitions of high-risk SMM ................................................................................ 14 
2.6 
Treatment of high risk SMM .................................................................................. 14 
2.7 
Elotuzumab ............................................................................................................. 15 
2.8 
Rationale for Elotuzumab in SMM ........................................................................ 15 
2.9 
Rationale for dose and schedule of Elotuzumab .................................................... 16 
2.10 
Trial Rationale ........................................................................................................ 21 
2.11 
Correlative Studies Background ............................................................................. 22 
3. 
PARTICIPANT SELECTION ........................................................................................... 23 
3.1 
Eligibility Criteria .................................................................................................. 23 
3.2 
Exclusion Criteria ................................................................................................... 25 
3.3 
Inclusion of Women and Minorities ....................................................................... 26 
4. 
REGISTRATION PROCEDURES .................................................................................... 26 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions .................................... 26 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions .................................. 26 
4.3 
General Guidelines for Other Investigative Sites ................................................... 27 
4.4 
Registration Process for Other Investigative Sites ................................................. 27 
5. 
TREATMENT PLAN ........................................................................................................ 27 
5.1 
Treatment Regimen ................................................................................................ 27 
5.2 
Pre-Treatment Criteria ............................................................................................ 30 
5.3 
Agent Administration ............................................................................................. 31 
5.4 
General Concomitant Medication and Supportive Care Guidelines ...................... 33 
5.5 
Criteria for Taking a Participant Off Protocol Therapy ......................................... 34 
5.6 
Duration of Follow Up ........................................................................................... 35 
5.7 
Criteria for Taking a Participant Off Study ............................................................ 36 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ................................................................ 36 
6.1 
Elotuzumab ............................................................................................................. 36 


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6.2 
Lenalidomide .......................................................................................................... 36 
6.3 
Dexamethasone ...................................................................................................... 40 
6.4 
Guidelines for Elotuzumab Infusion in Subjects with Infusion Reactions ............. 42 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ............................. 44 
7.1 
Expected Toxicities ................................................................................................ 44 
7.2 
Adverse Event Characteristics ................................................................................ 46 
7.3 
Expedited Adverse Event Reporting ...................................................................... 46 
7.4 
DF/HCC Expedited Reporting Guidelines ............................................................. 46 
Overdose of Lenalidomide ................................................................................................. 49 
7.5 
Expedited Reporting to the Food and Drug Administration (FDA) ....................... 49 
7.6 
Expedited Reporting to Bristol-Myers Squibb (BMS) ........................................... 49 
7.7 
Expedited Reporting to Celgene ............................................................................ 49 
7.8 
Expedited Reporting to Hospital Risk Management .............................................. 50 
7.9 
Routine Adverse Event Reporting .......................................................................... 50 
8. 
PHARMACEUTICAL INFORMATION .......................................................................... 50 
8.1 
Elotuzumab ............................................................................................................. 50 
8.2 
Lenalidomide .......................................................................................................... 52 
8.3 
Dexamethasone ...................................................................................................... 54 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ......................................... 56 
9.1 
Bone Marrow Aspirate Samples ............................................................................. 57 
9.2 
Peripheral Blood Samples ...................................................................................... 58 
10. 
STUDY CALENDAR ........................................................................................................ 61 
11. 
MEASUREMENT OF EFFECT ......................................................................................... 62 
11.1 
Development of symptomatic disease .................................................................... 62 
11.2 
Antitumor Effect .................................................................................................... 63 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ........................................... 70 
12.1 
Data Reporting ....................................................................................................... 70 
12.2 
Data Safety Monitoring ........................................................................................... 70 
13. 
STATISTICAL CONSIDERATIONS. .............................................................................. 70 
13.1 
Study Design/Endpoints ......................................................................................... 70 
13.2 
Sample Size, Accrual Rate and Study Duration ..................................................... 72 
13.3 
Stratification Factors .............................................................................................. 72 
13.4 
Interim Monitoring Plan ......................................................................................... 72 
13.5 
Stopping Rule for Safety ........................................................................................ 72 
14. 
PUBLICATION PLAN ...................................................................................................... 73 
15. 
REFERENCES ................................................................................................................... 74 
APPENDIX A: PERFORMANCE STATUS CRITERIA ............................................................. 78 


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APPENDIX B: PREPARATION AND ADMINISTRATION OF ELOTUZUMAB ................... 79 
APPENDIX C: 14-338 SPECIMEN COLLECTION SCHEDULE .............................................. 82 
APPENDIX D: 14-338 SPECIMEN REQUISITION .................................................................... 84 
APPENDIX E: DF/HCC MULTI-CENTER DATA AND SAFETY MONITORING PLAN ...... 85 
1. 
INTRODUCTION .............................................................................................................. 89 
1.1 
Purpose ................................................................................................................... 89 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions ................................... 89 
2. 
GENERAL ROLES AND RESPONSIBILITIES ................................................................ 90 
2.1 
DF/HCC Sponsor ................................................................................................... 90 
2.2 
Coordinating Center ............................................................................................... 91 
2.3 
Participating Institution .......................................................................................... 91 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS .............................. 92 
3.1 
Protocol Distribution .............................................................................................. 92 
3.2 
Protocol Revisions and Closures ............................................................................ 92 
3.3 
Informed Consent Requirements ............................................................................ 93 
3.4 
IRB Documentation ................................................................................................ 93 
3.5 
IRB Re-Approval ................................................................................................... 93 
3.6 
Participant Confidentiality and Authorization Statement ....................................... 94 
3.7 
DF/HCC Multi-Center Protocol Registration Policy.............................................. 94 
3.8 
DF/HCC Protocol Case Number ............................................................................ 95 
3.9 
Safety Assessments and Toxicity Monitoring ........................................................ 96 
3.10 
Data Management................................................................................................... 97 
4. 
REQUISITIONING INVESTIGATIONAL DRUG .......................................................... 97 
5. 
MONITORING: QUALITY CONTROL .......................................................................... 98 
5.1 
Ongoing Monitoring of Protocol Compliance ........................................................ 98 
5.2 
Monitoring Reports ................................................................................................ 99 
5.3 
Accrual Monitoring ................................................................................................ 99 
6. 
AUDITING: QUALITY ASSURANCE ............................................................................ 99 
6.1 
Audit Plan: DF/HCC Sponsored Trials .................................................................. 99 
6.2 
Audit Notification ................................................................................................... 99 
6.3 
Audit Reports ........................................................................................................ 100 
6.4 
Participating Institution Performance ................................................................... 100 


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


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Sponsor in order that he/she may fulfill the responsibilities outlined in the protocol 
document and DSMP, and as specified in applicable regulatory guidelines (i.e. CTEP 
Multi-Center Guidelines). In general, the Lead Institution is the Coordinating Center for 
the DF/HCC Multi-Center Protocol. Should the DF/HCC Sponsor decide to use a CRO, 
the CRO will be deemed the Coordinating Center. 
 
DF/HCC Quality Assurance Office for Clinical Trials: A group within DF/HCC 
responsible for registering human subjects for trials, ensuring high-quality standards are 
used for data collection and the ongoing management of clinical trials, auditing, and data 
and safety monitoring. QACT also coordinates quality assurance efforts related to multi- 
center clinical research. 
 
2. GENERAL ROLES AND RESPONSIBILITIES 
 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and 
the Participating Institutions are expected to adhere to the following general 
responsibilities: 
 
2.1 DF/HCC Sponsor 
 
The DF/HCC Sponsor, Irene Ghobrial, MD will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to: 
• Oversee the coordination, development, submission, and approval of the protocol 
as well as subsequent amendments. 
• Ensure that the investigators, study team members, and Participating Institutions 
are qualified and appropriately resourced to conduct the protocol. 
• Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol. 
• Ensure all Participating Institutions are using the correct version of the protocol. 
• Ensure that each participating investigator and study team member receives 
adequate protocol training and/or a Site Initiation Visit prior to enrolling 
participants and throughout trial’s conduct as needed. 
• Ensure the protocol will be provided to each participating site in a language 
understandable to all applicable site personnel when English is not the primary 
language. 
• Monitor progress and overall conduct of the study at all Participating Institutions. 
• Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable 
reporting requirements are met. 
• Review data and maintain timely submission of data for study analysis. 
• Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol. 
• Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the DF/HCC Sponsor. 


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• Identify and qualify Participating Institutions and obtain accrual commitments 
prior to extending the protocol to that site. 
• Monitor accrual and address Participating Institutions that are not meeting their 
accrual requirements. 
 
2.2 Coordinating Center 
 
The general responsibilities of the Coordinating Center may include but are not limited to: 
• Assist in protocol development. 
• Review registration materials for eligibility and register participants from 
Participating Institutions with DF/HCC QACT. 
• Distribute protocol and informed consent document updates to Participating 
Institutions as needed. 
• Oversee the data collection process from Participating Institutions. 
• Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by Participating Institutions and provide to the 
DF/HCC Sponsor for timely review. 
• Distribute serious adverse events reported to the DF/HCC Sponsor that fall under 
the DFCI IRB Adverse Event Reporting Policy to all Participating Institutions. 
• Provide 
Participating 
Institutions 
with 
information 
regarding 
DF/HCC 
requirements that they will be expected to comply with. 
• Carry out plan to monitor Participating Institutions either by on-site or remote 
monitoring. 
• Maintain Regulatory documents of all Participating Institutions which includes but 
is not limited to the following: local IRB approvals/notifications from all 
Participating Institutions, confirmation of Federalwide Assurances (FWAs) for all 
sites, all SAE submissions, Screening Logs for all sites, IRB approved consents 
for all sites 
• Conduct regular communications with all Participating Institutions (conference 
calls, emails, etc) and maintain documentation all relevant communications. 
 
2.3 Participating Institution 
 
Each Participating Institution is expected to comply with all applicable federal regulations 
and DF/HCC requirements, the protocol and HIPAA requirements. 
 
The general responsibilities for each Participating Institution may include but are not 
limited to: 
• Document the delegation of research specific activities to study personnel. 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Maintain regulatory files as per sponsor requirements. 
• Provide the Coordinating Center with regulatory documents or source documents 
as requested. 


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• Participate in protocol training prior to enrolling participants and throughout the 
trial as required (i.e. teleconferences). 
• Update Coordinating Center with research staff changes on a timely basis. 
• Register participants through the Coordinating Center prior to beginning research 
related activities. 
• Submit Serious Adverse Event (SAE) reports to local IRB per local requirements 
and to the Coordinating Center, in accordance with DF/HCC requirements. 
• Submit protocol deviations and violations to local IRB per local requirements and 
to the DF/HCC Sponsor in accordance with DF/HCC requirements. 
• Order, store and dispense investigational agents and/or other protocol mandated 
drugs per federal guidelines and protocol requirements. 
• Have office space, office equipment, and internet access that meet HIPAA 
standards. 
• Participate in any quality assurance activities and meet with monitors or auditors at 
the conclusion of a visit to review findings. 
• Promptly provide follow-up and/or corrective action plans for any monitoring 
queries or audit findings. 
 
3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
 
The following section will clarify DF/HCC Requirements and further detail the expectations for 
participating in a DF/HCC Multi-Center protocol. 
 
3.1 Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions. 
 
3.2 Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures 
from the Coordinating Center. It is the individual Participating Institution’s responsibility 
to notify its IRB of these revisions. 
 
• Non life-threatening revisions: Participating Institutions will receive written 
notification of protocol revisions regarding non life-threatening events from the 
Coordinating Center. Non-life-threatening protocol revisions must be IRB 
approved and implemented within 90 days from receipt of the notification. 
 
• Revisions for life-threatening causes: Participating Institutions will receive 
immediate notification from the Coordinating Center concerning protocol revisions 
required to protect lives with follow-up by fax, mail, e-mail, etc. Life-threatening 
protocol revisions will be implemented immediately followed by IRB request for 
approval. 


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• Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating 
Center. Closures and holds will be effective immediately. In addition, the 
Coordinating Center, will update the Participating Institutions on an ongoing basis 
about protocol accrual data so that they will be aware of imminent protocol 
closures. 
 
3.3 Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for Participating Institutions. The Participating Institution consent form 
must follow the consent template as closely as possible and should adhere to specifications 
outlined in the DF/HCC Guidance Document on Model Consent Language for PI-Initiated 
Multi-Center Protocols. This document will be provided separately to each Participating 
Institution. 
 
Participating Institutions are to send their version of the informed consent document and 
HIPAA authorization, if a separate document, to the Coordinating Center for review and 
approval prior to submission to their local IRB. The approved consent form must also be 
submitted to the Coordinating Center after approval by the local IRB for all consent 
versions. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form 
for therapeutic protocols. Participating institutions must follow the DF/HCC requirement 
that only attending physicians obtain informed consent and re-consent to interventional 
trials (i.e. drug and/or device trials). 
3.4 IRB Documentation 
 
The following must be on file with the Coordinating Center: 
• Initial approval letter of the Participating Institution's IRB. 
• Copy of the Informed Consent Form(s) approved by the Participating Institution’s 
IRB. 
• Participating Institution’s IRB approval for all amendments. 
• Annual approval letters by the Participating Institution's IRB. 
 
3.5 IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities. There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received 
from the Participating Institution on or before the anniversary of the previous approval 
date. 


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3.6 Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information 
known as the Health Insurance Portability and Accountability Act (HIPPA). Any 
information, related to the physical or mental health of an individual is called Protected 
Health Information (PHI). HIPAA outlines how and under what circumstances PHI can be 
used or disclosed. 
 
In order for covered entities to use or disclose protected health information during the 
course of a study, the study participant must sign an authorization statement. This 
authorization statement may or may not be separate from the informed consent document. 
The Coordinating Center, with the approval from the DFCI IRB, will provide a consent 
template, with information regarding authorization for the disclosure of protected health 
information. 
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in 
its trials. However, because of the nature of these trials, certain protected health 
information must be collected. DF/HCC has chosen to use authorizations, signed by the 
participant in the trial, rather than limited data sets with data use agreements. 
3.6.1 DF/HCC Multi-Center Protocol Confidentiality 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center 
should be de-identified. It is recommended that the assigned DF/HCC QACT case number 
(as described below) be used for all participant specific documents. Participant initials 
may be included or retained for cross verification of identification. 
3.7 DF/HCC Multi-Center Protocol Registration Policy 
 
3.7.1 Participant Registration 
 
See Sections 4.3 and 4.4 of the protocol. 
 
3.7.2 Initiation of Therapy 
 
Participants must be registered with the DF/HCC QACT before receiving treatment. 
Treatment may not be initiated until the Participating Institution receives confirmation of 
the participant’s registration from the Coordinating Center. The DF/HCC Sponsor and 
DFCI IRB must be notified of any violations to this policy. 
 
3.7.3 Eligibility Exceptions 


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The DF/HCC QACT will make no exceptions to the eligibility requirements for a protocol 
without DFCI IRB approval. The DF/HCC QACT requires each institution to fully 
comply with this requirement. 
 
3.8 DF/HCC Protocol Case Number 
 
At the time of registration, QACT requires the following identifiers for all subjects: 
initials, date of birth, gender, race and ethnicity. Once eligibility has been established and 
the participant successfully registered, the participant is assigned a unique protocol case 
number. 
Participating 
Institutions 
should 
submit 
all 
de-identified 
subsequent 
communication and documents to the Coordinating Center, using this case number to 
identify the subject. 
 
3.8.1 Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 
participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn is responsible 
for reporting to the DFCI IRB. 
 
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” 
to describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional 
policy for reporting to their local IRB. 
 
3.8.2 Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB- 
approved protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception: Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
 
Protocol Violation: Any protocol deviation that was not prospectively approved by the 
IRB prior to its initiation or implementation. 
 
3.8.3 Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations 
and violations. The DF/HCC Sponsor will also be responsible for ensuring that all 
protocol violations/deviations are promptly reported per DFCI IRB guidelines. 


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Participating Institutions: Protocol deviations require prospective approval from the DFCI 
IRB. The Participating Institution must submit the deviation request to the Coordinating 
Center who will then submit the deviation request to the DFCI IRB. Upon DFCI IRB 
approval the deviation is submitted to the Participating Institution IRB, per institutional 
policy. A copy of the Participating Institution’s IRB report and determination will be 
forwarded to the Coordinating Center within 10 business days after the original 
submission. 
 
All protocol violations must be sent to the Coordinating Center in a timely manner. 
 
Coordinating Center: Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for 
review. Subsequently, the Participating Institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines. DF/HCC will 
forward all violation reports to CTEP via an internal DF/HCC process, as applicable. 
 
3.9 Safety Assessments and Toxicity Monitoring 
 
The study teams at all participating institutions are responsible for protecting the safety, 
rights and well-being of study participants. Recording and reporting of adverse events that 
occur during the course of a study help ensure the continuing safety of study participants. 
 
All participants receiving investigational agents and/or other protocol mandated treatment 
will be evaluated for safety. The safety parameters include all laboratory tests and 
hematological abnormalities, physical examination findings, and spontaneous reports of 
adverse events reported by participants. All toxicities encountered during the study will 
be evaluated according to the NCI criteria specified in the protocol. Life-threatening 
toxicities must be reported immediately to the DF/HCC Sponsor via the Coordinating 
Center. 
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
3.9.1 Guidelines for Reporting Serious Adverse Events 
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in Section 7 of the protocol. 
 
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB Adverse Event Reporting Policy. 
 
The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating to all participating 
investigators, any observations reportable under the DFCI IRB Reporting Requirements. 
Participating Institutions will review and submit to their IRB according to their 
institutional policies and procedures 


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3.9.2 Guidelines for Processing IND Safety Reports 
 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety 
Reports are distributed to the Participating Institutions. Participating Institutions will 
review and submit to their IRB according to their institutional policies and procedures. 
 
3.10 Data Management 
 
The DF/HCC QACT develops case report forms (CRF/eCRFs), for use with the protocol. 
These forms are designed to collect data for each study. The DF/HCC QACT provides a 
web based training for eCRF users. 
 
3.10.1 Data Forms Review 
 
Data submissions are monitored for timeliness and completeness of submission. 
Participating Institutions are notified of their data submission delinquencies in accordance 
with the following: 
 
Incomplete or Questionable Data 
If study forms are received with missing or questionable data, the submitting institution 
will receive a written or electronic query from the DF/HCC QACT Data Analyst, 
Coordinating Center or designee. Responses to all queries should be completed and 
submitted within 14 calendar days. Responses may be returned on the written query or on 
an amended paper case report form, or in the case of electronic queries, within the 
electronic data capture (eDC) system. In the case of a written query for data submitted on 
a paper case report form, the query must be attached to the specific data being re- 
submitted in response. 
 
Missing Forms 
If study forms are not submitted on schedule, the Participating Institution will receive a 
Missing Form Report from the Coordinating Center noting the missing forms. These 
reports are compiled by the DF/HCC QACT and distributed on a monthly basis. 
 
4. REQUISITIONING INVESTIGATIONAL DRUG 
 
The ordering of investigational agent is specified in Section 8 of the protocol. 
Participating Institutions should order their own agent regardless of the supplier. 
If the agent is commercially available, check with the local Director of Pharmacy and/or 
the Research Pharmacy to ensure that the agent is in stock. If the agent is not stocked, 
ensure that the agent can be ordered once the protocol is approved by the local IRB. 
 
If the agent is investigational, ensure that the pharmacy will be able to receive and store the 
agent according to state and federal requirements. The local IRB should be kept informed 


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of who will supply the agent so that any regulatory responsibilities can be met in a timely 
fashion. 
 
5. MONITORING: QUALITY CONTROL 
 
The quality control process for a clinical trial requires verification of protocol compliance 
and data accuracy. The Coordinating Center, with the aid of the QACT provides quality 
control oversight for the protocol. 
 
5.1 Ongoing Monitoring of Protocol Compliance 
 
The Participating Institutions will be required to submit subject source documents to the 
DF/HCC Lead Institution or designee for monitoring. Also, the Participating Institution 
may be subject to on-site monitoring conducted by the DF/HCC Lead Institution. 
 
The DF/HCC Lead Institution will implement on-site as well as virtual monitoring 
activities to ensure that Participating Institutions are complying with regulatory and 
protocol requirements, data quality, and subject safety. At a minimum, the DF/HCC Lead 
Institute, or designee, will monitor each participating site twice a year while patients are 
receiving treatment. Should a Participating Institution be monitored once and then not 
accrue any additional patients or participant visits, then a second monitoring visit may not 
be necessary. 
 
Monitoring practices may include but are not limited to; source verification, review and 
analysis of the following: eligibility requirements of all participants, informed consent 
procedures, adverse events and all associated documentation, study drug administration / 
treatment, regulatory records and site trial master files, protocol deviations, pharmacy 
records, response assessments, and data management. Additionally, regular and ongoing 
communication with Participating Institutions will be accomplished by holding all site 
teleconferences at least monthly. The Lead Institution will keep in close touch with the 
Participating Institutions via email and phone. Source documents from Participating 
Institutions, will be collected at specific data points that support the primary and or 
secondary endpoints. 
 
On-Site Monitoring: On-site monitoring will occur at least once per year. Participating 
Institutions will be required to provide access to participants’ complete medical record and 
source documents for source documentation verification during the on-site visit. In 
addition, upon request from a monitor or auditor, Participating Institutions should provide 
access to regulatory documents, pharmacy records, local policies related to the conduct of 
research, and any other trial-related documentation maintained by the participating site. If 
there are concerns for protocol compliance, issues that impact subject safety or the 
integrity of the study are found, or trends identified based on areas of need, additional 
monitoring visits may be scheduled. On site monitoring visits can be supplemented with 
virtual monitoring assessments, provided that the minimum monitoring frequencies are 
adhered to. 


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Virtual Monitoring: The Coordinating Center will request source documentation from 
Participating Institutions as needed to complete monitoring activities. Participating 
Institutions will be asked to forward de-identified copies of participants’ medical record 
and source documents to the Coordinating Center to aid in source documentation 
verification. 
5.2 Monitoring Reports 
 
The DF/HCC Sponsor will review all monitoring reports for on-site and remote 
monitoring of Participating Institutions to ensure protocol compliance. The DF/HCC 
Sponsor may increase the monitoring activities at Participating Institutions that are unable 
to comply with the protocol, DF/HCC Sponsor requirements or federal and local 
regulations. Participating Institutions may also be subject to an audit as determined by the 
DF/HCC Sponsor. 
 
5.3 Accrual Monitoring 
 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish 
accrual requirements for each participating institution. Accrual will be monitored for each 
participating institution by the DF/HCC Sponsor or designee. Sites that are not meeting 
their accrual expectations may be subject to termination. Due to the small patient 
population, the accrual minimum requirement is at least 1 patient every two years. 
 
6. AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards 
and procedures were followed. Auditing is the systematic and independent examination of 
all trial related activities and documents. Audits determine if evaluated activities were 
appropriately conducted and whether data was generated, recorded and analyzed, and 
accurately reported per the protocol, Standard Operating Procedures (SOPs), and the Code 
of Federal Regulations (CFR). 
 
6.1 Audit Plan: DF/HCC Sponsored Trials 
 
One on-site audit will be scheduled by the QACT, assuming at least three participants 
have been treated on protocol at the site, or at the discretion of the DF/HCC sponsor. 
Approximately 3-4 participants would be audited at the site over a 2 day period. If 
violations which impact participant safety or the integrity of the study are found, more 
participant records may be audited. 
 
6.2 Audit Notification 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which involve 
this protocol. All institutions will forward a copy of final audit and/or re-audit reports and 


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corrective action plans (if applicable) to the Coordinating Center, within 12 weeks after 
the audit date. 
 
6.3 Audit Reports 
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans if 
applicable. The Coordinating Center, must forward these reports to the DF/HCC QACT 
per DF/HCC policy for review by the DF/HCC Audit Committee. Based upon the audit 
assessments the DF/HCC Audit Committee could accept or conditionally accept the audit 
rating and final report. Conditional approval could require the DF/HCC Sponsor to 
implement recommendations or require further follow-up. For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the DFCI IRB as applicable. 
 
6.4 Participating Institution Performance 
 
The DF/HCC Sponsor and DFCI IRB is charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol. 
 
6.4.1 Corrective Actions 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of 
timely and accurate data, adherence to protocol requirements, and compliance with state 
and federal regulations, may be recommended for a six-month probation period. Such 
institutions must respond with a corrective action plan and must demonstrate during the 
probation period that deficiencies have been corrected, as evidenced by the improved 
performance measures. Participating Institutions that fail to demonstrate significant 
improvement will be considered by the DF/HCC Sponsor for revocation of participation. 
A DF/HCC Sponsor and/or the DFCI IRB may terminate a site’s participation if it is 
determined that a site is not fulfilling its responsibilities as described above. 

ICF_001.pdf: 
Research Consent Form                   
for Biomedical Research 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 04.07.14 
 
Page 1 of 27 
DFCI Protocol Number:  
         14-338 
Approved Date (DFCI IRB Approval):  
02/11/2020 
Date Posted for Use:  
02/12/2020 
 
Protocol Title:  E- PRISM (Precision Intervention Smoldering Myeloma): A Phase II 
Trial of Combination of Elotuzumab, Lenalidomide and Dexamethasone in High-
Risk Smoldering Multiple Myeloma 
DF/HCC Principal Research Doctor / Institution:  Irene Ghobrial, MD/Dana Farber 
Cancer Institute 
DF/HCC Site-Responsible Research Doctor(s) / Institution(s): Andrew Yee, MD / 
Massachusetts General Hospital; Irene Ghobrial, MD/ Broad Institute 
 
A. INTRODUCTION 
 
You are invited to take part in a clinical trial, a type of research study because 
you have smoldering multiple myeloma (SMM). Patients with smoldering multiple 
myeloma do not have symptoms but are at risk for progressing to active multiple 
myeloma. Multiple myeloma is a cancer of the plasma cell, which is an important 
part of the immune system. Patients with active multiple myeloma generally 
require treatment. There are currently no approved therapies for smoldering 
multiple myeloma. 
 
This research study is a way of gaining new knowledge about a new drug called 
“elotuzumab”. For purposes of this research, you will be referred to as a 
“participant”.  This research study is evaluating a new drug called “elotuzumab” 
as a possible treatment for smoldering multiple myeloma.  
 
It is expected that about 51 people will take part in this research study.  
 
Bristol-Myers Squibb and Celgene are supporting this research study by 
providing funding for the research study and the study drug.  
 
This research consent form explains why this research study is being done, what 
is involved in participating in the research study, the possible risks and benefits 
of participation, alternatives to participation, and your rights as a research 
participant.  The decision to participate is yours.  If you decide to participate, 
please sign and date at the end of this form. We will give you a copy so that you 
can refer to it while you are involved in this research study. If you choose not to 
participate in this research study, the research doctors will discuss other 
treatment options with you and/or refer you back to your primary doctor.  
 
We encourage you to take some time to think this over, to discuss it with other 
people and your primary doctor, and to ask questions now and at any time in the 
future. 
2/12/2020 11:34 am


Research Consent Form                   
for Biomedical Research 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 04.07.14 
 
Page 2 of 27 
DFCI Protocol Number:  
         14-338 
Approved Date (DFCI IRB Approval):  
02/11/2020 
Date Posted for Use:  
02/12/2020 
 
B. WHY IS THIS RESEARCH STUDY BEING DONE?  
 
This research study is a Phase II clinical trial, which tests the effectiveness of an 
investigational drug(s). The investigational drugs used in this research study are 
elotuzumab, lenalidomide and dexamethasone. Recent research studies have 
shown that early treatment of smoldering multiple myeloma may delay or prevent 
the progression to active multiple myeloma. The purpose of this research study is 
to learn whether the combination of elotuzumab and lenalidomide or the 
combination of elotuzumab, lenalidomide and dexamethasone works in treating 
your smoldering multiple myeloma.  
 
“Investigational” means that the FDA (the U.S. Food and Drug Administration) 
has not approved the combination of elotuzumab, lenalidomide and 
dexamethasone as a treatment regimen for your specific disease.  
 
The FDA has approved lenalidomide for the treatment of many types of cancer 
including multiple myeloma, and myelodysplastic syndromes. Dexamethasone, 
also FDA approved, is a type of steroid and is usually combined with other 
chemotherapy for the treatment of blood cancers, such as myeloma and 
leukemias. Elotuzumab is approved by the FDA for treatment of multiple 
myeloma, and is currently being evaluated for use in the treatment of several 
other types of cancers, including smoldering multiple myeloma.  
 
C. WHAT OTHER OPTIONS ARE THERE? 
 
Taking part in this research study is voluntary. Instead of being in this research 
study, you have other options which may include the following:  
 
• Take part in another research study.  
• Receive no therapy specific to your cancer. 
 
Please talk to the research doctor about your options before you decide whether 
you will take part in this research study. 
 
D. WHAT IS INVOLVED IN THE RESEARCH STUDY? 
 
Sometimes it is hard to keep track of all of the details and procedures that are 
part of a research study. We will describe them in this consent form and you can 
refer to this at any time during the research study. We can also provide you with 
a calendar that will be an easy reference for you to keep track of the procedures 
and treatments required at each timepoint in the study. 
2/12/2020 11:34 am


Research Consent Form                   
for Biomedical Research 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 04.07.14 
 
Page 3 of 27 
DFCI Protocol Number:  
         14-338 
Approved Date (DFCI IRB Approval):  
02/11/2020 
Date Posted for Use:  
02/12/2020 
 
Before the research starts (screening): After signing this consent form, you will 
be asked to undergo some screening tests or procedures to find out if you can be 
in the research study.  Many of these tests and procedures are likely to be part of 
regular cancer care and may be done even if it turns out that you do not take part 
in the research study.  If you have had some of these tests or procedures 
recently, they may or may not have to be repeated.   
 
• A medical history includes questions about your health, current 
medications, and any allergies. 
• Performance status evaluates how you are able to carry on with your 
usual activities.  
• An assessment of your disease (Metastatic Bone Survey) by CT 
(Computerized Tomography) scan, MRI (Magnetic Resonance Imaging) 
and PET (Positron Emission Tomography) scans.  
• Physical Exam including height and weight as well as checking your body 
for signs and symptoms of cancer. 
• Electrocardiogram (ECG) measures the electrical activity and health of 
the heart. 
• Blood or Urine Pregnancy Test is required if you are a woman who is 
able to get pregnant. The test will need to be negative within 24 hours of 
starting Cycle 1 and then again every cycle thereafter on Day 1. 
• Urine Test (in clinic) to assess your overall health. 
• Blood tests to check your overall health (1-2 tablespoons of blood). 
• Bone marrow aspirate and biopsy will be done to evaluate your 
disease. For the bone marrow aspirate, a sample of bone marrow cells is 
taken by a needle and inserted into a bone in your body. For the biopsy, a 
small piece of bone is removed. These tests are done under local 
anesthesia.  
 
If these tests show that you are eligible to participate in the research study, you 
will begin the study treatment.  If you do not meet the eligibility criteria, you will 
not be able to participate in this research study. 
 
Additional Optional Research procedures to be performed at the time of 
screening:   
• Blood Sample: Approximately 2 tablespoons of blood will be drawn for 
research to assess your disease status by DNA and RNA sequencing. 
• Bone Marrow Aspirate Sample: for bone marrow procedures that are 
done as standard of care, a small amount of extra bone marrow cells will 
be taken for research tests. This additional sample will be taken at the 
same time as the other sample; you will not need an additional procedure. 
Even if your doctor determines the bone marrow sample is not required for 
2/12/2020 11:34 am


Research Consent Form                   
for Biomedical Research 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 04.07.14 
 
Page 4 of 27 
DFCI Protocol Number:  
         14-338 
Approved Date (DFCI IRB Approval):  
02/11/2020 
Date Posted for Use:  
02/12/2020 
 
your type of disease, this sample will still be taken for research purposes. 
The research tests will help determine how Elotuzumab affects your 
disease 
• Buccal Swab will be collected when you are in clinic at the beginning of 
the study (or at any time during the trial). The purpose is to harvest your 
normal DNA. You will not be provided with results about the genetic tests, 
nor will the information be placed in your medical record 
 
After the screening procedures confirm that you are eligible to participate 
in the research study and you are ready to begin treatment.  
 
If you take part in this research study, you will be given a study drug-dosing diary 
for each treatment cycle. Each treatment cycle lasts 28 days (4 weeks), during 
which time you will be taking each drug on different days of the cycle. The diary 
will also include special instructions for taking the study drug.  
 
The tables below outline the schedule of drug administration for this study. 
 
Study Drug Dosing Table: (28 Day Cycles) 
 
Cycles 1-2  
Drug 
Route 
Schedule 
Elotuzumab 
IV 
Days 1,8,15, 22 
Lenalidomide 
Oral 
Days 1-21 
Dexamethasone 
Oral and IV 
Days 1,8,15, 22 
 
Cycles 3-8 
Drug 
Route 
Schedule 
Elotuzumab 
IV 
Days 1 and 15 
Lenalidomide 
Oral 
Days 1-21 
Dexamethasone 
Oral and IV 
Days 1,8,15  
 
If you complete treatment on either cohort through cycle 8, please see your 
maintenance schedule below:  
 
Maintenance  
Drug 
Route 
Schedule 
Elotuzumab 
IV 
Day1 
Lenalidomide 
Oral  
Days 1-21 
Dexamethasone** 
Oral and IV 
Day 1 
**Dexamethasone may be given on days 8 and 15 in maintenance at your 
provider’s discretion. 
2/12/2020 11:34 am


Research Consent Form                   
for Biomedical Research 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 04.07.14 
 
Page 5 of 27 
DFCI Protocol Number:  
         14-338 
Approved Date (DFCI IRB Approval):  
02/11/2020 
Date Posted for Use:  
02/12/2020 
 
 
Elotuzumab Administration: This drug will be administered intravenously 
(through your vein) by the study team in clinic over about 60 minutes. Your 
physician may also order other medications to be administered before you get 
dosed in order to decrease the risk of experiencing an infusion reaction related to 
the administration of the drug. Depending on if you do experience an infusion 
reaction, these drugs may be changed.  
 
Lenalidomide Administration: This drug will be given as a single dose that you 
will take orally once daily on the days instructed. You must record all 
administrations of this drug at home and in clinic in the study drug diary provided 
to you.  
 
Dexamethasone Administration: This drug will be given both orally and 
intravenously (through your vein). You must record all oral administrations of this 
drug in your study drug diary provided to you.  
 
On Study Visits: Please see research required test table below. 
 
If specified, visits will involve the following: 
 
• Medical History and Physical Exam will be performed and you will be 
asked questions about your general health and specific questions about 
any problems that you might be having and any medication changes.  
• Electrocardiogram (ECG) will be conducted to measure the electrical 
activity and health of the heart (Only required at screening, at end of 
treatment or if clinically indicated). 
• Blood or Urine Pregnancy Test is required if you are a woman who is 
able to get pregnant. The test will need to be negative within 24 hours of 
starting Cycle 1 and then again every cycle thereafter on Day 1. 
• 24 hour Urine Sample will be required, which you will return to clinic on 
Day 1 of each cycle for some patients whose disease is assessed by their 
urine result. This is to perform a specific test that shows signs of disease 
that sometimes does not show in blood or marrow. 
• Blood tests will be done to check your overall health (1-2 tablespoons).  
• Bone marrow aspirate and biopsy will be done to evaluate your 
disease. For the bone marrow aspirate, a sample of bone marrow cells is 
taken by a needle and inserted into a bone in your body. For the biopsy, a 
small piece of bone is removed. These tests are done under local 
anesthesia. Your physician may require this procedure more often to 
assess your disease. 
• Scans (or Imaging tests) will assess your tumor by MRI or PET/CT at the 
end of your treatment. 
2/12/2020 11:34 am


Research Consent Form                   
for Biomedical Research 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 04.07.14 
 
Page 6 of 27 
DFCI Protocol Number:  
         14-338 
Approved Date (DFCI IRB Approval):  
02/11/2020 
Date Posted for Use:  
02/12/2020 
 
• Side effects will be evaluated   
• Buccal swab is a way to collect DNA from the cells on the inside of your 
cheek 
 
Research Study Schedule 
Cycle 1 and 2   (28 Day Cycles) 
 
Baseline 
Day 1 
Day 8 
Day 15 
Day 22 
End of Treatment 
Medical History and Physical Exam 
X 
X 
 
 
 
X 
Routine Blood Tests 
X 
X 
X 
X 
X 
X 
Urine Test 
X 
X 
 
 
 
X 
Pregnancy Test (If applicable) 
X 
X 
 
 
 
 
MRI and PET/CT 
X 
 
 
 
 
X 
EKG 
X 
 
 
 
 
X 
Bone Marrow Aspirate and Biopsy 
X 
 
 
 
 
X 
Research Blood Sample 
X 
X 
 
 
 
X 
Research Marrow Sample 
X 
 
 
 
 
X 
Buccal Swab* 
X 
 
 
 
 
 
* Buccal Swab can be obtained at any time during the trial  
2/12/2020 11:34 am


Research Consent Form                   
for Biomedical Research 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 04.07.14 
 
Page 7 of 27 
DFCI Protocol Number:  
         14-338 
Approved Date (DFCI IRB Approval):  
02/11/2020 
Date Posted for Use:  
02/12/2020 
 
Cycle 3 through 24   (28 Day Cycles) 
 
Day 1 
Day 8 
Day 15 
End of Cycle 
8 or Cycle 9, 
Day 1 
End of 
Treatment 
Follow Up-
Every 3 
Months  
Medical History and 
Physical Exam 
X 
 
 
 
X 
 
X 
Routine Blood Tests 
X 
 
X 
 
X 
 
X 
Urine Test 
X 
 
 
 
X 
 
X 
Pregnancy Test (if 
applicable) 
X 
 
 
 
 
 
MRI and PET/CT 
 
 
 
 
X 
 
EKG 
 
 
 
 
X 
 
Bone Marrow Aspirate 
and Biopsy 
X 
 
 
X 
X 
 
Research Blood** 
Sample 
X 
 
 
X 
X 
 
Research Marrow 
Sample 
 
 
 
X 
X 
 
** Research blood samples are requested at  Day 1 of each cycle in addition to baseline, EOT, and to 
confirm disease response  
 
Planned Follow-up: We would like to keep track of your medical condition for up 
to three years after you stop treatment.  We would like to do this by calling you 
on the telephone or during a visit to your doctor’s office to see how you are 
doing.   
 
E. HOW LONG WILL I BE IN THIS RESEARCH STUDY? 
 
You will be on the study treatment for up to 18 months and be followed for an 
additional 3 years.  
 
The research doctor may decide to take you off the research study for many 
reasons including if: 
• It is considered to be in your best interest 
• The study treatment or procedures are found to be unsafe or ineffective 
• There is any problem with following study treatments and procedures 
• Your condition worsens 
• A decision is made to close the study 
• Or for other unforeseen reasons that make it necessary to stop your 
participation in the research study 
2/12/2020 11:34 am


Research Consent Form                   
for Biomedical Research 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 04.07.14 
 
Page 8 of 27 
DFCI Protocol Number:  
         14-338 
Approved Date (DFCI IRB Approval):  
02/11/2020 
Date Posted for Use:  
02/12/2020 
 
If you are removed from the research study, the research doctor will explain to 
you why you were removed.   
 
In addition, you can stop participating in the research study at any time, however, 
the FDA requires that any information collected up to the point of your withdrawal 
cannot be removed from the study.  If you decide to stop participating in this 
research study, we encourage you to talk to the research doctor and your 
primary doctor first. 
 
F. WHAT ARE THE RISKS OR DISCOMFORTS OF THE RESEARCH STUDY? 
 
There are risks to taking part in any research study. One risk is that you may get 
a study drug that does not help treat your disease or that makes your condition or 
disease worse.  Another risk is that there may be side effects.   
 
All cancer treatments can have side effects, which can range from mild and 
reversible to severe, long lasting and possibly life-threatening.  There is a great 
deal of variability among side effects of different cancer treatments and between 
individuals.  In a research study, all of the risks or side effects may not be known 
before you start the study. You need to tell your doctor or a member of the 
study team immediately if you experience any side effects.  
 
Everyone in the research study will be watched carefully for side effects.  You will 
be monitored during the administration of study drugs to keep track of your blood 
counts and organ function, particularly your kidney and liver function.  If you 
experience side effects, they may go away after you stop taking the study drug.  
Some side effects can be mild; but others can be long lasting and may never go 
away.  Some may be life-threatening or fatal.  
 
Since the effect of the study drug(s) taken with other medications may not be 
known, it is important that you tell the research doctor about all prescription and 
non-prescription drugs, herbal preparations and nutritional supplements that you 
are taking or planning to take. There may also be some foods that you should 
avoid while on this research study and your research doctor will review this 
information with you. 
 
During the research study, you will be notified of newly discovered side effects or 
significant findings, which may affect your health or willingness to participate.  
You may be asked to sign a new consent form that shows that you have been 
informed of new information relating to this research study. 
 
Since this is the first clinical study of these three drugs combined for the 
treatment of smoldering multiple myeloma, information on expected combination 
2/12/2020 11:34 am


Research Consent Form                   
for Biomedical Research 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 04.07.14 
 
Page 9 of 27 
DFCI Protocol Number:  
         14-338 
Approved Date (DFCI IRB Approval):  
02/11/2020 
Date Posted for Use:  
02/12/2020 
 
drug side effects in humans is limited, although potential side effects for each of 
the three drugs are well known and listed below: 
 
Risks Associated with Elotuzumab  
 
Likely (More than a 20% chance that this will happen) 
• Tiredness 
• Fever 
• Swelling of the injection site, joints, and/or areas of the face 
• Diarrhea 
• Constipation 
• Nausea 
• Low white blood cell counts which can put you at risk for developing an 
infection, which can be life threatening 
• Low red blood cell counts (anemia) which can make you feel tired, 
lightheaded or short of breath, and may require you to have red blood 
cell transfusions 
 
Occasional (Between a 3-20% chance that this will happen) 
 
• Allergic type infusion reactions that may occur during or after 
elotuzumab administration and include symptoms such as chills, fever, 
nausea, rash, flushing, chest discomfort, increased sweating, high 
blood pressure, abdominal pain, swelling around the eyes or muscle 
spasms 
• Vomiting 
• Mouth sores or pain 
• Upset stomach or heartburn 
• General weakness 
• Back pain 
• Bone, joint or muscle pain 
• Chest pain 
• Pain, numbness or tingling in the arms, hands, legs or feet  
• Dizziness 
• Difficulty sleeping 
• Tremor 
• Taste change 
• Cough 
• Shortness of breath 
• Voice changes 
• Nose bleeds 
2/12/2020 11:34 am


Research Consent Form                   
for Biomedical Research 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 04.07.14 
 
Page 10 of 27 
DFCI Protocol Number:  
         14-338 
Approved Date (DFCI IRB Approval):  
02/11/2020 
Date Posted for Use:  
02/12/2020 
 
• Hiccups 
• Poor appetite 
• Increase in blood sugar 
• Changes in electrolytes (body salts), which do not usually cause any 
symptoms but can sometimes cause tiredness, muscle weakness, 
cramping, rigidity, irregular heartbeat or seizures. This can be severe 
and possibly life threatening. This could require hospitalization and 
intravenous treatment 
• Decreased weight 
• Changes in liver or kidney function tests which can indicate damage to 
cells in the liver and kidney 
• Increase in susceptibility to infections of the throat, mouth, lung, sinus, 
blood, kidney, bladder, skin, stomach or intestine 
• Itching or hives 
• Anxiety 
• Depression 
• Low blood pressure which might make you feel dizzy or light-headed 
• Blurred vision or reduced vision 
 
Rare (Less than a 1-3% chance that this will happen or serious side effects 
in at least 1 patient) 
 
• Abnormal walking or falling 
•  Irritability or agitation 
• Sudden death due to gastric perforation, multi-organ failure, sepsis, 
pneumonia, or vascular event 
• Mood changes 
• Confusion 
• Dry eyes 
• Cataract (clouding of lens of eye) 
• Pink eye (inflammation of the eye) 
• Dry mouth or skin 
• Skin inflammation 
• Hair loss 
• Gas or bloating 
• Difficulty swallowing 
• Hemorrhoids 
• Inflammation of the colon which can cause abdominal pain, loss of 
appetite, fatigue, diarrhea, cramping, fecal urgency and bloating 
(colitis). 
2/12/2020 11:34 am


Research Consent Form                   
for Biomedical Research 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 04.07.14 
 
Page 11 of 27 
DFCI Protocol Number:  
         14-338 
Approved Date (DFCI IRB Approval):  
02/11/2020 
Date Posted for Use:  
02/12/2020 
 
• Inflammation of the liver which can lead to jaundice, poor appetite, and 
malaise (hepatitis) 
• Neck or jaw pain 
• Toothache 
• Joint or muscle stiffness 
• Sleepiness 
• Memory loss 
• Fainting 
• Runny or stuffy nose 
• Sinus congestion 
• Wheezing 
• Fluid in lungs 
• Inflammation of the lung 
• Viral infections such as herpes virus or the flu 
• Fever with low white blood cell counts (febrile neutropenia), a condition 
marked by fever and lower-than-normal number of neutrophils in the 
blood which could increase the risk of infection 
• Life threatening infections/infections leading to death 
• Dehydration 
• Excess amount of uric acid in the blood, (gout), which can cause pain in 
the joints as well as decrease kidney function. 
• Blood clots in the veins of the leg or lung 
• Localized collection of blood outside the blood vessel (ecchymosis or 
hematoma) that are usually due to a weakening in the wall of a blood 
vessel 
• Inflammation of the vein(s) 
• Kidney damage or failure 
• Problems with urination or bladder control 
• Pain while urinating 
• Frequent urination 
• Ringing in ears 
• Rapid or slow heart rate 
• Abnormal heart rhythm, which may be life threatening or fatal 
• Palpitations 
• Heart failure 
• Irregular heart beat that is slow due to impaired electrical conduction 
across the heart (3rd degree AV block) 
• Heart attack 
• Inflammation of the heart muscle 
• Weight gain 
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for Biomedical Research 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 04.07.14 
 
Page 12 of 27 
DFCI Protocol Number:  
         14-338 
Approved Date (DFCI IRB Approval):  
02/11/2020 
Date Posted for Use:  
02/12/2020 
 
• Increased destruction of red blood cells that leads to anemia 
(hemolysis) that can cause a reduction in the delivery of oxygen to the 
tissues, fatigue, increased heart rate, chills, dark urine, yellow skin, 
and rapid heartbeat 
 
Other unexpected reactions may occur. It is also possible that your immune 
system could make antibodies against elotuzumab, which would limit how well it 
works against the myeloma. Blood samples will be taken during the study to test 
for the development of an immune reaction to elotuzumab. 
 
All side effects will be closely monitored. If any new information about the study 
drug or any other information becomes available which may influence your 
decision to continue in the study, you will be told in a timely manner. 
 
Risks Associated with Lenalidomide  
 
Lenalidomide has been studied in healthy volunteers and in patients with cancer 
of the blood and other organs of the body as well as in patients with other 
diseases.  As with any other experimental treatment there may be side effects or 
risks associated with lenalidomide, some of which are not yet known. The early 
treatment of smoldering multiple myeloma with lenalidomide is an investigational 
approach. 
  
The following is a list of the most medically significant or most common side 
effects reported in completed and ongoing studies considered to be related to 
lenalidomide. In some cases, side effects can be serious, long-lasting, may never 
go away, or can cause death.  This list is not complete, but your study doctor will 
answer any questions you might have and provide you with more information.  
 
The use of lenalidomide therapy has been known to hinder the collection of your 
own stem cells in patients with multiple myeloma. If your disease progresses to 
multiple myeloma and you are deemed a candidate for autologous (using your 
own cells) stem cell transplant, it is unknown if the long term use of lenalidomide 
therapy will rule out stem cell collection from your peripheral blood.  
 
Likely (More than a 50% chance that this will happen) 
 
• Low number of red blood cells (anemia) which can cause tiredness, 
shortness of breath, and may require a blood transfusion 
• Constipation or difficult bowel movements 
• Diarrhea or loose/frequent bowel movements 
• Fatigue  
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Research Consent Form                   
for Biomedical Research 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 04.07.14 
 
Page 13 of 27 
DFCI Protocol Number:  
         14-338 
Approved Date (DFCI IRB Approval):  
02/11/2020 
Date Posted for Use:  
02/12/2020 
 
• A serious or life threatening decrease in the number of a type of white 
blood cell (neutrophil/ granulocyte) that helps to protect against infection 
which causes an increased risk of infection 
• Decreased number of a type of blood cell that help to clot blood (platelet). 
This may result in bleeding.  
 
Frequent (Chance of 10-50% that this will happen) 
 
• Abnormally low level of thyroid gland hormone. This may cause fatigue, 
weight gain, fluid retention, sensitivity to cold and mental apathy. Can be 
serious or life threatening.  
• Nausea or the urge to vomit 
• Vomiting 
• Chills 
• Swelling or tingling of the arms and legs 
• Fever 
• Infection, which may be serious and life threatening 
• A decrease in the number of a type of white blood cell (lymphocyte) and 
decrease in the total number of white blood cells (leukocytes) which may 
increase the risk of infection. 
• Weight loss 
• Loss of appetite 
• Back, joint and muscle pain 
• Muscle cramps/spasms 
• Dizziness (or sensation of lightheadedness, unsteadiness, giddiness, 
spinning or rocking) 
• Headache or head pain 
• Difficulty sleeping or falling asleep 
• Cough 
• Shortness of breath 
• Itching 
• Skin rashes that may be flat (macular), raised (papular) or red and 
irritated.  
• Excess sweating 
• Formation of a blood clot that may break loose and be carried by the blood 
stream to plug another blood vessel. May be serious and life threatening.  
• Abnormal liver function tests that mean the liver is not functioning properly 
and can cause fatigue, jaundice (yellowing of the skin or eyes). Although 
this is usually mild and reversible, this can be serious or life threatening 
 
 
 
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Research Consent Form                   
for Biomedical Research 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 04.07.14 
 
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Rare (Chance of less than 1% that this will happen) 
 
• Inflammation of the pancreas. This may cause abdominal pain and require 
hospitalization and intravenous treatment. It may be accompanied by 
increased blood levels of a fat digesting enzyme called lipase.  
• Serious life-threatening allergic reaction requiring immediate medical 
treatment. The reaction may include extremely low blood pressure, swelling of 
the throat, difficulty breathing, and loss of consciousness. 
• Tumor lysis syndrome, which is the result of rapid destruction of cancer cells 
that can occur after treatment of cancer has started and may cause an 
electrolyte imbalance, increased uric acid buildup (gout), and kidney damage 
• Decreased production of blood cells by the bone marrow (marrow aplasia) 
including cells that fight infection, clot the blood, and carry oxygen to tissue 
• Temporary growth in tumor or worsening of tumor related problems 
• Tissue death of a part of the brain without inflammation  
• Sudden decrease of kidney function. When the kidneys do not work properly, 
wastes can build up in your blood, leading to swelling in the arms and legs, 
tiredness and weakness. This could become severe, requiring hospitalization 
and dialysis to clean the wastes out of your blood. If the wastes are not 
removed from your blood, this could cause seizures and be life threatening. 
• Severe reaction of the skin and gut lining that may include rash and shedding 
or death of tissue. This can include conditions in which the death is skin 
tissue causes the outer layer of the skin to separate from the middle layer and 
be serious and life threatening.  
• Development of a second cancer including leukemia. 
• Lenalidomide is a member of a class of drug that causes damage to a fetus 
(teratogen). It is important that mandatory contraceptive measures be used 
while taking lenalidomide. It also requires special prescription forms 
(RevAssist) and frequent counseling. Your physician will discuss this with 
you. 
 
There may be an increased risk of second cancers in patients who are on 
lenalidomide maintenance therapy after a bone marrow transplant. 
 
In addition, lenalidomide has been shown to increase the level of digoxin in the 
blood in some patients. Please tell your doctor if you are taking digoxin. 
 
Risks Associated with Dexamethasone 
 
Occasional (Chance of less than 10% that this will happen): 
• Increased blood sugar. If you have diabetes, this may lead to a need to 
adjust your medications used to treat the diabetes. 
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Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
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• Increased appetite. 
•  Weight gain. 
• Fluid retention (edema), which can cause a buildup of fluid in the body or 
extremities causing swelling. 
• Elevation of blood pressure 
• Mood changes (depression, or abnormal feelings of well-being and 
excitement) 
• Difficulty sleeping 
• Skin changes leading to thinning and easy bruising 
• Gradual changes to bones that may increase their risk of breaking 
• Muscle weakness 
• Stomach irritation/ulcer 
• Increased risk of infection 
• Acne 
 
Rare (Less than 1% chance that this will happen): 
• Loss of potassium, which may lead to weakness and abnormal heart 
beats. 
• Increased eye pressure in patients with glaucoma which may cause 
damage to the optic nerve and vision loss 
• Gradual development of cataracts, or a clouding of the lens of the eye 
causing hazy or blurry vision 
• If used for a long time it can suppress the function of the normal glands 
that make steroids (adrenal glands) leading to the need for continued 
replacement with steroid medication. 
• Glaucoma, or optic nerve and vision damage which can be caused by an 
increase in pressure within the eye 
• Pancreatitis or an inflammation of the pancreas causing pain in the upper 
abdomen that can become severe and cause nausea, vomiting, and could 
require hospitalization and may be life threatening. 
 
Cancer research often includes biopsies, scans, x-rays that are also provided as 
routine care.  The following describes the side effects of procedures done only 
for the purposes of research.  
 
Risks Associated with Bone Marrow Biopsies: 
 
Risks associated with bone marrow biopsies include pain, redness, swelling, 
excessive bleeding, bruising or infection at the needle site and or scarring at the 
biopsy site. An allergic reaction to the local anesthetic medication used to numb 
the skin over the biopsy site may occur. These risks can be discussed with the 
study doctor. 
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for Biomedical Research 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 04.07.14 
 
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Approved Date (DFCI IRB Approval):  
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Date Posted for Use:  
02/12/2020 
 
 
Uncommonly, complications from biopsies can be life threatening. As with any 
interventional procedure, other potentially serious complications from bleeding or 
organ damage may occur. These might require additional surgical intervention. 
 
Radiation Risks Associated with Scans and X-Rays:  
 
While you are in this research study, CT scans, Bone Scans, and x-rays utilizing 
radioactivity may be used to evaluate your disease. The frequency of these 
exams is the same as what you would receive as standard care. In the long term, 
over many years, there is a very low risk of developing a new cancer as a result 
of the radiological evaluation and treatment for your cancer. 
 
Risks Associated with MRI Scans:  
 
When having an MRI (Magnetic Resonance Imaging) scan, you will lie still on a 
table that slides into a tunnel slightly wider than your body. People who feel 
uncomfortable in confined spaces (claustrophobia) may feel uncomfortable in the 
narrow cylinder. If you feel uncomfortable in confined spaces, please tell your 
research doctor. Your doctor may give you a medication to make you feel more 
comfortable. As images are taken, a loud banging noise will be produced.  
Earplugs or headphones will be available if needed. The MRI can be stopped at 
any time at your request, but the scan may not be complete. 
 
Reproductive Risks:  
 
The drugs used in this research study may affect a fetus.  While participating in 
this research study, you should not become pregnant or father a baby, and 
should not nurse a baby.  Let your doctor know immediately if you become 
pregnant or find out that you are going to be the father of a child.  We can 
provide counseling about preventing pregnancy for either male or female study 
participants.  
 
In the event that your partner becomes pregnant, it may be critical to share 
information regarding your participation in this research study with that person.  
Your research doctor should also be told if this happens.  The study sponsor may 
want to collect data on your partner’s pregnancy.  The research doctor can 
provide you with the study sponsors contact information and your partner can 
decide whether or not they want to provide this information.  For more 
information about what to do if your partner becomes pregnant please contact 
your research doctor.   
 
Lenalidomide is related to thalidomide. Thalidomide is known to cause severe 
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Dana-Farber/ Harvard Cancer Center 
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life-threatening human birth defects. Findings from a laboratory study indicate 
that lenalidomide caused birth defects in the offspring of females who received 
the drug during pregnancy. If lenalidomide is taken during pregnancy, it may 
cause birth defects or death to any unborn baby. Females should not become 
pregnant while taking lenalidomide. You have been informed that the risk of birth 
defects is unknown. If you are female, you agree not to become pregnant while 
taking lenalidomide 
 
Patients with blood cancers who take lenalidomide and dexamethasone have 
a greater chance of having blood clots. Because of this, it is recommended 
patients discuss the use of birth control pills or hormone replacement therapy 
with the study doctor to better understand the risks and benefits of these choices 
 
Pregnancy Risk – Females: 
If you are a female of childbearing potential*, you will be required to have a 
negative pregnancy tests prior to receiving lenalidomide. 
 
• For the purposes of this study, a female of childbearing potential is a 
sexually mature female who: 
  
o Has not undergone a hysterectomy (the surgical removal of the uterus)     
or bilateral oophorectomy (the surgical removal of both ovaries)  
o Has not been naturally postmenopausal for at least 24 consecutive 
months (i.e., has had menses at any time during the preceding 24 
consecutive months)  
 
You will be required to use TWO reliable forms of birth control, one highly 
effective method and one additional effective method at the same time or 
practice complete abstinence from heterosexual intercourse during the following 
time periods related to this study: 1) throughout lenalidomide therapy, including 
interruptions in therapy; and 2) for at least 28 days after discontinuation of 
lenalidomide 
 
Pregnancy Risk – Males: 
Lenalidomide is present at very low levels in human semen of healthy men for 
three days after stopping the drug according to a study. For some men, such as 
men with kidney problems, lenalidomide may be present in semen for more than 
three days. For these reasons, to be safe, all male patients receiving 
lenalidomide must use a latex condom during any sexual contact with a pregnant 
female or with a female of childbearing potential while you are participating in this 
study, including during times when lenalidomide is temporarily stopped, and for 
at least 28 days after permanently stopping therapy, even if you have had a 
successful vasectomy. You must NEVER donate blood, sperm, or semen while 
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Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 04.07.14 
 
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you are participating in this study and for at least 28 days after you have stopped 
therapy. 
 
All Patients: 
 
You must NEVER share lenalidomide (or other study drugs) with someone else. 
You must NEVER donate blood while you are participating in this study and for at 
least 28 days after you have been discontinued from the study. You must receive 
counseling and complete phone surveys as required by the Revlimid REMS® 
program. Females of childbearing potential that might be caring for you should 
not touch the lenalidomide capsules or bottles unless they are wearing gloves. 
Any unused lenalidomide should be returned to the study staff. 
Non-Physical Risks: 
 
Because of side effects or the time required for tests and clinic visits while you 
are on this research study, you may be unable to keep up with your normal daily 
activities. 
 
G. WHAT ARE THE BENEFITS OF THE RESEARCH STUDY? 
 
This study may or may not help you because researchers do not know how 
elotuzumab/lenalidomide/dexamethasone or elotuzumab/lenalidomide will 
compare to the usual approach. This study may help researchers learn things 
that may help people in the future. 
 
H. CAN I STOP BEING IN THE RESEARCH STUDY AND WHAT ARE MY RIGHTS? 
 
You have the right to choose not to sign this form.  If you decide not to sign this 
form, you cannot participate in this research study.  
You can stop being in the research study at any time.  Tell the research doctor if 
you are thinking about stopping or decide to stop.  He or she will tell you how to 
stop.  Leaving the research study will not affect your medical care outside of the 
research study.   
 
If you choose not to participate, are not eligible to participate, or withdraw from 
this research study, this will not affect your present or future care and will not 
cause any penalty or loss of benefits to which you are otherwise entitled.  
 
It is important to tell the research doctor if you are thinking about stopping so 
your research doctor can evaluate the risks from stopping the 
elotuzumab/lenalidomide/dexamethasone or elotuzumab/lenalidomide. 
 
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Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 04.07.14 
 
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I. WILL I BE PAID TO TAKE PART IN THIS RESEARCH STUDY? 
 
We may use your samples and information to develop a new product or medical 
test to be sold.  The sponsor and hospital may benefit if this happens. There are 
no plans to pay you if your samples are used for this purpose.  
 
J. WHAT ARE THE COSTS? 
 
Taking part in this research study might lead to added costs to you or your 
insurance company. 
You will not be charged for elotuzumab or lenalidomide. 
 
You or your insurance company will be charged for portions of your care during 
this research study that are considered standard care, such as dexamethasone. 
You may be responsible for co-payments and deductibles that are typical for your 
insurance coverage. 
 
Dexamethasone is commercially available which means that the FDA has 
approved it for use in patients with your type of cancer. Because there is 
evidence that supports using this drug in patients with your type of cancer, you or 
your insurance company will be billed for the cost of dexamethasone. 
 
If you have questions about your insurance coverage, or the items you might be 
required to pay for, please call financial services for information.  The contact 
information for financial services are: 
• Dana-Farber Cancer Institute: (617) 632-3455 
• Massachusetts General Hospital: (617) 726-2191 
 
The National Cancer Institute provides an online resource to help people 
participating in cancer clinical trials understand which services their insurance 
company is required by law to pay.  This can be found at the website below or 
can be provided by the study team: 
 
www.cancer.gov or 1-800-4-CANCER (1-800-422-6237) 
 
K. WHAT HAPPENS IF I AM INJURED OR SICK BECAUSE I TOOK PART IN THIS 
RESEARCH STUDY? 
 
If you think you have been injured as a result of taking part in this research study, 
tell the person in charge of this research study as soon as possible.  The 
research doctor’s name and phone number are listed in this consent form. 
 
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for Biomedical Research 
 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 04.07.14 
 
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DFCI Protocol Number:  
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Approved Date (DFCI IRB Approval):  
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Date Posted for Use:  
02/12/2020 
 
We will offer you the care needed to treat injuries directly resulting from taking 
part in this research.  We may bill your insurance company or other third parties, 
if appropriate, for the costs of the care you get for the injury, but you may also be 
responsible for some of them. 
 
There are no plans for Dana-Farber/Partners CancerCare (DF/PCC) on behalf of 
the Dana-Farber/Harvard Cancer Center (DF/HCC) to pay you or give you other 
compensation for the injury.  You do not give up your legal rights by signing this 
form. 
L. WHAT ABOUT CONFIDENTIALITY? 
 
We will take measures to protect the privacy and security of all your personal 
information, but we cannot guarantee complete confidentiality of study data.  
 
Medical information created by this research study may become part of your 
hospital medical record and may be forwarded to your primary doctor. 
Information that does not become part of your medical record will be stored in 
your study file. It may also become part of a DF/HCC research database.   
 
The results of this research study may be published. You will not be identified in 
publications without your permission. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law.  This Web site will not include information that can 
identify you.  At most, the Web site will include a summary of the results.  You 
can search this Web site at any time. 
 
M. FINANCIAL DISCLOSURES 
 
It is possible that certain researchers on this study may have earned money 
from, or own some publicly-traded stock in, the company that makes or is 
developing the study drug. The amount of money that a researcher may earn and 
still take part in research is limited by the Harvard Medical School Faculty of 
Medicine Policy on Conflicts of Interest and Commitment. If you have further 
questions, please speak with a member of the study team or contact the Dana-
Farber Cancer Institute Office of Research Integrity at 617-432-4557 or 
researchintegrity@dfci.harvard.edu 
 
N. WHOM DO I CONTACT IF I HAVE QUESTIONS ABOUT THE RESEARCH STUDY? 
 
If you have questions about the study, please contact the research doctor or 
study staff as listed below: 
 
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Dana-Farber/ Harvard Cancer Center 
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02/12/2020 
 
Dana-Farber Cancer Institute 
• Irene Ghobrial, MD: Irene_Ghobrial@dfci.harvard.edu 
If you are experiencing an urgent medical issue, please go to the nearest 
emergency medical facility, or contact our site to have your physician paged.  
 
24-hour contact: DFCI: Irene Ghobrial, MD (617) 632-3352 and ask for your 
physician to be paged at beeper 41651 
 
 
  
 
Massachusetts General Hospital 
• Andrew Yee, MD: Ayee1@mgh.harvard.edu  
 
Broad Institute 
• Irene Ghobrial, MD: Irene_Ghobrial@dfci.harvard.edu 
 
For questions about your rights as a research participant, please contact a 
representative of the Office for Human Research Studies at DFCI (617) 632-
3029. This can include questions about your participation in the study, concerns 
about the study, a research related injury, or if you feel/felt under pressure to 
enroll in this research study or to continue to participate in this research study.  
 
O. PRIVACY OF PROTECTED HEALTH INFORMATION 
 
Federal law requires Dana-Farber/Harvard Cancer Center (DF/HCC) and its 
affiliated research doctors, health care providers, and physician network to 
protect the privacy of information that identifies you and relates to your past, 
present, and future physical and mental health conditions (“protected health 
information”).  If you enroll in this research study, your “protected health 
information” will be used and shared with others as explained below. 
 
1. What protected health information about me will be used or shared with 
others during this research? 
 
• Existing medical records, including mental health records. 
• New health information created from study-related tests, procedures, 
visits, and/or questionnaires 
 
2. Why will protected information about me be used or shared with others? 
 
The main reasons include the following: 
• To conduct and oversee the research described earlier in this form; 
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Dana-Farber/ Harvard Cancer Center 
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• To ensure the research meets legal, institutional, and accreditation 
requirements;  
• To conduct public health activities (including reporting of adverse events 
or situations where you or others may be at risk of harm); and 
• To provide the study sponsor with information arising from an adverse 
event or other event that relates to the safety or toxicity of the drug for the 
purpose of this or other research relating the study drug and its use in 
cancer; and, 
• Other reasons may include for treatment, payment, or health care 
operations.  For example, some medical information produced by this 
research study may become part of your hospital medical record because 
the information may be necessary for your medical care. (You will also be 
given a notice for use and sharing of protected health information.) 
 
3. Who will use or share protected health information about me? 
 
• DF/HCC and its affiliated research doctors and entities participating in the 
research will use and share your protected health information.  In addition, 
other DF/HCC offices that deal with research oversight, billing or quality 
assurance will be able to use and share your protected health information. 
 
4. With whom outside of DF/HCC may my protected health information be 
shared? 
 
While all reasonable efforts will be made to protect the confidentiality of your 
protected health information, it may also be shared with the following entities: 
 
• Outside individuals or entities that have a need to access this information 
to perform functions relating to the conduct of this research such as 
analysis by outside laboratories on behalf of DF/HCC and its affiliates (for 
example, data storage companies, insurers, or legal advisors). 
• Bristol-Myers Squibb, who is supporting this research study by providing 
funding for the research study and the study drug  
• Celgene, who is supporting this research study by providing funding for 
the research study and the study drug 
• Other research doctors and medical centers participating in this research, 
if applicable 
• Federal and state agencies (for example, the Department of Health and 
Human Services, the Food and Drug Administration, the National 
Institutes of Health, and/or the Office for Human Research Protections), or 
other domestic or foreign government bodies if required by law and/or 
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Dana-Farber/ Harvard Cancer Center 
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necessary for oversight purposes. A qualified representative of the FDA 
and the National Cancer Institute may review your medical records. 
• Hospital accrediting agencies 
• A data safety monitoring board organized to oversee this research, if 
applicable 
Some who may receive your protected health information may not have to 
satisfy the privacy rules and requirements.  They, in fact, may share your 
information with others without your permission.  
 
5. For how long will protected health information about me be used or 
shared with others? 
 
• There is no scheduled date at which your protected health information that 
is being used or shared for this research will be destroyed, because 
research is an ongoing process.   
 
 
 
6. Statement of privacy rights: 
 
• You have the right to withdraw your permission for the research doctors 
and participating DF/HCC entities to use or share your protected health 
information.  We will not be able to withdraw all the information that 
already has been used or shared with others to carry out related activities 
such as oversight, or that is needed to ensure quality of the study. To 
withdraw your permission, you must do so in writing by contacting the 
researcher listed above in the section: “Whom do I contact if I have 
questions about the research study?” 
• You have the right to request access to your protected health information 
that is used or shared during this research and that is related to your 
treatment or payment for your treatment, but you may access this 
information only after the study is completed.  To request this information, 
please contact the researcher listed above in the section: “Whom do I 
contact if I have questions about the research study?” 
 
P. PRIVACY OF PROTECTED HEALTH INFORMATION 
 
A federal law (Genetic Information Non-Discrimination Act, GINA) will help lower 
the risk from health insurance or employment discrimination on the basis of 
genetic information. The federal law does not include other types of misuse by 
life insurance, long term care or disability insurance. If you want to learn more 
about the GINA Law, which went into effect in 2009, you can find information 
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Dana-Farber/ Harvard Cancer Center 
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about it on the internet or ask the study staff. In addition to the federal law, some 
states have laws that also help to protect against genetic discrimination. 
While we believe that the risks to you and your family are very low, we cannot tell 
you exactly what all of the risks are from taking part in genetic research studies. 
Your privacy and confidentiality will be protected to the fullest extent possible.  
 
Optional Research studies:  
 
Optional Assessment Participation: You have the option of volunteering to 
participate in several correlative studies that are optional throughout this trial. 
These samples are not required, and do not affect your participation in the main 
research study. You will not be given results from these tests. Please refer to 
Section D for details about the procedures and their frequencies. 
Please read the following carefully and indicate your decision by initialing and 
dating below. 
 
 
1. You will be asked to provide a buccal swab (an inner cheek skin sample) 
for DNA analysis as it relates to your disease. This is optional for the 
following time point:  (Study #1) 
 
• At any time during the trial 
 
I agree to give a sample of my DNA (Buccal swab) for this 
research study (Study #1) 
 
 
 
 
 
Yes:□ 
 No:□ 
 
Initials ________ Date _________ 
 
 
 
 
 
 
 
 
 
 
 
 
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2. A bone marrow biopsy is mandatory at screening, to confirm that your 
disease has responded, and at end of treatment however, extra marrow 
fluid samples will be taken for extended research on cellular immunity.  
 
Approximately 1 extra tablespoon of bone marrow aspirate will be used for 
this research and is optional at the following time points: (Study #2) 
 
• Prior to treatment  
• To confirm disease response (whenever that may occur while on 
study) or when clinically indicated by your doctor 
• End of treatment 
 
Approximately 2 tablespoons of blood will be used for this research and is 
optional at the following time points: (Study #2) 
 
• Prior to treatment  
• Each Day 1 from Cycle 1-24 
• To confirm disease response (whenever that may occur while on 
study)  
• End of treatment 
 
 
I agree to give additional samples of my blood and bone marrow for 
research purposes (Study #2) 
 
 
 
 
 
Yes:□ 
 No:□ 
 
Initials ________ Date _________ 
 
 
 
 
 
 
 
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Q. DOCUMENTATION OF CONSENT 
 
My signature below indicates: 
• I have had enough time to read the consent and think about 
participating in this study; 
• I have had all of my questions answered to my satisfaction; 
• I am willing to participate in this study; 
• I have been told that my participation is voluntary and I can withdraw at 
any time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Participant 
 
 
 
Date 
or Legally Authorized Representative   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relationship of Legally Authorized Representative to Participant   
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Adult Participants 
 
To be completed by person obtaining consent: 
 
The consent discussion was initiated on   
 (date). 
 
Signature of individual obtaining consent:  
 
 
Printed name of above:   
 
 
Date:  
 
 
 A copy of this signed consent form will be given to the participant or legally authorized 
representative, or, where the participant is a minor, the participant’s parent or legal guardian. 
For Adult Participants 
 1)  The participant is an adult and provided consent to participate. 
 
 1a)  Participant (or legally authorized representative) is a non-English speaker and 
 
signed the translated Short Form in lieu of English consent document: 
 
As someone who understands both English and the language spoken by the participant, I 
interpreted and/or witnessed, in the participant’s language, the researcher’s presentation 
of the English consent form.  The participant was given the opportunity to ask questions.  
Signature of Interpreter/Witness:  
 
Printed Name of Interpreter/Witness:  
 
Date:  
 
 
 1b)  Participant is illiterate 
 
The consent form was read to the participant who was given the opportunity  
 
to ask questions.  
Signature of Witness:  
 
Printed Name of Witness:  
 
Date:  
 
 2)  The participant is an adult who lacks capacity to provide consent and his/her legally 
authorized representative: 
 2a) gave permission for the adult participant to participate  
 2b) did not give permission for the adult participant to participate  
2/12/2020 11:34 am