Clinical trial NCT02272803
Conditions: Multiple Myeloma
Sponsor: Bristol-Myers Squibb
Start date: 2015-02-20; Completion date: 2021-07-21
Enrollment: 82 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the efficacy of Lenalidomide/Dexamethasone + Elotuzumab in the subjects with newly diagnosed, previously untreated Multiple Myeloma (MM) in Japan.

Detailed description:

Arms: arm 1: Drug: Lenalidomide

Capsules, Oral, 25 mg, once daily, on Days 1-21, Repeat every 28 days until subject meets criteria for discontinuation of study drug

Drug: Dexamethasone

Tablets, Oral 28 mg and 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

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

Biological: Elotuzumab (BMS-901608)

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

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 arm 2: Drug: Lenalidomide

Capsules, Oral, 25 mg, once daily, on Days 1-21, Repeat every 28 days until subject meets criteria for discontinuation of study drug

Drug: Dexamethasone

Tablets, Oral, 40 mg, weekly, on Days 1, 8, 15, 22, Repeat every 28 days until subject meets criteria for discontinuation of study drug
Interventions: intervention 1: Lenalidomide intervention 2: Dexamethasone intervention 3: Elotuzumab (BMS-901608)
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
SAP_002.pdf: 
Official Title of Study: 
A PHASE2, RANDOMIZED, OPEN LABEL TRIAL OF 
LENALIDOMIDE/DEXAMETHASONE WITH OR WITHOUT ELOTUZUMAB IN 
SUBJECTS WITH PREVIOUSLY UNTREATED MULTIPLE MYELOMA IN JAPAN 
 
NCT Number:  NCT02272803 
Document Date (Date in which document was last revised): April 2, 2017 


STATISTICAL ANALYSIS PLAN
FOR CSR
A PHASE2, RANDOMIZED, OPEN LABEL TRIAL OF 
LENALIDOMIDE/DEXAMETHASONE WITH OR WITHOUT ELOTUZUMAB IN 
SUBJECTS WITH PREVIOUSLY UNTREATED MULTIPLE MYELOMA IN JAPAN
PROTOCOL(S) CA204116
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CSR ...........................................................................1
TABLE OF CONTENTS............................................................................................................2
1
BACKGROUND AND RATIONALE......................................................................5
1.1
Unmet Medical Needs in Multiple Myeloma.............................................................5
1.2
Non-clinical Rationale for Elotuzumab in Combination with Lenalidomide 
and Dexamethasone..................................................................................................5
1.2.1
Elotuzumab...............................................................................................................5
1.2.2
Combination of Elotuzumab with Lenalidomide/dexamethasone ...............................6
2
STUDY DESCRIPTION ..........................................................................................7
2.1
Study Design ............................................................................................................7
2.2
Treatment Assignment..............................................................................................9
2.3
Blinding and Unblinding...........................................................................................9
2.4
Protocol Amendments...............................................................................................9
3
OBJECTIVES ..........................................................................................................9
3.1
Primary Objectives ...................................................................................................9
3.2
Secondary Objective.................................................................................................9
3.3
Exploratory Objectives .............................................................................................9
4
ENDPOINTS..........................................................................................................10
4.1
Endpoint Definitions...............................................................................................10
4.1.1
Objective Response Rate (ORR)..............................................................................10
4.1.2
Progression-Free Survival......................................................................................10
4.1.2.1
Definition of an Adequate Tumor Assessment .........................................................10
4.1.2.2
Date of Progression or Censoring When Different Components of a Per Time 
Point Tumor Assessment Conducted at Different Times ..........................................10
4.1.2.3
Primary Definition of Progression-Free Survival (PFS) .........................................11
4.1.2.4
Secondary Definition of Progression-Free Survival – ITT Definition ......................11
4.1.3
Duration of Response .............................................................................................11
4.1.4
Time to Tumor Response.........................................................................................12
5
SAMPLE SIZE AND POWER...............................................................................12
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................12
6.1
Study Periods..........................................................................................................12
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6.2
Treatment Regimens...............................................................................................13
6.3
Populations for Analyses ........................................................................................13
7
STATISTICAL ANALYSES..................................................................................14
7.1
General Methods ....................................................................................................14
7.2
Study Conduct........................................................................................................14
7.2.1
Accrual Patterns.....................................................................................................14
7.2.2
Protocol Violations.................................................................................................14
7.3
Study Population ....................................................................................................15
7.3.1
Subject Disposition.................................................................................................15
7.3.2
Demographic and Subject Characteristics ..............................................................15
7.3.3
Disease Characteristics at Baseline........................................................................16
7.3.4
General Medical History ........................................................................................16
7.3.5
Baseline Safety Laboratory Tests............................................................................17
7.4
Extent of Exposure .................................................................................................17
7.4.1
Study Therapy.........................................................................................................17
7.4.1.1
Duration of Study Therapy......................................................................................17
7.4.1.2
Dose Modifications.................................................................................................17
7.4.1.3
Cumulative Dose, Dose Intensity, and Relative Dose Intensity................................20
7.4.2
Premedication Other than Dexamethasone for Hypersensitivity Reactions..............23
7.4.3
Concomitant Medication.........................................................................................23
7.4.4
Discontinuation of Study Therapy...........................................................................23
7.4.5
Subsequent Anti-Myeloma Therapy.........................................................................23
7.5
Efficacy..................................................................................................................24
7.5.1
Analyses of Objective Response ..............................................................................24
7.5.2
Analysis of Progression-Free Survival....................................................................24
7.5.3
Time to Tumor Response, and Duration of Response ..............................................25
7.5.4
Efficacy Laboratory Tests.......................................................................................25
7.6
Safety.....................................................................................................................25
7.6.1
Adverse Events .......................................................................................................25
7.6.2
Serious Adverse Events and Adverse Event Leading to Discontinuation..................26
7.6.3
Adverse Events of Special Interest ..........................................................................26
7.6.4
Second Primary Malignancies ................................................................................27
7.6.5
Deaths ....................................................................................................................27
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7.6.6
Clinical Laboratory Evaluations.............................................................................27
7.6.7
Echocardiogram, MUGA Scan and Electrocardiograms.........................................28
7.6.8
Vital Signs, Physical Measurements and Physical Examination..............................28
7.7
Pharmacokinetic Analysis.......................................................................................28
7.8
Anti-drug Antibody Analysis..................................................................................29
7.9
Biomarker Analyses ...............................................................................................29
8
CONVENTIONS....................................................................................................30
8.1
Baseline Definition.................................................................................................30
8.2
Age Definition........................................................................................................30
8.3
Duration and Study Day Definition.........................................................................30
8.4
Day Conversion of Date Imputation........................................................................30
8.5
AE, Laboratory Results and Concomitant Medication.............................................31
9
DOCUMENT HISTORY........................................................................................32
10
REFERENCES.......................................................................................................33
APPENDIX 1
LIST OF ABBREVIATIONS.................................................................34
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Research Hypothesis:
Elotuzumab + lenalidomide/dexamethasone will demonstrate Objective Response Rate (ORR) of 
> 71% when given to subjects with newly diagnosed, previously untreated MM.
Schedule of Analyses:
The primary endpoint of ORR will be performed at least 6 months after last subject’s first treatment
for the purpose of the CSR, which will contain all of the analyses specified in this Statistical 
Analysis Plan (SAP). Additional analyses may be performed, which depend on the timing of 
regulatory authority filing. The final analysis may be performed at the timing of the study 
discontinuation.
2
STUDY DESCRIPTION
2.1
Study Design
This 
is 
a 
Phase 
2, 
randomized,
open-label, 
multi-center 
trial 
investigating 
lenalidomide/dexamethasone with and without elotuzumab in subjects with newly diagnosed, 
previously untreated multiple myeloma who are ineligible for high-dose therapy plus stem-cell 
transplantation (SCT) because of age (65 years) or coexisting conditions.
The primary
objective of this study is to estimate the ORR of elotuzumab +
lenalidomide/dexamethasone in subjects with newly diagnosed, previously untreated MM.
Eligible 
subjects 
will 
be 
randomized 
in 
a 
1:1 
ratio 
to 
receive 
either 
elotuzumab/lenalidomide/dexamethasone 
(ELd)
[Investigational 
Arm]
or 
lenalidomide/dexamethasone (Ld) [Control Arm]. The randomization will be stratified by 
International Staging System (ISS) stage (1 - 2 versus 3). Approximately eighty subjects in total 
will be randomized to either arm.
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A cycle is defined as 28 days. Treatment with study drug continues until disease progression (PD), 
unacceptable toxicity or subject meets other criteria for discontinuation of study drug.
Disease assessments, based on the International Myeloma Working Group (IMWG) response 
criteria, will be conducted every 4 weeks relative to the first dose of study medication until disease 
progression. Response and progression assessment will be investigator-based and no central lab or 
independent review is planned.
For the subject who does not have documented disease progression at time of study drug 
discontinuation, tumor assessments should still be performed according to the same schedule until 
disease progression even if a subsequent anti-myeloma treatment is initiated prior to disease 
progression.
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, 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 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
Eligible subjects will be randomized in a 1:1 ratio to receive either ELd Arm [Investigational Arm] 
or Ld Arm [Control Arm].
The randomization will be stratified by ISS stage (1 -2 versus 3) and will be carried out via 
permuted blocks within the stratum.
2.3
Blinding and Unblinding
This is an open label trial.Protocol Amendments
Amendment 01 20-Nov-2014
The purpose of this amendment is to change and 
clarify the handling of Investigational Products, the 
dosage of premedication prior to elotuzumab 
infusion and the process of laboratory assessments. 
This amendment includes three changes: 1) 
Lenalidomide has to be stored at 15- 25C because 
it is provided as Investigational Product, 2) The 
dosage of Acetaminophen as a premedication prior 
to elotuzumab infusion is allowed from 300 mg to 
1,000 mg according to the package insert in Japan, 
and 3) The cytgenetic assessments will be 
performed at the local central laboratory designated 
by the sponsor because they require fresh bone 
marrow samples, and also these results will be 
collected using the eCRF.
3
OBJECTIVES
3.1
Primary Objectives
To estimate the ORR of elotuzumab + lenalidomide/dexamethasone in subjects with newly 
diagnosed, previously untreated MM.
3.2
Secondary Objective

To estimate the difference in ORR between elotuzumab + lenalidomide/dexamethasone (ELd)
and lenalidomide/dexamethasone (Ld).

To assess Progression Free Survival (PFS) in each arm;
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4
ENDPOINTS
4.1
Endpoint Definitions
The primary and secondary endpoints are Objective Response Rates (ORR) based on investigator 
tumor assessments using IMWG criteria.
4.1.1
Objective Response Rate (ORR)
The primary and secondary endpoints of Objective Response Rate (ORR) are defined as the
proportion of randomized subjects who achieve a partial response (PR) or better, i.e. stringent
complete response (sCR), complete response (CR), very good partial response (VGPR) and PR,
according to the IMWG criteria. Response assessment will be evaluated by the investigator using
the IMWG criteria during the trial for all randomized subjects.
4.1.2
Progression-Free Survival
4.1.2.1
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

Urine monoclonal paraprotein results, if measurable at baseline.

Serum free light chain results, if measurable at baseline. This is only relevant for subjects who 
do not have measurable serum and urine monoclonal paraprotein results.
4.1.2.2
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 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 latest date of the measurements associated with that time 
point.
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4.1.2.3
Primary Definition of Progression-Free Survival (PFS)
Primary Definition of PFS: PFS, under the primary definition, is the time from randomization to 
the date of the first documented tumor progression, as determined by the investigator using the 
IMWG criteria, 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 secondary 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 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
4.1.2.4
Secondary Definition of Progression-Free Survival – 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. 
4.1.3
Duration of Response
Duration of response will be measured for subjects whose best response is PR or better, from the 
time that the criteria for objective response are first met until the date of a progression event
(according to the primary definition of PFS). A subject with objective response who does not have 
a progression event will be censored at the same time they were censored under the primary 
definition of PFS.
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4.1.4
Time to Tumor Response
Time to response is defined as the time from randomization to the first objective documentation 
of PR or better. Time to response is restricted to the population of subjects who achieved a best 
response of PR or better.
The duration of all the above endpoints will be measured in months.
5
SAMPLE SIZE AND POWER
The number of subjects in the investigational arm (ELd arm) is based on the primary objective of 
assessment in objective response rate in ELd arm. The design will test the null hypothesis that the 
response rate 71% versus the alternative that the true response rate > 71%. The test will have a 
significance level of 15% (one-sided) and will have 80% power to reject the null hypothesis if the 
true response rate is 85%. If there are 32 or more responders out of 40 subjects in the ELd arm, the 
null hypothesis will be rejected. The study design requires 40 subjects in ELd arm.
The control arm (Ld arm) is designed to evaluate add-on efficacy clinically for Elotuzumab with 
40 subjects. The randomized ratio of ELd to Ld is 1:1.
This is a randomized study and the results from both treatment arms will help assess the effect of 
elotuzumab addition to Ld in the treatment of Japanese subjects with newly diagnosed MM, and 
put into the right perspective. However, no formal comparisons between treatment arms are 
planned since a formal comparative study would require a prohibitively large sample size. The 
efficacy of adding elotuzumab to Ld therapy in the treatment of subjects with newly diagnosed, 
previously untreated MM will be confirmed on the basis of the large global pivotal study CA204-
006, results of which will be used in conjunction with results from the current study to support the 
JNDA submission.
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, ECGs and concomitant medications, which can be 
done up to 28 days or 21 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.
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 
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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.
6.2
Treatment Regimens
Subjects will be randomized to one of two treatment arms, ELd or Ld. Subjects will receive these 
treatments in 28-day cycles until disease progression, unacceptable toxicity or withdrawal of 
consent.
On ELd arm subjects receive:

Elotuzumab: 10mg/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: 25mg orally (po) on Days 1-21 of each cycle.

Dexamethasone: Administered on Days 1, 8, 15 and 22 of cycle. 28mg po + 8mg IV whenever 
given prior to elotuzumab; 40mg po on weeks on which no elotuzumab is given.
On Ld arm subjects receive:

Lenalidomide: 25mg po on Days 1-21 of each cycle.

Dexamethasone: 40mg 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:

Enrolled subjects: all subjects who signed informed consent

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, and efficacy will be carried out on all 
randomized subjects. Analyses of safety will be based on all treated subjects.
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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. 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 
method17 will be used to compute a 95% confidence interval (CI) for the median of each time-to-
event endpoint. 
The 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 Investigator. 
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 
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 site number, overall and by treatment group will be generated.
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
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2. M-protein ≥ 200 mg in 24-hour urine.
3. Serum free light chain (sFLC) assay showing involved FLC level >= 10 mg/dL (>=100 
mg/l) provided the serum FLC ratio is abnormal
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 4.1.2.1, 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.
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), weight (kg) and ECOG performance status (0,1,2) .
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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, IgM, Light chain disease)

Number of lytic bone lesions (0, 1-3, >3)

Myeloma18 Risk Categories
High risk: ISS stage II or III and t(4;14) or del(17p) abnormality
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, 1 q21 amplification, t(14; 16), t(4; 
14), del 13, 1p32.3, 1q21, t(14;20), hypodiploidy)

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)

Creatinine Clearance (mL/sec) (<0.5, 0.5 -<1, 1-<1.5, >=1.5)

Soft tissue plasmacytomas (Yes, No) 

ISS Stage at randomization (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.
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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 before 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, and total bilirubin) and renal function/electrolytes (sodium, potassium, 
bicarbonate, chloride, calcium, glucose, and creatinine, creatinine clearance < 60 ml/min, ≥ 60 
ml/min). Sodium, potassium, chloride, calcium, and glucose will be presented separately, based 
on their high and low values.
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” 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. A summary of the number of subjects taking 
each drug in each cycle will also be presented 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:
(݀ܽݐ݁݋݂݈ܽݏݐ݀݋ݏ݁݋݂ݐℎ݁݀ݎݑ݃−݀ܽݐ݁݋݂݂݅ݎݏݐ݀݋ݏ݁݋݂ݐℎ݁݀ݎݑ݃+ 1)/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
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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 cycle 3, 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 change 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.

Dose Omission
An omission for Elotuzumab will be calculated based on records from the study medication 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 the second infusion of cycles 3-18), or > 35 days from 
cycle 19 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.
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
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
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 
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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 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
A subject’s cumulative dose of lenalidomide is defined as the sum of each dose they took, as 
recorded in their medication diary. 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 0.76. 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) and relative dose intensity per subject will be calculated 
separately for Cycles 1 and 2, and Cycles 3 and beyond cycle 18, since elotuzumab planned dose 
intensity in Cycles 1 and 2 differs from that in Cycles 3 and beyond. 
Cycle 1 and 2
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7 × ൭
௖௨௠௨௟௔௧௜௩௘ௗ௢௦௘௢௙௘௟௢௧௨௭௨௠௔௕ௗ௨௥௜௡௚௧௛௘௙௜௥௦௧ଶ௖௬௖௟௘௦
൬୫୧୬(ௗ௔௧௘௢௙௙௜௥௦௧ௗ௢௦௘௢௙௘௟௢௧௨௭௨௠௔௕௜௡௧௛௘௟௔௦௧௖௬௖௟௘௔௠௢௡௚௧௛௘௙௜௥௦௧ଶ௖௬௖௟௘௦ାଶ଼, ௗ௘௔௧௛ௗ௔௧௘)ି
ௗ௔௧௘௢௙௙௜௥௦௧ௗ௢௦௘௢௙௘௟௢௧௨௭௨௠௔௕௜௡஼௬௖௟௘ଵ
൰
൱
Cycle 3 and beyond
7 × ൮
ܿݑ݉ݑ݈ܽݐ݅ݒ݁݀݋ݏ݁݋݂݈݁݋ݐݑݖݑܾ݉ܽݏݐܽݎݐ݂݅݊݃ݎ݋݉ܥݕ݈ܿ݁3
൬min(݀ܽݐ݁݋݂݂݅ݎݏݐ݀݋ݏ݁݋݂݈݁݋ݐݑݖݑܾ݈݉ܽ݅݊ܽݏݐܿݕ݈ܿ݁+ 28, ݀݁ܽݐℎ݀ܽݐ݁) −
݀ܽݐ݁݋݂݂݅ݎݏݐ݀݋ݏ݁݋݂݈݁݋ݐݑݖݑܾ݉ܽ݅݊ܥݕ݈ܿ݁3
൰
൲
The relative dose intensity will be calculated as
Dose Intensity/Planned Dose Intensity(PDI)
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 e.g., elotuzumab PDI for a subject whose last 
dose was the first dose of third cycle would have the PDI computed as
ܧ݈݋ݐݑݖݑܾ݉ܽܲܦܫ((݉݃/݇݃/ݓ݇) = 4 × 10 + 4 × 10 + 4 × 5
12
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: 
൭
௖௨௠௨௟௔௧௜௩௘ௗ௢௦௘௢௙௟௘௡௔௟௜ௗ௢௠௜ௗ௘
൬௠௜௡(ௗ௔௧௘௢௙ଵ௦௧ௗ௢௦௘௢௙௟௘௡௔௟௜ௗ௢௠௜ௗ௘௜௡௟௔௦௧௖௬௖௟௘௜௡௪௛௜௖௛௟௘௡௔௟௜ௗ௢௠௜ௗ௘௪௔௦௔ௗ௠௜௡௜௦௧௘௥௘ௗ
ାଶ଼,ௗ௘௔௧௛ௗ௔௧௘)ିௗ௔௧௘௢௙௙௜௥௦௧ௗ௢௦௘௢௙௟௘௡௔௟௜ௗ௢௠௜ௗ௘
൰൱
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/day(10mg/day per protocol)).
Dexamethasone:
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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
൬୫୧୬(ௗ௔௧௘௢௙௙௜௥௦௧ௗ௢௦௘௢௙ௗ௘௫௔௠௘௧௛௔௦௢௡௘௜௡௟௔௦௧௖௬௖௟௘௔௠௢௡௚௙௜௥௦௧ଶ௖௬௖௟௘௦ାଶ଼,ௗ௘௔௧௛ௗ௔௧௘) ି
ௗ௔௧௘௢௙௙௜௥௦௧ௗ௢௦௘௢௙ௗ௘௫௔௠௘௧௛௔௦௢௡௘௜௡௙௜௥௦௧௖௬௖௟௘
൰
൱
Cycle 3-18:
7 × ൮
ܿݑ݉ݑ݈ܽݐ݅ݒ݁݀݋ݏ݁݋݂݀݁ݔܽ݉݁ݐℎܽݏ݋݊݁݀ݑݎ݅݊݃ܥݕ݈ܿ݁3 −ܥݕ݈ܿ݁18
൬min( ݀ܽݐ݁݋݂݂݅ݎݏݐ݀݋ݏ݁݋݂݀݁ݔܽ݉݁ݐℎܽݏ݋݈݊݁݅݊ܽݏݐܿݕ݈ܿ݁ܽ݉݋݊݃18 ܿݕ݈ܿ݁ݏ+ 28, ݀݁ܽݐℎ݀ܽݐ݁) −
݀ܽݐ݁݋݂݂݅ݎݏݐ݀݋ݏ݁݋݂݀݁ݔܽ݉݁ݐℎܽݏ݋݊݁݅݊ܥݕ݈ܿ݁3
൰
൲
Cycle 19 and beyond:
7 × ൮
ܿݑ݉ݑ݈ܽݐ݅ݒ݁݀݋ݏ݁݋݂݀݁ݔܽ݉݁ݐℎܽݏ݋݊݁ݏݐܽݎݐ݂݅݊݃ݎ݋݉ܥݕ݈ܿ݁19
൬min( ݀ܽݐ݁݋݂݂݅ݎݏݐ݀݋ݏ݁݋݂݀݁ݔܽ݉݁ݐℎܽݏ݋݈݊݁݅݊ܽݏݐܿݕ݈ܿ݁+ 28, ݀݁ܽݐℎ݀ܽݐ݁) −
݀ܽݐ݁݋݂݂݅ݎݏݐ݀݋ݏ݁݋݂݀݁ݔܽ݉݁ݐℎܽݏ݋݊݁݅݊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 
38.5mg 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 38.5mg 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 
39.25mg 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%. 
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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.
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 Therapy
A by-subject listing of all subsequent surgery, all subsequent radiation therapy, and all subsequent 
systemic anti-myeloma therapy will be provided using the BMS WHO drug dictionary.
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7.5
Efficacy
Efficacy analyses (ORR and PFS) will be conducted on the population of all randomized subjects.
All analyses of ORR and PFS will be based on the investigator evaluation. Unless stated otherwise, 
whenever a stratified analysis is specified, the stratifications factor will be those used in the 
randomization, that is:

Stage of disease (ISS 1 – 2 versus 3)
CIs will be at the two-sided 70% level and at the two-sided 95% level for ORR analysis as primary 
endpoint, and the other analyses, respectively. 
7.5.1
Analyses of Objective Response 
Analysis for Primary objective:
The response rate and its corresponding exact two-sided 70% confidence interval (Clopper and 
Pearson19) will be calculated in the ELd arm. 
The number and percentage of subjects in each category of best overall response per Investigator
(complete response [CR], and whether CR was stringent CR [sCR], PR and whether PR was very 
good partial response [VGPR], stable disease [SD], progressive disease [PD], or unable to 
determine [UD]) will be presented, by treatment group. 
Analysis for Secondary objective:
An estimate of the response rate and an associated exact two-sided 95% CI will be presented, by 
treatment group.
The difference in ORR between two treatment arms along with two-sided 95% CI will be estimated 
using the method of DerSimonian and Laird adjusted by stage of disease (ISS stage 1- 2 versus 3). 
In addition, the response rate and its corresponding exact two-sided 95% confidence interval will 
be calculated in both arms.
7.5.2
Analysis of Progression-Free Survival
The PFS analyses will be conducted using both the primary and the ITT definitions of PFS. 
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 one-year and two-year PFS if last 
patient is followed for at least 1 or 2 years correspondingly, will be presented along with their 
associated 95% CIs. These estimates will be come from the KM curve and their standard errors 
(SEs), for use in constructing CIs, will be computed using Greenwood’s formula20.
The estimate of the PFS hazard ratio, of ELd to Ld, will be calculated using a Cox proportional 
hazards model, with stage of disease (ISS 1 – 2 versus 3) as the stratification factor and treatment 
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as the sole covariate. Ties will be handled using the Breslow method2122. A two-sided, 95% CI 
for the hazard ratio will also be presented. 
A by-subject listing will be presented including treatment arm, PFS duration under the primary 
definition, PFS duration on the ITT definition, whether the subject was censored under the primary 
definition, and if censored, the reason, and whether the subject was censored under the ITT 
definition, and if censored, the reason.
7.5.3
Time to Tumor Response, and Duration of Response
The distributions of duration of response will be estimated, by arm, using the KM product limit 
method. The KM estimates will be presented graphically and tables will be produced presenting 
number of events, number of subjects involved, medians, and 95% CIs for the medians. 
Time to tumor response, which does not involve censoring, will be summarized by treatment 
group, using descriptive statistics. 
A by-subject listing will be presented including treatment arm, and, duration of response, whether 
the subject was censored for duration of response, and, if so, the reason. 
7.5.4
Efficacy Laboratory Tests
A by subject listing of efficacy will be provided to present the following:

Percent change in serum and urine M-protein, from baseline and nadir.

Serum free light chain kappa and lambda concentrations and the kappa/lambda ratio.

Serum and urine immunofixation test results.

Corrected Calcium results

Results of bone marrow analysis, including  plasma cells (%) and clonality of plasma cells.

Radiologic evaluation of extramedullary plasmacytoma and lytic bone lesions
7.6
Safety
Safety summaries will be based on the treated subject population, grouped by treatment regimen 
received. All subject’s treatment regimen received will equal the arm to which they were assigned 
at randomization as long as they did not receive the wrong regimen at every administration. 
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 (PT). 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.
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Unless specified otherwise, AEs will be counted only once within each SOC and PT, according to 
their worst CTC grade.
Tables will be sorted by SOC and PT, with SOCs ordered by decreasing frequency overall and 
then alphabetically. PTs 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.” The 
summary of combined grades 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 19 for subjects on the Elotuzumab arm

Exposure-adjusted AE incidence rates (including multiple occurrences of unique events) 
will be calculated for each SOC and PT.
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.
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. This last summary 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
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:
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
Frequency tables of the worst grade of on-study investigator infusion reaction (any grade and 
grade 1 through 5) by treatment group. 

Frequency of infusion reaction by infusion rate. 

Frequency of infusion reaction by cycle.
By subject listings of infusion reactions will be produced.
7.6.4
Second Primary Malignancies
By-subject listings of second primary malignancies (SPM) will be provided. Information on SPM
will be obtained from the “Survival Status” eCRF page.
7.6.5
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.
7.6.6
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, Leukocytes, Lymphocytes (absolute), Absolute neutrophil count and 
platelet count) 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 a post-baseline (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 (Alanine Aminotransferase, Albumin, Alkaline Phosphatase, Aspartate 
Aminotransferase, Total Bilirubin) with available CTC grades

Renal/electrolyte parameters (sodium, potassium, bicarbonate, calcium, glucose, and 
creatinine) with available CTC grades. Sodium, potassium, chloride, 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). 
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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.
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 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. 
7.6.7
Echocardiogram, MUGA Scan and Electrocardiograms
A by subject listing of echocardiogram and multi gated acquisition (MUGA) scan data collected 
at screening will be presented. A separate by subject listing of electrocardiogram (ECG) data 
collected at screening will also be presented.
7.6.8
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. 
Physical measurements (weight and ECOG Performance Status) will be presented by visit and 
timepoint in a subject listing.
7.7
Pharmacokinetic Analysis
Elotuzumab concentrations taken pre (elotuzumab) dose, at each scheduled visit, will be 
summarized, by cycle and day, for subjects in the elotuzumab arm only. In addition to the standard 
summary statistics, the geometric mean will also be presented. 
A by subject listing of elotuzumab concentrations will be provided.
Elotuzumab concentrations will be combined with concentration data from other studies and will 
be analyzed using population pharmacokinetic (PPK) analysis. Results of the PPK analysis may 
also be used to explore the relationship between elotuzumab and efficacy/safety endpoints. 
Results of the PPK analysis and potential exploratory exposure response analysis will be 
reported separately.
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7.8
Anti-drug Antibody Analysis
ADA status of a sample:

Baseline ADA positive sample: ADA is detected in the last sample prior to the first dosing 
date/time of elotuzumab.

On study ADA positive sample: after the first dosing date/time of elotuzumab:

ADA is detected in a subject whose baseline is negative

ADA is detected and ADA titer is at least 9-fold or greater () than the baseline positive 
ADA titers

On study ADA negative sample: after the first dosing date/time of elotuzumab, no ADA 
detected relative to baseline. 
Anti drug antibody (ADA) will be summarized for elotuzumab arm only with the following 
categories: 

Baseline ADA Positive Subject: A subject with Baseline ADA Positive Sample

ADA Positive Subject: A subject with at least one ADA positive sample after the first 
elotuzumab dose relative to baseline.

Persistent Positive: ADA positive sample at 2 or more sequential timepoints at least 3 
months apart

Only the Last Sample Positive: ADA positive sample only in the last sampling 
timepoint.

Other Positive: not persistent positive with ADA negative sample in the last sampling  

Neutralizing Positive: At least one ADA Positive Sample with neutralizing 
antibodies detected.

ADA Negative Subject: A subject with no ADA positive sample after the first elotuzumab 
dose relative to baseline.
A by subject listing of all ADA data at each time-point will be provided along with corresponding 
elotuzumab concentration values measured as a part of pharmacokinetic assessments.
 
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8
CONVENTIONS
8.1
Baseline Definition
Baseline evaluations will be those performed within 60 days before randomization and prior to 
first dosing date. When an assessment is repeated multiple times within the screening evaluation 
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݋݊ݏ݁݊ݐ−݀ܽݐ݁݋݂ܾ݅ݎݐℎ+ 1
365.25
8.3
Duration and Study Day Definition
In instances in which study period between two dates are to be calculated (for example, duration 
of response and PFS), 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.
8.4
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.
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
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:

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.
8.5
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.
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APPENDIX 1
LIST OF ABBREVIATIONS
ADA
Anti-Drug Antibody
ADCC
antibody dependent cell-mediated cytotoxicity
AE
Adverse Event
ALP
alkaline phosphatase
ALT
alanine transaminase
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical 
BMS
Bristol Myers Squibb
CI(s)
Confidence Interval(s)
CR
Complete Response
CRF 
Case Report Form
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CSR
Clinical Study Report
CS1
CD-2 subset 1
CTCAE
Common Terminology Criteria for Adverse Events
DILI
drug induced liver injury
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
ESRD
End Stage Renal Disease
FISH
Fluorescence in situ hybridization
IHC
immunohistochemistry
IMiDs
induction, and bortezomib or immune modulatory drugs
IMWG
International Myeloma Working Group
ISS
International Staging System
ITT
Intent-to-Treat
IV
Intravenous
JNDA
Japan New Drug Application
KM
Kaplan-Meier
Ld
Lenalidomide, (low-dose) Dexamethasone
LdE
Lenalidomide, (low-dose) Dexamethasone, Elotuzumab
LDH
lactate dehydrogenase 
MedDRA
Medical Dictionary for Regulatory Activities
MHLW
Ministory of Health, Labor and Welfare
MM 
Multiple Myeloma
M-proteins
Monoclonal immunoglobulin
MUGA
Multi Gated Acquisition
NCI
National Cancer Institute 
ORR
Objective Response Rate
OS
Overall Survival
PBMCs
peripheral blood mononuclear cells
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PD
Progression
PFS
Progression-Free Survival
PK
Pharmacokinetic
PO
Oral
PPK
Population Pharmacokinetics
PR
Partial Response
PT
Preferred Term
SAE
Serious Adverse Event
SAP 
Statistical Analysis Plan
SCID
severe combined immunodeficient
sCR
Stringent Complete Response
SCT
stem-cell transplantation
SD
Stable Disease
SE
Standard Error
sFLC
Serum free light chain
SI
International System of Units (SI)
SOC
System Organ Class
SOP
Standard Operating Procedure
STD
Standard Deviation
TBILI
total bilirubin
UD
Unable to Determine
ULN
Upper Limit of Normal 
VGPR
Very Good Partial Response
WHO
World Health Organization
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Prot_003.pdf: 
Page:
1
Protocol Number:
CA204116
IND Number:
N/A
Ex-US
Non-IND
EUDRACT Number
N/A
Date:
10-Sep-2014
Revised Date
16-Feb-2017
CLINICAL PROTOCOL CA204116
A Phase 2, Randomized, Open Label Trial of Lenalidomide/dexamethasone With or Without 
Elotuzumab in Subjects with Previously Untreated Multiple Myeloma in Japan
Revised Protocol Number: 03
Incorporates amendment(s) 03 and administrative letter 05
Study Director 
Medical Monitor
Su Tien Nguyen
 
 
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 
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. References to BMS in this 
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protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
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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SYNOPSIS
Clinical Protocol CA204116
Protocol Title: A Phase 2, Randomized, Open Label Trial of Lenalidomide/dexamethasone With or Without 
Elotuzumab in Subjects with Previously Untreated Multiple Myeloma in Japan
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):
Investigational Arm:

Elotuzumab

Cycle 1 - 2: 10 mg/kg IV, Days 1, 8, 15, 22

Cycle 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 of each cycle

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 elotuzumab is NOT administered:

40 mg po
Control Arm:

Lenalidomide: 25 mg po QD, Days 1 - 21 of each cycle

Dexamethasone: 40 mg po, Days 1, 8, 15, and 22 of each cycle
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:  2
Research Hypothesis: Elotuzumab + lenalidomide/dexamethasone will demonstrate Objective Response Rate
(ORR) of > 71% when given to subjects with newly diagnosed, previously untreated multiple myeloma (MM).
Objectives: 
Primary Objective
To estimate the ORR of elotuzumab + lenalidomide/dexamethasone in subjects with newly diagnosed, previously 
untreated MM.
Secondary Objectives

To estimate the difference in ORR between elotuzumab + lenalidomide/dexamethasone (ELd) and 
lenalidomide/dexamethasone (Ld);

To assess Progression Free Survival (PFS) in each arm.
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Study Design:  
This is a Phase 2, randomized, open-label, multi-center trial investigating lenalidomide/dexamethasone with and 
without elotuzumab in subjects with newly diagnosed, previously untreated multiple myeloma.
Eligible subjects will be randomized in a 1:1 ratio to receive either elotuzumab/lenalidomide/dexamethasone (ELd) 
or lenalidomide/dexamethasone (Ld). The randomization will be stratified by International Staging System (ISS) 
stage (1 - 2 versus 3).
Figure 1:
Study Design Schematic
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.
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Disease assessments, based on the International Myeloma Working Group (IMWG) response criteria, will be 
conducted every 4 weeks relative to the first dose of study medication until disease progression. Response and 
progression assessment will be investigator-based and no central lab or independent review is planned.
For the subject who does not have documented disease progression at time of study drug discontinuation, tumor 
assessments should still be performed according to the same schedule until disease progression even if a subsequent 
anti-myeloma treatment is initiated prior to disease progression.
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 Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational 
[Medicinal] Products (Non-IP/Non-IMP) as listed:
Study Drug for CA204116
Medication 
Potency 
IP/Non-IP 
Elotuzumab Powder for Solution for 
Infusion
400 mg/vial
IP
Lenalidomide (Revlimid) capsule
5 mg, 10 mg, 15 mg and 25 mg
IP
Dexamethasone Tablets
2 mg and 4 mg & various strengths
Non-IP
Dexamethasone Solution
4 mg/ml, 8 mg/ml & various strengths
Non-IP
Elotuzumab and lenalidomide will be supplied by the BMS.
Dexamethasone tablets and solution for IV infusion will be obtained by the investigating site’s standard 
prescribing procedures.
Study Assessments: 
Tumor response assessment will be evaluated by the investigator using the IMWG criteria during the trial for all 
treated subjects. Objective Response Rate (ORR) is defined as stringent complete response (sCR), complete 
response (CR), very good partial response (VGPR) and partial response (PR) according to the IMWG criteria.
Statistical Considerations:
Sample Size: The number of subjects in ELd arm is based on the primary objective of assessment in objective 
response rate in ELd arm. The design will test the null hypothesis that the response rate 71% versus the alternative 
that the true response rate > 71%. The test will have a significance level of 15% (one-sided) and will have 80% 
power to reject the null hypothesis if the true response rate is 85%. The study design requires 40 subjects in ELd 
arm.
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The Ld arm is set to evaluate add-on efficacy clinically for Elotuzumab with 40 subjects. The randomized ratio of 
ELd to Ld is 1:1.
Endpoints: The primary and secondary endpoint of Objective Response Rate (ORR) is defined as the proportion of 
treated subjects who achieve a partial response (PR) or better, i.e. stringent complete response (sCR), complete 
response (CR), very good partial response (VGPR) and PR, according to the IMWG criteria
Analyses:  
Primary Endpoint:
The response rate and its corresponding exact one-sided 85% confidence interval will be calculated in the ELd arm. 
In addition, the two-sided 95% confidence interval will be computed for the ELd arm.
Secondary Endpoints:
The difference in ORR between two treatment arms along with two-sided 95% CI will be estimated using the 
method of DerSimonian and Laird adjusted by stage of disease (ISS stage 1 - 2 versus 3). In addition, the response 
rate and its corresponding exact two-sided 95% confidence interval will be calculated in the Ld arm.
The PFS analyses will be conducted using both the primary and the ITT definitions of PFS. 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 treatment arm. PFS rates at 1, 2, and 3 
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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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Unmet Medical Needs in Multiple Myeloma ........................................... 
1.1.2 Non-clinical Rationale for Elotuzumab in Combination with 
Lenalidomide and Dexamethasone ............................................................. 
1.1.2.1 Elotuzumab ..................................................................................... 
1.1.2.2 Combination of Elotuzumab with Lenalidomide/dexamethasone ... 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
1.3.3 Exploratory Objectives ............................................................................ 
1.4 Product Development Background ................................................................... 
1.4.1 Non-clinical Toxicology ........................................................................... 
1.4.2 Clinical Experience with Elotuzumab in Multiple Myeloma ................... 
1.4.2.1 Non-Japanese Clinical Study Results ............................................. 
1.4.2.2 Japanese Clinical Trial Results ...................................................... 
1.4.2.3 Infusion Reactions ........................................................................... 
1.4.2.4 Clinical Pharmacokinetics .............................................................. 
1.4.3 Rationale of Selection of Dosage and Administration in this Study ........ 
1.4.3.1 Elotuzumab Dosing ......................................................................... 
1.4.3.2 Elotuzumab Infusion Rate ............................................................... 
1.4.4 Rationale for Study Design ...................................................................... 
1.4.4.1 Rationale for Treating with Ld Until Progression .......................... 
1.4.4.2 Population of Untreated Subjects Ineligible for SCT ..................... 
1.4.5 Rationale for Inclusion of Subjects with Mild to Moderate Renal 
Impairment .................................................................................................. 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board ............................................................................... 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.2 Post Study Access to Study............................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
1
3
4
8
12
12
12
12
12
13
14
14
14
14
14
14
14
15
15
19
20
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3.4.1 Required ................................................................................................... 
3.4.2 Permitted at Investigator’s Discretion ..................................................... 
3.4.3 Prohibited and/or Restricted Treatments................................................. 
3.4.4 Surgery and Radiation ............................................................................. 
3.5 Discontinuation of Subjects followings any Treatment with Study Drug ........ 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.3.1 Elotuzumab .............................................................................................. 
4.3.2 Lenalidomide............................................................................................ 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Study Drug Administration ...................................................................... 
4.5.1.1 Premedication Regimen in Subjects Without a Prior Infusion 
Reaction ................................................................................................ 
4.5.1.2 Premedication Regimen in Subjects With a Prior Infusion Reaction
............................................................................................................... 
4.5.2 Guidelines for Elotuzumab Infusion in Subjects with Infusion Reactions
..................................................................................................................... 
4.5.2.1 Grade 1 Infusion Reaction .............................................................. 
4.5.2.2 Grade  2 Infusion Reaction ........................................................... 
4.5.3 Dose Delay or Interruption ...................................................................... 
4.5.3.1 Elotuzumab ..................................................................................... 
4.5.3.2 Dexamethasone ............................................................................... 
4.5.3.3 Lenalidomide................................................................................... 
4.5.4 Recommended Dose Reductions .............................................................. 
4.5.4.1 Elotuzumab ..................................................................................... 
4.5.4.2 Dexamethasone ............................................................................... 
4.5.4.3 Lenalidomide................................................................................... 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.2 Retesting During Screening or Lead-in Period ................................................. 
5.3 Study Materials ................................................................................................. 
5.4 Safety Assessments ........................................................................................... 
5.4.1 Vital Signs, Physical Measurements, and Physical Examination ............ 
5.4.2 Performance Status .................................................................................. 
5.4.3 Echocardiogram or MUGA scan and Electrocardiogram ...................... 
5.4.4 Laboratory Assessments for Safety .......................................................... 
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5.5 Efficacy Assessments ........................................................................................ 
5.5.1 Primary and Secondary Efficacy Assessment .......................................... 
5.5.2 Laboratory Assessments for Myeloma ..................................................... 
5.5.3 Imaging Assessments for Myeloma .......................................................... 
5.5.3.1 Skeletal Survey ................................................................................ 
5.5.3.2 Assessment of Extramedullary Plasmacytoma................................ 
5.5.4 Definitions of Response Based on IMWG ................................................ 
5.6 Pharmacokinetic Assessments .......................................................................... 
5.7 Biomarker Assessments .................................................................................... 
 
 .......................................................................... 
5.8 Outcomes Research Assessments ..................................................................... 
5.9 Other Assessments ............................................................................................ 
5.10 Results of Central 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 Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
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 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
8.3.2.1 Objective Response Rate ................................................................. 
8.3.2.2 Progression-Free Survival .............................................................. 
8.3.3 Exploratory Endpoint(s) .......................................................................... 
8.3.3.1 Safety ............................................................................................... 
8.3.3.2 Time to Response and Duration of Response ................................. 
8.3.3.3 Immunogenicity Endpoints .............................................................. 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Primary Efficacy Analysis............................................................... 
8.4.2.2 Secondary Efficacy Analysis ........................................................... 
8.4.2.3 Exploratory Efficacy Analysis ......................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
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8.4.5 Biomarker Analyses ................................................................................. 
 ............................................................................. 
 ................................................................ 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 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 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 INTERNATIONAL STAGING SYSTEM ........................................... 
APPENDIX 2 PERFORMANCE STATUS SCALES ................................................. 
 
APPENDIX 3 PREPARATION AND ADMINISTRATION OF ELOTUZUMAB ... 
 
 
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1.2
Research Hypothesis 
Elotuzumab + lenalidomide/dexamethasone will demonstrate Objective Response Rate (ORR) of 
> 71% when given to subjects with newly diagnosed, previously untreated MM.
1.3
Objectives(s)
1.3.1
Primary Objectives
To estimate the ORR of elotuzumab + lenalidomide/dexamethasone in subjects with newly 
diagnosed, previously untreated MM.
1.3.2
Secondary Objectives

To estimate the difference in ORR between elotuzumab + lenalidomide/dexamethasone
(ELd) and lenalidomide/dexamethasone (Ld);

To assess Progression Free Survival (PFS) in each arm.
 
 
 
 
 
 
 
 
 
 
 
 
 
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with the standards specified by Article 14 Paragraph 
3 and Article 80-2 of the Pharmaceutical Affairs Law (PAL) in Japan, and Good Clinical 
Practice (J-GCP), as defined by the International Conference on Harmonisation (ICH) and the 
Ministerial Ordinance Concerning the Standards for the Implementation of Clinical Studies on 
Pharmaceutical Products and concerning notifications in Japan, and in accordance with the 
ethical principles underlying European Union Directive 2001/20/EC, the United States Code of 
Federal Regulations, Title 21, Part 50 (21CFR50) and J-GCP. article 1.
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 (IRB) approval 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.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
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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 
Before study initiation, BMS and the investigator must have written and dated approval from the 
IRB for the protocol, consent form, subject recruitment materials (eg, advertisements), and any 
other written information to be provided to subjects, which are submitted to by BMS via the head 
of the study sites. BMS should also provide the IRB via the head of the study site with a copy of 
the Investigator Brochure or product labeling information to be provided to subjects and any 
updates. 
The investigator or BMS should provide the IRB via the head of the study site 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 are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate 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. 
4) Obtain the IRB’s written approval of the written informed consent form and any other 
information to be provided to the subjects, via the head of the study site, prior to the 
beginning of the study, and after any revisions are completed for new information.
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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 his 
or her informed consent during the study, 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 head of the 
study site, 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 confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, and the subjects' signed 
ICF.
The consent form must also include a statement that BMS, the IRB, and regulatory authorities 
have direct access to subject records. 
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The subject 
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this subject become capable, he or she should personally sign and date 
the consent form as soon as possible. The explicit wish of a subject who is unable to give his or 
her written consent, but who is capable of forming an opinion and assessing information to 
refuse participation in, or to be withdrawn from, the clinical study at any time should be 
considered by the investigator.
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 
2, 
randomized,
open-label, 
multi-center 
trial 
investigating 
lenalidomide/dexamethasone with and without elotuzumab in subjects with newly diagnosed, 
previously untreated multiple 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 
elotuzumab/lenalidomide/dexamethasone 
(ELd)
[Investigational 
Arm]
or 
lenalidomide/dexamethasone (Ld) [Control Arm]. The randomization will be stratified by 
International Staging System (ISS) stage (1 - 2 versus 3). Approximately eighty subjects in total 
will be randomized to either arm.
The study design schematic is presented in Figure 3.1-1.
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Figure 3.1-1:
Study Design Schematic
A cycle is defined as 28 days. Treatment with study drug continues until disease progression
(PD), unacceptable toxicity or subject meets other criteria for discontinuation of study drug
outlined in Section 3.5.
Disease assessments, based on the IMWG response criteria, will be conducted every 4 weeks 
relative to the first dose of study medication until disease progression. Response and progression 
assessment will be investigator-based and no central lab or independent review is planned.
For the subject who does not have documented disease progression at time of study drug 
discontinuation, tumor assessments should still be performed according to the same schedule 
until disease progression even if a subsequent anti-myeloma treatment is initiated prior to disease 
progression.
3.2
Post Study Access to Study
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study drug up to 12 months after the approval of investigational 
product by the responsible health authority or until the investigational product becomes 
commercially available within the country, whichever occurs sooner. Study drug will be 
provided via an extension of the study, a rollover study requiring approval by responsible health 
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authorities and ethics committee, or through another mechanism at the discretion of BMS. BMS 
reserves the right to terminate access to study drug if any of the following occur: 
a) the marketing application is rejected by the 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.
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) Eastern Cooperative Oncology Group (ECOG) performance status 2.
b) Life-expectancy > 3 months.
c) 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 CA204116 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) Urine M-protein 200 mg/24-hour OR
(e) Serum free light chain (sFLC) assay showing involved FLC level 10 mg/dL
(100 mg/l) provided the serum FLC ratio is abnormal
d) Subject Re-enrollment: This study does not permit the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure.
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3. Age and Reproductive Status
a) Males and Females, ages 20 years, inclusive
b) Subjects must be willing to refrain from blood donations during study drug therapy and 
for 90 days after therapy.
c) 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 study treatment and women for up to 120 days, men for up to 
180 days after the last dose of study drug 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.
d) Women of childbearing potential (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 study drug. 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.
e) Women must not be breastfeeding.
f)
WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of 
treatment 
with 
study 
drug 
(s), 
elotuzumab 
in 
combination 
with 
lenalidomide/dexamethasone, plus the time to washout (90 days) plus 30 days (duration 
of ovulatory cycle) for a total of 120 days post-treatment completion.
g) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug (s), elotuzumab 
in combination with lenalidomide/dexamethasone, plus the time to washout (90 days)
plus 90 days (duration of sperm turnover) for a total of 180 days post-treatment 
completion.
h) Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However they must still undergo pregnancy 
testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% when used consistently and correctly.
At a minimum, subjects must agree to the use of two methods of contraception, with one method 
being highly effective and the other method being either highly effective or less effective as 
listed below:
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HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

Progestogen only hormonal contraception associated with inhibition of ovulation.

Hormonal methods of contraception including oral contraceptive pills containing combined 
estrogen + progesterone, vaginal ring, injectables, implants and intrauterine devices (IUDs) 
such as Mirena

Nonhormonal IUDs, such as ParaGard

Bilateral tubal occlusion

Vasectomised partner with documented azoospermia 90 days after procedure
Vasectomised partner is a highly effective birth control method provided that partner 
is the sole sexual partner of the WOCBP trial participant and that the vasectomised 
partner has received medical assessment of the surgical success.

Intrauterine hormone-releasing system (IUS)

Complete Abstinence
Complete abstinence is defined as the complete avoidance of heterosexual intercourse 
(refer to Glossary of Terms)
Complete abstinence is an acceptable form of contraception for all study drugs and 
must be used throughout the duration of the study treatment (plus the washout time of 
the investigational drug plus 30 days).
It is not necessary to use any other method of contraception when complete 
abstinence is elected.
Subjects who choose complete abstinence must continue to have pregnancy tests, as 
specified in Section 6.4.
Acceptable alternate methods of highly effective contraception must be discussed in 
the event that the subject chooses to forego complete abstinence.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the subject.
LESS EFFECTIVE METHODS OF CONTRACEPTION

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal sponge with spermicide

Male or female condom with or without spermicide*

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action
* A male and female condom must not be used together
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UNACCEPTABLE METHODS OF CONTRACEPTION

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus interruptus)

Spermicide only

Lactation amenorrhea method (LAM)
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Subjects with non-secretory 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;
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.
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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) 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
4. Prior Therapy or Surgery
a) Administration of systemic chemotherapy, biologics, 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;
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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. 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 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
A Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 24 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In 
addition, females under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40mIU/mL to confirm menopause.
*Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. If the serum FSH level is > 40 mIU/mL at any time 
during the washout period, the woman can be considered postmenopausal :

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
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3.4
Concomitant Treatments
3.4.1
Required
Subjects must receive thrombo-embolic prophylaxis, per institutional guidelines or PI discretion. 
Examples of commonly used thrombo-embolic prophylaxis medications include aspirin, low 
molecular weight heparin, and vitamin K antagonists.
Subjects must receive pre-medications (Sections 4.5.1.1 and 4.5.1.2) prior to each dose of 
elotuzumab.
3.4.2
Permitted at Investigator’s Discretion

IV corticosteroids, diphenhydramine, or hydroxyzine, acetaminophen/paracetamol, H2 
inhibitors (ie, cimetidine), leukotriene inhibitors (montelukast sodium) for the management 
of infusion reactions. Additional supportive measures should be provided as indicated 
including:

oxygen inhalation

epinephrine

bronchodilators

oral antiviral and antimicrobial prophylaxis

anti-emetics

and bisphosphonates.
Per the ASCO 2007 Clinical Practice Guidelines, 39 bisphosphonate therapy should be 
administered for a period of 2 years. At 2 years, the investigator should seriously consider 
discontinuing bisphosphonates in subjects with at least stable disease, although further use is at 
the discretion of the investigator.
Routine clinical practice for monitoring and prevention of osteonecrosis of the jaw 
(ie, comprehensive dental exam, treating active oral infections, eliminating sites of high risks for 
oral infection, excellent oral hygiene and avoiding invasive dental procedures while on 
treatment) must be followed.

Erythropoietin (EPO) or darbepoetin (prior and ongoing use according to the package insert 
and institutional guidelines)

Red blood cell or platelet transfusion

Prophylactic administration of G-CSF in a subject who is experiencing recurrent difficulties 
with neutropenia, or therapeutic use in subjects with serious neutropenic complications (such 
as tissue infection, sepsis syndrome or fungal infection) may be considered at the 
investigator's discretion, consistent with American Society of Clinical Oncology guidelines 
(American Society of Clinical Oncology 2006).
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3.4.3
Prohibited and/or Restricted Treatments
Any systemic, anti-myeloma therapy other than lenalidomide, dexamethasone and elotuzumab 
are prohibited while on study. Concomitant steroids, other than weekly dexamethasone 
(Section 4.5.1) or steroids allowed (as defined in eligibility criteria) are prohibited unless used to 
treat an adverse event. Guidelines for selection and use of other concomitant medications should 
be derived from the lenalidomide and dexamethasone prescribing information. Other than study 
medications, administration of any therapeutic or diagnostic investigational agent (for any 
indication) is prohibited while on study without prior Sponsor approval.
3.4.4
Surgery and Radiation
Use of radiotherapy or surgical intervention must be recorded on the Case Report Form.
Localized radiation therapy to a site of pre-existing disease may be permitted while on study. 
Following approval by the medical monitor, the patient may initiate or continue with protocol 
therapy without interruption during the course of palliative radiation therapy if the investigator 
believes that the risk of excessive bone marrow suppression or other toxicity is acceptable, and it 
is in the best interest of the patient to do so.
If the subject develops a definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas that meets the criteria for disease progression, treatment must be discontinued for 
progressive disease regardless of whether radiation therapy is initiated.
Kyphoplasty, vertebroplasty or emergency orthopedic surgery is permitted.
3.5
Discontinuation of Subjects followings any Treatment with Study Drug
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

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 5.5.4 for definition of disease progression).

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 4.5.2.2.
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
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.
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
All subjects who discontinue study drug 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 including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Study Follow up
Subjects who discontinue study drug may continue to be followed as out lined in Section 5.
Subjects should be encouraged to continue participation in the trial until the protocol definition
of disease progression is met (Section 5.5.4). 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. 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.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for 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, as 
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to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. 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.
3.6.2
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 
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 
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.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Products (Non-IP/Non-IMP) and can consist of the following:

All products, active or placebo, being tested or used as a comparator in a clinical trial. 

Study required premedication, and 

Other drugs administered as part of the study that are critical to claims of efficacy 
(eg, background therapy, rescue medications)

Diagnostic agents: (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection.
All protocol-specified investigational product and non- investigational products are considered 
study drug. See Table 4-1
for product description of elotuzumab, lenalidomide and 
dexamethasone.
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Table 4-1:
Study Drugs for CA204116 Treatment Period
Product Description /
Class and Dosage Form
Potency
IP/Non-IMP
Blinded or 
Open Label
Packaging/
Appearance
Storage Conditions
(per label)
Elotuzumab Powder for 
Solution for Infusion
400 mg/vial
IP
Open Label
20 mL Vial/
Sterile, white to off-white, 
preservative-free, lyophilized cake
Store at 2- 8 C
Lenalidomide 
(Revlimid)capsule
5 mg, 10 mg,
15 mg and 25 mg
IP
Open Label
21 capsules per bottle
Store at 15- 25C.
Dexamethasone
Tablets
2 mg and 4 mg & 
various strengths
Non-IMP
NA
Various
Refer to label on 
container or package 
insert/summary of 
product characteristics
Dexamethasone Solution
4 mg/mL, 8 mg/mL
& various strengths
Non-IMP
NA
Various
Refer to label on 
container or package 
insert/summary of 
product characteristics
Elotuzumab and lenalidomide will be supplied by the BMS. Dexamethasone tablets and solution for IV infusion will be obtained by the investigating site’s 
standard prescribing procedures.
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined 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) differently than 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.
4.2
Non-investigational 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 non-investigational products. 
In this protocol, non-investigational product(s) are: dexamethasone tablets and concentrate for 
solution for IV infusion, diphenhydramine (or equivalent H1 blocker), ranitidine (or equivalent 
H2 blocker), acetaminophen, thrombo-embolic prophylaxis medications include aspirin, low 
molecular weight heparin, and vitamin K antagonists.
4.3
Storage 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 BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
4.3.1
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, and then further diluted 
in 0.9% sodium chloride normal saline, as per the instructions in Appendix 3. 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 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 
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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 3.
4.3.2
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 116 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. This program is called the 
Revlimid Risk Management Plan and provided from the sponsor separately for this study. 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.
4.4
Method of Assigning Subject Identification
When the investigator obtained informed consent from a subject, the site staff will fax the 
enrollment form to the enrollment center or enter subject information into an enrollment form on 
a website which was generated by the enrollment center, and receive Patient Identification 
number (PID) via a fax or web site. Once the investigator confirm that the subject met the
eligibility criteria determined in the protocol, the site staff will send the registration form with 
the result of subject eligibility to the enrollment center via a fax or web site, and then receive the 
confirmation sheet from the enrollment center. Eligible subjects will be randomized in a 1:1 ratio 
to receive either ELd Arm [Investigational Arm] or Ld Arm [Control Arm]. The randomization 
will be stratified by ISS stage (1 - 2 versus 3).
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4.5
Selection and Timing of Dose for Each Subject
4.5.1
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 (300 - 1000 mg po).
See Appendix 3 for elotuzumab dosing instructions.
Lenalidomide
Lenalidomide will be taken orally 25 mg once daily for the first 3 weeks of a 4-week cycle. On 
the days of elotuzumab administration, the dose of lenalidomide is to be administered at least 
2 hours after completion of elotuzumab dosing. Subjects should not break, chew or open the 
capsules.
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Table 4.5.1-1:
Treatment Schedule
Investigational Arm (ELd Arm)
Cycle #
1 - 2
3 - 18
19 +
Day # (-1/+3 days)a
1
8
15
22
1
8
15
22
1
8
15
22
Dexamethasone - PO
28 mg
28 mg
28 mg
28 mg
28 mg
40 mg
28 mg
40 mg
28mg
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
-
-
-
Lenalidomide - PO
25 mg Days 1 - 21
25 mg Days 1 - 21
25 mg Days 1 - 21
Control Arm (Ld Arm)
Cycle #
1 - 2
3 - 18
19 +
Day # (-1/+3 days)
1
8
15
22
1
8
15
22
1
8
15
22
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
Lenalidomide - PO
25 mg Days 1 - 21
25 mg Days 1 - 21
25 mg Days 1 - 21
a For elotuzumab and dexamethasone dosing, a window -1 to +3 days is permitted. In Cycles 3 and beyond, elotuzumab dosing may be delayed for up to 1 week 
as clinically indicated.
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4.5.1.1
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 4.5.1) which will also serve as premedication for 
elotuzumab.
Intravenous and po dexamethasone doses are calculated to prevent an imbalance in 
dexamethasone exposure between the investigational and control arms (Refer to Section 
4.5.1.2 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 (300 - 1000 mg po).
4.5.1.2
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 4.5.1.2-1. 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 4.5.1 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 4.5.1.2-1:
Corticosteroid Premedicationa
Prior Infusion Reaction
Corticosteroid Premedicationbb 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 
4.5.1.2.
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 hours prior to elotuzumab) AND 16 mg dexamethasone po (at least 3 hours 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.
4.5.2
Guidelines for Elotuzumab Infusion in Subjects with Infusion Reactions
4.5.2.1
Grade 1 Infusion Reaction
Grade 1 elotuzumab infusion-related reactions by definition, require,no intervention; however, 
increased monitoring is recommended.
4.5.2.2
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 elotuzumab 
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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 5.0 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 4.5.1.2-1.
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 5.0 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 5.0 mL/minute. If tolerated, all subsequent infusions may start at a rate per 
investigator’s discretion, up to a maximum rate of 5.0 mL/minute.
4.5.3
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.
4.5.3.1
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.
4.5.3.2
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 4.5.1.
4.5.3.3
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.
4.5.4
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.
4.5.4.1
Elotuzumab
No dose reduction is allowed for elotuzumab.
4.5.4.2
Dexamethasone
Dexamethasone dose reductions for toxicity must be performed as clinically indicated. 
Recommended management is described in Table 4.5.4.2-1 and Table 4.5.4.2-2. Deviations to 
the recommended dose reductions are allowed based on the clinical judgment of the investigator.
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Table 4.5.4.2-1:
Dexamethasone Dose Reductions
CTC AE 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 4.5.4.2-1
and Table 4.5.4.2-2.
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 4.5.1. 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.
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On weeks without elotuzumab, no IV dexamethasone should be administered.
Table 4.5.4.2-2:
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
4.5.4.3
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 4.5.4.3-1 and Table 4.5.4.3-2
is based on current standard of clinical practice.
Table 4.5.4.3-1:
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.
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Table 4.5.4.3-2:
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
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 4.5.4.3-3:
Lenalidomide Dose Adjustments in Subjects with Renal 
Impairment
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
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.
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4.6
Blinding/Unblinding
Not applicable.
4.7
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.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of study drug.
It is the study drug storage manager’s responsibility to arrange for disposal of all empty 
containers, provided that procedures for proper disposal have been established according to 
applicable local, and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible Study Monitor. 
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elotuzumab
It is the study drug storage manager’s responsibility to arrange for disposal of all empty 
containers, provided that procedures for proper disposal have been established according to 
applicable local, and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept.
Arrangements for the return of study drug will be made by the responsible Study Monitor.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (CA204116)
Procedure
Screening Visit
(-28 to -1 days of randomization)
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
Include height and weight (Section 5.4.1) within 14 days of randomization
Vital Signs
X
Temperature, BP, HR, RR (Section 5.4.1) 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 21 days of randomization
2-D Echocardiogram or MUGA
X
Within 28 days of randomization (Section 5.4.3)
ECG
X
Within 28 days of randomization (Section 5.4.3)
Laboratory Assessment for Safety
CBC, differential, platelets
X
Within 14 days of randomization (Section 5.4.4)
Serum Chemistry
X
Within 14 days of randomization (Section 5.4.4)
Serum 2-microgloblin
X
Within 14 days of randomization (assessment of ISS stage)
Serum Albumin
X
Within 14 days of randomization (assessment of ISS stage)
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Table 5.1-1:
Screening Procedural Outline (CA204116)
Procedure
Screening Visit
(-28 to -1 days of randomization)
Notes
Urinalysis
X
Within 14 days of randomization (Section 5.4.4)
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
Within 28 days of randomization. Central lab analysis. (Section 5.5.2)
Bone Marrow Aspiration/Biopsy
X
Within 28 days of randomization. Bone marrow aspirate is mandatory.
Bone marrow biopsy is optional. (Section 5.5.2)
Cytogenetic analysis and FISH
X
Within 28 days of randomization. Local Central lab analysis. (Section 5.5.2
and 5.7.2)
Skeletal Survey
X
Within 28 days of randomization
CT/MRI assessment for extramedullary 
soft tissue plasmacytoma
X
Within 28 days of randomization, if clinically indicated.
Study Drug
Randomize
X
First dose of study drug must occur within 3 days of randomization
Dispense Study Drug
X
Those supplied by BMS or sourced by the investigator
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elotuzumab
Table 5.1-2:
Short-term Procedural Outline (CA204116) Cycles 1 & 2
Procedure
Day 1
Day 8
Day 15
Day 22
Rest Days
23 - 28a
Notes
Safety Assessments
Targeted Physical Examination
X
Perform up to 3 days prior to dosing, include weight
(Section 5.4.1)
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
Section 6.7
Concomitant Medications
X
X
X
X
Evaluate prior to dosing
Laboratory Test for Safety
CBC, differential, platelets
X
X
X
X
Can be drawn up to 3 days prior to study visit.
(Section 5.4.4)
Serum Chemistry
X
Can be drawn up to 3 days prior to study visit. 
(Section 5.4.4)
Serum calcium and albumin every 4 weeks from 
date of first dose of study drug until disease 
progression, even if subject is on subsequent 
therapy
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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elotuzumab
Table 5.1-2:
Short-term Procedural Outline (CA204116) Cycles 1 & 2
Procedure
Day 1
Day 8
Day 15
Day 22
Rest Days
23 - 28a
Notes
Efficacy Assessments
Myeloma Urine and Serum Lab Tests
Every 4 weeks from date of first dose of study drug until 
progression, regardless of whether patient is on study 
therapy or subsequent therapy.
Day 1 of each cycle (except Cycle 1 - refer to 
Screening visit for defined window) until disease 
progression.
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.
Subjects without measurable urine M protein at 
baseline and at next two subsequent cycles 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. In order 
to full fill CR/sCR criteria, both serum and urine 
immunofixation must be performed and be negative 
on two consecutive assessment. Therefore, at the 
time SPEP becomes undetectable, UPEP sample 
collection must promptly resume for these subjects, 
and also continue q4 weeks until SPEP becomes 
detectable.
Central lab analysis. (Section 5.5.2)
Bone Marrow Aspiration/Biopsy
For confirmation of CR/sCR if applicable or, if clinically
indicated at time of suspected disease progression
Bone marrow aspirate is mandatory. Bone marrow 
biopsy is optional. Bone marrow samples must be 
assessed for clonal cells at the local lab by 
immunohistochemistry of the biopsy or 
immunoflourescence (flow cytometry) of the 
aspirate. Plasma cell percentage and light chain 
restriction assessments are required. (Section 5.5.2)
Skeletal Survey
If clinically indicated
Section 5.5.3.1
CT/MRI assessment for extramedullary 
soft tissue plasmacytoma
As clinically indicated and at the time of CR/sCR 
assessments
Section 5.5.3.2
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elotuzumab
Table 5.1-2:
Short-term Procedural Outline (CA204116) Cycles 1 & 2
Procedure
Day 1
Day 8
Day 15
Day 22
Rest Days
23 - 28a
Notes
Response per IMWG based criteria
Every 4 weeks from date of first dose of study drug until 
progression, regardless of whether patient is on study 
therapy or subsequent therapy.
Investigator assessment
All response categories require two consecutive 
assessments. (Section 5.5.4)
Serum PK (Investigational arm only)

Refer to Section 5.6 for specific time points
Anti-Drug Antibody (ADA)
(Investigational arm only)

Refer to Section 5.6 for specific time points

Refer to Section 5.7.1 for specific time points
Study Drug
Premedication for Elotuzumab
(Investigational arm only)
X
X
X
X
Elotuzumab Infusion (Investigational 
arm only)
X
X
X
X
In Cycles 1 and 2, an elotuzumab dose that falls 
outside of the pre-specified window (-1 to +3 days) 
must be skipped.
Lenalidomide Administration
Day 1 - 21 of each cycle
Dexamethasone Administration
X
X
X
X
Dispense Lenalidomide
X
Dispense lenalidomide on Day 1 of cycle per the 
Revlimid Risk Management Plan
a For the patients who discontinue in Cycle 1 or 2, the procedure of "End of Treatment" and "Post End of Treatment" in Table 5.1-3 must be applied.
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Table 5.1-3:
Long-term Procedural Outline (CA204116) Cycles 3 and Beyond
Procedure
Day 
1
Day 
8
Day 
15
Day 
22
Rest 
Day
23 - 28
End of 
Treatment
Days 30 & 
60 Post End 
of
Treatmenta
Notes
Safety Assessments
Targeted Physical Examination
X
X
Perform up to 3 days prior to dosing, include 
weight (Section 5.4.1)
Vital Signs
X
X*
X
Measure vital signs prior to administration of 
premedication, 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 Events Assessment
X
X*
X
X
Evaluate prior to dosing
*Not required in Cycles 19 and beyond
All SAEs must be collected that occur within 
60 days of discontinuation of dosing
Adverse Events Assessment
X
X*
X
X
Evaluate prior to dosing
*Not required in Cycles 19 and beyond
Second Primary Malignancy
X
X
X
Section 6.7
Performed at 30 and 60 day 1 week EOT 
follow up visits.
Concomitant Medications
X
X*
X
X
Evaluate prior to dosing
*Not required in Cycles 19 and beyond
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Table 5.1-3:
Long-term Procedural Outline (CA204116) Cycles 3 and Beyond
Procedure
Day 
1
Day 
8
Day 
15
Day 
22
Rest 
Day
23 - 28
End of 
Treatment
Days 30 & 
60 Post End 
of
Treatmenta
Notes
Laboratory Test for Safety
CBC, differential, platelets
X
X
Can be drawn up to 3 days prior to study visit. 
(Section 5.4.4)
Serum Chemistry
X
X
Can be drawn up to 3 days prior to study visit. 
(Section 5.4.4)
Serum calcium and albumin every 4 weeks 
from date of first dose of study drug until 
disease progression, even if subject is on 
subsequent therapy.
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.
WOCBP must perform a pregnancy test 
90 days off treatment. This test may be 
performed locally if the patient is unable to 
return to your center.
*Not required in Cycles 19 and beyond. 
However, patients with irregular menstrual 
cycles must have a pregnancy test every two 
weeks.
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elotuzumab
Table 5.1-3:
Long-term Procedural Outline (CA204116) Cycles 3 and Beyond
Procedure
Day 
1
Day 
8
Day 
15
Day 
22
Rest 
Day
23 - 28
End of 
Treatment
Days 30 & 
60 Post End 
of
Treatmenta
Notes
Efficacy Assessments
Myeloma Urine and Serum Lab 
Tests
Every 4 weeks from date of the first dose of study drug until 
progression, regardless of whether patient is on study therapy or 
subsequent therapy.
Day 1 of each cycle until disease 
progression.
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.
Subjects without measurable urine M protein 
at baseline and at next two subsequent cycles 
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. In order to full fill CR/sCR 
criteria, both serum and urine immunofixation 
must be performed and be negative on two 
consecutive assessment. Therefore, at the time 
SPEP becomes undetectable, UPEP sample 
collection must promptly resume for these 
subjects, and also continue q4 weeks until 
SPEP becomes detectable.
Central lab analysis. (Section 5.5.2)
Bone Marrow Aspiration/Biopsy
For confirmation of CR/sCR if applicable or, if clinically indicated at 
time of suspected disease progression
Bone marrow aspirate is mandatory. Bone 
marrow biopsy is optional. Bone marrow 
samples must be assessed for clonal cells at 
the local lab by immunohistochemistry of the 
biopsy or immunoflourescence (flow 
cytometry) of the aspirate. Plasma cell 
percentage and light chain restriction 
assessments are required. (Section 5.5.2)
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Table 5.1-3:
Long-term Procedural Outline (CA204116) Cycles 3 and Beyond
Procedure
Day 
1
Day 
8
Day 
15
Day 
22
Rest 
Day
23 - 28
End of 
Treatment
Days 30 & 
60 Post End 
of
Treatmenta
Notes
Skeletal Survey
If clinically indicated
Section 5.5.3.1
CT/MRI assessment for 
extramedullary soft tissue 
plasmacytoma
As clinically indicated and at the time of CR/sCR assessments
Section 5.5.3.2
Response per IMWG based criteria
Every 4 weeks from date of first dose of study drug until 
progression, regardless of whether patient is on study therapy or 
subsequent therapy.
Investigator assessment
All response categories require two 
consecutive assessments. (Section 5.5.4)
Serum PK (Investigational arm 
only)

Refer to Section 5.6 for specific time points
Anti-Drug Antibody (ADA)
(Investigational arm only)

Refer to Section 5.6 for specific time points
X
Cycle 3 Day 1 only
Refer to Section 5.7.1 for specific time points
Study Drug
Premedication for Elotuzumab
(Investigational arm only)
X
X*
*Not required in Cycles 19 and beyond
Elotuzumab Infusion
(Investigational arm only)
X
X*
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.
*Not required in Cycles 19 and beyond. 
Elotuzumab dose will be 20 mg/kg at 
Cycle 19 and beyond as the subject will 
receive elotuzumab at only Day 1 of each 
cycle.
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Table 5.1-3:
Long-term Procedural Outline (CA204116) Cycles 3 and Beyond
Procedure
Day 
1
Day 
8
Day 
15
Day 
22
Rest 
Day
23 - 28
End of 
Treatment
Days 30 & 
60 Post End 
of
Treatmenta
Notes
Lenalidomide Administration
Day 1 - 21 of each cycle
Dexamethasone Administration
X
X
X
X
Dispense Lenalidomide
X
Dispense lenalidomide on Day 1 of cycle per 
the Revlimid Risk Management Plan
a For subjects who discontinue study therapy before progression (eg, due to toxicity), the necessary laboratory results must be collected and the 
efficacy assessments must be performed until progression is confirmed even if it is beyond 60 days post end of treatment.
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5.2
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments during the Screening or Lead-in 
period will not be permitted (this does not include parameters that require a confirmatory result).
Any new result will override the previous result (i.e., the most current result prior to 
Registration) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
5.3
Study Materials
The following will be distributed to sites for use in this study:

Registration Forms

NCI CTCAE booklets version 3.0

Elotuzumab Investigator Brochure

Lenalidomide (Revlimid) Package Insert

Drug Preparation Guidelines

Subject Dosing Diary

Laboratory Manuals

CRFs (electronic)

Pregnancy Surveillance Forms

Revlimid Risk Management Plan.
5.4
Safety Assessments
All subjects who receive study drug will be evaluated for safety parameters. Additionally, any 
occurrence of an SAE from the time of consent forward will be documented.
Safety assessment will be performed prior to study drug dosing at dosing visits, unless otherwise 
specified.
Safety will be evaluated for all treated subjects using the NCI CTCAE version 3.0. Safety 
assessments will be based on medical review of AE reports and the results of vital sign 
measurements, physical examinations, and clinical laboratory tests.
Additional procedures and assessments may be performed as part of standard of care however 
data for these assessments should remain in the subject’s medical record and should not be 
provided to BMS, unless specifically requested by the sponsor. If additional safety assessments 
are performed for adverse events, then results should be submitted on the CRF.
5.4.1
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 measurement. Subjects in the control arm will have vital signs measured once 
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at each visit. Subjects randomized to the investigational 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.
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.
5.4.2
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.
5.4.3
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.
5.4.4
Laboratory Assessments for Safety
All safety laboratory assessments indicated in Table 5.4.4-1 should be done at a local laboratory.
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Table 5.4.4-1:
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
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 (if total billirubin is 
abnormal)
X
X
Lactate Dehydrogenase
X
X
BUN (or Urea)
X
X
Creatinine and Creatinine 
Clearanceb
X
X
Glucose
X
X
Calcium
X
X
Total Protein
X
X
Coagulation Test
PT
X
Xc
PTT
X
INR
X
Xc
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
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Table 5.4.4-1:
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
Urinalysis
Protein
X
Glucose
X
Urobilinogen
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 measured by 24-hour urine collection or estimated by the Cockcroft and Gault formula in sites.
c 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
5.5
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 locally at screening. If SPEP and UPEP M 
protein are performed at a local laboratory, results must be recorded in the CRF/eCRF.
5.5.1
Primary and Secondary Efficacy Assessment
Response assessments according to the international diagnostic criteria of the International 
Myeloma Working Group (IMWG criteria)21 will be used for the primary analysis. For the 
purposes of this study, all subjects’ tumor assessments by SPEP M protein and UPEP M protein 
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 IMWG criteria, 
irrespective of dose delays or treatment cycle. If subject does not have documented disease 
progression at time of study drug discontinuation, then tumor assessments should still 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.
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 Immunohistochemistry 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 
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the study site), M protein quantification must be performed. Any laboratory samples analyzed 
locally, including for efficacy, must be entered on the appropriate CRF.
5.5.2
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.
Twenty-four-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. Subjects who have urine M protein of < 200 mg/24 hours at baseline and at next 
2 subsequent assessments do not have to submit q4 week urine samples with each cycle (but 
must submit q12 week urine samples) until SPEP M protein values becomes undetectable. In 
order to full fill CR/sCR criteria, both serum and urine immunofixation must be performed and 
be negative on two consecutive assessment. Therefore, at the time SPEP becomes undetectable, 
24-hr UPEP collection should promptly resume and continue q4 weeks until SPEP becomes 
detectable. Any local serum and urine myeloma lab tests that may also have been performed 
must also be reported in the CRF.
1) Serum: serum protein electrophoresis (SPEP) for M protein quantification, total serum 
protein, immunofixation, and quantitative immunoglobulin assay.
a) Immunofixation: Immunofixation of serum is required at baseline and to confirm CR 
regardless of whether measurable M-protein was present at baseline.
b) Serum free light chain: Serum should be collected at screening and time of CR for 
serum free light chain analysis. This measurement is required to document sCR.
c) Other: All other serum tests will be followed at each tumor assessment.
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 subsequent time points.
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.
3) Bone marrow aspiration/biopsy: Assessment of bone marrow for percentage plasma cells 
is required within 28 days of randomization and while on study to confirm CR (ie, subjects 
who become immunofixation negative) or, if clinically indicated, at time of suspected disease 
progression (a second confirmation bone marrow analysis for CR is not needed). The 
percentage CD138+ cells and clonality (based on kappa/lambda ratio) will also be assessed to 
confirm stringent CR (sCR). Flow cytometry will be performed only to confirm CR. In 
addition, biomarker tests must also be performed on the fresh bone marrow sample obtained 
at screening (if applicable; refer to Section 5.7.2).
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Table 5.5.2-1:
Bone marrow samples
Bone marrow 
sample
Local Laboratory
Local Central Laboratory
Aspiratea
Samples required at the following times to 
evaluate percentage plasma cells:

Screening 
(within
28 
days 
of 
randomization)

When subject is immunofixation negative 
in both serum and urine (second bone 
marrow 
sample 
not 
required 
for 
confirmation)
In addition, evaluate flow cytometry to 
assess plasma cell clonality (i.e., lambda 
and kappa IHC or flow cytometry to 
assess light chain restriction).

At time of suspected disease progression, 
if needed (see Section 5.5.4) to assess 
progression in subjects who’s myeloma 
become nonsecretory
Screening (within 28 days of 
randomization)

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 at the local central laboratory designated by the 
Sponsor 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 of randomization, the local results must be entered into 
the eCRF.
4) Serum corrected calcium: Serum corrected calcium should be collected with each cycle for 
all subjects until disease progression.
5.5.3
Imaging Assessments for Myeloma
5.5.3.1
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 
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recorded on the eCRF. On treatment survey should record whether there is an increase in the 
number or size of lytic lesions.
5.5.3.2
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.
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.
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5.5.4
Definitions of Response Based on IMWG
See Table 5.5.4-1 and Table 5.5.4-2 for definitions of response and progression. All criteria are 
derived from IMWG.21 All response categories require 2 consecutive assessments. The second of 
the 2 consecutive assessments should occur at the next planned tumor assessment (every 4 weeks 
after the first dose).
Table 5.5.4-1:
IMWG Criteria for Response
Category
Criteriaa
Stringent Complete response 
(sCR)
CR as defined below plus
Normal serum free light chain (FLC) ratio and
Absence of clonal cells in bone marrowb by immunohistochemistry or 
immunofluorescence.c
Complete response (CR)
The first two bullet points must be met. The remaining bullet points must be met 
only as indicated.
Negative immunofixation on both serum and urine and,
Bone marrow aspirateb containing < 5% plasma cells,
No increase in size or number of lytic lesions should occur (development of a 
compression fracture does not exclude response) with disappearance of soft 
tissue plasmacytomas,
Skeletal survey must be performed ONLY if clinically indicated.
Very Good partial Response 
(VGPR)
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or
90% or greater reduction in serum M-protein plus urine M-protein < 100 mg per 
24h.
If the serum and urine M-protein are unmeasurable, a 90% decrease in the 
difference between involved and uninvolved FLC levels is required in place of 
M-protein criteria.
Partial response (PR)
All of the following conditions must be met for PR:
Greater than or equal to 50% reduction in serum M-protein and
Reduction of 90% in urinary M-protein or a decrease to < 200 mg/24 hours,
If the serum and urine M-protein are unmeasurable, a 50% decrease in the 
difference between involved and uninvolved FLC levels is required in place of 
M-protein criteria.
Greater than or equal to 50% reduction in the size of soft tissue plasmacytomas 
present at baseline,
No increase in size or number of lytic bone lesions (development of a 
compression fracture does not exclude response).
Skeletal survey must be performed ONLY if clinically indicated to confirm that 
lytic lesions have not increased and that no new lesions are seen; if done, this 
should occur at the 4-week confirmatory time point following initial 
determination of PR.
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Table 5.5.4-1:
IMWG Criteria for Response
Category
Criteriaa
Stable disease (SD)
Not meeting criteria for CR, VGPR, PR or progressive disease.
a All response categories require two consecutive assessments made at anytime; all categories also require no 
known evidence of progressive or new bone lesions if radiographic studies were performed. Radiographic studies 
are not required to satisfy these response requirements.
b Confirmation with repeat bone marrow biopsy not needed.
c Presence/absence of clonal cells is based upon the /ratio. An abnormal /ratio by immunohistochemistry 
and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting 
presence of an abnormal clone is /of > 4:1 or < 1:2.
Table 5.5.4-2:
IMWG Criteria for Progression
Category
Criteriaa
Progression of Disease 
(PD)
Progression describes a definite increase in disease activity relative to the nadir in 
subjects. One or more of the following constitutes PD:
Increase of 25% in serum monoclonal paraprotein (must also be an absolute 
increase of at least 5 g/L)b and confirmed by at least one investigation,
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 one investigation, 
Only in subjects without measureabel serum and urine M-protein levels: the 
difference between involved and uninvolved FLC levels must increase by 25% 
and confirmed by at least one investigation.  The absolute increase must be 
> 10 mg/dL.
Increase of 25% plasma cell percentage in the marrow (which must also be an 
absolute increase of at least 10%)
Definite increase in the size of lytic bone lesions or soft tissue plasmacytomas,
Development of new bone lesions or soft tissue plasmacytomas or definite increase 
in the size of residual bone lesions (development of a compression fracture does not 
exclude continued response and may not indicate progression),
Development of hypercalcemia (corrected serum calcium greater than 11.5 mg/dL; 
2.65 mmol/L) not attributable to any other cause.
a All categories require two consecutive assessments made at any time before classification as disease progression 
and/or the institution of any new therapy.
b For progressive disease, serum M-component increase of 1 g/dl is sufficient to define progression if starting 
M-component is 5 g/dL.
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5.6
Pharmacokinetic Assessments
Blood samples for PK assessment will be drawn according to the PK sampling schedule given in 
Table 5.6-1. PK samples will be collected according to the schedule listed in Table 5.6-1 in all 
subjects received elotuzumab. Blood samples for the analysis of serum concentrations of 
elotuzumab should be drawn from the arm not used for infusion of study drug.
In addition, Development of anti-drug antibodies (ADA) to elotuzumab will be evaluated in all 
subjects received elotuzumab at specified time points as noted in Table 5.6-1.
Table 5.6-1:
PK and ADA Sampling Schedule
Cycle Number
Study Day
Time (Event)a
PK
ADA
1
1
0 H (pre-dose)
X
X
2 hours post-end of infusion
X
8
0 H (pre-dose)
X
2 hours post-end of infusion
X
15
0 H (pre-dose)
X
2 hours post-end of infusion
X
22
0 H (pre-dose)
X
2 hours post-end of infusion
X
2
1
0 H (pre-dose)
X
X
2 hours post-end of infusion
X
22
0 H (pre-dose)
X
2 hours post-end of infusion
X
3
1
0 H (pre-dose)
X
X
2 hours post-end of infusion
X
8
168 hours
X
15
0 H (pre-dose)
X
4
1
0 H (pre-dose)
X
6
1
0 H (pre-dose)
X
X
9
1
0 H (pre-dose)
X
X
12
1
0 H (pre-dose)
X
X
15
1
0 H (pre-dose)
X
X
18
1
0 H (pre-dose)
X
X
Every 3 cycles 
thereafter (eg, Cycle 
21, 24, 27, etc.)
1
0 H (pre-dose)
X
X
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Table 5.6-1:
PK and ADA Sampling Schedule
Cycle Number
Study Day
Time (Event)a
PK
ADA
End of Study / Discontinuationb
X
X
30-Day Follow-upb
X
X
60-Day Follow-upb
X
X
a For subjects who miss a dose(s) of elotuzumab, collect PK and ADA samples on the planned day, or if the 
sampling is unavailable, collect samples on the day (predose) that elotuzumab is restarted (noting the actual time 
of collection and dosing), and then continue following the schedule in Table 5.6-1.
b For subjects who discontinue elotuzumab only, but otherwise continue on study treatment, collect PK and ADA 
samples at the day of elotuzumab discontinuation, 30 and 60 days after the last elotuzumab dose.
 
 
 
 
 
 
 
 
 
5.8
Outcomes Research Assessments
Not Applicable
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5.9
Other Assessments 
Not Applicable
5.10
Results of Central Assessments
Not Applicable
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.
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 Adverse Event (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.) 
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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, pathogenic or nonpathogenic) via the study 
drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 
6.1.1 for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
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 an important medical or life-threatening event)

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 other than to remedy ill health and 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, caregiver respite, family circumstances, administrative reason).

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.
The investigator should report any SAE that occurs after these time periods and that is believed 
to be related to study drug or protocol-specified procedure.
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An SAE report should 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 should 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, and the head of the study site to comply with procedures of the study 
site. 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: worldwide.safety@bms.com.
SAE Facsimile Number: +1 (609) 818-3804.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, 
the original paper forms are to remain on site.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should 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, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should 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 and for those 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.
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6.3
Laboratory Test Result Abnormalities
The following laboratory test result 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 test result abnormality that required the subject to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject or a 
female partner of a male study participant is pregnant or may have been pregnant at the time of 
study exposure, including during the 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 investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours and in accordance with SAE reporting procedures 
described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for subject safety). 
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough 
discussion of benefits and risk with the subject
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 (or designee) Medical Monitor 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 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
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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 SAEs (see Section 6.1.1 for reporting details).
6.6
Potential Drug Induced Liver Injury (DILI)
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 drug induced liver injury 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, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by 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. 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
Not applicable
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The number of subjects in the investigational arm (ELd arm) is based on the primary objective of 
assessment in objective response rate in ELd arm. The design will test the null hypothesis that 
the response rate 71% versus the alternative that the true response rate > 71%. The test will 
have a significance level of 15% (one-sided) and will have 80% power to reject the null 
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hypothesis if the true response rate is 85%. If there are 32 or more responders out of 40 subjects 
in the ELd arm, the null hypothesis will be rejected. The study design requires 40 subjects in 
ELd arm.
The control arm (Ld arm) is set to evaluate add-on efficacy clinically for Elotuzumab with 
40 subjects. The randomized ratio of ELd to Ld is 1:1.
8.2
Populations for Analyses
The following subject populations will be used in this study:

Enrolled subjects: all subjects who signed informed consent

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, and efficacy will be carried out on 
all randomized subjects. Analyses of safety will be based on all treated subjects.
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary and secondary endpoints of Objective Response Rate (ORR) is defined as the 
proportion of treated subjects who achieve a partial response (PR) or better, i.e. stringent 
complete response (sCR), complete response (CR), very good partial response (VGPR) and PR,
according to the IMWG criteria. Response assessment will be evaluated by the investigator using 
the IMWG criteria during the trial for all treated subjects.
8.3.2
Secondary Endpoint(s)
8.3.2.1
Objective Response Rate
See Section 8.3.1
8.3.2.2
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, as determined by the investigator using the 
IMWG criteria, 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.
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
Subjects who do not progress and who do not receive subsequent therapy will be censored at 
their last tumor assessment.

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 their last tumor assessment. There will be no censoring for subsequent therapy prior 
to progression or for progression events following missing assessments.
PFS is elevated from an exploratory endpoint to a secondary endpoint in the protocol amendment 
03. The study duration is expanded, and PFS is expected to be sufficiently mature at the updated 
targeted follow-up, which is the time of final PFS analysis for the randomized global phase 3 
study for the subjects with previously untreated multiple myeloma.
 
 
 
 
 
 
 
 
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 response rate and its corresponding exact one-sided 85% confidence interval will be 
calculated in the ELd arm. In addition, the two-sided 95% confidence interval will be computed 
for the ELd arm.
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8.4.2.2
Secondary Efficacy Analysis
The difference in ORR between two treatment arms along with two-sided 95% CI will be 
estimated using the method of DerSimonian and Laird adjusted by stage of disease (ISS 
stage 1- 2 versus 3). In addition, the response rate and its corresponding exact two-sided 95% 
confidence interval will be calculated in the Ld arm.
The PFS analyses will be conducted using both the primary and the ITT definitions of PFS. 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 treatment arm. PFS rates at 1, and 2 years will be estimated from the KM 
curve. Each analysis will be performed after all subjects have been followed for the appropriate 
time.
 
 
 
8.4.3
Safety Analyses
Safety analyses will be conducted on all treated population. Adverse events and laboratory 
parameters will be summarized using CTCAE version 3.0. 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.
8.4.4
Pharmacokinetic Analyses
Summary statistics will be calculated for elotuzumab concentrations and summarized by 
scheduled collection time. Elotuzumab concentrations will be combined with concentration data 
from other studies and will be analyzed using population pharmacokinetic (PPK) analysis. 
Results of the PPK analysis may also be used to explore the relationship between elotuzumab 
and efficacy/safety endpoints. Results of the PPK analysis and potential exploratory exposure 
response analysis will be reported separately.
 
 
 
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8.4.6
Outcomes Research Analyses
Not Applicable
8.4.7
Other Analyses 
Anti-Drug Antibodies (ADAs) will be summarized by cycle (samples are taken on Day 1 of each 
cycle, prior to elotuzumab administration) for subjects in the elotuzumab arm only. The number 
and percentage of subjects with a positive and negative result to the test for antibodies will be 
presented. For subjects with a positive result, their titer value will be summarized.
8.5
Interim Analyses
The primary analysis will be done 6 months after last subject’s first treatment. Additional 
analyses may be performed which depend on the timing of regulatory authority filing. The final 
analysis may be performed at the timing of the study discontinuation.
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 from the IRB 
of an amendment, except where necessary to eliminate an immediate hazard(s) to study subjects. 
Any deviations must be documented.
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB approval, as soon as possible the deviation or change will be submitted to:

Head of the study site

IRB for review and approval via the head of the study site

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(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) via the head of the 
study site for review and approval; (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 done via an administrative letter, BMS must inform the IRB(s).
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9.1.2
Monitoring
Representatives of BMS 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. Source documents are defined as follows: subject 
identification code sheet, medical records, written informed consent, study drug management 
sheets. 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 internal auditors, the IRB, 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 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. 
9.1.3
Investigational Site Training
BMS 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 head of the study site 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 BMS, whichever is longer. The head of the study site must contact BMS 
prior to destroying any records associated with the study.
BMS will notify the head of the study site when the study records are no longer needed.
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If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to the personnel designated by the head of the study site. Notice of such transfer will 
be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the study drug storage manager designated by the head of the study site 
to ensure that a current disposition record of study drug (inventoried and dispensed) is 
maintained at the study site to include investigational product and the non-investigational 
product(s). 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.
BMS 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 that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS 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 paper or electronic 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 BMS. 
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).
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BMS and the investigator will maintain an original and a copy of the 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 or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator. For electronic CRFs, review and 
approval/signature is completed electronically through the BMS 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 electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the 
following criteria:

Subject recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study require approval by BMS prior to publication or presentation 
and must adhere to BMS’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 BMS 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. BMS 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
Complete Abstinence
Complete Abstinence is defined as complete avoidance of 
heterosexual intercourse and is an acceptable form of 
contraception for all study drugs. This also means that 
abstinence is the preferred and usual lifestyle of the patient. 
This does not mean periodic abstinence (eg, calendar, 
ovulation, symptothermal, profession of abstinence for entry 
into a clinical trial, post-ovulation methods) and withdrawal, 
which are not acceptable methods of contraception. Women 
must continue to have pregnancy tests. Acceptable alternate 
methods of highly or less effective contraception’s must be 
discussed in the event that the subject chooses to forego 
complete abstinence.
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11
LIST OF ABBREVIATIONS
Term
Definition
ADA
anti-durg antibodies
ADCC
antibody dependent cell-mediated cytotoxicity
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of 
the last quantifiable concentration
BMS
Bristol-Myers Squibb
BUN
blood urea nitrogen
CBC
complete blood count
CFR
Code of Federal Regulations
CI
confidence interval
CLT
total body clearance
Cmax
maximum observed concentration
Cmin
trough observed concentration
CR
complete response
CrCl
creatinine clearance
CRF
Case Report Form, paper or electronic
CS1
CD-2 subset 1
CT
computerized tomography
CYP
cytochrome p-450
DILI
drug induced liver injury
DLT
dose-limiting toxicity
DVT
deep venous thrombosis
EBMT
European Group for Blood and Bone Marrow Transplant
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
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CA204116
BMS-901608
elotuzumab
Term
Definition
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
ELd
elotuzumab, lenalidomide, (low-dose) dexamethasone
EPO
Erythropoietin
FLC
free light chain
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GM-CSF
granulocyte macrophage colony stimulating factor
HIV
Human Immunodeficiency Virus
HRT
hormone replacement therapy
ICH
International Conference on Harmonisation
IHC
Immunohistochemistry
IMiDs
Immune Modulary Drugs
IMP
investigational medicinal products
IMWG
International Myeloma Working Group
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
ISS
International Staging System
IV
intravenous
Ld
lenalidomide, (low-dose) dexamethasone
LD
lenalidomide, (high-dose) dexamethasone
MGUS
Monoclonal Gammopathy of Undetermined Significance
MHLW
Ministry of Health, Labour and Welfare
MM
Multiple Myeloma
MPT
melphalan, prednisolone, thalidomide
MR
minor (minimal) response
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
Revised Protocol No: 03
Date: 16-Feb-2017
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Clinical Protocol
CA204116
BMS-901608
elotuzumab
Term
Definition
NK
natural killer
NKT
natural killer T-cell
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cells
PE
pulmonary embolism
PFS
progression-free survival
PK
pharmacokinetics
PO
per os (by mouth route of administration)
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
QD
quaque die, once daily
SAE
serious adverse event
SCID
severe combined immunodeficient
SCT
stem-cell transplantation
SPEP
serum protein electrophoresis
sCR
stringent complete response
SOP
Standard Operating Procedures
SPM
second primary malignancy
TTP
time to progression
ULN
upper limit of normal
UPEP
urine protein electrophoresis
USPI
United States Package Insert
VGPR
very good partial response
WBC
white blood cell
WOCBP
women of childbearing potential
Revised Protocol No: 03
Date: 16-Feb-2017
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Clinical Protocol
CA204116
BMS-901608
elotuzumab
12
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1
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CA204116
BMS-901608
elotuzumab
Pre-Clinical 
Models 
of 
Myeloma. 
Blood 
(ASH 
Annual 
Meeting 
Abstracts) 
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17 Investigator Brochure for Elotuzumab, BMS 901608, Version No.: 10, 2014.
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19 Jakubowiak AJ, Benson DM, Bensinger W, et al. Phase I Trial of Anti-CS1 Monoclonal 
Antibody Elotuzumab 
in Combination 
With Bortezomib 
in the Treatment of 
Relapsed/Refractory Multiple Myeloma. J Clin Oncol. 2012;30(16):1960-1965.
20 Blade J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression 
in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell 
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multiple myeloma in North America. N Engl J Med. 2007;357:2133-2142.
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plus dexamethasone is associated with improved clinical outcomes in patients with relapsed 
or refractory multiple myeloma. Haematologica 2010 Oct;95(10):1738-1744.
27 Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in 
transplant-ineligible patients with myeloma. N Engl J Med. 2014;371(10): 906-917.
28 Zonder J, Crowley J, Hussein MA, et al. Lenalidomide and high-dose dexamethasone 
compared with dexamethasone as initial therapy for multiple myeloma: a randomized 
Southwest Oncology Group trial (S0232). Blood 2010;116(26):5838-5841.
29 Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone 
versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed 
multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29-37.
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CA204116
BMS-901608
elotuzumab
30 Palumbo A, Rajkumar SV, San Miguel JF, et al.  IMWG. International Myeloma Working 
Group consensus statement for the management, treatment, and supportive care of patients 
with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Oncol. 
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31 National Comprehensive Cancer Network (NCCN) Clinical practice guidelines in oncology 
for Multiple Myeloma. Version 2. 2014.
32 San Miguel JF, Richardson PG, Sonneveld P, et al. Efficacy and safety of bortezomib in 
patients with renal impairment: results from the APEX phase 3 study. Leukemia
2008;22(4):842-849.
33 Chen M, Lau H, Kong L, et al. Pharmacokinetics of Lenalidomide in subjects with various 
degrees of renal impairment and in subjects on hemodialysis. J Clin Pharmacol. 2007 
Dec;47(12):1466-1475.
34 Dimopoulos MA, Christoulas D, Roussou M, et al. Lenalidomide and dexamethasone for the 
treatment of refractory/relapsed multiple myeloma: dosing of lenalidomide according to renal 
function and effect on renal impairment. Eur J Haematol. 2010 Jul;85(1):1-5.
35 Dimopoulos MA, et al. The efficacy and safety of lenalidomide plus dexamethasone in 
relapsed and/or refractory multiple myeloma patients with impaired renal function. Cancer 
2010;116:3807-3814
36 Ozols RF, Bundy BN, Greer BE, et al. Gynecologic Oncology Group. Phase III trial of 
carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally 
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37 Parikh B, Khanolkar S, Advani SH, et al. Safety profile of single-dose dexamethasone 
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38 Czock D, Keller F, Rasche FM, et al. Pharmacokinetics and pharmacodynamics of 
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Date: 16-Feb-2017
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Clinical Protocol
CA204116
BMS-901608
elotuzumab
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
Greipp PR, San Miguel JF, Brian GM, et al. International Staging System for Multiple Myeloma.  J Clin Oncology 
2005;23:3412-3420.
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.
Revised Protocol No: 03
Date: 16-Feb-2017
99
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