Clinical trial NCT01335399
Conditions: Multiple Myeloma
Keywords: Newly Diagnosed Previously Untreated
Sponsor: Bristol-Myers Squibb
Start date: 2011-08-04; Completion date: 2021-09-03
Enrollment: 748 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to determine whether the addition of Elotuzumab to Lenalidomide/low-dose Dexamethasone will increase the progression free survival (PFS)

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Lenalidomide intervention 2: Dexamethasone intervention 3: Dexamethasone intervention 4: Dexamethasone intervention 5: Dexamethasone intervention 6: Elotuzumab (BMS-901608; HuLuc63) intervention 7: Elotuzumab (BMS-901608; HuLuc63)
Intervention descriptions: intervention 1: Capsules, Oral, 25 mg, once daily, on Days 1-21, Repeat every 28 days until subject meets criteria for discontinuation of study drug intervention 2: Tablets, Oral, 40 mg, weekly, on Days 1, 8, 15, 22, Repeat every 28 days until subject meets criteria for discontinuation of study drug intervention 3: Tablets, Oral, 28 mg, once daily, on Days 1, 8, 15, 22 (cycles 1\&2) ; Days 1 \&15 (cycles 3-18); Day 1 (cycle 19 and beyond), Repeat every 28 days until subject meets criteria for discontinuation of study drug intervention 4: Tablets, Oral, 40 mg, once daily, on Days 8 \& 22 (cycles 3-18); Days 8, 15, 22 (cycle 19 and beyond), Repeat every 28 days until subject meets criteria for discontinuation of study drug intervention 5: Solution, Intravenous (IV), 8 mg, Once daily, on Days 1, 8, 15, 22 (cycles 1\&2) ; Days 1 \&15 (cycles 3-18); Day 1 (cycle 19 and beyond), Repeat every 28 days until subject meets criteria for discontinuation of study drug intervention 6: Solution, Intravenous (IV), 10 mg/kg, weekly, on Days 1, 8, 15, 22 (cycles 1\&2); Days 1 and 15 (cycles 3-18), Repeat every 28 days until subject meets criteria for discontinuation of study drug intervention 7: Solution, Intravenous (IV), 20 mg/kg, Day 1 (cycle 19 and beyond), Repeat every 28 days until subject meets criteria for discontinuation of study drug

Protocol documents:
Prot_001.pdf: 
Page:
1
Protocol Number:
CA204006
IND Number:
100, 043
Ex-US
Non-IND
EUDRACT Number
2010-022445-20
Date:
15-Mar-2011
Revised Date:
24-Aug-2016
Clinical Protocol CA204006
A Phase 3, Randomized, Open Label Trial of Lenalidomide/dexamethasone With or Without 
Elotuzumab in Subjects with Previously Untreated Multiple Myeloma
Revised Protocol Number: 05
Incorporates Amendment 07
Study Director/Central Medical Monitor
Suresh Shelat, MD PhD
 
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
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be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved.
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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Elotuzumab
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 
05
24-Aug-2016
Incorporates Amendment 07
Amendment 07
24-Aug-2016

 
 


Remove the following sentence from Section 4.3.1. “On the 
days of elotuzumab administration, the dose of lenalidomide is 
to be administered at least 2 hours after completion of 
elotuzumab dosing.

Change referencing of Experimental treatment arm of 
lenalidomide/dexamethasone + elotuzumab from LdE to E-Ld.


Add Section 9.1.2.1 Source Documentation

Update Section 9.2.2 Study Drug Records
Revised Protocol 
04
17-Aug-2015
Incorporates Amendment 6 and Administrative Letters 07 and 08
Amendment 06
17-Aug-2015

Update statistical assumptions and protocol treatment rationale 
based on currently available published data

Clarify requirements for subjects with no measureable urine M 
protein at baseline

Inclusion of new PK/HAHA collection after Cycle 18

Inclusion of updated safety information regarding use of adequate 
contraception based on recent elotuzumab PK data.

Change recommended diluent volume of elotuzumab from fixed 
volumes to range of 100-500 mL.    
Administrative 
Letter 08
08-Dec-2014
Supersedes Administrative Letter 07, corrects typographical errors in 
Appendix 6 and Sec.4.3.2.2 of protocol
Administrative 
Letter 07
04-Nov-2014
Correct typographical errors and align text in Appendix 6 with 
corresponding text in Sec. 4.3.2.2 of protocol.
Revised Protocol 
03
21-Aug-2014
Incorporates Amendment 5 and Administrative Letter 6
Administrative 
Letter 06
08-Jul-2014
Revision of typographical errors in the protocol and appendix.  
Amendment 05
21-Aug-2014

Planned Interim Analysis will now take place at 70% of events 
(338 events) compared to the previous timepoint of 241 (50%) 
progression events

BPI-SF pain severity and pain interference will be evaluated as a 
secondary endpoint, and formal comparison between treatment 
arms will be conducted, though it will not be included hierarchical 
testing.

 
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Document
Date of Issue
Summary of Change

Correction of typographical errors in the protocol and appendix 
documents.
Revised Protocol 
02
21-May-2014
Incorporates Amendment 4 and Administrative Letters 1-5
Amendment 04
21-May-2014

Elotuzumab infusion rate escalation plan added to decrease the 
infusion of elotuzumab to approximately 1 hour

Change to the UPEP efficacy testing to reduce the requirement of 
24 hour urine collection in a subset of patients

Broadening of the medications that can be used for 
thromboprophylaxis. 

Additional Clarifications in the protocol serve to reduce any 
ambiguity regarding study procedures, and provide additional 
guidance of the EBMT efficacy requirements.
Admin Letter 05
21-Aug-2013
Document change in BMS Medical Monitor
Admin Letter 04
25-Jan-2013
Document change in BMS Medical Monitor
Admin Letter 03
19-Jul-2012
Document change in BMS Medical Monitor
Admin Letter 02
24-May-2012
Correct error in Dexamethasone Dose Level Table 4.3.4.2B
Admin Letter 01
04-Apr-2012
Correct date of original protocol modified in error.
Revised Protocol 
01
15-Mar-2012
Incorporates Amendment 02.
Amendment 02
15-Mar-2012

Clarification of subject eligibility or study procedures.

Modification of screening requirements to conform to the standard 
of care and to enhance overall study conduct.

A revision was made to timing of when pregnancy testing must be 
completed. This change is in compliance with a recently approved, 
company-wide SOP for women of childbearing potential 
participating in clinical trials conducted by the Sponsor.

The inclusion criteria have been revised to clarify that refusal to 
undergo high dose therapy with SCT is NOT sufficient for entry 
onto 006 for a subject < 65 years old. There must be a comorbidity 
that prevents SCT for a subject < 65 years old.

Instructions for what should be done with missed doses of 
lenalidomide or dexamethasone.

Revisions are made to exclusion criteria for clarity and consistency 
throughout the development program.

The requirement to discontinue elotuzumab and lenalidomide if a 
subject becomes pregnant.

Timing and details surrounding when certain study assessments are 
performed.

An update to the shelf-life of reconstituted elotuzumab.

Correction of typographical errors.
Original Protocol
15-Mar-2011
Not applicable.
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SYNOPSIS
Clinical Protocol CA204006
Title of Study: A Phase 3, Randomized, Open Label Trial of Lenalidomide/dexamethasone With or without 
Elotuzumab in Subjects with previously untreated Multiple Myeloma
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):
Control Arm: 

Lenalidomide: 25 mg po QD Days 1 - 21

Dexamethasone: 40 mg po Days 1, 8, 15, and 22
Investigational Arm:

Elotuzumab 

Cycles 1 - 2: 10 mg/kg IV Days 1, 8, 15, and 22

Cycles 3 - 18: 10 mg/kg IV Days 1 and 15

Cycle 19 and beyond: 20 mg/kg IV Day 1

Lenalidomide: 25 mg po QD, Days 1 - 21

Dexamethasone administered on Days 1, 8, 15, and 22 of each cycle:

On weeks when elotuzumab is administered:
o
28 mg po (3 - 24 hours prior to start of elotuzumab infusion) AND
o
8 mg IV (at least 45 minutes prior to elotuzumab administration)

On weeks when elotuzumab is NOT administered:
o
40 mg po 
A cycle is defined as 28 days. Treatment with study drug continues until disease progression, unacceptable toxicity 
or subject meets other criteria for discontinuation of study drug outlined in Section 3.5. 
Study Phase: 3
Research Hypothesis: The addition of elotuzumab to lenalidomide/dexamethasone will increase the Progression 
Free Survival (PFS).
Primary Objective: To compare the PFS of lenalidomide/dexamethasone + elotuzumab (E-Ld) versus 
lenalidomide/dexamethasone (Ld) in subjects with newly diagnosed, previously untreated multiple myeloma (MM).
Secondary Objectives:

To compare objective response rate between treatment arms

To compare overall survival between treatment arms

To compare the change from baseline of the mean score of pain severity and the change from baseline of the 
mean score of pain interference using the Brief Pain Inventory - Short Form (BPI-SF) between treatment arms

To assess PFS rates at 1, 2, 3, 4, and 5 years 
 
 
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Figure 1:
Study Design: 
This is a Phase 3, open-label, multi-center trial investigating lenalidomide/dexamethasone with and without 
elotuzumab in subjects with newly diagnosed, untreated, symptomatic, measurable myeloma who are ineligible for 
high-dose therapy plus stem-cell transplantation (SCT) because of age (65 years) or coexisting conditions.
Eligible subjects will be randomized in a 1:1 ratio to receive either lenalidomide/dexamethasone (Ld) or 
lenalidomide/dexamethasone/elotuzumab (E-Ld). The randomization will be stratified by:

ISS stage (1 - 2 versus 3)

Age (< 75 years old versus 75 years old)

ECOG status (0 versus 1 - 2)
E
N
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L
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N
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(n = 375)
(n = 375)
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A
N
D
O
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A
T
I
O
N
Control Arm
Lenalidomide
25 mg po: Days 1 - 21 
Dexamethasone
40 mg po Day 1,8,15, and 22
28 DAY Cycle
Tumor Assessments every 4 weeks
FOLLOW UP
Follow-up every 
4 weeks for 
tumor response 
until PD then 
survival every 
16 weeks, or 
more frequently
FOLLOW UP
Follow-up every 
4 weeks for 
tumor response 
until PD then 
survival every 
16 weeks, or 
more frequently
Investigational Arm
Elotuzumab
10 mg/kg IV
Cycles 1 - 2: Day 1, 8, 15, 22
Cycles 3 - 18: Day 1, 15
20mg/kg IV
Cycles 19 and beyond: Day 1 
Lenalidomide
25 mg po: Days 1 - 21 
Dexamethasone
Weeks with Elo - 8 mg IV + 28 mg po
(per Section 4.3)
Weeks without Elo - 40 mg po 
28 DAY Cycle
Tumor Assessments every 4 weeks
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Tumor assessments, based on the EBMT criteria, must be conducted every 4 weeks (-1/+3 days) relative to the first 
dose of study medication until disease progression, death or withdrawal of consent. The date of progression, best 
response and date of response used in the efficacy analysis will be based on the independent review committee 
(IRC). Subjects will be followed at least every 16 weeks, or more frequently, after disease progression for survival 
and subsequent myeloma therapy. Cross-over between the arms is not permitted.
An independent Data Monitoring Committee (DMC) will review the safety of the trial on a routine basis. In addition 
there will be an interim analysis for safety and efficacy once the following two conditions have been met: at least 
338 progression events (70%) have been observed and all subjects have been randomized.
Blood samples for pharmacokinetic and immunogenicity analysis will be collected in all subjects who received 
elotuzumab.
Study Population:
Subjects who are newly diagnosed with symptomatic Multiple Myeloma and who:

have not received any prior systemic anti-myeloma therapy AND

have measurable disease AND

are not candidates for high-dose therapy plus stem-cell transplantation because of age (65 years) or coexisting 
conditions
Study Assessments and Primary Endpoint: 
Tumor response assessment by EBMT criteria will be evaluated during the trial for all randomized subjects. An IRC 
(Independent Review Committee) will conduct a blinded, independent review of these tumor assessments. The 
primary endpoint of PFS will be based on the IRC assessment. 
Statistical Methods:
Power
The primary objective in this study is to compare PFS between treatment groups at the two-sided, 5% type I error 
rate. There will be 1 interim analysis of PFS, which will allow for early stopping for superiority. An O’Brien and
Fleming function will be employed to determine the stopping boundaries for superiority. The comparisons of PFS 
will be carried out using log-rank tests stratified by stage of disease (International Staging System 1 - 2 versus 3), 
ECOG performance status (0 versus 1 - 2), and age (< 75 years old versus 75 years old).
Approximately 750 subjects will be randomized to the 2 treatment groups in a one-to-one ratio to obtain at least 
482 progression events (as per IRC), ie, documented progressions or deaths. Four hundred eighty two (482) events 
ensure that a two-sided test procedure with a family-wise type I error rate of 5% and 1 interim analysis after 70% of 
the total events (338) will have 90.5% power if the median PFS times in the control and experimental arms are
25 and 33.75 months, respectively, ie, if the hazard ratio of the experimental to control arm is 0.74. Assuming an 
accrual rate of 24 subjects per month, it will take approximate 60 months to obtain the required number of events, 
31 months for accrual and 29 months for PFS follow-up.
Survival, a key secondary endpoint, will be compared at an interim analysis between the two arms at the time of the 
interim analysis of PFS provided that PFS and ORR analyses are positive. The final survival analysis will take place 
after 354 deaths, which is projected to occur 7 years (84 months) after the initiation of the study. An O’Brien and 
Fleming -spending function will be used to obtain the nominal significance levels for the interim and final analyses 
of survival. Three hundred and fifty-four (354) deaths ensure that a two-sided 5% level sequential test procedure 
with one interim analysis will have 80% power for a 8.7 percentage point improvement in 4-year survival rate from 
59.0% to 67.7%, ie, for a HR = 0.74.
Power calculations were done using East v5.1 software. (See Section 8.1, Sample Size Determination, for more 
detail.)
Endpoint Definitions and Analyses
The primary endpoint in this study is progression-free survival (PFS), which is defined as the time from 
randomization to the date of the first documented tumor progression, as determined by the IRC using EBMT criteria, 
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or to death. Subjects who neither progress nor die will be censored on the date of their last disease assessment, 
provided death does not occur more than 10 weeks after the last tumor assessment.
The following censoring rules will be applied to PFS:

Subjects who receive systemic secondary anti-myeloma therapy prior to documented progression will be 
censored on the date of their last tumor assessment prior to initiation of new therapy

Subjects who have an event > 10 weeks after the last prior tumor assessment will be censored at the last prior 
assessment

Subjects who do not progress and who do not receive subsequent therapy will be censored at their last tumor 
assessment
See Section 8.3, Endpoint Definitions, for more detail on the definition of PFS.
A stratified log-rank test will be used to compare PFS between treatment arms. The factors will be the same as those 
used in the randomization. The hazard ratio of the experimental to the control arm and corresponding two-sided 95% 
confidence interval will be calculated using a stratified Cox proportional hazards model with treatment as the sole 
covariate. The Kaplan-Meier product limit method will be used to display PFS curves and PFS rates at 1-5 years will 
be obtained from those curves. Each rate will be estimated after all subjects have been followed for the appropriate 
time.
The key secondary endpoints are:

Objective response rate

Overall survival
Objective response rate (ORR) is defined as the proportion of randomized subjects who have a best overall response 
of partial response or better. Overall survival is the time from randomization until death. Subjects who do not die 
will be censored at the date of last contact.
A hierarchical procedure will be used to ensure a two sided family-wise type I error rate of 5% for testing the one 
primary and two key secondary endpoints. If there is a statistically significant improvement in PFS, then ORR will 
be compared between arms at the two-sided 5% level. If the comparison of ORR is also statistically significant, then 
survival will be compared between arms using a two-sided 5% level sequential test procedure. 
Objective response rate will be compared between randomized arms using a two-sided 5% level Cochran-Mantel 
Haenszel (CMH) test stratified by the same factors used in the analysis of PFS. An associated odds ratio and 
95% confidence interval will be calculated. The response rate and its corresponding 95% confidence interval will 
also be calculated for each treatment arm. There will be no interim comparison of this endpoint.
Survival will be compared between treatment arms using two-sided, stratified log-rank tests at the interim and final 
looks. The family-wise type I error rate for the sequential testing procedure will be 5% and the stratification factors 
will be the same as those used for the randomization. The significance level at the interim and final analyses of 
survival will be determined using an O’Brien and Fleming spending function.
Other Secondary endpoints include change from baseline in mean score of pain severity and mean score of pain 
interference using the BPI-SF. The two endpoints will be tested at the 2-sided 2.5% level each and will not be part of 
the hierarchical testing procedure. For these two endpoints, comparison will be conducted using a longitudinal 
mixed model with treatment arm and time point (categorical) and baseline score as fixed effects and a banded 
covariance matrix (covariances are constant on each diagonal of the matrix).
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
 
 
 
 
 
 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives ......................................................................................................... 
1.3.1 Primary Objective .................................................................................... 
1.3.2 Secondary Objectives ............................................................................... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.2.1 Withdrawal of Consent ............................................................................ 
3.2.2 Lost to Follow-Up .................................................................................... 
3.3 Study Population ............................................................................................... 
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3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
 
 
 
 
 
3.5 Discontinuation of Subjects from Treatment .................................................... 
3.6 Post Study Drug Study Follow up .................................................................... 
4 TREATMENTS ......................................................................................................... 
4.1 Study Treatments .............................................................................................. 
4.1.1 Investigational Product ............................................................................ 
4.1.2 Noninvestigational Product ..................................................................... 
4.1.3 Handling and Dispensing ........................................................................ 
4.1.3.1 Elotuzumab ..................................................................................... 
4.1.3.2 Lenalidomide................................................................................... 
4.2 Method of Assigning Subject Identification ..................................................... 
4.3 Selection and Timing of Dose for Each Subject ............................................... 
4.3.1 Study Drug Administration ...................................................................... 
4.3.1.1 Premedication Regimen in Subjects Without a Prior Infusion 
Reaction ................................................................................................ 
4.3.1.2 Premedication Regimen in Subjects With a Prior Infusion Reaction
............................................................................................................... 
4.3.2 Guidelines for Elotuzumab Infusion in Subjects with Infusion Reactions
..................................................................................................................... 
4.3.2.1 Grade 1 Infusion Reaction .............................................................. 
4.3.2.2 Grade  2 Infusion Reaction ........................................................... 
4.3.3 Dose Delay or Interruption ...................................................................... 
4.3.3.1 Elotuzumab ..................................................................................... 
4.3.3.2 Dexamethasone ............................................................................... 
4.3.3.3 Lenalidomide................................................................................... 
4.3.4 Recommended Dose Reductions .............................................................. 
4.3.4.1 Elotuzumab ..................................................................................... 
4.3.4.2 Dexamethasone Reductions ............................................................ 
4.3.4.3 Lenalidomide................................................................................... 
4.4 Blinding/Unblinding ......................................................................................... 
4.5 Treatment Compliance ...................................................................................... 
4.6 Destruction and Return of Study Drug ............................................................. 
4.6.1 Destruction of Study Drug ....................................................................... 
4.6.2 Return of Study Drug ............................................................................... 
4.7 Retained Samples for Bioavailability / Bioequivalence ................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
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5.3.1 Vital Signs, Physical Measurements, and Physical Examination ............ 
5.3.2 Performance Status .................................................................................. 
5.3.3 Echocardiogram or MUGA scan and Electrocardiogram ...................... 
5.3.4 Laboratory Assessments for Safety .......................................................... 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Efficacy Assessment ................................................................................. 
5.4.2 Laboratory Assessments for Myeloma ..................................................... 
5.4.3 Imaging Assessments for Myeloma .......................................................... 
5.4.3.1 Skeletal Survey ................................................................................ 
5.4.3.2 Assessment of Extramedullary Plasmacytoma................................ 
5.4.4 Independent Review Committee ............................................................... 
5.4.5 Definitions of Response............................................................................ 
5.4.5.1 Complete Response (CR)/stringent CR (sCR) ................................. 
5.4.5.2 Partial Response (PR)..................................................................... 
5.4.5.3 Very Good Partial Response (VGPR) ............................................. 
5.4.5.4 Minor (Minimal) Response (MR) .................................................... 
5.4.5.5 Progression of Disease (PD) .......................................................... 
5.4.5.6 Stable Disease/No Change .............................................................. 
 
 
 
 
5.8 Outcomes Research Assessments ..................................................................... 
5.8.1 HRQoL Assessments ................................................................................ 
5.8.2 Healthcare Resource Utilization .............................................................. 
5.9 Other Assessments ............................................................................................ 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Abnormalities ......................................................................... 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury ................................................................. 
6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoint Definitions ......................................................................................... 
8.3.1 Progression-Free Survival ....................................................................... 
8.3.2 Objective Response Rate .......................................................................... 
 
 
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8.3.6 Survival .................................................................................................... 
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Primary Efficacy Analysis............................................................... 
 
8.4.2.3 Secondary Efficacy Analyses .......................................................... 
8.4.3 Safety Analyses......................................................................................... 
 
 
 
8.4.7 Outcomes Research Analyses .................................................................. 
8.4.7.1 Analysis of HRQoL Data ................................................................ 
8.4.7.2 Analysis of Healthcare Resource Utilization Data ......................... 
8.4.8 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Publications ....................................................................................................... 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
APPENDIX 1 INTERNATIONAL STAGING SYSTEM ........................................... 
APPENDIX 2 PERFORMANCE STATUS SCALES ................................................. 
 
 
APPENDIX 5 BRIEF PAIN INVENTORY (SHORT FORM) .................................... 
APPENDIX 6 PREPARATION AND ADMINISTRATION OF ELOTUZUMAB ... 
 
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1
INTRODUCTION AND STUDY RATIONALE
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.2
Research Hypothesis
The addition of elotuzumab to lenalidomide/dexamethasone will increase the progression free 
survival (PFS).
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1.3
Objectives
1.3.1
Primary Objective
To 
compare 
PFS 
of 
lenalidomide/dexamethasone 
+ 
elotuzumab 
(E-Ld)
versus 
lenalidomide/dexamethasone (Ld) in subjects with newly diagnosed, untreated multiple myeloma 
(MM).
1.3.2
Secondary Objectives

To compare objective response rate between treatment arms

To compare overall survival between treatment arms

To compare the change from baseline of the mean score of pain severity and the change from 
baseline of the mean score of pain interference using the Brief Pain Inventory- Short Form 
(BPI-SF) between treatment arms

To assess PFS rates at 1, 2, 3, 4, and 5 years.
 
 
 
 
 
 
 
 
 
 
 
 
 
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
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The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective task(s).
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion
from the IRB/IEC for the protocol, consent form, subject recruitment materials/process 
(eg, advertisements), and any other written information to be provided to subjects. The 
investigator or sponsor should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling, information to be provided to subjects and any updates. 
The investigator or sponsor should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects, or, in those situations where consent cannot be given by 
subjects, their legally acceptable representatives, are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they 
volunteer to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood
2) Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study
3) Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion
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4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating their 
informed consent during the study, then consent must additionally be obtained from the 
subject
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a Phase 3, open-label, multi-center trial investigating lenalidomide/ dexamethasone with 
and without elotuzumab in subjects with newly diagnosed, untreated, symptomatic, measurable 
myeloma who are ineligible for high-dose therapy plus stem-cell transplantation (SCT) because 
of age (65 years) or coexisting conditions.
Eligible subjects will be randomized in a 1:1 ratio to receive either lenalidomide/ dexamethasone 
(Ld) [Control Arm] or lenalidomide/dexamethasone/elotuzumab (E-Ld) [Investigational Arm]. 
The randomization will be stratified by:

Stage of disease (International Staging System 1 - 2 versus 3), see Appendix 1

Age (< 75 years old versus 75 years old)

ECOG Performance status (0 versus 1 - 2)
Control Arm: 

Lenalidomide: 

25 mg po QD Days 1 - 21 

Dexamethasone: 

40 mg po weekly Days 1, 8, 15, and 22 
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Investigational Arm: 

Elotuzumab 

Cycles 1 - 2: 10 mg/kg IV Days 1, 8, 15, and 22 

Cycles 3 - 18: 10 mg/kg IV Days 1 and 15 

Cycle 19 and beyond: 20 mg/kg IV Day 1

Lenalidomide: 

25 mg po QD, Days 1 - 21 

Dexamethasone administered on Days 1, 8, 15 and 22 of each cycle: 

On weeks when elotuzumab is administered: 
28 mg po (3 - 24 hours prior to start of elotuzumab infusion) AND
8 mg IV (at least 45 minutes prior to elotuzumab administration)

On weeks when no elotuzumab is administered:
40 mg po 
Figure 3.1-1:
Study Schema
E
N
R
O
L
L
M
E
N
T
(n = 375)
(n = 375)
R
A
N
D
O
M
I
Z
A
T
I
O
N
Control Arm
Lenalidomide
25 mg po: Days 1 - 21 
Dexamethasone
40 mg po Day 1,8,15, and 22
28 DAY Cycle
Tumor Assessments every 4 weeks
FOLLOW UP
Follow-up every 
4 weeks for 
tumor response 
until PD then 
survival every 
16 weeks, or 
more frequently
FOLLOW UP
Follow-up every 
4 weeks for 
tumor response 
until PD then 
survival every 
16 weeks, or 
more frequently
Investigational Arm
Elotuzumab
10 mg/kg IV
Cycles 1 - 2: Day 1, 8, 15, 22
Cycles 3 - 18: Day 1, 15
20 mg/kg IV
Cycles 19 and beyond: Day 1 
Lenalidomide
25 mg po: Days 1 - 21 
Dexamethasone
Weeks with Elo - 8 mg IV + 28 mg po
(per Section 4.3)
Weeks without Elo - 40 mg po 
28 DAY Cycle
Tumor Assessments every 4 weeks
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Figure 3.1-2:
Dosing Schedule
Control Arm
Cycle #
1 - 2
3 - 18
19+
Day # (-1/+3 days)
1
8
15
22
1
8
15
22
1
8
15
22
Lenalidomide - po
25 mg Days 1 - 21
25 mg Days 1 - 21
25 mg Days 1 - 21
Dexamethasone - po
40 mg
40 mg
40 mg
40 mg
40 mg
40 mg
40 mg
40 mg
40 mg
40 mg
40 mg
40 mg
Investigational Arm
Cycle #
1 - 2
3 - 18
19+
Day # (-1/+3 days)
1
8
15
22
1
8
15
22
1
8
15
22
Lenalidomide - po
25 mg Days 1 - 21
25 mg Days 1 - 21
25 mg Days 1 - 21
Dexamethasone - po
28 mg
28 mg
28 mg
28 mg
28 mg
40 mg
28 mg
40 mg
28 mg
40 mg
40 mg
40 mg
Dexamethasone - IV
8 mg
8 mg
8 mg
8 mg
8 mg
-
8 mg
-
8 mg
-
-
-
Elotuzumab - IV
10 mg/kg
10 mg/kg
10 mg/kg
10 mg/kg
10 mg/kg
-
10 mg/kg
-
20 mg/kg
-
-
-
A cycle is defined as 28 days. Treatment with study drug continues until disease progression, unacceptable toxicity or subject meets 
other criteria for discontinuation of study drug outlined in Section 3.5
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Tumor assessments, based on the EBMT criteria, will be conducted every 4 weeks (-1/+3 days) 
relative to the first dose of study medication until disease progression, death or withdrawal of 
consent. The date of progression, best response and date of response used in the primary efficacy 
analyses will be based on the independent review committee (IRC) assessments as well as the 
investigators. All subjects must continue to have protocol-specified tumor assessments until 
disease progression (even if the subject is off study therapy or has started on a new anti-myeloma 
therapy, as specified in the ITT definition of PFS in Section 8.3.1), death, or withdrawal of 
consent from the study. Once subjects reach disease progression, they shall be followed at least 
every 16 weeks after disease progression for overall survival and subsequent myeloma therapy. 
Cross-over between the arms is not permitted.
An independent DMC will conduct regular safety reviews throughout this trial. In addition, there 
will be a pre-planned interim analysis for safety and PFS once the following two conditions have 
been met: at least 338 (70%) progression events have been observed per IRC and all subjects 
have been randomized. 
Subjects who receive any non-protocol specified systemic anti-myeloma therapy prior to 
documented progression will be discontinued from study treatment (see Section 3.5). However, 
tumor assessments should continue at 4 week intervals until documented progression to comply 
with the intent to treat analysis (Section 8.3.1).
Subjects will continue to be followed until the last subject has the last follow-up visit which is 
projected to occur approximately 7 years from the first randomized subject.
3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive study drug. Study drug will be provided via an extension of the study, a 
rollover study requiring approval by responsible health authority and ethics committee or 
through another mechanism at the discretion of the sponsor. The sponsor reserves the right to 
terminate access to study drug if any of the following occur: a) the marketing application is 
rejected by responsible health authority; b) the study is terminated due to safety concerns; 
c) the subject can obtain medication from a government sponsored or private health program; or 
d) therapeutic alternatives become available in the local market.
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3.2.1
Withdrawal of Consent
Subjects should be encouraged to continue participation in the trial until the laboratory definition 
of disease progression is met (Section 5.4.5.5). Subjects who discontinue study therapy before 
progression (eg, due to toxicity) should be encouraged to allow the necessary laboratory results 
(eg, M-protein data, radiologic data, calcium results) to be collected until progression criteria are 
fulfilled, even if the subject is on subsequent therapy (as per the PFS ITT definition in 
Section 8.3.1). These data can be obtained by the subject’s local health care provider or the site 
staff and then analyzed and entered into the CRF/database by the central or local lab. Withdrawal 
of consent should be minimized because:
1. The subject in this trial who discontinues study therapy before progression will most likely 
subsequently be followed in any case by a healthcare provider locally or at the site via 
routine standard of care assessments (ie, monthly M-protein data, calcium, etc) and
2. In most cases, this protocol would not require any additional samples beyond those 
considered standard of care
If there is uncertainty about the progression criteria, investigators are encouraged to contact the 
BMS medical monitor/study director prior to:
1. starting a subject on another myeloma regimen or 
2. performing the end of treatment visit for progression
Subjects who request to discontinue study drug will remain in the study and must continue 
protocol specified follow-up procedures. The only exception to this is when a subject specifically 
withdraws consent for any further contact with him/her or persons previously authorized by 
subject to provide this information. Subjects should notify the investigator of the decision to 
withdraw consent from future follow-up in writing, whenever possible. The withdrawal of 
consent should be explained in detail in the medical records by the investigator (and entered onto 
the appropriate CRF page), as to whether the withdrawal is from further:
1. study medication but subject is willing to continue to perform visits for PFS follow-up. study 
medication and study visits for PFS but agrees to provide the results of future myeloma 
assessments from another site/local site
2. study treatments, results from another site/local sites, but agrees to be contacted for overall 
survival follow-up
In the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
3.2.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
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follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death. 
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public
health registries, obituary listings, and databases, in order to obtain updated contact information. 
If after all attempts, the subject remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the subject’s medical 
records.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subject is, in the investigator’s opinion, willing and able to comply with the protocol 
requirements.
b) Subject has given 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 their future 
medical care.
2. Target Population
a) Age 18 years or legal age of consent per local regulations.
b) ECOG performance status 2.
c) Life-expectancy > 3 months.
d) Newly diagnosed, untreated, symptomatic, documented myeloma AND;
i)
Who are not candidates for high-dose therapy plus SCT because of age (65 years) 
or coexisting conditions. Refusal to undergo high dose therapy with SCT is NOT 
sufficient for entry onto CA204006 for a subject < 65 years old. There must be a 
comorbidity that prevents SCT for a subject < 65 years old, AND;
ii) Measureable disease (patient must meet one of these criteria)
(a) serum IgG M-protein 0.5 g/dL OR
(b) serum IgA M-protein 0.5 g/dL OR
(c) serum IgM M-protein 0.5 g/dL OR
(d) serum IgD M-protein 0.05 g/dL OR
(e) Urine M-protein 200 mg/24-hour
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3. Age and Reproductive Status
a) Women of childbearing potential (WOCBP) and men must be using 2 acceptable 
methods of contraception to avoid pregnancy throughout the study for a period of at least 
1 month (4 weeks) before and women for up to 120 days, men for up to 180 days after the 
last dose of investigational product in such a manner that the risk of pregnancy is 
minimized. See Section 3.3.3 for the definition of WOCBP and also refer to the Revlimid 
risk management plan guidelines.
b) WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG). The first should be performed within 10 - 14 days 
and the second within 24 hours prior to the start of the investigational product. A 
prescription for lenalidomide for a female of childbearing potential must not be issued by 
the prescriber until negative pregnancy tests have been verified by the prescriber.
c) Women must not be breastfeeding.
d) Women who are not of childbearing potential (ie, who are postmenopausal or surgically 
sterile; see Section 3.3.3 for the definition of WOCBP) and men.
e) Sexually active fertile men must use effective birth control if their partners are WOCBP. 
Men must agree to use a latex condom and a second form of birth control during sexual 
contact with WOCBP, even if they have had a successful vasectomy, and must agree to 
not donate semen during study drug therapy and for 180 days after therapy.
f)
Subjects must be willing to refrain from blood donations during study drug therapy and 
for 90 days after therapy.
3.3.2
Exclusion Criteria
1) Target Disease Exceptions 
a) Subjects with non-secretory or oligo-secretory or serum free light-chain only myeloma.
b) Smoldering MM, defined as asymptomatic MM with absence of lytic bone lesions.
c) Monoclonal Gammopathy of Undetermined Significance (MGUS) defined by all of the 
following: serum M protein < 3 g/dL, absence of lytic bone lesions, anemia, 
hypercalcemia and renal insufficiency related to monoclonal protein and (if determined) 
proportion of plasma cells in the bone marrow of 10% or less.
d) Diagnosis of Waldenstrom's disease or other conditions in which IgM M protein is 
present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
e) Plasma cell leukemia (defined as either 20% of peripheral WBC comprised of 
plasma/CD138+ cells or an absolute count of 2 x 109/L).
2) Medical History and Concurrent Diseases 
a) POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein, and skin changes).
b) Significant cardiac disease as determined by the investigator including:
i)
Known or suspected cardiac amyloidosis;
ii) Congestive heart failure of Class III or IV of the NYHA classification;
iii) Uncontrolled angina, hypertension or arrhythmia;
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iv) Myocardial infarction in past 6 months;
v) Any uncontrolled or severe cardiovascular disease.
c) Prior cerebrovascular event with persistent neurologic deficit.
d) Known HIV infection or active hepatitis A, B, or C.
e) Any medical conditions that, in the investigator’s opinion, would impose excessive risk 
to the subject. Examples of such conditions include:
i)
Any uncontrolled disease, such as pulmonary disease, infection, seizure disorder;
ii) Active infection that requires parenteral anti-infective treatment;
iii) Any altered mental status or any psychiatric condition that would interfere with the 
understanding of the informed consent.
f)
Prior or concurrent malignancy, except for the following:
i)
Adequately treated basal cell or squamous cell skin cancer;
ii) Or any other cancer from which the subject has been disease-free for > 5 years.
g) Uncontrolled diabetes (defined as Hgb A1C 8.0%).
h) Unable to tolerate thromboembolic prophylaxis including, aspirin, Coumadin (warfarin) 
or low-molecular weight heparin as clinically indicated.
3) Physical and Laboratory Test Findings
a) Corrected serum calcium 11.5 mg/dl within 2 weeks of randomization (despite 
appropriate measure such a short course of steroids, bisphosphonates, hydration, 
calcitonin).
b) Absolute neutrophil count < 1000 cells/mm3. No granulocyte colony stimulating factors 
(G-CSF or GM-CSF) allowed within 1 week of randomization. No pegylated granulocyte 
colony stimulating factors allowed within 3 weeks of randomization.
c) Platelets < 75,000 cell/mm3 (75 x 109/L). Qualifying laboratory value must occur at most 
recent measurement prior to randomization and must be no more than 14 days prior to 
randomization. No transfusions are allowed within 72 hours prior to qualifying laboratory 
value. 
d) Hemoglobin < 8 g/dL. Qualifying laboratory value must occur at most recent 
measurement prior to randomization and must be no more than 14 days prior to 
randomization. No transfusions are allowed within 72 hours prior to qualifying laboratory 
value.
e) Total bilirubin 2 x ULN or direct bilirubin 2.0 mg/dL.
f)
AST or ALT 3 x ULN.
g) Creatinine clearance (CrCl) < 30 mL/min measured by 24-hour urine collection or 
estimated by the Cockcroft and Gault formula:
Female CrCl = (140 - age in years) x weight in kg x 0.85
72 x serum creatinine in mg/dl
Male CrCl = (140 - age in years) x weight in kg x 1.00
72 x serum creatinine in mg/dl
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4) Prior Therapy or Surgery
a) Administration of systemic chemotherapy, biological, immunotherapy, clarithromycin or 
any investigational agent (therapeutic or diagnostic) for multiple myeloma except 
bisphosphonate therapy within 3 weeks prior to randomization. 
b) Treatment with plasmapheresis within 4 weeks prior to randomization.
c) Steroids within 3 weeks of randomization, except:
i)
short course (of 4 days) of 40 mg dexamethasone or equivalent for emergency use 
(baseline M proteins must be drawn after this short course and prior to 
randomization);
ii) 10 mg prednisone or equivalent per day;
iii) Steroid with little to no systemic absorption (ie, topical or inhaled steroids).
d) Major surgery within 4 weeks prior to randomization (kyphoplasty is not considered 
major surgery); subjects should have been fully recovered from any surgical related 
toxicities.
5) Allergies and Adverse Drug Reaction
a) Known hypersensitivity to lenalidomide, dexamethasone, any excipients in the 
elotuzumab formulation or recombinant protein.
6) Sex and Reproductive Status
a) Sexually active fertile men not using 2 forms of effective birth control if their partners are 
WOCBP.
7) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated.
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and to ensure that the results of the study can be used. It is imperative that subjects fully 
meet all eligibility criteria.
3.3.3
Women of Childbearing Potential
Women of childbearing potential include any female who has experienced menarche and who 
has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as: 

Amenorrhea 24 consecutive months without another cause and a documented serum 
follicle stimulating hormone (FSH) level > 35 mIU/mL or

Women with irregular menstrual periods and a documented serum follicle stimulating 
hormone (FSH) level > 35 mIU/mL or
NOTE: FSH level testing is not required for women 62 years old with amenorrhea of 1 year

Women on hormone replacement therapy (HRT)
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Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin 
patches, or implanted or injectable products), or mechanical products such as an intrauterine 
device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are 
practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be 
of childbearing potential.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.5
Discontinuation of Subjects from Treatment
Subjects MUST discontinue investigational product (elotuzumab, lenalidomide, and 
dexamethasone) for any of the following reasons:

Withdrawal of informed consent (subject’s decision to withdraw for any reason).

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject.

Pregnancy (Subject must discontinue elotuzumab and lenalidomide).

Termination of the study by Bristol-Myers Squibb (BMS).

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness.

Progressive Disease (see Section 5.4.5.5 for definition of disease progression).
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
Subjects who receive any non-protocol specified systemic anti-myeloma therapy prior to 
documented progression will be discontinued from all study treatment (including 
lenalidomide/dexamethasone), however, tumor assessments must continue at 4 week 
intervals until documented progression.

Subjects experiencing a Grade 4 infusion reaction must discontinue elotuzumab. Subjects 
may continue lenalidomide and dexamethasone treatment. Refer to Section 4.3.2.2.

Subjects experiencing angioedema, Grade 4 rash, exfoliative or bullous rash, 
Stevens-Johnson syndrome, or toxic epidermal necrolysis related to lenalidomide must 
discontinue lenalidomide. Subjects in the elotuzumab arm may continue elotuzumab and 
dexamethasone.

Subjects experiencing a 28 day delay in all study drugs lenalidomide, dexamethasone, and 
elotuzumab due to an adverse event(s) related to study treatment must be discontinued from 
study drug. Subjects experiencing delays unrelated to study therapy, for example due to 
radiation therapy may delay study treatment up to 42 days. Delays greater than 28 days must 
be discussed with the medical monitor.
All subjects who discontinue should comply with protocol specified follow-up procedures as 
outlined in Section 5. The only exception to this requirement is when a subject withdraws 
consent for all study procedures or loses the ability to consent freely (ie, is imprisoned or 
involuntarily incarcerated for the treatment of either a psychiatric or physical illness).
If a subject was withdrawn before completing the study, the reason for withdrawal must be 
entered on the appropriate case report form (CRF) page.
3.6
Post Study Drug Study Follow up
PFS and OS are key endpoints of the study. Post treatment study follow-up is essential to 
preserving subject safety and the integrity of the study. Subjects who discontinue study treatment 
prior to progression must continue to be followed for collection of protocol-defined PFS. 
Subjects who discontinue study therapy must also continue to be followed for overall survival 
data until death or the conclusion of the study.
BMS may request that survival data be collected on all randomized subjects outside of the 
protocol defined window, Table 5.1-3.
At the time of this request, each subject will be contacted to determine their survival status 
unless the subject has withdrawn consent for all contact.
4
TREATMENTS
All protocol-specified investigational and noninvestigational products are considered study drug.
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4.1
Study Treatments
Table 4.1-1:
Product Description: Treatment Period
Product 
Description and 
Dosage Form
Potency
Primary Packaging
(Volume)/ Label Type
Secondary Packaging
(Qty)/Label Type
Appearance
Storage Conditions
(per label)
Elotuzumab Powder 
for Solution for 
Infusion
400 mg/vial
20 mL Vial/ Open Label
TBD
Sterile, white to off-white, preservative-
free, lyophilized cake
Store at 2 C - 8 C
Protect from light. Do 
not freeze or shake.
Lenalidomide 
(Revlimid)capsule
5 mg, 10 mg,
15 mg and 
25 mg
21 capsules per bottle 
OR blisters containing 
7 capsules each/ 
Commercial or Open 
Label
NA/wallet or carton 
containing 21 capsules/ 
Commercial or Open 
Label
5 mg hard white capsule with
“5 mg REV” written on them
10 mg hard yellow/blue-green capsule 
with “10 mg REV” written on them
15 mg hard white/blue capsule with
“15 mg REV” written on them
25 mg: hard white capsule with
“25 mg REV” written on them
Store at 25 C (77 F). 
Excursions permitted to 
15 - 30 C (59 - 86 F)
Dexamethasone
Tablets
2 mg and 
4 mg & 
various 
strengths
Various packing 
configurations
NA
Various
Refer to label on 
container or package 
insert/summary of 
product characteristics
Dexamethasone 
Solution
4 mg/ml, 
8 mg/ml & 
various 
strengths
Various packing 
configurations
NA
Various
Refer to label on 
container or package 
insert/summary of 
product characteristics
Lenalidomide (Revlimid) capsules, dexamethasone tablets and solution for IV infusion will be obtained by the investigating site’s standard prescribing 
procedures. Lenalidomide (Revlimid) may be supplied by BMS according to country availability and specific regulatory requirements. 
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4.1.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined as follows:
A pharmaceutical form of an active substance or placebo being tested or used as a reference in a 
clinical study, including products already with a marketing authorization but used or assembled 
(formulated or packaged) in a way different from the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
In this protocol, investigational product(s) is/are: Elotuzumab powder for solution for infusion, 
lenalidomide (Revlimid) capsules 5 mg, 10 mg, 15 mg, and 25 mg, dexamethasone tablets and 
concentrate for solution for IV infusion.
4.1.2
Noninvestigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as noninvestigational products. 
In this protocol, non-investigational product(s) are: diphenhydramine (or equivalent H1 blocker), 
ranitidine (or equivalent H2 blocker), acetaminophen, warfarin, low-molecular weight heparin 
and aspirin.
4.1.3
Handling and Dispensing
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 investigator (or assigned designee, ie, study pharmacist) will dispense the proper number of 
each strength tablet to the subject to satisfy dosing requirements until the subject’s next visit. The 
subject must be instructed to return all unused study medications in the provided packaging at 
each subsequent visit.
Procedures for proper handling and disposal of anticancer drugs should be considered.
4.1.3.1
Elotuzumab
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 6. After 
the dose is diluted in normal saline, the elotuzumab infusion must be administered within 8 hours 
if stored at room temperature. If a delay is anticipated, the prepared dose may be refrigerated at 
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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 (20 mg/kg for Cycle 19 and beyond). The 
subject’s predose weight on Day 1 of each cycle will be used to calculate the dose for each cycle. 
Subjects will receive a dose of elotuzumab IV on Days 1, 8, 15, and 22 of the first 2 cycles and 
on Days 1 and 15 of subsequent cycles (day 1 only for Cycle 19 and beyond). Each dose should 
be infused as per instructions in Appendix 6.
4.1.3.2
Lenalidomide
Lenalidomide is an analogue of thalidomide. Thalidomide is a known human teratogen that 
causes severe life-threatening human birth defects. If lenalidomide is taken during pregnancy, it 
may cause birth defects or death to an unborn baby. Females should be advised to avoid 
pregnancy while taking lenalidomide (Revlimid) and for up to 8 weeks after the last dose of 
lenalidomide. Furthermore, subjects taking lenalidomide should refrain from donating blood 
until at least 8 weeks or sperm until at least 90 days after last dose of lenalidomide.
Because of this potential toxicity and to avoid fetal exposure to lenalidomide, lenalidomide is 
only available under a special restricted distribution program.42 This program is called the 
Revlimid Risk Management Plan. Under this program, only prescribers and pharmacists 
registered with the program can prescribe and dispense the product. In addition, lenalidomide 
must only be dispensed to subjects who are registered and meet all the conditions of the 
Revlimid Risk Management Plan. Subjects who have the potential of pregnancy in the Revlimid 
Risk Management Plan must be instructed about contraception and undergo the scheduled 
pregnancy tests. 
Please see the US package insert/SMPC48 for additional information for prescribing to, female 
subjects and male subjects about this restricted distribution program.
4.2
Method of Assigning Subject Identification
After the subject’s eligibility is established and informed consent has been obtained, the subject 
must be enrolled into the study by calling an interactive voice response system (IVRS) to obtain 
the subject number. The following information is required for subject enrollment:

Date of Birth

Site number

Date that informed consent was obtained
Instructions on the use of interactive voice response system will be provided at site initiation.
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When it has been determined that a subject is eligible for randomization, a call will be placed to 
IVRS 
to 
obtain 
treatment 
assignment. 
Subjects 
will 
be 
randomized 
to 
lenalidomide/dexamethasone + elotuzumab (Arm A) or lenalidomide/dexamethasone alone 
(Arm B) in a 1:1 ratio. The randomization will be stratified by the following factors:

Stage of Disease (International Staging System 1 - 2 versus 3)

Age (< 75 years old versus 75 years old)

ECOG Performance Status (0 versus 1 - 2)
and will be carried out via permuted blocks within each stratum.
4.3
Selection and Timing of Dose for Each Subject
4.3.1
Study Drug Administration
Dexamethasone
On weeks without elotuzumab (including the control arm), administer the weekly dose of 40 mg 
dexamethasone on Day 1, 8, 15, and 22 (-1 to +3 days). At the investigator’s discretion, the oral 
dexamethasone may be given as a split dose over 2 consecutive days each week.
On weeks of elotuzumab infusion, administer dexamethasone as a split dose of:

28 mg po ( between 3 - 24 hours prior to the start of elotuzumab infusion) AND

8 mg IV (on the day of elotuzumab infusion at least 45 min prior to the start of infusion).

At the discretion of the investigator, the oral dexamethasone component may be given as a 
split dose 12 - 24 and 3 hours prior to elotuzumab.
Elotuzumab
Elotuzumab will be administered intravenously at a dose of 10 mg/kg weekly (Days 1, 8, 15, and 
22 of a 4-week cycle) of the first 2 cycles and every 2 weeks (Day 1 and Day 15) for cycles 3 
through 18, then at a dose of 20 mg/kg every 4 weeks Cycle 19 (Day 1) and beyond. A window 
of -1 to + 3 days is permitted in Cycles 1 and 2.
In Cycle 1 and 2, an elotuzumab dose that falls outside of the pre-specified window must be 
skipped.
In Cycles 3 and beyond, elotuzumab dosing may be delayed for up to 1 week as clinically 
indicated. The reason for the delay must be recorded on the CRF. If unable to administer within 
1 week, then the dose should be skipped and resumption of the elotuzumab continues per the 
protocol defined schedule.
In addition, the following must also be administered 30 - 90 min prior to any elotuzumab:

H1 blocker: diphenhydramine (25 - 50 mg po or IV) or equivalent;

H2 blocker: ranitidine (50 mg IV) or equivalent

acetaminophen (650 - 1000 mg po)
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See Appendix 6 for elotuzumab dosing instructions.
Lenalidomide
Lenalidomide will be taken orally once daily for the first 3 weeks of a 4-week cycle. Subjects 
should not break, chew or open the capsules.
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Table 4.3.1-1:
Treatment Schedule
Control Arm
Cycle #
1 - 2
3 - 18
19+
Day # (-1/+3 days)
1
8
15
22
1
8
15
22
1
8
15
22
Lenalidomide - PO
25 mg Days 1 - 21
25 mg Days 1 - 21
25 mg Days 1 - 21
Dexamethasone -
PO
40 mg
40 mg
40 mg
40 mg
40 mg
40 mg
40 mg
40 mg
40 mg
40 mg
40 mg
40 mg
Investigational Arm
Cycle #
1 - 2
3 - 18
19+
Day # (-1/+3 days)
1
8
15
22
1
8
15
22
1
8
15
22
Lenalidomide - PO
25 mg Days 1 - 21
25 mg Days 1 - 21
25 mg Days 1 - 21
Dexamethasone -
PO
28 mg
28 mg
28 mg
28 mg
28 mg
40 mg
28 mg
40 mg
28 mg
40 mg
40 mg
40 mg
Dexamethasone - IV
8 mg
8 mg
8 mg
8 mg
8 mg
-
8 mg
-
8 mg
-
-
-
Elotuzumab - IV
10 mg/kg
10 mg/kg
10 mg/kg
10 mg/kg
10 mg/kg
-
10 mg/kg
-
20 mg/kg
-
-
-
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4.3.1.1
Premedication Regimen in Subjects Without a Prior Infusion Reaction 
Consult the Sponsor for further guidance regarding premedication management eg, alternative 
medications for subjects allergic or intolerant to any premedication or to determine if locally 
used equivalent medications are acceptable.
On weeks of elotuzumab infusion, the weekly dexamethasone will be split into a po and IV 
administration (described in Section 4.3.1) which will also serve as premedication for 
elotuzumab.
Intravenous and po dexamethasone doses are calculated to prevent an imbalance in 
dexamethasone exposure between the control and investigational arms (Refer to Section 
4.3.1.2 for premedication in subjects with prior infusion reaction).
In addition, the following must also be administered 30 - 90 minutes prior to elotuzumab:

H1 blocker: diphenhydramine (25 - 50 mg po or IV) or equivalent;

H2 blocker: ranitidine (50 mg IV) or equivalent

acetaminophen (650 - 1000 mg po)
4.3.1.2
Premedication Regimen in Subjects With a Prior Infusion Reaction
To be re-treated with elotuzumab, subjects with prior infusion reaction must receive H1, H2 
blockers and acetaminophen at maximum doses specified (ie, 50 mg diphenhydramine, 
50 mg ranitidine, and 1000 mg acetaminophen).
To prevent imbalance in dexamethasone exposure between the two arms in the study, doses of 
intravenous dexamethasone above 10 mg require a decrease in the po dexamethasone. 
Recommended dexamethasone dosing is summarized below and in Table 4.3.1.2-1. Decisions to 
use more aggressive premedication schemes in subjects with only prior Grade 1 or only one prior 
Grade 2 infusion reaction must be approved by the Sponsor or designee.

For subjects with prior Grade 1 infusion reaction, the same dexamethasone premedication 
regime as in Section 4.3.1 may be used.

For subjects with prior Grade 2 infusion reaction, administer 10 mg IV dexamethasone 
(instead of 8 mg) as the premedication steroid at least 45 minutes prior to elotuzumab. 
Subjects should still take 28 mg oral dexamethasone either as a single dose or split dose 
(16 mg 12 - 24 hours AND 12 mg at least 3 hours prior to elotuzumab).

For subjects with Grade 3 or recurrent Grade 2 elotuzumab infusion reactions, consultation 
with the Sponsor or designee is recommended. For these subjects, administer 18 mg IV 
dexamethasone as the premedication steroid at least 45 minutes prior to elotuzumab. To 
prevent imbalance in dexamethasone exposure between the two arms in the study, on the 
weeks that subjects receive 18 mg IV dexamethasone, they must only receive a total of 
16 mg oral dexamethasone (8 mg 12 - 24 hours AND 8 mg at least 3 hours prior to 
elotuzumab). Eighteen mg of IV dexamethasone has similar exposure to approximately
24 mg oral dexamethasone.
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Table 4.3.1.2-1:
Corticosteroid Premedicationa
Prior Infusion Reaction
Corticosteroid Premedicationb Prior to Elotuzumab 
None or 
Only Grade 1 infusion reactionc
28 mg po dexamethasone (3 - 24 hrs prior to elotuzumab) AND
8 mg IV dexamethasone at least 45 min prior to elotuzumab
Prior Grade 2 infusion reactiond
28 mg po dexamethasone (3 - 24 hrs prior to elotuzumab) AND
10 mg IV dexamethasone at least 45 min prior to elotuzumab
Prior Grade 3 or recurrent Grade 2 
infusion reaction
8 mg oral dexamethasone (12 - 24 hrs prior to elotuzumab) AND
8 mg oral dexamethasone (at least 3 hrs prior to elotuzumab) AND
18 mg IV dexamethasone at least 45 min prior to elotuzumab
a For prior infusion reactions, use maximum doses H1, H2 blockers and acetaminophen as described in 
Section 4.3.1.2.
b At the discretion of the investigator, the oral dexamethasone component may be given as a split dose 12 - 24 and 
3 hours prior to elotuzumab.
c Subjects with prior Grade 1 infusion reaction may be premedicated as per Grade 2 infusion reactions.
d Subjects with prior Grade 2 infusion reaction may be premedicated as per Grade 3 infusion reactions.
If a subject with a prior Grade 2 - 3 infusion reaction also requires dose reduction of 
dexamethasone, the weekly dexamethasone on the days of elotuzumab infusion should be no 
lower than 8 mg IV (on the day of elotuzumab infusion at least 45 minutes prior to elotuzumab).
The oral portion of dexamethasone may be split between the day prior and day of infusion as this 
may further reduce the incidence of infusion reactions. For example, for subjects with only a 
prior Grade 1 infusion reaction, the following split dose may be given: 12 mg dexamethasone po 
(12 - 24 hrs prior to elotuzumab) AND 16 mg dexamethasone po (at least 3 hrs prior to 
elotuzumab) AND 8 mg IV dexamethasone at least 60 minutes prior to elotuzumab.
Subjects with Grade 4 infusion reaction are not eligible to receive additional elotuzumab. These 
subjects should still continue to receive lenalidomide and dexamethasone.
4.3.2
Guidelines for Elotuzumab Infusion in Subjects with Infusion Reactions
4.3.2.1
Grade 1 Infusion Reaction
Grade 1 elotuzumab infusion-related reactions by definition, require,no intervention; however, 
increased monitoring is recommended.
4.3.2.2
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 4 
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elotuzumab infusion reaction must have elotuzumab permanently discontinued. These subjects 
should continue to receive lenalidomide and dexamethasone per protocol.
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 starting at a rate per investigator’s discretion, and increasing 
up to a rate per investigator’s discretion, up to a maximum of 5 mL/minute.
Subjects who experience an infusion reaction require vital signs to be monitored every 30 
minutes for 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 in Table 4.3.1.2-1
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 the next infusion started at 
0.5 ml/min and then escalated in a stepwise fashion (0.5 mL/minute every 30 minutes to a 
maximum of 2 mL/min). If no Grade 2 infusion reaction occurs, the next infusion may be
increased in a stepwise fashion starting at a rate per investigator’s discretion, and up to a 
maximum of 5 mL/minute. If tolerated, all subsequent infusions may start at a rate per 
investigator’s discretion, up to a maximum rate of 5 ml/minute.
4.3.3
Dose Delay or Interruption
If the dose of one drug in the regimen (ie, lenalidomide, dexamethasone or elotuzumab) is 
delayed or interrupted, the treatment with the other drugs may continue as scheduled. Subjects 
experiencing a 28 day delay in all study drugs lenalidomide, dexamethasone, and elotuzumab 
due to an adverse event(s) related to study treatment must be discontinued from study drug. 
Subjects experiencing delays unrelated to study therapy, for example due to radiation therapy 
may delay study treatment up to 42 days. Delays greater than 28 days must be discussed with the 
medical monitor.
Each cycle is 28 days. While dose delays or interruptions are permitted, the start of each cycle 
cannot be delayed and is fixed relative to Cycle 1 Day 1. Adjustments to the Cycle 1 Day 1 
anchored schedule should not be performed. Missed doses should be skipped, not delayed, if not 
given within the allowed window.
Subjects may continue on study therapy even if components of the study therapy must be 
discontinued. For example, a subject on lenalidomide and dexamethasone may continue on study 
therapy even if dexamethasone must be discontinued for an adverse event. Likewise, a subject on 
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the investigational arm may continue on study therapy if elotuzumab must be discontinued for an 
adverse event or other reason. Patients are considered still on study therapy even if they continue 
solely on lenalidomide.
Please consult the BMS medical monitor or any questions regarding dose interruption or study 
therapy discontinuation.
4.3.3.1
Elotuzumab
In Cycle 1 and 2, an elotuzumab dose that falls outside of the pre-specified window 
(-1 to +3 days) must be skipped.
In Cycles 3 and beyond, elotuzumab dosing may be delayed for up to 1 week. If unable to 
administer within 1 week, then the dose should be skipped and resumption of the elotuzumab 
continues per the protocol defined schedule.
4.3.3.2
Dexamethasone
Dexamethasone delay should be performed as clinically indicated at the discretion of the 
investigator.
For subjects receiving elotuzumab, the weekly dexamethasone dose that coincides with or is 
temporally closest to the elotuzumab dosing must be administered as part of the premedication 
for elotuzumab per the guidance in Section 4.3.1.
4.3.3.3
Lenalidomide
Lenalidomide delay should be performed as clinically indicated at the discretion of the 
investigator.
Subjects should be instructed that if a dose of lenalidomide has been missed and it has been less 
than 12 hours since the subject’s regular dosing time, to take lenalidomide as soon as the subject 
remembers. If it has been more than 12 hours, the dose must be skipped. Subjects should not take 
2 doses at the same time.
4.3.4
Recommended Dose Reductions
The criteria presented in this section for dose modification are meant as general guidelines, and 
they are based on current US standards of clinical practice. Local standards may differ and may 
be followed. Dose modification may occur in the setting of lower grade toxicity if the 
investigator, in consultation with the Medical Monitor/Sponsor, believes that it is in the interest 
of subject safety.
4.3.4.1
Elotuzumab 
No dose reduction is allowed for elotuzumab.
4.3.4.2
Dexamethasone Reductions 
Dexamethasone dose reductions for toxicity must be performed as clinically indicated. 
Recommended management is described in Table 4.3.4.2-1and Table 4.3.4.2-2. Deviations to the 
recommended dose reductions are allowed based on the clinical judgment of the investigator. 
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Table 4.3.4.2-1:
Dexamethasone Dose Reductions
CTCAE 
CATEGORY
ADVERSE EVENT
TREATMENT ADJUSTMENT
Gastrointestinal
Dyspepsia, gastric or duodenal 
ulcer, gastritis
Grade 1 - 2 
(requiring medical management)
Treat with a proton pump inhibitor.
If symptoms persist despite above measures, decrease 
by one dose level.
Grade 3 
(requiring hospitalization or 
surgery)
Hold dexamethasone until symptoms adequately 
controlled. Reduce by one dose level and resume 
along with concurrent therapy with a proton pump 
inhibitor. 
If symptoms persist despite above measures, reduce to 
dose level -3.
Acute pancreatitis
Reduce to dose level -3.
Cardiovascular
Edema
Grade 3 (limiting function and 
unresponsive to therapy or 
anasarca)
Use diuretics as needed, and decrease dexamethasone 
by one dose level. If edema persists despite above 
measures, decrease by another dose level.
Neurology
Confusion or Mood alteration 
Grade 2 (interfering with 
function interfering with 
activities of daily living)
Hold dexamethasone until symptoms resolve.
Decrease by one dose level and resume.
If symptoms persist despite above measures, decrease 
by another dose level.
Musculoskeletal
Muscle weakness 
Grade 2 (symptomatic and 
interfering with function 
interfering with activities of daily 
living)
Hold dose until muscle weakness is ≤ Grade 1.
Decrease dexamethasone by 1 dose level and resume.
If weakness persists despite above measures, decrease 
by another dose level.
Metabolic
Hyperglycemia
Grade 3 or higher
Treat with insulin or oral hypoglycemics as needed. If 
uncontrolled despite above measures, decrease by one 
dose level until levels are satisfactory.
Constitutional
Insomnia Grade 2
Decrease by one dose level and resume.
Dose reduction for persistent Grade 2 or Grade 3 AEs believed to be related to dexamethasone 
and not listed above are permitted. Dose reductions should follow guidance in Table 4.3.4.2-1
and Table 4.3.4.2-2.
For subjects receiving elotuzumab, regardless of dexamethasone dose reduction, at least 8 mg of 
the weekly dexamethasone dose must be administered IV as part of the premedication for 
elotuzumab with the remainder of the weekly dexamethasone dose administered orally as 
described in Section 4.3.1. Contact the medical monitor to discuss dexamethasone IV 
premedication for subjects in the investigational arm who reach dose level -3 and must 
discontinue oral dexamethasone due to dose limiting toxicity.
On weeks without elotuzumab, no IV dexamethasone should be administered.
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CA204006
BMS-901608
Elotuzumab
Table 4.3.4.2-2:
Dexamethasone Dose Levels
Dose Level
Weeks with Elotuzumab
Weeks without Elotuzumab
PO
IV
PO
IV
0
28 mg
8 mg
40 mg
0 mg
-1
12 mg
8 mg
20 mg
0 mg
-2
0 mg
8 mg
12 mg
0 mg
-3
0 mg
contact Medical Monitor
0 mg
0 mg
4.3.4.3
Lenalidomide 
Dose adjustments, as summarized below, are recommended for the management of NCI CTCAE 
Grade 3 and 4 toxicities for thrombocytopenia, neutropenia or other toxicities that are judged by 
the investigator to be related to lenalidomide. Information in Table 4.3.4.3-1 and Table 4.3.4.3-2
is based on current standard of clinical practice.
Table 4.3.4.3-1:
Treating Thrombocytopenia Related to Lenalidomide
When Platelet Counts:
Recommended Course

Fall to < 30,000/mm3

Return to 30,000/ mm3
Interrupt lenalidomide treatment; follow complete blood counts 
weekly.
Resume lenalidomide at 15 mg, Days 1 - 21, once daily.
For each subsequent drop < 30,000/ mm3
Return to 30,000/ mm3
Interrupt lenalidomide treatment.
Resume lenalidomide at 5 mg less than previous dose, Days 1 - 21, 
once daily. Do not dose below 5 mg.
Table 4.3.4.3-2:
Treating Neutropenia Related to Lenalidomide
When Neutrophil Counts:
Recommended Course
Fall to < 1000/ mm3
Return to 1000/ mm3 and neutropenia is the 
only toxicity
Interrupt lenalidomide treatment, add G-CSF;a follow 
complete blood counts weekly.
Resume lenalidomide at 25 mg, Days 1 - 21, once daily.
Return to 1000/mm3 and if other toxicity
Resume lenalidomide at 15 mg, Days 1 - 21, once daily.
For each subsequent drop < 1000/ mm3
Return to 1000/ mm3
Interrupt lenalidomide treatment. 
Resume lenalidomide at 5 mg less than previous dose, 
Days 1 - 21, once daily. Do not dose below 5 mg.
In case of neutropenia, consider the use of growth factors in subject management.
a G-CSF = Granulocyte Colony-Stimulating Factor
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CA204006
BMS-901608
Elotuzumab
Lenalidomide Dose Adjustments in Subjects with Renal Impairment
Since lenalidomide is primarily excreted via the kidney, adjustments to the dose of lenalidomide 
are provided based on the lenalidomide country prescribing information. The regimen of 21 day 
dosing every 28 days remains the same despite the dose reductions described below.
Table 4.3.4.3-3:
Lenalidomide Dose Adjustments in Subjects with Renal 
Impairmenta
Creatinine Clearance (CRCL):
Recommended Course
Moderate renal impairment
(30 CRCL< 60 mL/min)
10 mg, every 24 hours
Severe renal impairment (CRCL < 30 mL/min, 
not requiring dialysis)
15 mg every 48 hours
End Stage Renal Disease (CRCL < 30 mL/min, 
requiring dialysis)
5 mg once daily. On dialysis days, dose should be 
administered following dialysis
a Source: Lenalidomide USPI
Dose Adjustments During Treatment for Other Grade 3 and 4 Toxicities
Angioedema, Grade 4 rash, exfoliative or bullous rash, Stevens-Johnson syndrome or toxic 
epidermal necrolysis requires permanent discontinuation of lenalidomide. For Grade 2 - 3 skin 
rash judged to be related to lenalidomide interruption or discontinuation should be considered.
For other Grade 3 and 4 toxicities judged to be related to lenalidomide, hold treatment and restart 
lenalidomide at the next lower dose level when toxicity has resolved to Grade 2.
4.4
Blinding/Unblinding
Not applicable.
4.5
Treatment Compliance
Starting at Cycle 1 Day 1, all treated patients will be assessed for drug compliance of all 
treatments administered during the course of the study. Treatment compliance will be monitored 
by drug accountability and recorded in the subject’s medical record. For those medications taken 
at home (lenalidomide and dexamethasone), subjects will be provided with a medication diary in 
which to record study drug doses and will be instructed to bring this diary and study drug 
containers (lenalidomide and oral dexamethasone) to clinic visits.
4.6
Destruction and Return of Study Drug
4.6.1
Destruction of Study Drug
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 
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CA204006
BMS-901608
Elotuzumab
been documented. The unused study drugs can only be destroyed after being inspected and 
reconciled by the responsible BMS Study Monitor.
4.6.2
Return of Study Drug
Study drug will not be returned to BMS after on site reconciliation. All unused and/or partially 
used study drug may be destroyed on site providing the site has an applicable standard operating 
procedure on file.
4.7
Retained Samples for Bioavailability / Bioequivalence
Not applicable. 
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CA204006
BMS-901608
Elotuzumab
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Short-term Procedural Outline - Screening
Procedure
Screening
Visit 
Notes
Eligibility Assessments
Informed Consent
X
Prior to any screening procedures
Inclusion/Exclusion Criteria
X
Within 14 days of randomization
Medical History
X
Includes date of diagnosis MM. Med Hx should be completed within 28 days of 
randomization
Safety Assessments
Physical Examination
X
Includes height and weight (Section 5.3.1) Within 14 days of randomization
Vital Signs
X
Temperature, BP, HR, RR (Section 5.3.1) Within 14 days of randomization
Performance Status (ECOG)
X
Within 14 days of randomization
Serious Adverse Events Assessment
X
Collected from the time of informed consent
Second Primary Malignancy
X
Collected from the time of informed consent (Section 6.7)
Concomitant Medications
X
Within 14 days of randomization
2-D Echocardiogram or MUGA
X
Section 5.3.3 (Within 28 days of randomization)
ECG
X
Section 5.3.3 (Within 28 days of randomization) 
Laboratory Assessments for Safety
CBC, differential, platelets
X
Section 5.3.4 (Within 14 days of randomization)
Serum Chemistry
X
Section 5.3.4 (Within 14 days of randomization)
Coagulation Tests
X
Section 5.3.4 (Within 14 days of randomization)
Serum 2-microglobulin
X
Within 28 days of randomization. Central lab analysis for stratification
Serum Albumin
X
Within 28 days of randomization. Central lab analysis for stratification.
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CA204006
BMS-901608
Elotuzumab
Table 5.1-1:
Short-term Procedural Outline - Screening
Procedure
Screening
Visit 
Notes
Urinalysis
X
Section 5.3.4 (Within 14 days of randomization)
Pregnancy Test
X
For WOCBP only. 2 pregnancy tests, one 10 - 14 days prior to start of study drug 
and one within 24 hours prior to start of study drug. Urine tests must have a 
sensitivity of at least 25 IU/L.
Efficacy Assessments
Myeloma Urine and Serum Lab tests
X
Section 5.4.2. Within 28 days of randomization. Central laboratory analysis.
Bone Marrow Aspiration/Biopsy
X
Section 5.4.2. Within 28 days of randomization. Bone marrow aspirate is mandatory. 
Bone marrow biopsy is optional.
Cytogenetic analysis and FISH
X
Sections 5.4.2 and 5.7. Central lab analysis.
Skeletal Survey
X
Within 28 days or randomization
CT/MRI assessment for 
extramedullary soft tissue 
plasmacytoma
X
Within 28 days of randomization, if clinically indicated.
Serum soluble major 
histocompatibility complex class 
I-related chain A (sMICA)
X
Section 5.7. Central laboratory analysis.
Clinical Drug Supplies
Randomize
X
First dose of study drug must occur within 3 days of randomization
QOL assessments
EORTC QLQ-C30
X
EORTC QLQ-MY20
X
Brief Pain Inventory - Short Form 
(BPI-SF)
X
Healthcare Resource Utilization 
X
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Date: 24-Aug-2016
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CA204006
BMS-901608
Elotuzumab
Table 5.1-2:
Short-term Procedural Outline (CA204006) Cycles 1 & 2
Procedure
Day 1
Day 8
Day15
Day 22
Rest Days 
23 - 28
Notes
Safety Assessments
Targeted Physical Examination
X
Perform up to 3 days prior to dosing, include weight 
(Section 5.3.1) 
Vital Signs
X
X
X
X
Measure vital signs prior to pre-medication, pre-elotuzumab 
infusion, 30 minutes after the start of elotuzumab infusion, at 
the end of infusion, and 30 and 120 minutes after the 
completion of infusion.
Control arm measure vital signs once at each visit.
Performance Status (ECOG)
X
Evaluate prior to dosing
Serious Adverse Event Assessment
X
X
X
X
Evaluate prior to dosing
Adverse Events Assessment
X
X
X
X
Evaluate prior to dosing
Second Primary Malignancy
X
X
X
X
Section 6.7
Concomitant Medications
X
X
X
X
Evaluate prior to dosing
Laboratory Tests for Safety
CBC, differential, platelets
X
X
X
X
Section 5.3.4. Can be drawn up to 3 days prior to study visit.
Serum Chemistry
X
X
X
X
Section 5.3.4. Can be drawn up to 3 days prior to study visit.
Coagulation Tests
X
X
X
X
For subjects treated with warfarin thromboembolic prophylaxis
Pregnancy Test
X
X
X
X
For WOCBP only. Urine tests must have a sensitivity of at least 
25 IU/L.
Weekly test within 24 hours of study medication. 
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CA204006
BMS-901608
Elotuzumab
Table 5.1-2:
Short-term Procedural Outline (CA204006) Cycles 1 & 2
Procedure
Day 1
Day 8
Day15
Day 22
Rest Days 
23 - 28
Notes
Efficacy Assessments
Myeloma Urine and Serum Lab tests
Every 4 weeks from date of
first dose of study drug until disease progression.
Section 5.4.2. Day 1 of each cycle (except Cycle 1 - refer to 
Screening visit for defined window) until disease progression, 
even if subject is on subsequent therapy;
24 - hour urine sample can be collected within 7 days of visit, 
and must be obtained with each cycle in all subjects who have 
measurable UPEP M protein (200 mg / 24 hours) at baseline.
In order to fulfill CR/sCR criteria, both serum and urine 
immunofixation must be performed and be negative for a
minimum of 6 weeks, in addition to CR criteria in 
section 5.4.5.1
Subjects without measurable urine M protein at baseline and at
the next two consecutive cycles do not have to submit q4 week 
urine samples with each cycle (but must submit q12 week urine 
samples). However, when SPEP M protein becomes 
undetectable, 24-hr UPEP collection must promptly resume and 
continue q4 weeks until SPEP becomes detectable.
Corrected Calcium
Every 4 weeks from date of
first dose of study therapy, regardless of whether 
subject is on study therapy or subsequent therapy 
until disease progression.
Serum calcium and albumin from peripheral blood at D1 of 
each cycle until disease progression, even if subject is on 
subsequent therapy; if used as criteria for disease progression, 
must be confirmed by second value
Bone Marrow Aspiration/Biopsy
For confirmation of CR/sCR if applicable or, if 
clinically indicated at time of suspected disease 
progression
Section 5.4.2. Bone marrow aspirate is mandatory. Bone 
marrow biopsy is optional. However, if a patient has a CR and 
flow cytometry is unavailable then a bone marrow biopsy is 
required for immunohistochemistry. Plasma cell percentage and 
light chain restriction assessments must be performed.
Flow Cytometry 
To assess for sCR, if applicable. Performed locally 
per institution standard practice.
Section 5.4.2. Performed locally per institution standard 
practice; Plasma cell percentage and light chain restriction 
assessments are required. If not available, IHC can be 
performed on bone marrow core biopsy.
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Date: 24-Aug-2016
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Clinical Protocol
CA204006
BMS-901608
Elotuzumab
Table 5.1-2:
Short-term Procedural Outline (CA204006) Cycles 1 & 2
Procedure
Day 1
Day 8
Day15
Day 22
Rest Days 
23 - 28
Notes
Serum Free Light Chain
To assess for sCR at the time of CR assessments
Section 5.4.2. Normal values require confirmatory values at 
least 6 weeks apart to fulfill criteria of sCR.
Skeletal Survey
If clinically indicated
Section 5.4.3.1
CT/MRI assessment for 
extramedullary soft tissue 
plasmacytoma
As clinically indicated and at the time of CR/sCR 
assessments
Section 5.4.3.2
Response per EBMT based criteria
Every 4 weeks from date of first dose of study 
drug until disease progression, regardless of 
whether patient is still on study therapy
Section 5.4.5
Response assessments require repeat values over 6 weeks 
minimum. Progression assessments require repeat values over 
any time interval.
Serum PK Elotuzumab arm only
<----------------------------------------->
Refer to Table 5.5.1-1 for specific time points
Human Anti-Human Antibody 
(HAHA) Elotuzumab arm only
<----------------------------------------->
Refer to Table 5.5.1-1for specific time points
Serum soluble major 
histocompatibility complex class 
I-related chain A (sMICA)
X*
*Cycle 2 Day 1 only. Section 5.7. Central lab analysis. 
Dosing
Premedication for Elotuzumab
(Investigational Arm only)
X
X
X
X
Elotuzumab Infusion (Investigational 
Arm only)
X
X
X
X
In Cycle 1 and 2, an elotuzumab dose that falls outside of the 
pre-specified window (-1 to +3 days) must be skipped. See 
Section 4.3.3.1.
Lenalidomide Administration
Days 1 - 21 of each cycle 
Dexamethasone Administration
X
X
X
X
Section 4.1
Dispense Lenalidomide
X
Dispense lenalidomide on Day 1 of cycle per the Revlimid Risk 
Management Plan
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CA204006
BMS-901608
Elotuzumab
Table 5.1-2:
Short-term Procedural Outline (CA204006) Cycles 1 & 2
Procedure
Day 1
Day 8
Day15
Day 22
Rest Days 
23 - 28
Notes
QOL assessments
 
 
Brief Pain Inventory - Short Form 
(BPI-SF)
X
Complete up to 2 days prior to any study-related procedures, 
treatment or clinician assessment
 
 
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Date: 24-Aug-2016
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Clinical Protocol
CA204006
BMS-901608
Elotuzumab
Table 5.1-3:
Long-term Procedural Outline (CA204006) Cycles 3 and Beyond
Procedure
Day 
1
Day 
8
Day 
15
Day 
22
Rest 
Days 
23 - 28
End of 
Treatment
Days 30 & 
60 Post 
End of 
Treatment
Every 16 
weeks after 
progression
Notes
Safety Assessments
Targeted Physical Examination
X
X
Perform up to 3 days prior to dosing, includes 
weight, Section 5.3.1
Vital Signs
X
X*
X
Measure vital signs prior to administration of 
pre-medication, pre-elotuzumab infusion, 
30 minutes after the start of elotuzumab infusion, 
at the end of infusion, and 30 minutes after the 
completion of elotuzumab infusion.
Control arm measure vital signs once at each 
visit.
*Not required in Cycles 19 and beyond
Performance Status (ECOG)
X
X
Evaluate prior to dosing
Serious Adverse Event 
Assessment
X
X*
X
X
Evaluate prior to dosing
*Not required in Cycles 19 and beyond
Adverse Events Assessment
X
X*
X
X
Evaluate prior to dosing
*Not required in Cycles 19 and beyond
Second Primary Malignancy
X
X
X
X
X
Section 6.7: 
Performed at 30 and 60 day 1 week EOT follow 
up visits. After 30 and 60 day EOT visits, second 
primary malignancy should be assessed every 
16 weeks (2 weeks), or more frequently.
Subjects should be followed monthly (if no 
Progression) or every 16 weeks (if Progression 
occurred), or more frequently.
Concomitant Medications
X
X*
X
X
Evaluate prior to dosing
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Clinical Protocol
CA204006
BMS-901608
Elotuzumab
Table 5.1-3:
Long-term Procedural Outline (CA204006) Cycles 3 and Beyond
Procedure
Day 
1
Day 
8
Day 
15
Day 
22
Rest 
Days 
23 - 28
End of 
Treatment
Days 30 & 
60 Post 
End of 
Treatment
Every 16 
weeks after 
progression
Notes
Subsequent Myeloma Therapy
X
X
X
30 and 60 day visits may be performed ±1 week. 
After 30 and 60 day EOT visits and EBMT based 
progression subsequent myeloma should be
assessed every 16 weeks (±2 weeks), or more 
frequently. 
Subjects should be followed monthly (if no 
Progression) or every 16 weeks (if Progression 
occurred), or more frequently.
Start date and end date for second and third line 
therapy and date of progression after second line 
therapy will be collected.
Laboratory Tests for Safety
CBC, differential, platelets
X
X*
X
Section 5.3.4
Can be drawn up to 3 days prior to visit.
*Not required in Cycles 19 and beyond
Serum Chemistry
X
X*
X
Section 5.3.4
Can be drawn up to 3 days prior to visit
*Not required in Cycles 19 and beyond
Coagulation Tests
X
X*
X
For subjects treated with warfarin 
thromboembolic prophylaxis
*Not required in Cycles 19 and beyond
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Date: 24-Aug-2016
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Clinical Protocol
CA204006
BMS-901608
Elotuzumab
Table 5.1-3:
Long-term Procedural Outline (CA204006) Cycles 3 and Beyond
Procedure
Day 
1
Day 
8
Day 
15
Day 
22
Rest 
Days 
23 - 28
End of 
Treatment
Days 30 & 
60 Post 
End of 
Treatment
Every 16 
weeks after 
progression
Notes
Pregnancy Test
X
X*
X
X**
For WOCBP only. Urine tests must have a 
sensitivity of at least 25 IU/L. Test must be 
completed on Day 1 and Day 15 within 24 hours 
prior to dosing. 
* Not required in Cycles 19 and beyond. 
However, patients with irregular menstrual cycles 
must have a pregnancy test every two weeks.
** WOCBP must have a pregnancy test 30, 60, 
and 90 days Post End of Treatment. 
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Date: 24-Aug-2016
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Clinical Protocol
CA204006
BMS-901608
Elotuzumab
Table 5.1-3:
Long-term Procedural Outline (CA204006) Cycles 3 and Beyond
Procedure
Day 
1
Day 
8
Day 
15
Day 
22
Rest 
Days 
23 - 28
End of 
Treatment
Days 30 & 
60 Post 
End of 
Treatment
Every 16 
weeks after 
progression
Notes
Efficacy Assessments
Myeloma Urine and Serum Lab 
tests
Every 4 weeks from date of the first dose of study drug therapy until 
disease progression, regardless of whether subject is on study therapy or 
subsequent therapy.
Section 5.4.2. 
Day 1 of each cycle until disease progression , 
even if subject is on subsequent therapy;
24 - hour urine sample can be collected within 
7 days of visit, and must be obtained with each 
cycle in all subjects who have measurable UPEP 
M protein (200 mg / 24 hours) at baseline. 
In order to fulfill CR/sCR criteria, both serum and 
urine immunofixation must be performed and be 
negative for a minimum of 6 weeks, in addition to 
CR criteria in section 5.4.5.1.
Subjects without measurable urine M protein at 
baseline and at the next two consecutive cycles do 
not have to submit q4 week urine samples with 
each cycle (but must submit q12 week urine 
samples). However, when SPEP M protein 
becomes undetectable, 24-hr UPEP collection 
must promptly resume and continue q4 weeks 
until SPEP becomes detectable.
Revised Protocol No.: 05
Date: 24-Aug-2016
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Clinical Protocol
CA204006
BMS-901608
Elotuzumab
Table 5.1-3:
Long-term Procedural Outline (CA204006) Cycles 3 and Beyond
Procedure
Day 
1
Day 
8
Day 
15
Day 
22
Rest 
Days 
23 - 28
End of 
Treatment
Days 30 & 
60 Post 
End of 
Treatment
Every 16 
weeks after 
progression
Notes
Corrected Calcium
Every 4 weeks from date of first dose of study therapy until disease 
progression, regardless of whether subject is on study therapy or 
subsequent therapy.
Serum calcium and albumin from peripheral 
blood at D1 of each cycle until disease 
progression, even if subject is on subsequent 
therapy; if used as criteria for disease progression, 
must be confirmed by second value.
Bone Marrow 
Aspiration/Biopsy
For confirmation of CR/sCR if applicable or, if clinically indicated at time 
of suspected disease progression
Section 5.4.2. Bone marrow aspirate is 
mandatory. Bone marrow biopsy is optional if a 
patient has a CR and flow cytometry is 
unavailable then a bone marrow biopsy is 
required for immunohistochemistry. Plasma cell 
percentage and light chain restriction assessments 
are required.
Flow cytometry 
To assess for sCR, if applicable. Performed locally per institution standard 
practice.
Section 5.4.2. Performed locally per institution 
standard practice; Plasma cell percentage and 
light chain restriction assessments are required. If 
not available, IHC can be performed on bone 
marrow core biopsy.
Serum Free Light Chain
To assess for sCR at the time of CR assessments
Section 5.4.2. Normal values require 
confirmatory values at least 6 weeks apart to 
fulfill criteria of sCR
Skeletal Survey
If clinically indicated
Section 5.4.3.1
CT/MRI assessment for 
extramedullary soft tissue 
plasmacytoma
As clinically indicated and at the time of CR/sCR assessments
Section 5.4.3.2
Response per EBMT-based 
criteria
Every 4 weeks from date of the first dose of study drug until disease 
progression regardless of whether on study therapy or subsequent
Section 5.4.5
Response assessments require repeat values over 
6 weeks minimum. Progression assessments 
require repeat values over any time interval.
Serum PK Elotuzumab arm only
<------------------------------------------------------------------------------------>
Refer to Table 5.5.1-1for specific time points
Revised Protocol No.: 05
Date: 24-Aug-2016
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Clinical Protocol
CA204006
BMS-901608
Elotuzumab
Table 5.1-3:
Long-term Procedural Outline (CA204006) Cycles 3 and Beyond
Procedure
Day 
1
Day 
8
Day 
15
Day 
22
Rest 
Days 
23 - 28
End of 
Treatment
Days 30 & 
60 Post 
End of 
Treatment
Every 16 
weeks after 
progression
Notes
Human Anti-Human Antibody 
(HAHA) Elotuzumab arm only
<------------------------------------------------------------------------------------>
Refer to Table 5.5.1-1for specific time points
Serum soluble major 
histocompatibility complex 
class I-related chain A (sMICA)
X
Section 5.7. Central lab analysis.
Survival Status
X
X
30 and 60 day visits may be performed 1 week. 
After 30 and 60 day EOT visits survival status 
should be assessed every 16 weeks 2 weeks, or 
more frequently.
Dosing
Premedication for Elotuzumab
(Investigational Arm only)
X
X*
*Not required in Cycles 19 and beyond
Elotuzumab Infusion 
(Investigational A only)
X
X*
*Not required in Cycles 19 and beyond
In Cycles 3 and beyond, elotuzumab dosing may 
be delayed for up to 1 week. If unable to 
administer within 1 week, then the dose should be 
skipped and resumption of the elotuzumab 
continues per the protocol defined schedule. See 
Section 4.3.3.1
Lenalidomide Administration
Days 1 - 21
Dexamethasone Administration
X
X
X
X
Dispense Lenalidomide
X
Dispense lenalidomide on Day 1 of cycle per the 
Revlimid Risk Management Plan
QOL assessments
 
Revised Protocol No.: 05
Date: 24-Aug-2016
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Clinical Protocol
CA204006
BMS-901608
Elotuzumab
Table 5.1-3:
Long-term Procedural Outline (CA204006) Cycles 3 and Beyond
Procedure
Day 
1
Day 
8
Day 
15
Day 
22
Rest 
Days 
23 - 28
End of 
Treatment
Days 30 & 
60 Post 
End of 
Treatment
Every 16 
weeks after 
progression
Notes
 
Brief Pain Inventory - Short 
Form (BPI-SF)
X
X
Complete up to 2 days prior to any study-related 
procedures, treatment or clinician assessment
 
 
Revised Protocol No.: 05
Date: 24-Aug-2016
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Clinical Protocol
CA204006
BMS-901608
Elotuzumab
5.2
Study Materials
The following will be distributed to sites for use in this study:

NCI CTCAE booklets version 3.0

Elotuzumab Investigator Brochure

Lenalidomide (Revlimid) Package Insert

Site Manual for operation of interactive voice response system

Subject Dosing Diary

Subject Quality of Life questionnaires

Serious Adverse Event (SAE) case report form (CRF) pages

Pregnancy Surveillance Forms.
5.3
Safety Assessments
Only data for the procedures and assessments specified in this protocol should be submitted to 
BMS. Additional procedures and assessments may be performed as part of standard of care; 
however, the data for these assessments should remain in the subject’s medical record and should 
not be provided to BMS, unless specifically requested from the Sponsor. The local safety labs 
(CBC, electrolytes, coagulation test) may be collected up to 3 days prior to the visit. The local 
urine pregnancy test (collected within 24 hours of dosing) for females of reproductive potential 
must be negative for these subjects to proceed to dosing. The serum 2 microglobulin and 
albumin will be sent to the central lab for analysis for ISS stratification. 
5.3.1
Vital Signs, Physical Measurements, and Physical Examination
Vital signs (body temperature, respiratory rate, seated blood pressure and heart rate) will be 
recorded as outlined in Table 5.1-1, Table 5.1-2, and Table 5.1-3. Blood pressure, respiratory 
rate and heart rate should be measured after the subject has been seated quietly for at least 
5 minutes prior to dosing. Subjects in the control arm will have vital signs measured once at each 
visit. Subjects randomized to the elotuzumab arm will have additional vital signs as follows:

Prior to pre-medication administration

Prior to the start of the elotuzumab infusion

Thirty minutes after the start of infusion

At the end of the infusion

Thirty and 120 minutes post completion of the elotuzumab infusion for Cycle 1 and 2

Cycle 3 and beyond post infusion vital signs will be measured at 30 minutes

Subjects who experience a Grade 2 infusion reaction require vital signs to be monitored 
every 30 minutes for 2 hours after the end of the elotuzumab infusion
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Height will be recorded at screening. Weight will be measured at study visits as indicated in 
Table 5.1-1, Table 5.1-2, and Table 5.1-3. A full physical examination will be performed at the 
screening visit, whereas a targeted exam will occur at Day 1 and during on-treatment up to 3 
days prior to dosing and post-treatment visits. A targeted physical examination may be 
performed by a qualified professional guided by the examiner’s observations and/or subject 
complaints on new or changed conditions, symptoms, or concerns. Targeted physical exam 
includes assessment of heart, lung, and abdomen.
5.3.2
Performance Status
Performance assessment will be performed at Screening, on-treatment Day 1 of each cycle and at 
End of Treatment visit using ECOG performance scale and criteria as described in Appendix 2. 
The assessment should be completed prior to any study-related procedures, treatment or clinician 
assessment. 
5.3.3
Echocardiogram or MUGA scan and Electrocardiogram
A MUGA scan or 2-dimensional echocardiogram and electrocardiogram (ECG) will be 
performed at screening within 28 days of randomization to study medication.
5.3.4
Laboratory Assessments for Safety
Table 5.3.4-1:
Safety Laboratory Assessments (may be drawn up to three days 
prior to visit)
Screening as outlined in
Table 5.1-1 within 14 days of 
randomization
Study Visits as outlined in
Table 5.1-2 and Table 5.1-3
Hematology
X
X
CBC
X
X
Differential
X
X
Platelets
X
X
Chemistry
Sodium
X
X
Potassium
X
X
Chloride
X
X
Carbon Dioxide or Bicarbonatea
X
X
Albumin
X
X
Alkaline Phosphatase
X
X
ALT (SGPT)
X
X
AST (SGOT)
X
X
Total Bilirubin
X
X
Direct Bilirubin
X
X
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Table 5.3.4-1:
Safety Laboratory Assessments (may be drawn up to three days 
prior to visit)
Screening as outlined in
Table 5.1-1 within 14 days of 
randomization
Study Visits as outlined in
Table 5.1-2 and Table 5.1-3
Lactate Dehydrogenase
X
X
BUN (or Urea)
X
X
Creatinine
X
X
Glucose
X
X
Calcium
X
X
Total Protein
X
X
Coagulation Test
PT
X
Xb
PTT
X
INR
X
Xb
Pregnancy Test
Urine or Serum Pregnancy
X (2 tests: one 10 - 14 days prior to 
the start of study drug and one 
within 24 hours prior to the start of 
study drug)
X
Urinalysis
X
a
To be done in sites where this is a standard part of the chemistry panel. In sites where testing for CO2/HCO3 is 
not standard, the test is optional.
b
To be done if subject is being treated with warfarin for thromboembolic prophylaxis. Subjects who are not on 
vitamin K antagonists do not require coagulation tests after screening
5.4
Efficacy Assessments
Efficacy endpoints will be based on serum and urine protein electrophoresis (SPEP and UPEP), 
corrected calcium (serum calcium and serum albumin), and bone marrow assessments at 
predefined intervals as specified in Table 5.1-1, Table 5.1-2, and Table 5.1-3. Assessments for 
SPEP and UPEP will be based on central lab results, whereas assessments of bone marrow, bone 
lesions, extramedullary plasmacytomas, and corrected calcium will be based on local analysis at 
the site. Serum 2 microglobulin will be performed centrally at screening for stratification. If 
SPEP and UPEP M protein are performed at a local laboratory, results must be recorded in the 
CRF/eCRF as requested by Sponsor to properly assess efficacy per protocol criteria.
5.4.1
Efficacy Assessment
Response criteria according to Section 5.4.5 will be used for the efficacy analyses. For the 
purposes of this study, all subjects’ tumor assessments by SPEP M protein and UPEP M protein 
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quantification, corrected calcium (calcium and albumin), and serum free light chain 
(when indicated for CR assessment), should be re-evaluated per the protocol-stated frequency 
relative to the date of first dose of study drug until disease progression based on the EBMT 
criteria, irrespective of dose delays or treatment cycle. If subject does not have documented 
EBMT-based disease progression as defined in Section 5.4.5.5 (eg, disease progression was 
determined by sFLC or other non-protocol-defined criteria) at time of study drug 
discontinuation, then tumor assessments must continue to be performed according to the 
same schedule described above until disease progression even if a subsequent anti-myeloma 
treatment is initiated prior to disease progression. Subjects will be followed every 16 weeks 
(or more frequently) after disease progression for survival, subsequent myeloma therapy, and 
development of second primary malignancy.
All efficacy laboratory assessments should be done through the central laboratory, except 
corrected calcium, and bone marrow assessments for plasma cell percentage and light chain 
restriction (clonality by IHC or flow cytometry). All bone marrow aspirate and core biopsy 
samples should be assessed locally. For any SPEP or UPEP assessment performed locally, in lieu 
of a central lab assessment, (ie, if the subject cannot complete a visit at the study site), M protein 
absolute quantification (eg, g/dL or g/L for SPEP and mg/24 hrs for UPEP) must be performed.
Any laboratory samples analyzed locally, including for efficacy, must be entered on the 
appropriate CRF as requested by Sponsor to properly assess efficacy per protocol criteria.
5.4.2
Laboratory Assessments for Myeloma
All serum and urine lab tests must be sent to the central lab, except serum calcium and albumin 
which are performed locally, until disease progression or withdrawal of consent, even if the 
subject is discontinued from study therapy and has started new myeloma therapy. 
Subjects without measureable urine M protein (< 200 mg/24 hours) at baseline and at the next 
two consecutive assessments do not have to submit q4 week urine samples with each cycle (but 
must submit q12 week urine samples) until SPEP M protein becomes undetectable. Therefore, at 
the time SPEP becomes undetectable, 24-hr UPEP collection should promptly resume and 
continue q4 weeks until SPEP becomes detectable.
Assessment of UPEP M protein and urine immunofixation at the time of possible CR/sCR is 
mandatory for all subjects, that is negative urine immunofixation for a minimum of 6 weeks is 
required to fulfill CR/sCR criteria, even in subjects with nonmeasurable values at baseline. Any 
local serum and urine myeloma lab tests that may also have been performed must also be 
reported in the CRF as requested by Sponsor to properly assess efficacy by protocol criteria.
1) Serum: serum protein electrophoresis (SPEP) for M protein quantification, total serum 
protein, immunofixation, and quantitative immunoglobulin assay.
a) Immunofixation of serum is required at baseline and to confirm CR regardless of whether 
measurable M-protein was present at baseline.
b) All other serum tests will be followed at each tumor assessment. Confirmation of PR is 
required at least 6 weeks later.
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2) Urine: 24-hour urine collection electrophoresis for M protein quantification, urinary light 
chains, and immunofixation. 24-hour urine must be collected with each cycle for all subjects, 
except for those subjects with no measurable M protein in the urine at baseline and at next 
two consecutive assessments.
a) Immunofixation of urine is required at baseline and to confirm CR regardless of whether 
measurable M-protein was present at baseline.
b) All other urine tests will be followed at each tumor assessment. Confirmation of PR is 
required at least 6 weeks later.
3) Bone marrow aspiration/biopsy:
Bone marrow 
sample
Local Laboratory
Central Laboratory
Aspiratea
1)
Samples required at the following times to 
evaluate percentage plasma cells:
g)
Screening (within 28 days of 
randomization)
h)
When subject is immunofixation 
negative in both serum and urine
(second bone marrow sample not required 
for confirmation) for a minimum of 6 
weeks
In addition, evaluate flow cytometry to assess 
plasma cell clonality 
(ie, lambda and kappa IHC or flow cytometry to 
assess light chain restriction).
a) At time of suspected disease 
progression, if needed (see 
Section 5.4.5.5) to assess progression in 
subjects who’s myeloma become 
nonsecretory
1) Screening (within 28 days of 
randomization)
a) send for genetic assessments 
(karyotype and FISH)b
Biopsy
Not required by protocol unless an aspirate sample 
(at any time point above) is not available due to a 
dry tap or due to laboratory preferences of the 
local pathologist. IHC of biopsy for clonality by 
local lab if aspirate is not available.
a Should be replaced by core biopsy sample only if: 1) aspirate is not available at any time point due to a dry tap or 
2) subject is immunofixation negative in serum and urine and flow cytometry is not available at the site.
b Genetic assessments (karyotype and FISH) should be performed by the central laboratory on a fresh bone marrow 
sample. However, if a new bone marrow sample collection is not feasible and if this assessment was performed 
locally within the 28 days prior to randomization, the local results must be entered into the eCRF.
4) Serum free light chain: Serum should be collected at baseline and time of serum and urine 
IFE negativity for a minimum of 6 weeks to confirm CR and be sent to the central lab for 
serum free light chain analysis. Two values at least 6 weeks apart should be provided. The
measurement of sFLC is required to document sCR using Section 5.4.5, but is not a criteria 
for determining disease progression (see Sections 5.4.1 and 5.4.5.5).
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5) Serum Corrected Calcium: Serum corrected calcium should be collected with each cycle for 
all subjects until disease progression.
5.4.3
Imaging Assessments for Myeloma
5.4.3.1
Skeletal Survey
Skeletal survey, by conventional radiography, for metastatic disease will be performed at 
screening (within 28 days prior of randomization), and on study if clinically indicated 
(development of compression fracture does not exclude response). Use of conventional or low 
dose CT scan (ie, of the spine) or MRI bone survey is acceptable. If imaging is performed on 
treatment for assessment of progression, the site must use the same modality of imaging as used 
in screening. The number and location of skeletal lesions and whether they are lytic should be 
recorded on the eCRF. On treatment survey should record whether there is an increase in the 
number or size of lytic lesions.
5.4.3.2
Assessment of Extramedullary Plasmacytoma
CT or MRI should be performed in all subjects if clinically indicated at baseline to assess for the 
presence of extramedullary plasmacytoma. To minimize unnecessary radiation in myeloma 
subjects where progression is primarily based on serum and urine M-protein, on study 
assessments should only be performed if clinically indicated (ie, pain, concern for disease 
progression), whether or not present at baseline, and at the time of CR/sCR assessment.
A sum of the products of the longest diameters and longest perpendicular diameter for all 
measurable lesions will be calculated at baseline. This sum will be used as the reference for 
on-study assessments by which to characterize the objective tumor response.
All tumor measurements must be made in millimeters. All documented measurable lesions are to 
be followed throughout the trial. All assessments to be used for tumor response evaluation, 
including the baseline assessment, must be performed using the same method for repeat 
assessment. CT and MRI scanning are the preferable methods of assessment. Conventional CT 
and MRI should be performed with contiguous cuts of 10 mm or less or with cuts of 
5 (or 10) mm if spiral CT scanning is used. Imaging-based evaluation is preferred to evaluation 
by clinical examination. Evaluation by chest x-ray is less preferable than CT or MRI, and should 
only be used for well-defined lesions surrounded by aerated lung. Clinical examination is only 
acceptable when lesions are superficial, such as a skin nodule or palpable lymph node. Skin 
lesions must be documented by a photograph with a ruler. Ultrasound is not acceptable for 
documentation of measurable disease.
Duplicate copies of all imaging studies used for tumor response evaluation will be made 
available for review by the Sponsor upon request.
Measurable disease are lesions that can be accurately measured in 2 dimensions and both 
diameters must be 20 mm when evaluated by standard CT scanning or 10 mm when 
evaluated by spiral CT scanning. The minimum diameter size should be at least twice the slice 
thickness.
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Non-measurable disease are all other lesions (or sites of disease), including those that are too 
small (ie, do not meet above criteria), occur within a previously irradiated area (unless they are 
documented as new lesions since the completion of radiation therapy), bone lesions, 
leptomeningeal disease, ascites, pleural or pericardial effusion (exception for effusions 
documented by cytology as not malignant or present at baseline without progression), 
lymphangitis cutis/pulmonis, abdominal masses that are not pathologically/cytologically 
confirmed and followed by imaging techniques, and cystic lesions.
5.4.4
Independent Review Committee
The following information will be submitted to an Independent Review Committee (IRC) for 
final assessment of objective response based on:
1. The subject’s laboratory results (electronically and via CRF)
2. All imaging results via CRF
3. Local pathology results via CRF
4. Local pathology results of bone marrow samples for confirmation of stringent CR.
The criteria for IRC review are defined in a separate IRC charter.
5.4.5
Definitions of Response
5.4.5.1
Complete Response (CR)/stringent CR (sCR)
A CR requires that all of the following criteria be achieved:
1. Negative immunofixation (“IF”) on both serum and urine, maintained for a minimum of 
6 weeks and
2. A bone marrow aspirate or biopsy containing < 5% plasma cells. It is not essential to perform 
a trephine biopsy, but if a biopsy is performed this must also contain < 5% plasma cells 
(although not required for documentation of CR using the EBMT criteria, light chain 
restriction (flow or IHC for kappa and lambda light chain in the bone marrow should also be 
assessed to assist in classification of stringent CR using the IMWG criteria)17 and
3. If skeletal survey showed osteolytic bone lesions, there should be no increase in the size or 
number (development of a compression fracture does not exclude response) and
4. If screening scans showed extramedullary plasmacytomas, complete disappearance of any 
must be noted.
5. For assessment of stringent CR, per IMWG criteria, all criteria for CR must be upheld. In 
addition, bone marrow sample must be assessed for light chain restriction (as mentioned in 
bullet 2 above) and serum free light chains must be normalized at two time points at least 
6 weeks apart, at the time of CR assessment. 
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5.4.5.2
Partial Response (PR)
Subjects in whom some, but not all, the criteria for CR are fulfilled are classified as PR, 
providing the remaining criteria satisfy the requirements for PR. This includes subjects in whom 
routine electrophoresis is negative but in whom IF has not been performed.
1. Greater than or equal to 50% reduction in serum M-protein, maintained for a minimum of 
6 weeks.
2. Reduction of 90% in urinary light chain excretion or a decrease to < 200 mg/ 24 hours, 
maintained for a minimum of 6 weeks.
3. Greater than or equal to 50% reduction in the size of extramedullary plasmacytomas present 
at baseline (by radiography or clinical examination using bidimensional measurements).
4. If a skeletal survey is performed, no increase in the size or number of lytic lesions 
(development of a compression fracture does not exclude response).
5.4.5.3
Very Good Partial Response (VGPR)
VGPR, a subset of PR, is not formally included in the EBMT criteria but is derived from the 
IMWG criteria.17 Because VGPR is commonly used to measure depth of response in MM, this 
response must be reported by investigator and IRC and is defined by:
1. Serum and Urine M-protein detectable by immunofixation but not on electrophoresis and that 
is confirmed in a subsequent assessment OR
2. 90% or greater reduction in serum M-protein plus urine M-protein level < 100 mg per 24 h 
and that is confirmed in a subsequent assessment.
5.4.5.4
Minor (Minimal) Response (MR)
Subjects who have reduction in M-protein or plasmacytoma but do not meet the criteria for PR 
are classified as MR if they meet all the following definition:
1. Between 25 - 49% reduction in serum M-protein, maintained for a minimum of 6 weeks.
2. Between 50 - 89% reduction in urinary light chain excretion which still exceeds 
200 mg/24 hours, maintained for a minimum of 6 weeks.
3. Between 25 - 49% reduction in the size of extramedullary plasmacytomas.
4. If a skeletal survey is performed, no increase in the size or number of lytic lesions 
(development of a compression fracture does not exclude response).
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5.4.5.5
Progression of Disease (PD)
Progression
Progression describes a definite increase in disease activity relative to the nadir in 2 consecutive 
assessments in subjects not in CR, whereas the term “relapse from CR” applies to a recurrence of 
evident disease in subjects previously in CR. The date of EBMT based disease progression is the 
first date of two consecutive values fulfilling the criteria for disease progression. 
Any of the following list is sufficient for PD:
1. Increase of > 25% in serum M-protein (also an absolute increase of at least 5 g/L) and 
confirmed by at least 1 investigation.
2. Increase of > 25% urinary light chain excretion (which must also be an absolute increase of 
at least 200 mg/24-hours and confirmed by at least 1 investigation.
3. Increase of > 25% plasma cell percentage in the marrow (which must also be an absolute 
increase of at least 10%).
4. Definite increase in the size or number of lytic bone lesions or extramedullary 
plasmacytomas (development of a compression fracture does not exclude continued response 
and may not indicate progression).
5. Development of hypercalcemia (corrected serum calcium greater than 11.5 mg/dL; 
2.8 mmol/L) not attributable to any other cause.
Relapse from CR (for subjects in CR)
Subjects who have documented CR and then achieve at least one of the following criteria are 
classified as relapse from CR. According to the EBMT criteria, relapse from CR is considered to 
be progression of disease. The date of EBMT based relapse from CR is the first date of two 
consecutive values fulfilling the criteria for relapse. 
1. Reappearance of serum or urinary M-protein on immunofixation or routine electrophoresis, 
confirmed by at least one further investigation and excluding oligoclonal reconstitution.
2. Greater than or equal to 5% plasma cells in a bone marrow aspirate or on trephine bone 
biopsy.
3. Any of the definitions met for Progression.
5.4.5.6
Stable Disease/No Change
Does not meet criteria for any of the categories above.
 
 
 
 
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5.8
Outcomes Research Assessments
5.8.1
HRQoL Assessments 
To assess the impact of treatment, subject’s quality of life will be measured using 3 validated 
QoL instruments: 
 
 
and the Brief Pain Inventory- Short Form (BPI-SF).
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All three questionnaires will be administered per the schedule in Table 5.1-1, Table 5.1-2, and 
Table 5.1-3. Subjects should fill out the questionnaire prior to any study-related procedures, 
treatment or clinician assessment in order to prevent these variables from influencing QoL 
results. Non-English speaking subjects will complete the questionnaire using validated language 
transitions developed and recommended for each instrument.
 
 
 
 
 
 
 
 
The BPI-SF is a 15-item (Appendix 5) instrument designed to assess pain in patients with cancer 
and other diseases.50,51 It measures the pain intensity (5-item sensory dimension), and it also 
includes questions to measure the interference of pain in the patient’s daily life, including 
general activity, mood, ability to walk, normal work both outside the home and housework, 
relations to other people, sleep, as well as enjoyment of life (7-item reactive dimension).52 In 
multiple myeloma patients, significant associations were found between pain intensity measured 
by the BPI-SF and mood disturbance scores. As pain interference increased, so did levels of 
mood disturbance. A joint predictive model explained 74.6% of the variability in total QOL 
scores.53 The BPI-SF has demonstrated both reliability and validity across cultures and 
languages, and has been used to study the effectiveness of pain treatment.50 A score of 6 on a 
scale of 0 to 10 on any single item is generally considered to be clinically significant.54
Pre-testing was carried out in the UK, Norway, Sweden, Denmark, and Germany. Field testing of 
the module has been conducted in a range of Phase 3 trials.55 The module has been validated in a 
large number of languages (see www.eortc.be/home/qol).
 
 
 
5.9
Other Assessments 
Not applicable.
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6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a patient or clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of investigational product, whether or not considered related to the investigational product.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1
Serious Adverse Events
A serious AE (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) Potential drug induced liver injury (DILI) is also considered an 
important medical event (See Section 6.6 for the definition of potential DILI).
Suspected transmission of an infectious agent (eg, any organism, virus or infectious particle, 
pathogenic or non-pathogenic) via the study drug is an SAE.
Although pregnancy, overdose, cancer, and potential DILI are not always serious by regulatory 
definition, these events must be handled as SAEs for data transmission purposes 
(See Section 6.1.1 for reporting pregnancies).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered "important medical event" or event life 
threatening)
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
elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)

medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study. Appropriate documentation is required in these 
cases

admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative).

Admission for administration of anticancer therapy in the absence of any other SAEs
(applies to oncology protocols).
6.1.1
Serious Adverse Event Collection and Reporting 
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 60 days of discontinuation of dosing or within 30 days of the last visit for screen 
failures.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or 
designee) within 24 hours of awareness of the event. SAEs must be recorded on the SAE Report 
Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The preferred 
method for SAE data reporting collection is through the eCRF. The paper SAE/pregnancy 
surveillance forms are only intended as a back-up option when the eCRF system is not 
functioning. In this case, the paper forms are to be transmitted via email or confirmed facsimile 
(fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number:  Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
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paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug, or those that are present at the end of study 
treatment as appropriate. All identified nonserious AEs must be recorded and described on the 
nonserious AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3
Laboratory Test Abnormalities
The following laboratory abnormalities should be captured on the nonserious AE CRF page or 
SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory abnormality that required the subject to have study drug discontinued or 
interrupted

Any laboratory abnormality that required the subject to receive specific corrective therapy.
It is expected that wherever possible, the clinical, rather than the laboratory term would be used 
by the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
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, 
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including during at least time to washout (90 days) plus one ovulatory cycle (30 days) for a total 
of 120 days, or plus one spermatogenesis cycle (90 days) for a total of 180 days after product 
administration, the investigational product will be permanently discontinued in an appropriate 
manner (eg, 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 (eg, x-ray studies). Other appropriate pregnancy follow-up procedures should be 
considered if indicated.
The investigator must immediately notify the BMS Medical Monitor (or designee)of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
and in accordance with SAE reporting procedures described in Section 6.1.1. 
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. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the sponsor. Information on this pregnancy will be collected on the Pregnancy Surveillance 
Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
6.6
Potential Drug Induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (See Section 6.1.1. for reporting details).
Potential DILI is defined as:
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
6.7
Other Safety Considerations
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
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procedures are required by the protocol, should also be recorded as a nonserious or serious AE, 
as appropriate, and reported accordingly.
Second primary malignancies (SPMs) will be collected throughout the study which includes 
assessments during survival follow-up. All SPMs that occur during the screening period and 
within 60 days of discontinuation of dosing will be reported as an SAE regardless of relationship 
to study drug. Additionally, any SPM that occurs after this timeframe and considered related to 
study drug will be reported as an SAE. All other SPMs will be collected and reported as adverse 
events.
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
A data monitoring committee (DMC) will be established before the first subject is treated and 
will monitor safety throughout the study. (The DMC will receive SAE tables every 4 months and 
more comprehensive safety data every 8 months.) In addition, the DMC will review safety and 
efficacy data, including a formal comparison of PFS for early stopping, once the following two 
conditions have been met: at least 338 progression events have been observed and all subjects 
have been randomized. A separate charter will describe the activities of this committee. (Also see 
Section 8.5, Interim Analyses, for details on the interim analyses of safety and efficacy).
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The number of events and power for PFS were calculated assuming an exponential distribution 
in each arm. One interim analysis of PFS is planned. The comparisons of PFS will be carried out 
using log-rank tests stratified by stage of disease (International Staging System 1 - 2 versus 3), 
ECOG performance status (0 versus 1 - 2), and age (< 75 years old versus 75 years old). The 
interim analysis will allow for early stopping for superiority. An O’Brien and Fleming 
spending function will be employed to determine the stopping boundaries. 
Approximately 750 subjects will be randomized to the 2 treatment groups in a 1 to 1 ratio in 
order to obtain at least 482 progression events, ie, documented progressions or deaths as 
determined by the IRC. Four hundred and eighty-two (482) events ensure that a two-sided, 5% 
level, sequential test procedure with 1 interim analysis after 70% of the total events (338) will 
have 90.5% power if the median PFS times in the control and experimental arms are 25 and 
33.75 months, respectively, ie, if the hazard ratio of the experimental to control arm is 0.74.
Assuming an accrual rate of 24 subjects per month, it will take approximately 60 months to 
obtain the required number of events, 31 months for accrual and 29 months for PFS follow-up. It 
is projected that at the time of final PFS analysis (at least 482 events), an observed hazard ratio 
of 0.84 or less, which corresponds to a 4.8 month or greater improvement in median PFS (25 vs 
29.8 months), would result in a statistically significant improvement in PFS for the 
elotuzumab-containing arm. In view of evolving results with frontline lenalidomide therapy, a 
reassessment of the sample size could be made. The decision to reevaluate sample size would be 
based on external data only and would not involve a change in the required number of PFS 
events.
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Survival, a key secondary endpoint, will be compared between the two arms at the time of the 
interim analysis of PFS (if and only if both PFS and ORR are positive), and again after 354
deaths, which is projected to occur 7 years (84 months) after the initiation of the study. An 
O’Brien and Fleming -spending function will be used to obtain the nominal significance levels 
for the interim and final analyses of survival. Three hundred and fifty-four (354) deaths ensure 
that a two-sided 5% level sequential test procedure with one interim analysis will have 80% 
power for a 8.7 percentage point improvement in 4-year survival rate from 59.0%36 to 67.7%, 
ie, for a HR = 0.74.
Power calculations were done using East v5.1.
8.2
Populations for Analyses
The following subject populations will be used in this study:

Randomized subjects: all subjects who were randomized to either treatment group

Treated subjects: all randomized subjects who received at least one dose of study treatment
Analyses of baseline characteristics, including demography, patient-reported outcomes, and 
efficacy will be carried out on all randomized subjects. Analyses of safety will be based on all 
treated subjects.
8.3
Endpoint Definitions
8.3.1
Progression-Free Survival
The primary definition of progression-free survival (PFS) is the time from randomization to the 
date of the first documented tumor progression, using the criteria in Section 5.4.5.5, or to death 
due to any cause, provided death does not occur more than 10 weeks (2 or more assessment 
visits) after the last tumor assessment. Clinical deterioration will not be considered progression. 
The following censoring rules will be applied for PFS:

Subjects who receive systemic secondary anti-myeloma therapy prior to documented 
progression will be censored on the date of the last tumor assessment prior to the initiation of 
the new therapy.

Subjects who have an event (documented progression or death) > 10 weeks (2 assessment 
visits) after the last prior tumor assessment will be censored at the last prior assessment.

Subjects who do not progress and who do not receive subsequent therapy will be censored at 
their last tumor assessment.
The main analysis of PFS will be by IRC assessments.
IRC PFS also will be analyzed applying an intent-to-treat (ITT) definition that utilizes all data on 
each randomly assigned subject until either a progression event or the end of the study. PFS 
under the ITT definition will be defined as the time from randomization to the date of the first
documented tumor progression or to death due to any cause. Clinical deterioration will not be 
considered progression. Subjects who neither progress nor die will be censored on the date of 
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their last tumor assessment. There will be no censoring for subsequent therapy prior to 
progression or for progression events following missing assessments. 
Finally, PFS based on investigator assessments will also be analyzed applying both the primary 
and the ITT definitions.
8.3.2
Objective Response Rate
Best overall response is determined as the best assessment based on all study efficacy data for 
the subject. Subjects with objective response are subjects with a best overall response on study of 
partial response (PR) or better based on criteria in Section 5.4.5.
Objective Response Rate (ORR) is defined as the proportion of subjects with objective response 
among all randomized subjects. The main ORR analysis will be based on IRC assessments.
 
 
 
 
 
 
 
 
 
 
 
8.3.6
Survival
Survival is defined as the time from randomization to the date of death. A subject who has not 
died will have his or her survival duration censored at the date of last contact (‘last known date 
alive”).
 
 
 
 
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8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Subject characteristics including demographics, baseline performance status, disease 
characteristics, and baseline laboratory parameters will be summarized by randomized treatment 
arm as well as pooled across randomized arms using descriptive statistics.
8.4.2
Efficacy Analyses
8.4.2.1
Primary Efficacy Analysis
The primary endpoint for the study is progression-free survival based on IRC assessment. The 
primary analysis of PFS will be to compare the 2 randomized arms at the interim and final looks 
via two-sided, log-rank tests stratified by stage of disease (International Staging System 1 - 2 
versus 3), ECOG performance status (0 versus 1 - 2), and age (< 75 years old versus 75 years 
old). An O’Brien-Fleming spending function will be employed to determine the significance 
levels and stopping boundaries at the interim and final looks. (See Section 8.5, Interim Analysis, 
for more detail). 
Further analysis of PFS will include the computation of hazard ratios and estimation of PFS 
functions. The PFS hazard ratio of lenalidomide/dexamethasone + elotuzumab to 
lenalidomide/dexamethasone alone and an associated two-sided confidence interval will be 
computed using a stratified Cox proportional hazards model with treatment arm as the sole 
covariate. The alpha level () for the confidence interval will be the same as the nominal 
significance level for the hypothesis testing. The stratification factors will be the same as those 
used in the randomization. The PFS functions for each randomized arm will be estimated using 
the Kaplan-Meier product-limit method. Two-sided, 95% confidence intervals for median PFS 
and the first and third quartiles will be computed by randomized arm.
 
 
 
 
 
 
 
 
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8.4.2.3
Secondary Efficacy Analyses
The key secondary endpoints are:

Objective response rate (ORR)

Overall survival
A hierarchical procedure will be used to ensure a two-sided, family-wise type I error rate of 5% 
for testing the one primary and two key secondary endpoints. If there is a statistically significant 
improvement in PFS, ORR will be compared between arms at the 5% level. If the comparison of 
ORR is also statistically significant at the 5% level, then survival will be compared between arms 
using a 5% level sequential test procedure.
Objective response will be compared between randomized arms using a two-sided 5% level 
Cochran-Mantel Haenszel (CMH) test stratified by the same factors used in the analysis of PFS. 
An associated odds ratio and 95% confidence interval will be calculated. The response rate and 
its corresponding 95% confidence interval will also be calculated for each treatment arm. There 
will be no interim comparison of this endpoint.
Survival will be compared between treatment arms using two-sided, stratified log-rank tests at 
the interim and final looks. The family-wise type I error rate for the sequential testing procedure 
will be 5% and the stratification factors will be the same as those used for the randomization. 
The significance level at the interim and final analyses of survival will be determined using an 
O’Brien and Fleming α spending function.
Other Secondary objectives are:

Change from baseline of mean score of pain severity and change from baseline of mean score 
of pain interference (BPI-SF)
Each of the two comparisons will be made at the two-sided type I error of 2.5% and will be 
tested independent of the significance of the comparison of the progression-free survival, 
objective response rate and overall survival. See Section 8.4.7.1 for details about analyses.   
8.4.3
Safety Analyses
Summary tables will be presented on safety parameters for each treatment arm. Toxicity rates 
(worst CTC grade per subject) of adverse events and laboratory tests, both of any occurrence and 
severe (Grade 3) will be tabulated. Shift tables for selected laboratory parameters will be 
produced.
 
 
 
 
 
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8.4.7
Outcomes Research Analyses
8.4.7.1
Analysis of HRQoL Data
All analyses will be conducted on randomized subjects. Questionnaire completion rate, defined 
as the proportion of questionnaires actually received out of the expected number (ie, the number 
of subjects still on treatment), will be calculated and summarized at each assessment point. 
Subjects without any post-baseline assessment will be excluded from the analysis.
The comparison between the 2 treatment arms of the change from baseline in the mean score of 
pain severity will be conducted using a longitudinal mixed model with treatment arm, time point 
(categorical), and baseline score as fixed effects and a banded covariance matrix (constant 
covariances on each diagonal of the matrix). Similar model will be used to analyze change from 
baseline in mean score of pain interference.
Adjusted mean change from baseline at each assessment point will be graphically presented by 
randomized arm for the three questionnaires 
 and BPI-SF).
 
 
 
8.4.8
Other Analyses
 
 
PFS rates at 1, 2, 3, 4, and 5 years will be estimated from the KM curve. Each analysis will be 
performed after all subjects have been followed for the appropriate time.
 
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8.5
Interim Analyses
A data monitoring committee (DMC) will be established before the first subject is treated and 
will monitor safety throughout the study. (The DMC will receive SAE tables every 4 months and 
more comprehensive safety data every 8 months.) In addition, the DMC will review safety and 
efficacy data once the following two conditions have been met: at least 338 progression events 
have been observed and all subjects have been randomized.
A key feature of the interim analysis after at least 338 (70%) progression events will be a formal 
comparison of PFS between treatment arms. This formal comparison of PFS will allow for early 
stopping for superiority. The stopping boundaries will be derived based on the O’Brien and 
Fleming spending function in East v5.1. (Under current accrual assumptions, the 
338 progression event milestone will occur approximately 41 months after study start.)
The stopping boundaries for superiority will depend on the actual number of events observed at 
the time of the interim analysis, and will be determined using the interim monitoring tool in East 
v5.1. However, if there were exactly 338 events the DMC could stop the study for superiority if 
the p-value were 0.0148. (It should be noted that survival follow-up would continue even if the 
study were stopped at the interim analysis of PFS for superiority.)
A formal interim analysis of OS will be conducted provided that both the analyses of PFS and 
ORR are positive (refer to Section 8.4.2.3 for further detail). The final analysis of survival, 
provided that the survival portion of the study is not stopped early, will take place after at least 
354 deaths have been observed, which is projected to occur approximately 7 years after the first 
subject is randomized. The nominal significance levels for the interim and final survival 
comparisons will be determined by an O’Brien and Fleming alpha spending function.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:
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
IRB/IEC for review and approval/favorable opinion

Bristol-Myers Squibb

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
Representatives of BMS (or designee) must be allowed to visit all study site locations 
periodically to assess the data quality and study integrity. On site they will review study records 
and directly compare them with source documents, discuss the conduct of the study with the 
investigator, and verify that the facilities remain acceptable. Certain CRF pages and/or electronic 
files may serve as the source documents: such as outcomes research assessments.
In addition, the study may be evaluated by BMS (or designee) internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS (or designee) promptly of any inspections scheduled by 
regulatory authorities, and promptly forward copies of inspection reports to BMS. 
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any other kind of 
electronic devices) as part of regulated clinical trial activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health records 
(EMRs/EHRs), adverse event tracking/reporting, protocol required assessments, and/or drug 
accountability records).
When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original.
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9.1.3
Investigational Site Training
Bristol-Myers Squibb (or designee) will provide quality investigational staff training prior to 
study initiation. Training topics will include but are not limited to: GCP, AE reporting, study 
details and procedure, electronic CRFs, study documentation, informed consent, and enrollment 
of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by the sponsor, whichever is longer. The investigator must contact BMS prior to 
destroying any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
Records for IMP and non-investigational products (whether supplied by BMS, its vendors, or the 
site) must substantiate IMP integrity and traceability from receipt, preparation, administration, 
and through destruction or return. Records must be made available for review at the request of 
BMS/designee or a Health Authority.
If...
Then...
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include: 

amount received and placed in storage area

amount currently in storage area

label identification number or batch number

amount dispensed to and returned by each subject, 
including unique subject identifiers

amount transferred to another area/site for 
dispensing or storage

nonstudy disposition (eg, lost, wasted)

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, 
if applicable

dates and initials of person responsible for 
Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
Sourced by site, and not supplied by BMS or its 
vendors (examples include IP sourced from the sites 
The investigator or designee accepts responsibility for 
documenting traceability and study drug integrity in 
accordance with requirements applicable under law and 
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If...
Then...
stock or commercial supply, or a specialty pharmacy)
the SOPs/standards of the sourcing pharmacy.
These records should include:

label identification number or batch number

amount dispensed to and returned by each subject, 
including unique subject identifiers

dates and initials of person responsible for 
Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements
The sponsor will provide forms to facilitate inventory control if the investigational site does not 
have an established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data reported on the CRF that are derived from 
source documents must be consistent with the source documents or the discrepancies must be 
explained. 
For sites using the BMS (or designee) electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which 
will be reported on the SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by the sponsor. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper SAE/pregnancy CRFs, must be promptly reviewed, 
signed, and dated by a qualified physician who is an investigator or subinvestigator. For 
electronic CRFs, review and approval/signature is completed electronically through the BMS 
(or designee) electronic data capture tool. The investigator must retain a copy of the CRFs 
including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS (or designee) electronic data capture tool using the unique user 
account provided by the sponsor. User accounts are not to be shared or reassigned to other 
individuals.
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9.3
Publications
The data collected during this study are confidential and proprietary to the sponsor. Any 
publications or abstracts arising from this study require approval by the sponsor prior to 
publication or presentation and must adhere to the sponsor’s publication requirements as set forth 
in the approved clinical trial agreement (CTA). All draft publications, including abstracts or 
detailed summaries of any proposed presentations, must be submitted to the sponsor at the 
earliest practicable time for review, but at any event not less than 30 days before submission or 
presentation unless otherwise set forth in the CTA. Sponsor shall have the right to delete any 
confidential or proprietary information contained in any proposed presentation or abstract and 
may delay publication for up to 60 days for purposes of filing a patent application.
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10
GLOSSARY OF TERMS
Term
Definition
Adverse Reaction
An adverse event that is considered by either the investigator 
or the sponsor as related to the investigational product
Unexpected Adverse Reaction
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (eg, 
Investigator Brochure for an unapproved investigational 
product)
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11
LIST OF ABBREVIATIONS
Term
Definition
ADCC
Antibody dependent cell-mediated cytotoxicity
AE
Adverse event
BMS
Bristol-Myers Squibb
CS1
CD-2 subset 1
CR
Complete response
CT
Computerized tomography
DILI
Drug induced liver injury
DLT
Dose-limiting toxicity
DMC
Data monitoring committee
EBMT
European Group for Blood and Bone Marrow Transplant
ECG
Electrocardiogram
E-Ld
Lenalidomide, (low-dose) dexamethasone, elotuzumab
EORTC
European Organization for Research and Treatment of Cancer
EPO
Erythropoietin
FSH
Follicle-stimulating hormone
G-CSF
Granulocyte colony-stimulating factor
HAHA
Human-Anti-Human elotuzumab Antibodies
HRQoL
Health Related Quality of Life
HRT
Hormone replacement therapy
ICH
International Council on Harmonization
IF
Immunofixation
IHC
Immunohistochemistry
IMiDs
Immune Modulary Drugs
IMWG
International Myeloma Working Group
IRC
Independent Review Committee
ISS
International Staging System
IV
Intravenous
Ld
Lenalidomide (low-dose) dexamethasone
LD
Lenalidomide (high-dose) dexamethasone
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Term
Definition
MM
Multiple Myeloma
MR
Minor (Minimal) Response
MRI
Magnetic Resonance Imaging
MTD
Maximum tolerated dose
NK
Natural Killer 
NKT
Natural Killer T-cell
ORR
Objective Response Rate
OS
Overall Survival
PBMC
Peripheral blood mononuclear cells
PFS
Progression-free survival
PK
Pharmacokinetic
PR
Partial Response
SAE
Serious adverse event
SCID
Severe combined immunodeficient 
sCR
Stringent complete response
sMICA
Soluble major histocompatibility complex class I-related chain A
SPM
Second primary malignancy
TEAE(s)
Treatment-emergent adverse event(s)
TTP
Time to progression
VGPR
Very Good Partial Response
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APPENDIX 1
INTERNATIONAL STAGING SYSTEM
Stage
Criteria
Median Survival (months)
I
Serum 2-microglobulin < 3.5 mg/L
Serum albumin 3.5 g/dL
62
II
Not stage I or IIIa
44
III
Serum 2-microglobulin 5.5 mg/L
29
 
 
a There are two categories for stage II: serum 2-microglobulin < 3.5 mg/L but serum albumin < 3.5 g/dL; or serum 
2-microglobulin 3.5 to < 5.5 mg/L irrespective of the serum albumin level.
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APPENDIX 2
PERFORMANCE STATUS SCALES
STATUS
SCALES
STATUS
KARNOFSKY
ZUBROD-ECOG-WHO
Normal, no complaints
100
0
Normal activity
Able to carry on normal activities
Minor signs or symptoms of disease
90
1
Symptoms, but fully 
ambulatory
Normal activity with effort
80
Cares for self. Unable to carry on 
normal activity or to do active work
70
2
Symptomatic, but in 
bed < 50% of the day.
Requires occasional assistance, but 
able to care for most of his needs
60
Requires considerable assistance and 
frequent medical care
50
3
Needs to be in bed 
> 50% of the day, but 
not bedridden
Disabled. Requires special care and 
assistance
40
Severely disabled. Hospitalization 
indicated though death non imminent
30
4
Unable to get out of 
bed
Very sick. Hospitalization necessary. 
Active supportive treatment necessary
20
Moribund
10
Dead
0
5
Dead
 
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APPENDIX 5
BRIEF PAIN INVENTORY (SHORT FORM)
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APPENDIX 6
PREPARATION AND ADMINISTRATION OF ELOTUZUMAB
Note: Subjects must be premedicated as described in Section 4.3.1 prior to elotuzumab infusion.
Dose Preparation Instructions
After dilution in normal saline, elotuzumab infusion must be completed within 8 hours if kept at 
room temperature (25 C). In the United States and Puerto Rico, where a shortage of normal 
saline has been reported, dextrose 5% water (D5W) may be used. Normal saline is the preferred 
diluent and D5W should only be used if normal saline is not available. 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). The dose of elotuzumab will be calculated using the subject’s predose 
weight on Day 1 of each cycle, and then added to 0.9% saline for infusion.
Reconstitute elotuzumab lyophilized study drug, as described in steps 1 to 5.
Step 1:  For a 440 mg vial of lyophilized elotuzumab, draw 17 mL of Sterile Water for Injection 
(SWFI), USP into a syringe equipped with an 18-gauge or smaller needle.
Step 2:  Remove the flip-top from the elotuzumab vial.
Step 3:  Place the vial upright on a flat surface and, using standard aseptic techniques, insert the 
syringe needle into the vial through the center of the rubber stopper and deliver 17 mL (into the 
20-mL vial containing 440 mg elotuzumab) SWFI, USP, into the vial. Slowly remove the syringe 
needle out of the vial. The final volume of the reconstituted solution is approximately 17.6 mL, 
which includes the volume displaced by the solid cake. The concentration of elotuzumab in the 
reconstituted solution is approximately 25 mg/mL.
Step 4:  DO NOT SHAKE. 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. Avoid 
prolonged or vigorous agitation. DO NOT SHAKE.  
Step 5:  After the remaining solids are completely dissolved, allow the reconstituted solution to 
stand for 5 to 10 minutes.
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 
containing approximately 25 mg/mL of elotuzumab.
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Step 6:  Once the reconstitution is completed, withdraw the calculated drug volume and further 
dilute with 100-500 ml of normal saline into an infusion bag (see Pharmacy Manual for details). 
The volume of saline or D5W can be adjusted so as not to exceed 5 ml/kg of patient weight at 
any given dose of elotuzumab. The resulting elotuzumab concentration must be from 1.0 mg/ml 
to 6.0 mg/ml. Elotuzumab solutions are compatible with polyvinyl chloride and polyolefin bags. 
Examples of such bags include Viaflo, MacoPharma Easyflex N, Macoflex N, B Braun Excel, 
and Braun Ecobag.
Drug volume will be calculated based on subject weight: For example, a subject receiving 
10 mg/kg elotuzumab who weighs 80 kg on Day 1 [predose] will require 800 mg of study drug 
for infusion. Withdraw 32 mL of elotuzumab (25 mg/mL) from 2 vials and add to an infusion 
bag already containing 230 mL saline, for a total of 262 mL to be infused. 
Similarly, an 80 kg subject receiving 20 mg/kg elotuzumab [predose] will require 1600 mg of 
study drug for infusion. Withdraw 64 mL of elotuzumab (25 mg/mL) from 4 vials and add to an 
infusion bag already containing 340 mL saline, for a total of 404 mL to be infused.  
Use a new sterile needle for withdrawing solution from each vial.
The same vial must not be used to prepare elotuzumab for more than one subject. Used 
elotuzumab vials will be stored until study drug accountability has been completed by the BMS 
designee, and destruction or return is authorized. Used vials do not need to be refrigerated.
Note: Subjects must be premedicated as described in Section 4.3.1 prior to elotuzumab infusion.
Administration Instructions
1. Administer through a low-protein-binding 0.22 - micrometer or smaller 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 0.5 mL 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.
6. 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.
The first dose of elotuzumab will be administered following premedications (described in 
Section 4.3.1) to each subject as an IV infusion, using an automated infusion pump set at an 
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initial rate of 0.5 mL per minute (30 mL/hour). Please refer to Section 4.3.2 for detailed 
information on the management of infusion reaction and re-initiation of infusion.
If a patient is in cycle 1, infusion rate escalation may begin at the second infusion of elotuzumab, 
if no infusion reaction was noted with the first IV administration. If subjects are beyond cycle 1, 
subjects may begin infusion rate escalation at any subsequent cycle, as long as no infusion 
reaction was noted for greater than 4 doses.  
For those in cycle 1: 
The second dose of elotuzumab must be initiated at an infusion rate of 3 mL per minute if no 
infusion reactions were observed 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 to 4 mL per minute.
The third dose of elotuzumab must be initiated at an infusion rate of 5 mL per minute if no 
infusion reactions were reported with the second elotuzumab infusion.
The fourth and subsequent doses of elotuzumab must be initiated at an infusion rate of 5 mL
per minute if no infusion reactions were reported. 
Elotuzumab Infusion Rate (10 mg/kg)
The elotuzumab infusion rate will be increased gradually to a maximum of 5 mL/min as 
presented in Table 1. Table 1 represents an example starting from cycle 1; however, this can be 
applied to any cycle.
* Volume for 80 kg subject. Total volume varies according to the subject weight.
Please note that infusion rate increase to the next higher level only if no infusion reactions encountered.
Table 1:
Elotuzumab Infusion Rate Plan (10 mg/kg)
Infusion Rate
Duration of infusion
Volume delivered
Volume remaining
Cycle 1 Dose 1
Total Duration: 2hrs 50min
262 mL*
0.5 mL/min
30 min
15 mL
247 mL
1 mL/min
30 min
30 mL
217 mL
2 mL/min
110 min
217 mL
0 mL
Cycle 1 Dose 2
Total Duration: 1hrs 13min
262 mL
3 mL/min
30 min
90 mL
172 mL
4 mL/min
43 min
172 mL
0 mL
Cycle 1 Dose 3 and 4
Total Duration: 53min
262 mL
5 mL/min
53 min
262 mL
0 mL
Cycle 2 +
Total Duration: 53min
262 mL
5 mL/min
53 min
262 mL
0 mL
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If no infusion reactions were observed during the infusion rate escalation over these four doses 
of elotuzumab, all following doses must commence at the maximum rate of 5 mL per minute so 
long as there are no infusion reactions. Escalation above 5 mL per minute is not permitted.
For subjects beyond cycle 1 who have not escalated the infusion rate:
Subjects who have not escalated elotuzumab infusion rates beyond 2 mL per minute, despite 
administration of more than 4 doses of elotuzumab, and who have not experienced any infusion 
reactions, must begin the rate escalation paradigm as described above. That is, a subject in 
cycle X day 1 of study therapy must begin the elotuzumab infusion rate escalation, aiming first 
for an infusion rate of 3 mL per minute as described for the second dose of elotuzumab above. If 
the subject does not experience an infusion reaction during the first 30 minutes of the second 
dose of elotuzumab, escalate the infusion rate to 4 mL per minute. On the next dose of 
elotuzumab, ie, cycle X day 15, the elotuzumab infusion rate must start at 5 mL per minute as 
described above for the third dose of elotuzumab, if no infusion reactions were noted. With the 
next dose of elotuzumab (ie, cycle X+1 day 1), if no infusion reactions were noted, the subject 
must maintain the infusion rate at 5 mL per minute as described above for the third and 
subsequent doses of elotuzumab.
For subjects beyond cycle 18 receiving elotuzumab 20 mg/kg once a month who have not 
escalated the infusion rate to 5 ml/min:
Elotuzumab Infusion Rate (20 mg/kg) in Cycle 19 and subsequent cycles
The elotuzumab infusion rate will be increased gradually to a maximum of 5 mL/min as 
presented in Table 2. 
Subjects who have escalated to 5 mL/min at 10 mg/kg dose must decrease the rate to 
3 mL/min at the first infusion at 20 mg/kg. Subjects will escalate as described below.
* Volume for 80 kg subject. Total volume varies according to the subject weight.
Please note that infusion rate increase to the next higher level only if no infusion reactions 
encountered.
See section 4.3.2 for management of infusion reactions.
Table 2:
Elotuzumab Infusion Rate Plan (20 mg/kg)
Infusion Rate
Duration of infusion
Volume delivered
Volume remaining
Dose 1 at 20 mg/kg
Total Duration: 1 hrs 48.5 min
404 mL
3 mL/min
30 min
90 mL
314 mL
4 mL/min
78.5 min
314 mL
0 mL
Dose 2 and 3 at 20 mg/kg
Total Duration: 1 hr 21 min
404 mL
5 mL/min
81 min
404 mL
0 mL
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SAP_000.pdf: 
Official Title of Study: 
A Phase 3, Randomized, Open Label Trial of Lenalidomide/dexamethasone With or Without 
Elotuzumab in Subjects with Previously Untreated Multiple Myeloma 
 
NCT Number: NCT01335399 
 
Document Date (Date in which document was last revised): November 04, 2016 
 


STATISTICAL ANALYSIS PLAN
A PHASE 3, RANDOMIZED, OPEN LABEL TRIAL OF 
LENALIDOMIDE/DEXAMETHASONE WITH OR WITHOUT ELOTUZUMAB IN
SUBJECTS WITH PREVIOUSLY UNTREATED MULTIPLE MYELOMA
PROTOCOL CA204006
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2
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN ............................................................................................1
TABLE OF CONTENTS............................................................................................................2
2
STUDY DESCRIPTION ..........................................................................................6
2.1
Study Design ............................................................................................................6
2.2
Treatment Assignment..............................................................................................7
2.3
Blinding and Unblinding...........................................................................................7
2.4
Independent Data Monitoring Committee and Other External Committees ...............7
2.5
Interim Analyses.......................................................................................................8
3
OBJECTIVES ..........................................................................................................8
3.1
Primary.....................................................................................................................8
3.2
Secondary.................................................................................................................8
4
ENDPOINTS............................................................................................................9
4.1
Endpoint Definitions.................................................................................................9
4.1.1
Progression-Free Survival (PFS)..............................................................................9
4.1.1.1
Definition of an Adequate Tumor Assessment ...........................................................9
4.1.1.2
Date of Progression or Censoring When Different Components of a Per Time 
Point Tumor Assessment Conducted at Different Times ..........................................10
4.1.1.3
Primary Definition of PFS......................................................................................10
4.1.2
Objective Response Rate (ORR)..............................................................................11
4.1.3
Overall Survival .....................................................................................................11
5
SAMPLE SIZE AND POWER...............................................................................12
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................12
6.1
Study Periods..........................................................................................................12
6.2
Treatment Regimens...............................................................................................13
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6.3
Populations for Analyses ........................................................................................13
7
STATISTICAL ANALYSES..................................................................................14
7.1
General Methods ....................................................................................................14
7.2
Study Conduct........................................................................................................15
7.2.1
Accrual Patterns.....................................................................................................15
7.2.2
Protocol Violations.................................................................................................15
7.3
Study Population ....................................................................................................16
7.3.1
Subject Disposition.................................................................................................16
7.3.2
Demographic and Subject Characteristics ..............................................................16
7.3.3
Disease Characteristics at Baseline........................................................................16
7.3.4
General Medical History ........................................................................................17
7.3.5
Baseline Safety Laboratory Tests............................................................................17
7.4
Extent of Exposure .................................................................................................18
7.4.1
Study Therapy.........................................................................................................18
7.4.1.1
Duration of Study Therapy......................................................................................18
7.4.1.2
Dose Modifications.................................................................................................18
7.4.1.3
Cumulative Dose, Dose Intensity, and Relative Dose Intensity................................21
7.4.2
Premedication Other than Dexamethasone for Hypersensitivity Reactions..............23
7.4.3
Concomitant Medication.........................................................................................23
7.4.4
Discontinuation of Study Therapy...........................................................................24
7.4.5
Subsequent Anti-Myeloma Therapies ......................................................................24
7.5
Efficacy..................................................................................................................25
7.5.1
Primary Analysis of Progression-Free Survival ......................................................25
7.5.2
Supportive Analyses of Progression-Free Survival..................................................26
7.5.3
Concordance Between IRC and Investigator Assessments of Progression ...............27
7.5.5
Analysis of Objective Response...............................................................................29
7.5.9
Analyses of Overall Survival...................................................................................30
7.5.10
Currentness of PFS and OS Data............................................................................31
7.5.11
Hierarchy for Testing Secondary Endpoints............................................................31
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7.6
Safety.....................................................................................................................31
7.6.1
Adverse Events .......................................................................................................31
7.6.2
Serious Adverse Events and Adverse Event Leading to Discontinuation..................32
7.6.3
Safety by subgroups................................................................................................32
7.6.4
Adverse Events of Special Interest ..........................................................................33
7.6.5
Second Primary Malignancies ................................................................................33
7.6.6
Deaths ....................................................................................................................34
7.6.7
Clinical Laboratory Evaluations.............................................................................34
7.6.8
Electrocardiograms................................................................................................35
7.6.9
Vital Signs, Physical Measurements and Physical Examination..............................35
7.11
Healthcare Resource Utilization Data .....................................................................40
8
CONVENTIONS....................................................................................................40
8.1
Baseline Definition.................................................................................................40
8.2
Age Definition........................................................................................................40
8.3
Time Since Initial Diagnosis to Randomization Definition......................................41
8.4
Duration and Study Day Definition.........................................................................41
8.5
Day Conversion of Date Imputation........................................................................41
8.6
AE, Laboratory Results and Concomitant Medication.............................................42
8.7
Topline Analyses....................................................................................................42
APPENDIX 1: LIST OF ABBREVIATIONS............................................................................45
APPENDIX 2: LIST OF COUNTRIES BY REGIONS.............................................................48
9
DOCUMENT HISTORY........................................................................................49
LIST OF TABLES
Table 7.10-1:
Scheduled Visit ......................................................................................37
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2
STUDY DESCRIPTION
2.1
Study Design
This is a Phase 3, open-label, multi-center trial investigating lenalidomide/low-dose 
dexamethasone with and without elotuzumab in subjects with newly diagnosed, untreated MM. 
The study population will consist of subjects who:
•
are newly diagnosed with symptomatic MM
•
have not received any prior systematic anti-myeloma therapy AND
•
have measurable disease AND
•
are not candidates for high-dose therapy plus stem-cell transplantation (SCT) because of 
age (≥ 65 years) or coexisting conditions
•
Have met all the eligibility criteria (outlined in Protocol Section 3.3).
Eligible subjects will be randomized in a 1:1 ratio to receive either lenalidomide/low-dose 
dexamethasone (Ld) or elotuzumab/lenalidomide/low-dose dexamethasone (E-Ld). The 
randomization will be stratified as described in Section 2.2. Approximately 750 subjects will be 
randomized.
Subjects should receive Ld with or without elotuzumab in 28-day cycles until disease progression, 
unacceptable toxicity, or the subject meets other criteria for discontinuation of study drug (see 
Protocol Section 3.5), whichever occurs earlier. 
Tumor assessments will be conducted every four weeks relative to the first dose of study 
medication, until disease progression, death or withdrawal of consent. Subjects who discontinue 
study medication for reasons other than progression e.g. for toxicity, should continue to have tumor 
assessments until progression, even if they have gone on to receive subsequent anti-myeloma 
therapy. Subjects will be followed at least every 16 weeks after disease progression for survival 
and subsequent myeloma therapies. The primary analyses of efficacy endpoints (using European 
Group for Blood and Bone Marrow Transplant [EBMT] criteria) will be based on a blinded review 
of tumor assessments by an IRC.
Crossover between the arms is not permitted.
Blood samples for pharmacokinetic (PK) and immunogenicity analysis will be collected in all 
subjects who received elotuzumab, prior to elotuzumab infusion on Day 1 of Cycles 1 through 4, 
6, 9, 12, 15 and 18, every 3rd cycle after cycle 18 (21, 24, 27, etc..) as well as at the end of the 
study or discontinuation of treatment, and 30-day and 60-day follow-up visits. In addition, serial 
PK samples including 30 minutes post end of infusion and two hours post end of infusion will be 
drawn in Cycles 1, 2 and 3.
For full details of the schedule and timing of assessments see Protocol Section 5.
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2.2
Treatment Assignment
After a subject’s eligibility for randomization is established and informed consent has been 
obtained, the subject’s treatment will be assigned via an interactive voice response system (IVRS). 
Subjects will be randomized to Ld or E-Ld in a 1:1 ratio. The randomization will be stratified by:
•
Stage of disease (International Staging System (ISS) 1 - 2 versus 3) 
•
Age (< 75 years old versus ≥ 75 years old)
•
Eastern Cooperative Oncology Group (ECOG) Performance status (0 versus 1 - 2)
and will be carried out via permuted blocks within each stratum. 
2.3
Blinding and Unblinding
This is an open label trial. However, in order to maintain equipoise, the study team, including 
biostatisticians and programmers, will not have access to the randomization codes until the study 
is completed. Only the DMC and the reporting independent statistical group for the DMC, which 
is external to BMS, and completely independent from the study team, will be provided with the 
randomization information prior to the completion of the study.
The formal interim analysis of PFS will be reviewed by the DMC after at least 70% of the target 
events per IRC have occurred. The DMC will then notify the Sponsor to unblind the PFS data if 
the pre-specified criterion for statistical significance has been met.
The primary analysis of PFS and tumor response will be based on disease assessments made by 
the IRC. The assessments will be made retrospectively and the IRC will be blinded to the treatment 
arms.
2.4
Independent Data Monitoring Committee and Other External 
Committees
Two independent committees will be established for this study: (i) a DMC and (ii) an IRC.
An independent DMC will be established before the first subject has been treated and will monitor 
safety throughout the study. The first comprehensive safety review meeting will take place at the 
same time when 120 subjects have been randomized and followed up for at least 2 months in study 
 
 Subsequent comprehensive safety review 
meetings will take place every eight months after that. In addition, the DMC will be provided with 
serious adverse event (SAE) tables every four months. The DMC will also review the efficacy and 
safety data at the interim analyses to make formal decisions on stopping the trial for superiority
(see Section 0). A separate charter will provide further guidance and describe the activities of this 
committee, including details on the statistical stopping rules.
An IRC will be responsible for reviewing all tumor assessment data to determine the best response 
and date of progression, based on the EBMT criteria. IRC-determined response and progression 
will be used in the primary analyses of PFS and ORR. A separate charter describes the activities 
of this committee.
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2.5
Interim Analyses
The independent DMC will review the interim analysis of PFS data after at least 338 (70%) 
progression events (per IRC) have been observed and all subjects have been randomized. This 
formal comparison of PFS will allow for early stopping for superiority.  The stopping boundaries
will be derived based on the O’Brien and Fleming α spending function and will depend on the 
actual number of events observed at the time of the interim analysis. However, if there were exactly 
338 events, the DMC could stop the study for superiority if the p-value were ≤ 0.0148. The 
significance level for the final look after 482 events would then be 0.0455.
If more than 338 events have occurred by the time of the interim analysis, different stopping 
boundaries will be calculated in East v5.1. It should be noted that survival follow-up would 
continue even if the study were stopped at the interim analysis of PFS for superiority.
In addition, an interim analysis of OS will be conducted at the time both the PFS and ORR analyses 
are positive. The nominal significance levels for the interim and final survival comparisons will 
be determined by an O’Brien and Fleming alpha spending function.
3
OBJECTIVES
3.1
Primary
The primary objective of this study is to compare the PFS of E-Ld versus Ld in subjects with newly 
diagnosed, untreated MM.
3.2
Secondary
The secondary objectives are:
• To compare the objective response rate (ORR) between treatment arms
• To compare the overall survival (OS) between treatment arms.
• To assess PFS rates at 1, 2, 3, 4, and 5 years
• To compare the change from baseline of the means score of pain severity and the change 
from baseline of the mean score of pain interference using the Brief Pain Inventory - Short Form 
(BPI-SF) between treatment arms.
 
 
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4
ENDPOINTS
The primary endpoint is PFS based on IRC tumor assessments using the primary definition of PFS
(see section 4.1.1.3). Supportive analyses of PFS are:
The secondary endpoints are:
•
ORR. The primary analysis will be based on IRC tumor assessments using the EBMT 
assessment criteria. Supportive analysis of ORR will be based on investigator assessment 
of best response.
•
OS
•
Patient-reported Outcomes (BPI-SF)
•
PFS rates at 1, 2, 3, 4, and 5 years
4.1
Endpoint Definitions
4.1.1
Progression-Free Survival (PFS)
4.1.1.1
Definition of an Adequate Tumor Assessment
In the analysis of PFS, subjects who do not progress are censored. A non-progressing subject can 
be censored on the date of a tumor assessment only if there is sufficient information to rule out 
progression. An “adequate” tumor assessment visit for ruling out progression will require the 
following information:
•
Serum monoclonal paraprotein results, if measurable at baseline,  and
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•
Urine monoclonal paraprotein results, if measurable at baseline
4.1.1.2
Date of Progression or Censoring When Different Components of a Per 
Time Point Tumor Assessment Conducted at Different Times
As different tumor measurements may be conducted on different days, for instance, the blood draw 
for serum M-protein may be on a different date than 24-hour urine, the IRC and investigators were 
instructed to report the earliest date of the measurements associated with that time point for 
progression. In contrast, if tumor measurements are done on different dates and the subject is being 
censored, instructions were to report the latest date of the measurements associated with that time 
point.
4.1.1.3
Primary Definition of PFS
Primary Definition of PFS: PFS, under the primary definition, is the time from randomization to 
the date of the first documented tumor progression or to death due to any cause, provided
progression or death does not occur more than 10 weeks (two or more assessment visits) after the 
last adequate tumor assessment. Clinical deterioration will not be considered progression.
The following censoring rules will be applied to the primary definition of PFS:
•
Subjects who receive subsequent systemic anti-myeloma therapy prior to documented 
progression will be censored at the date of the last adequate tumor assessment prior to or 
on the initiation of the new therapy.
•
Subjects who have an event (documented progression or death) > 10 weeks (2 assessment 
visits) after their last tumor assessment will be censored at their last adequate tumor 
assessment prior to the event.
•
Subjects who neither receive subsequent therapy prior to progression nor have a 
progression event (including death) will be censored at their last adequate tumor 
assessment.
•
In addition, subjects who do not have any post-baseline tumor assessments and who do not 
die within 10 weeks of randomization will be censored on the date of randomization.
In all cases, if there are no adequate assessments for censoring then the subject is censored on the 
date of randomization.
4.1.1.4
Secondary Definition of PFS – ITT Definition
Intent-to-Treat (ITT) Definition of PFS:  PFS will also be analyzed applying an ITT definition that 
utilizes all of the data on each randomly assigned subject at the time of the PFS analysis. PFS 
under the ITT definition will be defined as the time from randomization to the date of the first 
documented tumor progression or death due to any cause. Clinical deterioration will not be 
considered progression. A subject who neither progresses nor dies will be censored on the date of 
their last adequate tumor assessment. A subject who does not have any post-baseline tumor 
assessments and who has not died will be censored on the date at which they were randomized. 
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4.1.2
Objective Response Rate (ORR)
Best overall response is determined as the best assessment based on all on-study efficacy data for 
the subject. Subjects with objective response are subjects with a best overall response on-study of 
partial response (PR) or better based on EBMT assessment criteria.
ORR is defined as the proportion of subjects with objective response among all randomized 
subjects. 
4.1.3
Overall Survival
Overall survival is defined as the time from randomization to the date of death from any cause. If 
a subject has not died, their survival time will be censored at the date of last contact (“last known 
alive date”). A subject will be censored at the date of randomization if they were randomized but 
had no follow-up.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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BMS-901608                                                                                                                                                  elotuzumab     
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5
SAMPLE SIZE AND POWER
The number of events and power for PFS were calculated assuming an exponential distribution for 
each arm. One interim analysis of PFS is planned, and will allow for early stopping for superiority. 
An O’Brien and Fleming α spending function will be employed to determine the stopping 
boundaries.
Approximately 750 subjects will be randomized to the two treatment groups in a 1:1 ratio in order 
to obtain at least 482 progression events i.e. documented progressions or deaths. Four hundred and 
eighty-two events ensures that a two-sided 5% level sequential test procedure with one interim 
analysis will have 90.5% power if the median PFS times in the control and experimental arms were 
25 and 33.75 months respectively; i.e. if the hazard ratio (HR) of the experimental arm to the 
control arm is 0.74.
The interim analysis of PFS will be conducted after 70% of the total events (i.e., at least 338 of the 
planned 482 events) have been observed.
Assuming an accrual rate of 24 subjects per month, it will take approximately 60 months to obtain 
the required number of events; 31 months of accrual and 29 months for PFS follow-up. At the time 
of final PFS analysis, an observed HR of 0.84 or less (which corresponds to a 4.8 months or greater 
improvement in median PFS (25 vs 29.8 months), would result in a statistically significant 
difference between the two treatment arms. 
Survival, a key secondary endpoint, will be formally compared between the two arms at the time 
both ORR and PFS analyses are positive (whether that occurs after 70% of PFS events or all 482 
events) and again after at least 354 deaths have been observed, which is expected to occur 7 years
(84 months) after the initiation of the study. An O’Brien and Fleming α-spending function will be 
used to obtain the nominal significance level for the interim and final analysis of survival. Three
hundred and fifty-four deaths ensure that a two-sided, α=0.05 level test procedure with one interim 
analysis will have 80% power to detect a 8.7 percentage point improvement in the 4-year survival 
rate1 (from 59% to 67.7%, i.e. a HR= 0.74).
Power calculations were performed using East v5.1.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
There are three periods in this study: screening, on-treatment and post-treatment follow-up.
Screening: Most screening procedures must be done no more than 14 days prior to randomization. 
Some exceptions include efficacy assessments and ECGs, which can be done up to 28 days prior 
to randomization. See Section 5 of the Protocol for full details of study procedures and timings. 
For analyses purposes data collected within 60 days of randomization and prior to first dose will 
fall into the screening/baseline period. Site personnel should make every effort to initiate study 
drug treatment within three days after randomization.
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BMS-901608                                                                                                                                                  elotuzumab     
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On-Treatment Period: The on-treatment period has three phases: the first two cycles, cycles 3-18, 
and cycle 19 and beyond. All cycles are 28 days in duration. The first two cycles are characterized 
by weekly visits, safety assessments, and, in the experimental arm, elotuzumab infusions. Cycles
3-18 are characterized by fortnightly visits, safety assessments and, in the experimental arm, 
elotuzumab infusions. Cycles 19 and beyond, are characterized by once every 4 weeks visit, safety 
assessments and, in the experimental arm, elotuzumab infusions. Subjects should have myeloma 
urine and serum laboratory assessments every four weeks while on treatment until they progress 
and should have imaging for extramedullary plasmacytomas, if indicated, and at the time of 
CR/sCR assessment. The timing of the tumor assessments will be independent of dosing. Study 
treatment ends when the subject progresses, experiences unacceptable toxicity, or withdraws 
consent.
Follow-up Period: Subjects who discontinue study therapy prior to progression must continue to 
undergo tumor assessments on the same schedule used in the on-treatment period, regardless of 
whether they are receiving new anti-myeloma therapy. The only exception to this is if the subject 
withdraws consent for all study procedures or loses the ability to consent freely.
Follow-up for survival and subsequent myeloma therapy will be conducted every 16 weeks until 
the subject dies or the study ends.
6.2
Treatment Regimens
Subjects will be randomized to one of two treatment arms, E-Ld or Ld. Subjects will receive these 
treatments in 28-day cycles until disease progression, unacceptable toxicity or withdrawal of 
consent.
On Arm A (E-Ld) subjects receive:
•
Elotuzumab: 10 mg/kg intravenous (IV) on Days 1, 8, 15 and 22 of the cycle during Cycles 
1 and 2; Days 1 and 15 during Cycles 3-18; and 20mg/kg intravenous (IV) on Day 1 of the 
cycle during subsequent cycles.
•
Lenalidomide: 25 mg orally (po) on Days 1-21 of each cycle.
•
Dexamethasone: Administered on Days 1, 8, 15 and 22 of cycle. 28 mg po + 8 mg IV 
whenever given prior to elotuzumab; 40 mg po on weeks on which no elotuzumab is given.
On Arm B (Ld) subjects receive:
•
Lenalidomide: 25 mg po on Days 1-21 of each cycle.
•
Dexamethasone: 40 mg po on Days 1, 8, 15 and 22 of each cycle.
6.3
Populations for Analyses
The following subject populations will be used for the statistical analysis:
All enrolled subjects: All subjects who gave signed informed consent and who were entered in the 
IVRS.
Randomized subjects: All enrolled subjects who were randomized. 
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Treated subjects: This population includes all randomized subjects who received at least one dose 
of study medication (lenalidomide, dexamethasone or elotuzumab).
The analysis of baseline characteristics, efficacy and subject-reported outcomes will be carried out 
on the “Randomized subjects” population, with subjects grouped according to the treatment arm 
to which they were randomized. The analysis of extent of exposure and safety will be based on the 
“Treated subjects” population, with subjects grouped according to the treatment received, where 
treatment received is defined as the treatment arm to which they were randomized, unless they 
received the wrong treatment throughout the study.
7
STATISTICAL ANALYSES
7.1
General Methods
Continuous variables will be summarized using descriptive statistics; i.e. number of non-missing 
observations (n), mean, standard deviation (STD), median, minimum, maximum, first quartile and 
third quartile. Categorical variables will be summarized by frequencies and percentages. Minimum 
and maximum values will be reported to the precision as the data collected; mean, median and 
quartiles will be rounded to one decimal place more than the data collected; STD will be rounded 
to one decimal place more than the summary statistic (e.g. mean) for which it is calculated, and 
percentages will be rounded to one decimal place. Percentages greater than zero but less than 0.1 
will be presented as “<0.1”. 
The Kaplan-Meier (KM) product limit method will be used to estimate the distribution and median 
of each time-to-event endpoint in which censoring is involved. The Brookmeyer and Crowley 
method9 will be used to compute a 95% confidence interval (CI) for the median of each time-to-
event endpoint using the log-log transformation of the survivor function S(t).
The stratified log-rank test will be performed to compare time to event distributions (PFS or OS) 
between treatment groups. Stratification factors will be obtained from IVRS randomization 
dataset. The stratified log-rank test will be based on the ‘proc lifetest’ procedure in SAS 9.2, in 
which the ‘strata statement’ specifies the stratification factors with ‘group option’ equal to 
randomized group.
A stratified Cox proportional hazards model will be used to compute an estimate of, and CI for, 
the hazard ratio of the investigational to the control arm, for each endpoint. Medians and hazard 
ratios for time-to-event variables will be rounded to two decimal places. 
The main analyses of tumor response and progression-free survival will be conducted using the 
best overall response, date of response, and date of progression assigned by the IRC. 
Laboratory results, adverse events, and other symptoms will be graded using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0, except 
where CTCAE grades are not available. Individual laboratory values will be presented in both the 
conventional US units and the International System of Units (SI). Adverse events will be 
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categorized using the most current version of Medical Dictionary for Regulatory Activities 
(MedDRA), by system organ class and preferred term. Prior therapies will be summarized using 
the most current version of the World Health Organization (WHO) drug dictionary.
Statistical analyses will be carried out in SAS (Statistical Analysis System, SAS Institute, North 
Carolina, USA), unless otherwise indicated.
7.2
Study Conduct
7.2.1
Accrual Patterns
Tables summarizing accrual by center, country, region (North America, European Union, and Rest 
of World) overall and by treatment group will be generated (see appendix 2 for a list of countries 
in each region).
Subject accrual will also be summarized by the randomization stratification 
factors per IVRS (Stage of disease [ISS 1 – 2 versus 3], Age [< 75 years old versus ≥ 75 years 
old], ECOG Performance status [0 versus 1 – 2]), overall and by treatment group. In addition, this 
summary will also be presented based on the stratification information obtained from the baseline 
CRF pages. A cross tabulation of IVRS vs. baseline stratification factors will also be summarized.
7.2.2
Protocol Violations
A relevant protocol deviation is defined as a deviation from the protocol which is programmed in 
the database and which could potentially affect the interpretability of the study results. 
The number and percentage of subjects with any relevant protocol deviation and each specific 
deviation will be presented overall and by treatment group. 
The following eligibility deviations are considered relevant in this study and will be summarized 
for all randomized subjects: 
1. Any prior systemic anti-myeloma therapy
2. Non-measurable disease. This occurs when none of the following three conditions are met:
1. IgG, IgA, or IgM M-protein ≥ 0.5 g/dL
2. Serum IgD M-protein ≥ 0.05 g/dL
3. M-protein ≥ 200 mg in 24-hour urine.
3. No baseline tumor assessment. This occurs when there are no tumor assessments at all 
(laboratory assessments) on or prior to first day of dosing. See section 4.1.1.1, for definition 
of adequate tumor assessment.
Also, the following on-treatment deviations are considered relevant in this study and will be
summarized for all treated subjects:
4. Non-protocol specified systemic anti-myeloma therapy prior to discontinuation of study 
therapy
5. Received non-assigned treatment regimen throughout the study.
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BMS-901608                                                                                                                                                  elotuzumab     
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6. Subjects continuing to receive study therapy after 10 weeks of first documented progression 
per investigator (as progression should be confirmed).
If assessments based on the central laboratory is unavailable, but the local laboratory results are 
available, then those will be used for evaluating deviations 2 and 3.
A by subject listing of relevant protocol deviations will be provided.
7.3
Study Population
7.3.1
Subject Disposition
A frequency table of enrolled subjects, broken down by whether or not they were randomized, and 
the reasons for not being randomized, will be produced. 
Subject disposition during the treatment period will be summarized, overall and by treatment 
group. The number and percentage of subjects randomized, treated, still on treatment and 
discontinued from the treatment will be presented. 
By-subject listings will also be produced to accompany the tables on enrollment and the subject 
disposition table. 
In addition, a by-subject listing indicating whether the subject was included in each of the analysis 
populations will be provided. 
7.3.2
Demographic and Subject Characteristics
Demographic and baseline characteristics will be summarized, overall and by treatment group. 
The following parameters will be summarized; age at the time of informed consent (years), age 
category at time of informed consent (<65 years, ≥65 years), and (<75 years, ≥75 years), gender 
(Male, Female), race (White, Black/African American, American Indian/Alaska Native, Asian, 
Native Hawaiian/Other Pacific Islander, Other), ethnicity – for US subjects only (Hispanic/Latino, 
Not Hispanic/Latino), weight (kg) and ECOG performance status (0,1,2) .
An accompanying by-subject listing of demographic and subject characteristics will be 
presented. 
7.3.3
Disease Characteristics at Baseline
Baseline disease characteristics will be summarized, overall and by treatment group. The following 
parameters will be presented to summarize baseline disease:
•
Serum M-protein (g/dL)
•
Urine M-protein (mg/24 hours)
•
Myeloma type (IgG, IgA, IgD, IgM, Light chain disease)
•
Number of lytic bone lesions (0, 1-3, >3)
•
Myeloma risk category
−
High risk: ISS stage II or III and t(4;14) or del(17p) abnormality
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−
Low risk: ISS stage I or II and absence of t(4;14), del(17p) and 1q21 abnormalities
and age < 55 years
−
Standard risk: any subjects not meeting the definition of high or low risk.
−
Not Evaluable: Subjects having missing data preventing the classification in the 
other 3 categories
•
Individual FISH /Cytogenetic abnormalities (del 17p, t(14; 16), t(4; 14), and del 13)
•
β2 microglobulin (mg/L) (<3.5, ≥3.5-5.5, ≥5.5)
•
Albumin (g/L) (<3.5, ≥3.5)
•
LDH (<300 IU/L, ≥300 IU/L)
•
Soft tissue plasmacytomas (Yes, No) 
•
ISS Stage at enrollment (I, II, III)
•
Time from disease diagnosis to randomization (months)
An accompanying by-subject listing of disease characteristics at baseline will be presented.
7.3.4
General Medical History
The number and percentage of subjects with any relevant medical history and by body system will 
be presented, overall and by treatment group. 
By subject listings of medical history will be provided. A by subject listing of pregnancy test data 
will also be provided.
7.3.5
Baseline Safety Laboratory Tests
Baseline safety laboratory evaluations will be the last available samples taken on or before Cycle 
1, Day 1 and within 60 days of randomization. 
Baseline safety laboratory values will be presented by CTC severity grade, by treatment group. 
Separate tables will be generated for hematology (hemoglobin, WBC, ANC [neutrophils plus 
bands], ALC [absolute lymphocyte count] and platelets, liver function (ALT, AST, alkaline 
phosphatase, albumin, direct bilirubin and total bilirubin) and renal function/electrolytes (sodium, 
potassium, bicarbonate, calcium, glucose, and creatinine, creatinine clearance < 60 ml/min, ≥ 60 
ml/min). Sodium, potassium, calcium, and glucose will be presented separately, based on their 
high and low values.
CTC grades will be derived as part of the analysis data set programming using version 3.0.
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7.4
Extent of Exposure
7.4.1
Study Therapy
Lenalidomide, oral dexamethasone and IV dexamethasone are given at fixed doses and are not 
adjusted for body surface area or weight. The elotuzumab dose, in contrast, is adjusted for weight. 
Throughout this SAP, a subject’s elotuzumab dose level at a particular time point will refer to the 
actual dose, in mg/kg, rather than their planned dose. A subject’s actual elotuzumab dose level will 
be computed by dividing their total dose delivered, in mg, as recorded on the “Record of Study 
Medication - Elotuzumab” eCRF page, by their latest pre-dose weight, in kg, on Day 1 of that 
cycle. 
7.4.1.1
Duration of Study Therapy
The number of cycles of treatment received by subjects will be summarized (using n, mean, STD, 
median, min, max, q1 and q3) by treatment group.
The duration of each treatment (elotuzumab, dexamethasone [oral, IV, and oral and IV combined] 
and lenalidomide), in months, will be calculated as:
ሺ݀ܽݐ݁݋݂݈ܽݏݐ݀݋ݏ݁݋݂ݐ݄݁݀ݎݑ݃െ݀ܽݐ݁݋݂݂݅ݎݏݐ݀݋ݏ݁݋݂ݐ݄݁݀ݎݑ݃൅1ሻ/30.4375
Duration of each of the study treatments will be summarized by treatment group.
7.4.1.2
Dose Modifications 
Elotuzumab:
•
Dose Reduction
Reduction of Elotuzumab dosing is not permitted as per the protocol. 
•
Dose Delay
A delay for Elotuzumab will be computed based on records from the dosing CRF page. A delay in 
Elotuzumab dosing will be defined as the number of days from the start date of the previous 
infusion to the start date of the current infusion being > 8 days and ≤10 days (if in cycles 1, 2 or 
first infusion of cycle 3) or > 15 days and ≤ 21 days (from second infusion of cycle 3 - cycle 19)
or > 29 days and ≤ 35 days (from cycle 20 onwards). 
For courses with a delay of Elotuzumab infusion, the time of delay in infusion will be summarized 
in the categories: 2 - 3 days, 4 - 7 days.
The number and percentage of subjects with any dose delay, with 1, 2, 3, or ≥ 4 reported delays 
will be summarized. For subjects with a delay, their reason for delay (from the dose modification 
page of the CRF) will be summarized in the groups: “hematologic toxicity”, “non-hematologic 
toxicity”, “AE”, “dosing error” and “other”. For subjects without an available reason for delay, the 
category “unknown” will be used. 
A by-subject listing for dose delay will be presented for all treated subjects. This listing will 
include all reported delays per CRF, regardless of whether the subject had a computed delay based 
on the actual dosing dates.
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•
Dose Omission
An omission for Elotuzumab will be calculated based on records from the dosing CRF page. If the 
interval between the two dosing dates for Elotuzumab is >10 days (in cycles 1, 2 or first infusion 
of cycle 3) or >21 days (from second infusion of cycles 3-19), or > 35 days from cycle 20 and 
beyond, the dose will be considered to have been omitted.
For courses with an omission of Elotuzumab infusion, the time between the previous and current 
infusion will be summarized in the categories: 11 - 14, 15 - 21, 22 - 27, 28 - 35, ≥36 days.
The number and percentage of subjects with a dose omission, and with 1, 2, 3, or ≥4 omissions 
will be summarized. For subjects with an omission, their reason for omission (from the dose 
modification page of the CRF) will be summarized in the groups: “hematologic toxicity”, “non-
hematologic toxicity”, “AE”, “dosing error” and “other”. For subjects without an available reason 
for omission, the category “unknown” will be used. 
A by-subject listing for dose omission will be presented for all treated subjects. This listing will 
include all reported omissions per CRF, regardless of whether the subject had a computed omission 
based on the actual dosing dates.
•
Dose Interruption
The number and percentage of subjects with any interruption in their elotuzumab infusion, with 1, 
2, 3, or ≥ 4 interruptions, with an interruption due to “infusion reaction”, “infusion administration 
issues” and “other” will be presented. In addition, duration of interruptions (in minutes) will be 
summarized via descriptive statistics. 
A by-subject listing will be generated for elotuzumab IV interruptions. This listing will include 
reason for interruption, whether the infusion was resumed, and duration of the interruption.
•
IV Rate Reduction
The number and percentage of subjects with any elotuzumab IV rate reduction, with 1, 2, 3, or ≥ 
4 rate reductions, and with rate reductions due to “infusion reaction,” “infusion administration 
issues,” and “other” will be presented. 
A by-subject listing will be generated for elotuzumab IV rate reductions.
Lenalidomide:
•
Dose Reduction
Reduction of Lenalidomide will be computed based on the actual dose received. In any study day 
(excluding, cycle 1, day 1), the drug will have a calculated reduction compared to the previous 
day, if the actual level of the administered dose is below the actual level of the administered dose 
in the previous instance. The information for this analysis will be derived programmatically, using 
the total daily dose on the “Record of Study Medication - lenalidomide” eCRF page. 
The daily dose levels are defined as follows:
•
Dose level 0 or full dose (25 mg): ≥ 20.0
•
Dose level -1 (15 mg): 12.5 mg to < 20.0
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•
Dose level -2 or starting dose for moderate renal impairment (10 mg): 8.75 to < 12.5 mg
•
Dose level -3 for subjects with severe renal impairment (15 mg every 48 hours): 6.25 to < 
8.75 mg
•
Dose level -4 for subjects with End Stage Renal Disease (ESRD) (5 mg): < 6.25 mg
The number and percentage of subjects with a dose reduction, and the lowest dose level achieved 
per subject (-1, -2, -3, ≤-4), will be presented by treatment group. This table will be broken out by 
whether the subject started at the standard dose level or at the 10 mg dose level. 
The reason for dose reduction as reported by the investigator will be tabulated for all instances 
with a calculated reduction based on the dose modification for Lenalidomide page. A category 
“unknown” will be defined for all calculated reductions with no reason reported by the 
investigator. 
A by-subject listing of dose reductions will be generated. This will include all reported reductions 
per investigator, regardless of whether it met the requirements for a calculated reduction.
•
Dose Interruption 
In any cycle, the Lenalidomide dose will be considered as interrupted if there is a gap of two or 
more days between two dosing dates within that cycle where the subject did not receive the study 
drug. This will be calculated based on the information from the dose modification CRF for 
Lenalidomide. 
The number and percentage of subjects with dose interruption, with 1, 2, 3, or ≥ 4 reported 
interruptions will be presented. For subjects with a computed interruption, their reason for 
interruption will be summarized from the dose modification CRF. For subjects without an 
available reason for interruption, the category “unknown” will be used.
Dexamethasone (IV) and Oral:
For IV dexamethasone the following summaries will be provided:
•
The number of subjects with any dose delay, with 1, 2, 3, or ≥ 4 reported delays, and with 
a reason for delay of “hematologic toxicity”, “non-hematologic toxicity”, “AE”, “dosing 
error” and “other”.
•
The number of subjects with any reported dose omission, with 1, 2, 3, or ≥ 4 reported 
omissions, and with a reported reason for omission of “hematologic toxicity”, “non-
hematologic toxicity”, “AE”, “dosing error” and “other”.
•
The number of subjects who discontinued the study drug, and reason for the 
discontinuation (hematologic toxicity, non-hematologic toxicity, AE, dosing error, or 
other).
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BMS-901608                                                                                                                                                  elotuzumab     
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•
The number of subjects with any reduction in the dose of the drug,  and with a reason for 
the reduction of “hematologic toxicity”, “non-hematologic toxicity”, “AE”, “dosing error”, 
and “other”).
For PO dexamethasone the following summaries will be produced:
•
The number of subjects with any dose modification, with 1, 2, 3, or ≥ 4 reported 
modifications, and with a reason for the modification of “hematologic toxicity”, “non-
hematologic toxicity”, “AE”, “dosing error” and “other”).
By subject listings of record of study medication for each of IV dexamethasone and PO 
dexamethasone will be provided.
7.4.1.3
Cumulative Dose, Dose Intensity, and Relative Dose Intensity
In order to compute the cumulative dose of dexamethasone, IV dexamethasone will have to be 
converted to its equivalent oral dose. This will be done by treating each mg of IV dexamethasone 
as 1.32 mg of oral dexamethasone, i.e. making use of the fact that the mean bioavailability of oral 
dexamethasone was estimated to be 0.7610.    A subject’s cumulative dose of dexamethasone will 
be defined as the sum of all dexamethasone doses, oral and IV, converted to oral equivalent. The 
cumulative dose administered will be summarized for each of these drugs, by treatment group.
Elotuzumab:
A subject’s cumulative dose of elotuzumab is measured in mg/kg, and is defined as the sum of 
their elotuzumab doses (mg/kg) (actual, not planned) over all infusions.
Elotuzumab dose intensity (mg/kg/week) per subject will be calculated separately for Cycles 1 and 
2, Cycles 3-18 and Cycle 19 and beyond, since elotuzumab planned dose intensity differ in those 
cycles. 
Cycle 1 and 2
7 ൈ൭
௖௨௠௨௟௔௧௜௩௘ௗ௢௦௘௢௙௘௟௢௧௨௭௨௠௔௕ௗ௨௥௜௡௚௧௛௘௙௜௥௦௧ଶ௖௬௖௟௘௦
൬୫୧୬ሺௗ௔௧௘௢௙௙௜௥௦௧ௗ௢௦௘௢௙௘௟௢௧௨௭௨௠௔௕௜௡௧௛௘௟௔௦௧௖௬௖௟௘௔௠௢௡௚௧௛௘௙௜௥௦௧ଶ௖௬௖௟௘௦ାଶ଼, ௗ௘௔௧௛ௗ௔௧௘ሻି
ௗ௔௧௘௢௙௙௜௥௦௧ௗ௢௦௘௢௙௘௟௢௧௨௭௨௠௔௕௜௡஼௬௖௟௘ଵ
൰
൱
Cycle 3-18:
7 ൈ൮
ܿݑ݉ݑ݈ܽݐ݅ݒ݁݀݋ݏ݁݋݂݈݁݋ݐݑݖݑܾ݉ܽ݀ݑݎ݅݊݃ܥݕ݈ܿ݁3 െܥݕ݈ܿ݁18
൬minሺ݀ܽݐ݁݋݂݂݅ݎݏݐ݀݋ݏ݁݋݂݈݁݋ݐݑݖݑܾ݈݉ܽ݅݊ܽݏݐܿݕ݈ܿ݁ܽ݉݋݊݃18 ܿݕ݈ܿ݁ݏ൅28, ݀݁ܽݐ݄݀ܽݐ݁ሻെ
݀ܽݐ݁݋݂݂݅ݎݏݐ݀݋ݏ݁݋݂݈݁݋ݐݑݖݑܾ݉ܽ݅݊ܥݕ݈ܿ݁3
൰
൲
Cycle 19 and beyond:
7 ൈ൮
ܿݑ݉ݑ݈ܽݐ݅ݒ݁݀݋ݏ݁݋݂݈݁݋ݐݑݖݑܾ݉ܽݏݐܽݎݐ݂݅݊݃ݎ݋݉ܥݕ݈ܿ݁19
൬minሺ݀ܽݐ݁݋݂݂݅ݎݏݐ݀݋ݏ݁݋݂݈݁݋ݐݑݖݑܾ݈݉ܽ݅݊ܽݏݐܿݕ݈ܿ݁൅28,݀݁ܽݐ݄݀ܽݐ݁ሻെ
݀ܽݐ݁݋݂݂݅ݎݏݐ݀݋ݏ݁݋݂݈݁݋ݐݑݖݑܾ݉ܽ݅݊ܥݕ݈ܿ݁19
൰
൲
The relative dose intensity will be calculated as
Dose Intensity/Planned Dose Intensity (PDI)
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Planned dose per week for elotuzumab is 10mg/kg/week for the first 2 cycles, 5mg/kg/week for 
cycles 3 and beyond. The PDI per subject for elotuzumab will be computed by averaging the 
planned doses per week over the treatment duration:
ܧ݈݋ݐݑݖݑܾ݉ܽܲܦܫሺሺ݉݃/݇݃/ݓ݇ሻൌሺDOSE1 ∗8 ൅DOSE2 ∗ሺܦܷܴെ8ሻሻ
ܦܷܴ
where DUR is defined as (min (date of death, date of first dose in last cycle in timepoint + 28) -
date of first dose in timepoint) / 7. 
Dose intensity and relative dose intensity of elotuzumab will be summarized for the E-Ld group 
only.
Lenalidomide:
A subject’s cumulative dose of lenalidomide is defined as the sum of each dose taken, as recorded 
in their medication diary.
Dose intensity and relative dose intensity for lenalidomide (mg/week) will be calculated separately 
for subjects who began the study at the standard daily dose, 25mg/day and those who, because of 
moderate renal impairment, began the study at < 25mg/day (at 10mg/day dose will be assumed 
when computing the RDI as this is the recommended dose for subject with moderate renal disease 
per protocol).
The lenalidomide dose intensity, per subject, will be calculated as: 
7ܺ൮
ܿݑ݉ݑ݈ܽݐ݅ݒ݁݀݋ݏ݁݋݂݈݈݁݊ܽ݅݀݋݉݅݀݁
൬݉݅݊ሺ݀ܽݐ݁݋݂1ݏݐ݀݋ݏ݁݋݂݈݈݁݊ܽ݅݀݋݈݉݅݀݁݅݊ܽݏݐܿݕ݈ܿ݁݅݊ݓ݄݄݈݈݅ܿ݁݊ܽ݅݀݋݉݅݀݁ݓܽݏܽ݀݉݅݊݅ݏݐ݁ݎ݁݀
൅28,݀݁ܽݐ݄݀ܽݐ݁ሻെ݀ܽݐ݁݋݂݂݅ݎݏݐ݀݋ݏ݁݋݂݈݈݁݊ܽ݅݀݋݉݅݀݁
൰
൲
The relative dose intensity of lenalidomide is the dose intensity per week divided by the planned 
dose intensity per week, 131.25mg (or 52.5mg for subjects who begin therapy at < 25mg 
(10mg/day per protocol)).
Dexamethasone:
The dose intensity (mg/week) of dexamethasone, per subject, will be calculated separately for the 
period encompassing Cycles 1 and 2, Cycle 3-18 and Cycle 19 and beyond since dexamethasone 
dosing is different in these 3 periods. 
Cycle 1 and 2:
7 ൈ൭
௖௨௠௨௟௔௧௜௩௘ௗ௢௦௘௢௙ௗ௘௫௔௠௘௧௛௔௦௢௡௘ௗ௨௥௜௡௚௧௛௘௙௜௥௦௧௧௪௢௖௬௖௟௘௦
൬୫୧୬ሺௗ௔௧௘௢௙௙௜௥௦௧ௗ௢௦௘௢௙ௗ௘௫௔௠௘௧௛௔௦௢௡௘௜௡௟௔௦௧௖௬௖௟௘௔௠௢௡௚௙௜௥௦௧ଶ௖௬௖௟௘௦ାଶ଼,ௗ௘௔௧௛ௗ௔௧௘ሻି
ௗ௔௧௘௢௙௙௜௥௦௧ௗ௢௦௘௢௙ௗ௘௫௔௠௘௧௛௔௦௢௡௘௜௡௙௜௥௦௧௖௬௖௟௘
൰
൱
Cycle 3-18:
7 ൈ൮
ܿݑ݉ݑ݈ܽݐ݅ݒ݁݀݋ݏ݁݋݂݀݁ݔܽ݉݁ݐ݄ܽݏ݋݊݁݀ݑݎ݅݊݃ܥݕ݈ܿ݁3 െܥݕ݈ܿ݁18
൬minሺ݀ܽݐ݁݋݂݂݅ݎݏݐ݀݋ݏ݁݋݂݀݁ݔܽ݉݁ݐ݄ܽݏ݋݈݊݁݅݊ܽݏݐܿݕ݈ܿ݁ܽ݉݋݊݃18 ܿݕ݈ܿ݁ݏ൅28, ݀݁ܽݐ݄݀ܽݐ݁ሻെ
݀ܽݐ݁݋݂݂݅ݎݏݐ݀݋ݏ݁݋݂݀݁ݔܽ݉݁ݐ݄ܽݏ݋݊݁݅݊ܥݕ݈ܿ݁3
൰
൲
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Cycle 19 and beyond:
7 ൈ൮
ܿݑ݉ݑ݈ܽݐ݅ݒ݁݀݋ݏ݁݋݂݀݁ݔܽ݉݁ݐ݄ܽݏ݋݊݁ݏݐܽݎݐ݂݅݊݃ݎ݋݉ܥݕ݈ܿ݁19
൬minሺ݀ܽݐ݁݋݂݂݅ݎݏݐ݀݋ݏ݁݋݂݀݁ݔܽ݉݁ݐ݄ܽݏ݋݈݊݁݅݊ܽݏݐܿݕ݈ܿ݁൅28, ݀݁ܽݐ݄݀ܽݐ݁ሻെ
݀ܽݐ݁݋݂݂݅ݎݏݐ݀݋ݏ݁݋݂݀݁ݔܽ݉݁ݐ݄ܽݏ݋݊݁݅݊ܥݕ݈ܿ݁19
൰
൲
The relative dose intensity of dexamethasone is the dose intensity per week divided by the planned 
dose intensity per week. The planned dose of dexamethasone in the experimental arm on 
elotuzumab dosing days, 8mg IV dexamethasone plus 28mg oral dexamethasone, is equivalent to 
38.56mg of oral dexamethasone. The planned dose in the experimental arm when dexamethasone 
is not being administered with elotuzumab is 40mg. Thus, the planned weekly dose of 
dexamethasone in the experimental arm for Cycles 1 and 2 will be equivalent to 38.56mg oral 
dexamethasone, the planned weekly dose of dexamethasone in the experimental arm for Cycle 3 -
Cycle 18, during which IV dexamethasone is given on Days 1 and 15 only, will be equivalent to 
39.28mg of oral dexamethasone and the planned weekly dose of dexamethasone in the 
experimental arm for Cycle 19 and beyond, during which IV dexamethasone is given on Days 1 
only, will be equivalent to 39.64mg of oral dexamethasone . The planned weekly dose of 
dexamethasone in the control arm is 40mg for all cycles.
In the dose intensity formulas, if the patient took a dose on his death date then 1 day will be added 
to the denominator.
Descriptive statistics (n, mean, STD, median, min, max, q1 and q3) will be presented for the 
cumulative dose, and dose intensity of each agent, by treatment group. The number and percentage 
of subjects whose relative dose intensity falls into the following categories will be presented, by 
treatment group: ≥90 %, 80% to < 90%, 70% to < 80%, 60% to < 70%, < 60%.
7.4.2
Premedication Other than Dexamethasone for Hypersensitivity 
Reactions
A by-subject listing of pre-medication for elotuzumab, other than dexamethasone, will be 
provided.  This listing will be generated from the “Pre-medication for Elotuzumab (other than 
Dexamethasone)” eCRF module and pre-medications will be coded using the BMS WHO drug 
dictionary. 
7.4.3
Concomitant Medication
Concomitant medications are medications, other than study medication or pre-medications for 
elotuzumab recorded on the “Pre-medication for Elotuzumab” eCRF page, which are taken by 
subjects any time on-study, no earlier than the first day of study drug and no later than 60 days 
after the last dose of study drug. Concomitant medications will be coded using the BMS WHO 
drug dictionary. If there is clear evidence to suggest that the medication stopped prior to the first 
dose of study medication, the medication will be assumed to be ‘Prior’ only.
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The number and percentage of subjects taking any concomitant medication and each medication 
(Anatomical Therapeutic Chemical [ATC] classification system drug name) will be summarized, 
overall and by treatment group. 
A by subject listing of concomitant medication will be provided. 
7.4.4
Discontinuation of Study Therapy
The number and percentage of subjects who have discontinued all study treatment and reason for 
discontinuation will be summarized by treatment group and overall using subject status eCRF page
from end of treatment. This summary, unlike other safety analyses, will include all randomized 
subjects and will be grouped by treatment group as randomized. This is done in order to give a full 
accounting of all subjects who are off study treatment, including those who were randomized but 
never treated. 
In addition, for subjects in the Elotuzumab arm, who discontinued one drug, while continuing at 
least one of the other two study drugs, their reason for treatment discontinuation will be 
summarized based on the dose modification CRF. Subjects will be counted in this summary if 
there is evidence from the dosing CRF that the subject received the combination therapy in at least 
one cycle, followed by additional cycles, where one of the drugs in the combination was 
discontinued.
7.4.5
Subsequent Anti-Myeloma Therapies
The number and percentage of subjects with any subsequent systemic anti-myeloma therapy (2nd 
line), reason for first subsequent systemic anti-myeloma therapy regimen (Documented 
progression of disease, Clinical deterioration without documented progression, Maintenance 
therapy without disease progression or clinical deterioration, Consolidation without documented 
disease progression or clinical deterioration, or Other) and all subsequent systemic anti-myeloma 
therapy agents given categorized using the BMS WHO drug dictionary will be presented by 
treatment group. 
The number and percentage of subjects with any second subsequent systemic anti-myeloma 
therapy (3rd line) and reason for second subsequent systemic anti-myeloma therapy regimen 
(Documented progression of disease, Clinical deterioration without documented progression, 
Maintenance therapy without disease progression or clinical deterioration, Consolidation without 
documented disease progression or clinical deterioration, or Other) will be presented by treatment 
group.
The number and percentage of subjects with any subsequent surgery, type of first subsequent 
surgery (Kyphoplasty, Orthopedic surgery, Debulking surgery or Other) will be presented by 
treatment group. 
The number and percentage of subjects with any subsequent radiation therapy will be presented 
by treatment group. 
A by-subject listing of all subsequent surgery, radiation therapy, and systemic anti-myeloma 
therapy will be provided.
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7.5
Efficacy
Efficacy analyses (PFS, ORR and OS) will be conducted on the population of all randomized 
subjects, grouped by arm assigned at randomization, unless otherwise noted.
The main analyses of PFS and ORR will be based on IRC evaluation. Unless stated otherwise, 
whenever a stratified analysis is specified, the stratifications factors will be those used in the 
randomization (per IVRS), that is:
•
Stage of disease (ISS 1 – 2 versus 3)
•
Age (< 75 years old versus ≥ 75 years old)
•
ECOG Performance status (0 versus 1 - 2)
All p-values reported will be two-sided. Confidence intervals (CI) for the PFS and OS endpoints 
will be based on the nominal significance level adjusted for the interim analyses to preserve the 
overall type I error rate. Two-sided 95% CI will also be provided. CIs for the other endpoints will 
be at the two-sided 95% level. The p-values presented in the clinical study report will be rounded 
to the fourth decimal place. Point estimates and confidence bounds for efficacy variables will be 
rounded to the second decimal place.
7.5.1
Primary Analysis of Progression-Free Survival
The primary analysis of PFS will be to compare the two treatment arms via a two-sided stratified 
log-rank test. The primary definition of PFS using IRC assessments will be used in this analysis. 
The stratification factors will be the same as those used in the randomization. The two-sided log-
rank p-value will be reported. An O’Brien and Fleming α spending function will be employed to 
determine the significance levels and stopping boundaries at the interim and final looks (see 
Section 5 for more details).
Further analysis of PFS will include estimation of the hazard ratio and estimation of the PFS 
distribution in each treatment group. 
The estimate of the PFS hazard ratio, of E-Ld to Ld, will be calculated using a stratified Cox 
proportional hazards model, with the stratification factors used at randomization and treatment as 
the sole covariate. Ties will be handled using the Breslow method11. Two-sided, 100 * (1-α) (α 
adjusted for the interim analysis) and 95% CI for the hazard ratio will also be presented.
The PFS function for each treatment arm will be estimated using the KM product limit method 
and will be displayed graphically. A two-sided 95% CI for median PFS in each arm will be 
computed via the Brookmeyer Crowley method. Estimates for 1, 2, 3, 4 and 5-years PFS rates 
when appropriate will be presented along with their associated 95% CIs. These estimates will come 
from the KM curve and their standard errors (SEs), for use in constructing CIs, will be computed 
using Greenwood’s formula12and log-log transformation applied on the survivor function.
The method of Gail and Simon13 will be used to test for a qualitative interaction between treatment 
and strata, stage of disease (ISS 1 – 2 versus 3), age (< 75 years old versus ≥ 75 years old) and 
ECOG Performance status (0 versus 1 – 2). This test will be conducted at the α= 0.10 level.  
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The proportional hazards assumption will be assessed via the following hazard rate model, which 
contains a time dependent covariate:
λሺݐ, ݖሻൌλ௜ሺݐሻ݁ሺሼ௕భା௕మൈሾ௟௢௚ሺ௧ሻሿሽൈ௓ሻ,
݅ൌሼ1 െ8ሽ
where i=1-8 corresponds to each of the eight levels the stratum can take, and Z is the treatment 
indicator, which is equal to 1 for the experimental combination arm and 0 for the control arm. The 
transformation of time that will be used is log (t). The null hypothesis, that the proportional hazards 
assumption is valid, i.e., that b2=0, will be tested against the alternative hypothesis that b2≠0 using 
a Wald statistic. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.5.5
Analysis of Objective Response 
The number and percentage of subjects in each category of best overall response per IRC (stringent 
complete response [sCR], complete response [CR], very good partial response [VGPR], partial 
response [PR], minor response [MR], stable disease [SD],  progressive disease [PD], or unable to 
determine [UD]) according to the IRC will be presented, by treatment group. An estimate of the 
response rate and an associated exact two-sided 95% CI (Clopper and Pearson14) will be presented, 
by treatment group. Also, the number and percentage of subjects in each category of best overall 
response according to the investigator tumor assessment will be presented by treatment group. 
The main analysis of ORR will be based on the IRC assessment and will compare the two treatment 
groups using a CMH test stratified by the same factors used in the analysis of PFS. An estimate of 
the treatment odds ratio and corresponding two-sided 95% CI will be presented. 
The same analysis will be repeated for the best response per IRC but modified for subsequent 
therapies. For this analysis only subjects with responses before, or on start of subsequent therapy 
date will be considered responders. The IRC when doing the blinded assessment of response and 
progression does not have data on subsequent therapy and discontinuation status. For this reason 
the IRC best response modified for subsequent therapy will be derived programmatically.
A 2-sided, 95% confidence interval for the difference of ORR between treatment arms will be 
computed for all randomized subjects by the method of DerSimonian and Laird 15 using a fixed-
effects model (setting Δ2 equal to zero), adjusting for the stratification factors. The weighted 
response rate difference and 95% CI can be determined using the following formula:
ߠ෠ൌ
∑
ߠప෡ݓ௜
ଵଶ
௜ୀଵ
∑
ݓ௜
ଵଶ
௜ୀଵ
∼ܰሺߠ, 1/ ෍ݓ௜ሻ
ଵଶ
௜ୀଵ
where ߠప෡is the response rate difference of the ith stratum and ݓ௜ൌ1/ݒܽݎሺߠ෠௜ሻ.
Similar analyses will be repeated based on the investigator’s assessment of ORR. A cross 
tabulation of IRC best response versus the investigator best response will be presented, by 
treatment group. These measures of concordance will be provided:
•
Number of subjects with same response divided by number of randomized subjects 
•
Number of subjects with same response evaluation: responders (PR or better), non-responder 
divided by number of randomized subjects
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7.5.9
Analyses of Overall Survival
Overall survival will be compared between the treatment arms at the interim and final analyses, 
using a two-sided stratified log-rank test. The stratification factors will be those used in the analysis 
of PFS. 
An O’Brien and Fleming α-spending function will be employed to determine the nominal 
significance levels for the interim and final analyses. 
All analyses performed for PFS (detailed in section 7.5.1) will be repeated for OS. Supportive 
analyses 1, 2, 4 and 5 of PFS (detailed in section 7.5.2) as well as the subset analyses (detailed in 
section 7.5.4) will also be repeated for OS. These will be conducted only at the time of the final 
analysis of OS.
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Estimates for 1, 2, 3, 4, and 5-year OS rates will be presented along with their associated 95% CIs
when appropriate follow-up time has occurred. These estimates will come from the KM curve and 
their standard errors (SEs) used in constructing CIs, will be computed using Greenwood’s 
formula17 and the log-log transformation applied on the survivor function.
7.5.10
Currentness of PFS and OS Data
Time from last tumor assessment to data cut-off in months will be summarized by treatment arm 
and overall for all randomized subjects. Subjects who have a PFS event will be considered as 
current for this analysis. The ITT definition of PFS as per IRC will be used for this summary. 
In addition Kaplan-Meier plots of time from randomization to post-baseline tumor assessment will 
be produced by treatment arm for the first twelve assessments.
Currentness of OS data will be summarized in months, by computing the time from “last known 
alive” date to data cut-off date. Subjects who have a death event will be considered as current for 
this analysis.
By-subject listings will also be produced to accompany the subject time from last tumor 
assessment table.
7.5.11
Hierarchy for Testing Secondary Endpoints
A hierarchical procedure will be used to preserve a two-sided family-wise type I error rate of 5% 
for testing one primary (PFS) and two key secondary endpoints (ORR and OS) in this study.
If there is a statistically significant improvement in PFS, ORR will be compared between treatment 
arms at the two-sided 5% alpha level. If, and only if, the comparison of ORR is statistically 
significant, then OS will be compared between treatment arms using a 5% sequential test 
procedure. 
The two QOL secondary endpoints will not be part of the hierarchical testing and will be tested 
independently of the significance of the other endpoints. Each of the two comparisons will be made 
at the two-sided type I error of 2.5%.
7.6
Safety
Safety summaries will be based on the treated subject population, grouped by treatment regimen 
received. 
7.6.1
Adverse Events
AEs will be categorized using the most recent version of the MedDRA, by system organ class 
(SOC) and preferred term. The severity of AEs will be graded using the NCI CTCAE (v 3.0).
On-study AEs are defined as non-serious and serious AEs with an onset date on or after the first 
dose until 60 days after the last dose. See Section 8.4, Imputing AE Onset Dates, for a discussion 
of imputation rules for incomplete or missing AE onset dates.  If the relationship to study drug is 
missing, then the AE will be assumed to be related to study drug.
Unless specified otherwise, AEs will be counted only once within each SOC and preferred term, 
according to their worst CTC grade.
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Tables will be sorted by SOC and preferred term, with SOCs ordered by decreasing frequency 
overall and then alphabetically. Preferred terms will be sorted within SOCs by descending 
frequency overall and then alphabetically. The sorting will be done based on the total column when 
arms are presented side-by-side.
Frequency tables of the worst grade of on-study AE will be presented.  One summary table will 
present AEs broken out by individual grade, 1, 2, 3, 4 or 5 along with an Any Grade category.  
Another one will present AEs by grouped grades as follows “Any, Grade 3-4 and Grade 5.” These 
summaries will be repeated for on-study drug-related AEs. 
A by-subject listing all AEs will be presented.
In addition the following will be presented by treatment arm:
•
Frequency of AE before and after cycle 18 for subjects on the Elotuzumab arm
•
Exposure-adjusted AE incidence rates (including multiple occurrences of unique events) 
will be calculated for each SOC and preferred term.
Exposure-adjusted incidence rate per 100 person-years will be used and will be calculated as:
100 ൈ
்௢௧௔௟௡௨௠௕௘௥௢௙௨௡௜௤௨௘஺ா௦
ቌ
ೞೠ್ೕ೐೎೟೏ೌ೟೐೚೑೗ೌೞ೟೏೚ೞ೐೚೑ೞ೟ೠ೏೤೏ೝೠ೒ష
ೞೠ್ೕ೐೎೟೏ೌ೟೐೚೑೑೔ೝೞ೟೏೚ೞ೐೚೑ೞ೟ೠ೏೤೏ೝೠ೒శలబశభ
యలఱ.మఱ
ቍ
and will be displayed along with a count of events. For these additional tables, AEs can be 
counted multiple times within each SOC and preferred term.
A by-subject listing of unique AEs will be provided.
7.6.2
Serious Adverse Events and Adverse Event Leading to Discontinuation
Summaries of worst grade of on-study SAE, both by individual grade (1, 2, 3, 4, or 5, along with 
an Any Grade category) and by grade grouped as “Any, Grade 3-4 and Grade 5” will also be 
presented. These summaries will be repeated for:
•
On-study drug-related SAEs 
•
On-study AEs leading to discontinuation.
•
Drug related AEs leading to discontinuation
By-subject listings of SAEs and AEs leading to study drug discontinuation will be produced.
7.6.3
Safety by subgroups 
Summaries of all adverse events with ≥5 % frequency, adverse events leading to discontinuation, 
serious adverse events (any grade, grade 3-4), and death within 60 days of last dose will be 
presented for the levels of the factors listed below.
In addition summaries by the same factors will be produced for SPM and infusion reaction.
•
Age:
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−
< 65
−
< 65 up to < 75
−
≥ 75 years
•
Gender (male, female)
•
Race 
•
Region (North America, European Union, and Rest of World)
7.6.4
Adverse Events of Special Interest
Infusion reaction is a known elotuzumab toxicity. It will be based on investigator assessment and 
will be defined as any non-serious or serious adverse event judged by the investigator to be infusion 
related and which also occurs on the day of or the day after the elotuzumab infusion. These 
summaries will be presented:
•
Frequency tables of the worst grade of on-study investigator infusion reaction (any grade 
and grade 1 through 5) by treatment group. The same summary will be presented with 
grades grouped as Any, Grade 3-4 and Grade 5. 
•
Frequency of infusion reaction by infusion rate. 
•
Frequency of infusion reaction by cycle.
By-subject listings of infusion reactions will be produced.
Multiple myeloma is associated with immune dysfunction and the natural course of the disease 
includes increased infection risk. In addition, elotuzumab may inhibit some cellular components 
of the immune system. Therefore, a thorough characterization of infections will be presented.
Infections will be based on the SOC ‘infections and infestations’ and opportunistic infections 
will be based on clinically pre-defined PT terms:
•
Time to onset and duration of first infection
•
Frequency of infections including opportunistic infections by treatment group. 
•
Absolute lymphocyte count at time of first infection
•
Kinetics of lymphocyte reduction
7.6.5
Second Primary Malignancies
A summary table and a by-subject listing of second primary malignancies (SPM) will be provided. 
In addition, exposure-adjusted SPM incidence rates (including multiple occurrences of unique 
events) will be presented by treatment group and will be calculated as follows: 
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100 ൈ
ܶ݋ݐ݈ܽ݊ݑܾ݉݁ݎ݋݂ݑ݊݅ݍݑ݁ܵܲܯ݁ݒ݁݊ݐݏ
൮
ݏݑܾ݆݁ܿݐ݀݁ܽݐ݄݀ܽݐ݁݋ݎ݈ܽݏݐ݇݊݋ݓ݈݊ܽ݅ݒ݁݀ܽݐ݁െ
ݏݑܾ݆݁ܿݐ݀ܽݐ݁݋݂݂݅ݎݏݐ݀݋ݏ݁݋݂ݏݐݑ݀ݕ݀ݎݑ݃൅1
365.25
൲
Information on SPM will be obtained from the on-treatment eCRF page for secondary 
malignancies and the “Survival Status” eCRF page.
7.6.6
Deaths
The number and percentage of deaths and the investigator-reported cause of death will be 
presented, by treatment group and overall. This will be summarized for all deaths, and for those 
reported on study treatment or within 60 days of discontinuing study treatment.
7.6.7
Clinical Laboratory Evaluations
On-treatment laboratory tests for safety are defined as those that occur after first dose of any study 
therapy until 60 days after last dose of any study therapy. 
The number and percentage of subjects with each worst severity grade for on-study hematology 
parameters (hemoglobin, WBC, ANC, ALC and platelets) will be presented, by treatment group. 
Grades will be categorized as Grade 1, Grade 2, Grade 3, Grade 4, Any Grade and Grade 3-4. 
Subjects will be counted only once for each parameter, according to their worst post baseline CTC 
grade. The percentage of subjects with each worst severity grade will be calculated out of the 
number of subjects with on-study assessment for each lab parameter. Subjects with no on treatment 
assessment for a lab parameter will be reported in the “Not Reported” category.
This summary will be repeated for:
•
Liver parameters (ALT, AST, alkaline phosphatase, albumin and total bilirubin) with 
available CTC grades
•
Renal/electrolyte parameters (sodium, potassium, bicarbonate, calcium, glucose and 
creatinine) with available CTC grades
Sodium, potassium, calcium, and glucose will be presented separately, based on their high and low 
values.
For blood urea nitrogen (BUN), direct bilirubin and total protein the worst category on-treatment 
will be presented. Results will be categorized as; below upper normal limits, above upper normal 
limits or not reported.
For reporting purposes, urea will be converted to BUN, using the conversion factor: urea 
(mmol/L) / 0.357 = BUN (mg/dL). 
Subjects experiencing any potential drug induced liver injury (DILI) will be summarized by 
treatment group as follows:
•
A summary of the number and percentage of subjects with (AST or ALT > 3 × upper limit 
of normal (ULN)) and (Total bilirubin > 2 × ULN and ALP < 2 × ULN) will be presented.
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If any potential cases of DILI are identified then clinical review will be conducted to ensure no 
other immediate apparent possible causes of AT elevation and hyperbilirubinemia are present, 
including but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drugs known to be hepatotoxic.
Note: The timing for total bilirubin rising to >2xULN needs to be concomitant with or within 30 
days after ALT or AST rising to >3xULN. ALP needs to be <2xULN at the time of or within 2 
weeks before ALT or AST rising to > 3xULN or TBILI>2xULN. This means a normal ALP 
value (<= 2xULN) must be present within 2 weeks of either the ALT/AST criteria or the TBILI 
criteria.
A by subject listing of all laboratory data will be provided. A separate listing will be provided for 
all subjects potentially experiencing DILI. 
7.6.8
Electrocardiograms
A by subject listing of electrocardiogram (ECG) data collected at screening will be presented.
7.6.9
Vital Signs, Physical Measurements and Physical Examination
Vital signs parameters (body temperature, respiratory rate, seated diastolic and systolic blood 
pressure and heart rate) will be presented by visit and time point in a subject listing. 
 
 
 
 
 
 
 
 
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8
CONVENTIONS
8.1
Baseline Definition
Baseline evaluations will be those performed within 60 days of randomization and prior to first 
dosing date. When an assessment is repeated multiple times within the screening period, the 
baseline evaluation will be the one closest to the first dosing date.
Laboratory tests and procedures (ECG, physical measurement and 2D echocardiogram MUGA, 
skeletal survey and plasmacytoma) done on the first date of dosing will be assumed to have 
occurred prior to dosing and therefore baseline evaluation for those parameters will be those prior 
or on the first dosing date.
8.2
Age Definition
Age (years) will be calculated as:
݀ܽݐ݁݋݂݂݅݊݋ݎ݉݁݀ܿ݋݊ݏ݁݊ݐെ݀ܽݐ݁݋݂ܾ݅ݎݐ݄൅1
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8.3
Time Since Initial Diagnosis to Randomization Definition
Time from disease diagnosis to randomization (months) will be calculated as:
݀ܽݐ݁݋݂ݎܽ݊݀݋݉݅ݖܽݐ݅݋݊െ݀ܽݐ݁݋݂݅݊݅ݐ݈݅ܽ݀݅ܽ݃݊݋ݏ݅ݏ൅1
30.4375
For the date of cancer diagnosis, the following conventions will be used for imputing partial dates:
•
If only the day of the month is missing, the 15th of the month will be used to replace the 
missing day.
•
If the day and month are missing or a date is completely missing, it will be considered as 
missing.
8.4
Duration and Study Day Definition
In instances in which study period between two dates are to be calculated (for example, duration 
of response, PFS and OS), the convention to be used is as follows: later date – earlier date + 1 day.
Study day is calculated as assessment date – first dose date + 1 day, if the assessment is taken on 
or after the first dose day. If the assessment is taken prior to the first dose day, study day will be 
calculated as assessment date – first dose date. Date of first dose is defined as Study Day 1.
8.5
Day Conversion of Date Imputation
Conversion from days to months or years:
•
1 year = 365.25 days
•
1 month = 30.4375 days
Imputation for partial or missing progression dates:
•
If only the day is missing, the 1st of the month will be used to replace the missing day.
•
If the day and month are missing or a date is completely missing, the date of progression 
will be moved back to the last complete tumor assessment date.
In both the cases given above, the imputed date will still be considered an event.
Imputation for partial or missing death dates:
•
If only the day is missing, the later of the last known alive date and the 1st of the month 
will be used to replace the missing day.
•
If both the day and the month are missing, the later of the last know alive date and Jan 1st
will be used to replace the missing information.
In both the cases given above, the imputed date will still be considered an event.
For partial dates of start of subsequent anti-myeloma therapy, the following conventions will be 
used:
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•
When the day is missing, the alternative therapy will be assumed to start on the first day of the 
given month if this day is later than the last dosing date. Otherwise the alternative therapy will 
be assumed to start on the day following the last dosing date.
•
When the day and the month are missing, the alternative therapy will be assumed to start on 
the first day of the given year if this day is later than the last dosing date. Otherwise the 
alternative therapy will be assumed to start on the day following the last dosing date.
8.6
AE, Laboratory Results and Concomitant Medication
Safety data will be handled according to the BMS safety data conventions (described in “Analysis 
of Safety Data - Reference to CT SOP 109”). This document includes descriptions on how to 
analyze AE data as well as how to handle partial dates, missing dates, and unknown end dates 
when analyzing safety data.
The following dictionaries will be used to code medical terms and to derive toxicity grades:
•
Adverse events and other symptoms will be graded according to the NCI CTC Version 3.0 
and categorized according to the latest version of MedDRA at the time of the database lock.
•
Laboratory results will be classified according to the CTC Version 3.0 grading system.  
•
All medications will be coded as per the latest version of the WHO Drug dictionary at the 
time of analysis.
•
Tables and listings for laboratory results will be available in SI and US units.
8.7
Topline Analyses
Outputs covering the following topics will be included in the top-line analyses:
Study conduct:
•
Relevant protocol deviations (Table and Listing)
Subject population:
•
End of Treatment Summary
•
Accrual by Region
•
Accrual by stratification factors at randomization 
•
Demographic Characteristics Summary
•
IVRS Stratification Factors Summary
•
Baseline Myeloma Characteristics Summary (SI units)
•
Other Baseline Laboratorty Measurements Summary
•
Baseline Myeloma (Cytogenetics and FISH) Risk Factors Summary 
•
Time from Diagnosis to Randomization Summary
•
Baseline Physical Measurements Summary
Extent of exposure:
•
Number of Cycles Summary
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•
Elotuzumab Dose Intensity Summary
•
Dexamethasone Dose Intensity Summary
•
Lenalidomide Dose Intensity Summary
•
Elotuzumab Delay Summary
•
Elotuzumab Omission Summary
•
Elotuzumab Infusion Interruption Summary
•
Lenalidomide Reduction Summary
•
Lenalidomide Interruption Summary
Progression free survival:
•
Currentness of Follow-Up for PFS (IRC, ITT definition) Summary 
•
PFS (IRC, Primary Def.) Analysis
•
Kaplan-Meier plot of PFS (IRC, Primary Def.) 
•
PFS (IRC, Primary Def.) Analysis Adjusting for Different Baseline Covariates
•
PFS (IRC, Primary def.) Hazard Ratio and 95% CI in Subsets (Forest plot)
•
PFS (IRC, ITT Analysis)
•
Kaplan-Meier plot of PFS (IRC, ITT)
•
PFS (IRC, ITT) Analysis Adjusting for Different Baseline Covariates
•
PFS (IRC,ITT) Hazard Ratio and 95% CI in Subsets (Forest plot)
•
Kaplan-Meier plot of PFS (Inv., Primary Def.) 
•
Kaplan-Meier plot of PFS (Inv., ITT.)
•
Concordance of PFS between the IRC and investigator
•
Concordance and Timing of PFS per IRC and Investigator
•
Assessment of Censoring Distributions with Reverse Kaplan Meier Plot of PFS (IRC, 
Primary Def.) 
•
Assessment of Censoring Distributions with Reverse Kaplan Meier Plot of PFS (IRC, 
ITT Def.) 
Tumor response:
•
Best Overall Response (IRC)
•
Best Overall Response (Inv)
•
Best Overall Response (IRC) Modified for Subsequent Therapy
•
Best Overall Response (IRC) Odds Ratio and 95% CI in Subsets (Figure)
•
Cross Tabulation of Modified Best Overall Response per IRC and Investigator 
•
Time to First Response (IRC) Summary 
•
Kaplan-Meier Plot of Duration of Response (IRC)
Overall survival (only when interim PFS and ORR analyses are positive):
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•
Currentness of Follow-Up for Overall Survival Summary Overall Survival Analysis 
•
Overall Survival Analysis Adjusting for Different Baseline Covariates
•
Kaplan-Meier plot of overall survival
•
Overall survival Hazard Ratio and 95% CI in Subsets (Forest plot)
Safety:
•
Hematologic Laboratory Test Results Summary of Worst Toxicity Grade - SI Units
•
Renal and Liver Laboratory Test Results Summary of Worst Toxicity Grade - SI Units
•
Chemistry Laboratory Test Results Summary of Worst Toxicity Grade - SI Units
•
Other Laboratory Test Results Summary (BUN, DBILI, TPRO)
•
Potential Drug Induced Liver Injury Cases Summary - SI Units
•
Adverse Event Summary by CTC Grade Combined
•
Pre and Post Cycle 19 Adverse Event Summary by CTC Grade Combined
•
Serious Adverse Event Summary by CTC Grade Combined
•
Adverse Event Leading to Discontinuation Summary by CTC Grade Combined
•
Infusion Reaction Summary by Common Terminology Criteria
•
Second Primary Malignancy Summary
•
Deaths
•
Deaths within 60 days of last study drug
Specific tables corresponding to these outputs will be identified in a separate Data Presentation 
Plan.
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APPENDIX 1: LIST OF ABBREVIATIONS
AE
Adverse Event
ATC
Anatomical Therapeutic Chemical 
BMS
Bristol Myers Squibb
BPI - SF
Brief Pain Inventory – Short Form
CI(s)
Confidence Interval(s)
CMH
Cochran Mantel Haenszel
CR
Complete Response
CRF 
Case Report Form
CT
Computerized Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
EBMT
European Group for Blood and Bone Marrow Transplant
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EMEA
European Agency for the Evaluation of Medicinal Products
EORTC
European Organization for Research and Treatment of Cancer
ESRD
End Stage Renal Disease
FDA
Food and Drug Administration
HAHA
Human Anti-Human Antibody
HRQOL
Health Related Quality of Life
IMiD
Immune Modulatory Drugs
IRC
Independent Review Committee
ITT
Intent-to-Treat
IV
Intravenous
IVRS
Interactive Voice Response System
Ld
Lenalidomide, (low-dose) Dexamethasone
E-Ld
Elotuzumab, Lenalidomide, (low-dose) Dexamethasone
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LS
Least Squares
MedDRA
Medical Dictionary for Regulatory Activities
MM 
Multiple Myeloma
MR
Minor Response
MRI
Magnetic Resonance Imaging
MUGA
Multi Gated Acquisition
NCI
National Cancer Institute 
ORR
Objective Response Rate
OS
Overall Survival
PD
Progression
PFS
Progression-Free Survival
PFS-2
Progression-Free Survival After Next Line of Treatment
PK
Pharmacokinetic
PO
Oral
PPK
Population Pharmacokinetics
PR
Partial Response
QLQ-C30
Quality of Life Questionnaire – Core
QLQ-MY20
Quality of Life Questionnaire – Myeloma Specific Module
QoL
Quality of Life
SAE
Serious Adverse Event
SAP 
Statistical Analysis Plan
sCR
Stringent Complete Response
SD
Stable Disease
SE
Standard Error
sMICA
Soluble Major Histocompatibility Complex Class I-related Chain A
SI
International System of Units (SI)
SOC
System Organ Class
STD
Standard Deviation
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UD
Unable to Determine
ULN
Upper Limit of Normal 
VGPR
Very Good Partial Response
WHO
World Health Organization
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APPENDIX 2: LIST OF COUNTRIES BY REGIONS
Regions will be defined according the following country groupings. This list will be updated at the 
time of the analysis if subjects are enrolled in additional countries.
Region
Countries
North 
America 
(NA)
Canada, Mexico, Puerto Rico, USA
Europe 
(EU)
Austria, Belgium, Croatia, Czech Republic, Denmark, 
France, Germany, Greece, Hungary, Ireland, Italy, Poland, 
Portugal, Romania, Russia, Spain, Sweden, Switzerland, UK
Rest of the 
World 
(ROW)
Australia, China, Israel, South Korea, Malaysia, Philippines, 
South Africa, Singapore, Taiwan, Thailand, Turkey, 
Argentina, Brazil, Chile, Peru 
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9
DOCUMENT HISTORY
Version Number
Author(s)
Description
Version 1.0
Version 2.0
 
Version 2.1
 
 
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