Open-label, Single-arm, Phase 2 Study of Initial Treatment With Elotuzumab, Carfilzomib (Kyprolis), Lenalidomide (Revlimid) and Low Dose Dexamethasone (E-KRd) in Newly Diagnosed, Multiple Myeloma Requiring Systemic Chemotherapy
Phase: PHASE2
Conditions: Multiple Myeloma
Sponsor: University of Chicago

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CLINICAL STUDY PROTOCOL 
 
PROTOCOL INFORMATION 
 
STUDY TITLE: 
 
Open-label, Single-arm, Phase 2 Study of Initial 
Treatment with Elotuzumab, Carfilzomib (Kyprolis), 
Lenalidomide (Revlimid) and Low dose Dexamethasone 
(E-KRd) in Newly Diagnosed, Multiple Myeloma 
Requiring Systemic Chemotherapy. 
 
COORDINATING CENTER: 
 
LEAD PRINCIPAL 
INVESTIGATOR: 
 
 
 
 
 
 
 
SPONSOR 
 
SPONSOR CONTACT 
 
 
 
 
 
 
 
STATISTICIAN 
 
 
The University of Chicago 
 
Andrzej Jakubowiak, MD, PhD 
The University of Chicago Medicine  
5841 S. Maryland Avenue  
Chicago, IL 60637 
773-834-1592 (Direct) 
773-702-0963 (Fax) 
ajakubowiak@medicine.bsd.uchicago.edu  
 
The University of Chicago 
 
Andrzej Jakubowiak, MD, PhD 
The University of Chicago Medicine  
5841 S. Maryland Avenue  
Chicago, IL 60637 
773-834-1592 (Direct) 
773-702-0963 (Fax) 
 
 
Ted Karrison 
5841 S. Maryland Ave., MC 2000, TE011 
Chicago, Illinois 60637 
(773) 702-9326 (Tel) 
773-702-1979 (Fax) 
karr@uchicago.edu 
 
TYPE OF RESEARCH: 
 
 
INTERVENTION: 
 
 
 
 
 
 
 
Interventional, clinical multi-center  
 
 
Drug Company Supplied:  
Bristol Myers Squibb (Elotuzumab)  
Amgen (Carfilzomib) 
 
 
 

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PROTOCOL NUMBER: 
 
IND NUMBER:  
 
PROTOCOL VERSION: 
 
 
IRB16-1138 
 
132598 
 
Ver 1, November 9th , 2016 (initial IRB submission) 
Ver 2, November 11th, 2016 (additional FDA changes) 
Ver 3, January 26th, 2018 
Ver 4, April 13th, 2018 
Ver 5, October 22nd, 2018 
Ver 6, February 15, 2019 
Ver 7, Septemebr 24, 2019 
Ver 8, March 26, 2020 
 
 
 
 
 
This study is being conducted by institutional members of the Personalized Cancer Care 
Consortium (PCCC), as well as additional sites. 
 
 
 
 
 
 
 

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CONFIDENTIALITY STATEMENT 
This document contains confidential information.  It is provided for the sole use of the Principal 
Investigator, Sub-investigators, Staff, Institutional Review Board or Independent Ethics 
Committee, and Regulatory Authorities.  By accepting this document, you agree to maintain the 
information as confidential and to use it only for the purpose of conducting the study. 
 
 
 
 
 
 
 
 

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Contents 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...................................................................... 17 
1. 
INTRODUCTION .............................................................................................................................................. 20 
1.1. 
Overview of Multiple Myeloma ...................................................................................................... 20 
1.2. 
Proteasome Background ................................................................................................................... 20 
1.3. 
Carfilzomib Background .................................................................................................................... 20 
1.4. 
Lenalidomide Background ............................................................................................................... 20 
1.4.1. 
Dose Rationale ................................................................................................................................ 21 
1.4.1.1. 
Carfilzomib Dose Rationale ............................................................................................... 21 
1.5. 
Elotuzumab Background ................................................................................................................... 22 
1.5.1.1. Infusion Reactions ......................................................................................................................... 23 
1.5.1.2. Overall Risk/Benefit Assessment ........................................................................................... 23 
1.6. 
Study Rationale ..................................................................................................................................... 23 
1.7. 
Study Population and Sample Size ......................................................................................... 24 
1.8. 
Assessment for Response ................................................................................................................. 24 
2. 
OBJECTIVES....................................................................................................................................................... 25 
2.1. 
Primary Objective ................................................................................................................................ 25 
2.2. 
Secondary Objectives .......................................................................................................................... 25 
2.3. 
Exploratory Objectives....................................................................................................................... 25 
3. 
STUDY ENDPOINTS ....................................................................................................................................... 25 
3.1. 
Primary Endpoints ............................................................................................................................... 25 
3.2. 
Secondary Endpoints .......................................................................................................................... 26 
3.3. 
Tertiary/Exploratory Endpoints ................................................................................................... 26 
4. 
INVESTIGATIONAL PLAN ............................................................................................................................ 26 
4.1. 
Overview of Study Design and Dosing Regimen ..................................................................... 26 
4.2. 
Study Procedures ................................................................................................................................. 26 
4.2.1. 
MRD Detection Methods ............................................................................................................. 28 
4.2.2. 
Number of Centers ........................................................................................................................ 28 
4.2.3. 
Definition of Treatment Cycle and Duration ...................................................................... 28 
4.2.4. 
Treatment Phase ............................................................................................................................ 28 

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4.2.5. 
End of Treatment Visit ................................................................................................................. 28 
4.2.6. 
Long Term Follow Up ................................................................................................................... 28 
5. 
SUBJECT SELECTION ..................................................................................................................................... 28 
5.1. 
Inclusion Criteria .................................................................................................................................. 28 
5.2. 
Exclusion Criteria ................................................................................................................................. 30 
5.3 
SUBJECT ENROLLMENT AND REGISTRATION ......................................................................... 31 
5.3.1 
Registration Process ......................................................................................................................... 31 
6. 
TREATMENT PLAN ........................................................................................................................................ 32 
6.1. 
Treatment Regimen............................................................................................................................. 33 
6.2. 
Study Procedures ................................................................................................................................. 34 
6.2.1. 
Screening Procedures .................................................................................................................. 34 
6.2.2. 
Treatment Phase Procedures ................................................................................................... 36 
6.2.3. 
End of Treatment Procedures and Long-Term Follow-Up ........................................... 38 
6.3. 
Pretreatment Preparation ................................................................................................................ 39 
6.3.1. 
Hydration .......................................................................................................................................... 39 
6.3.2. 
Concomitant Medications ........................................................................................................... 40 
6.3.2.1. 
Contraception ......................................................................................................................... 40 
6.3.3. 
Prohibited Concomitant Medications .................................................................................... 41 
6.3.4. 
Use of Blood Products .................................................................................................................. 41 
6.3.5. 
Radiation Treatment .................................................................................................................... 41 
6.4. 
Study Drug Administration .............................................................................................................. 42 
6.4.1. 
Elotuzumab Administration ............................................................................................. 42 
6.4.2. 
Carfilzomib Administration .............................................................................................. 43 
6.4.3. 
Lenalidomide Administration .......................................................................................... 43 
6.4.4. 
Dexamethasone Administration ..................................................................................... 44 
6.4.5. 
Maintenance treatment ............................................................................................................... 44 
6.4.6. 
Treatment Compliance ................................................................................................................ 45 
6.5. 
Instructions for Initiation of a New Cycle .................................................................................. 45 
6.6. 
Dose-Modification Guidelines ......................................................................................................... 45 
6.6.1. 
Toxicity Management Guidelines ............................................................................................ 47 
6.6.1.1. 
Hematologic Toxicity ........................................................................................................... 48 
6.6.1.2. 
Non-hematologic Toxicity.................................................................................................. 49 

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6.6.2. 
Guidelines for Elotuzumab Infusion and pre-medication in Subjects with 
Infusion Reactions ......................................................................................................................................... 58 
6.6.2.1. 
Elotuzumab Dose Delay or Interruption .......................................................................... 59 
6.7. 
Response Evaluation ........................................................................................................................... 59 
6.8. 
Study Termination ............................................................................................................................... 60 
6.9. 
Treatment Discontinuation .............................................................................................................. 60 
6.9.1. 
Duration of Follow Up .................................................................................................................. 61 
6.10. 
Safety Considerations & Supportive Care................................................................................ 61 
6.10.1. 
Elotuzumab Infusion Reactions ............................................................................................ 61 
6.10.2. 
First Dose Effect (Carfilzomib) .............................................................................................. 62 
6.10.3. 
Tumor Lysis Syndrome ............................................................................................................. 62 
6.10.4. 
Renal Function ............................................................................................................................. 63 
7. 
SAMPLES FOR MRD EVALUATION AND CORRELATIVE STUDIES ............................................. 63 
8. 
ADVERSE EVENTS .......................................................................................................................................... 66 
8.1. 
Causality ................................................................................................................................................... 68 
8.2. 
Adverse Event Reporting Procedures ......................................................................................... 68 
8.3. 
Serious Adverse Events ..................................................................................................................... 69 
8.3.1. 
Serious Adverse Event Definition ........................................................................................... 70 
8.3.2. 
Serious and Unexpected Suspected Adverse Reaction (SUSAR) ................................ 70 
8.3.3. 
Serious Adverse Event Reporting and Documentation Requirements ................... 71 
8.3.3.1. 
Serious Adverse Event Reporting to the University of Chicago ......................... 71 
8.3.3.2. 
Serious and Unexpected Adverse Event reporting by the University of 
Chicago 72 
8.4. 
Expedited Reporting by the Lead Principal Investigator to BMS and Amgen ............. 72 
8.4.1. 
Pregnancy Reporting .................................................................................................................... 75 
9. 
INVESTIGATIONAL MEDICINAL PRODUCT ......................................................................................... 76 
9.1. 
Elotuzumab ............................................................................................................................................. 76 
9.1.1. 
Description .......................................................................................................................................... 76 
9.1.2. 
Form ....................................................................................................................................................... 76 
9.1.3. 
Storage and Stability ....................................................................................................................... 76 
9.1.4. 
Handling ............................................................................................................................................... 77 
9.1.5. 
Availability .......................................................................................................................................... 77 
9.1.6. 
Preparation ......................................................................................................................................... 77 

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9.1.7. 
Administration ................................................................................................................................... 77 
9.1.8. 
Ordering ............................................................................................................................................... 78 
9.1.9. 
Accountability .................................................................................................................................... 78 
9.1.10. 
Destruction and Return ............................................................................................................... 78 
9.2. 
Carfilzomib .............................................................................................................................................. 78 
9.2.1. 
Description ....................................................................................................................................... 78 
9.2.2. 
Formulation ..................................................................................................................................... 78 
9.2.3. 
Storage ............................................................................................................................................... 78 
9.2.4. 
Accountability ................................................................................................................................. 79 
9.3. 
Lenalidomide ......................................................................................................................................... 79 
9.3.1. 
Description ....................................................................................................................................... 79 
9.3.2. 
Supply ................................................................................................................................................. 79 
9.3.3. 
Storage Conditions ........................................................................................................................ 79 
9.3.4. 
Accountability ................................................................................................................................. 79 
9.3.5. 
Prescribing Information ............................................................................................................. 80 
9.3.6. 
Special Handling Instructions ................................................................................................... 80 
9.4. 
Dexamethasone ..................................................................................................................................... 80 
9.4.1. 
Description ....................................................................................................................................... 80 
9.4.2. 
Formulation ..................................................................................................................................... 80 
9.4.3. 
Storage conditions ......................................................................................................................... 80 
9.4.4. 
Accountability ................................................................................................................................. 80 
10. 
STATISTICAL CONSIDERATIONS .......................................................................................................... 80 
10.1. 
Objectives .............................................................................................................................................. 80 
10.1.1. 
Primary Objective ....................................................................................................................... 80 
10.1.2. 
Secondary Objectives ................................................................................................................ 80 
10.1.3. 
Exploratory Objectives ............................................................................................................. 81 
10.2. 
Sample Size Justification & Analysis Plan ................................................................................ 81 
10.2.1. 
Primary Objective Sample Size Justification .................................................................... 81 
10.2.2. 
Secondary Objective Sample Size Justification ............................................................... 81 
10.2.3. 
Exploratory Objectives ............................................................................................................. 82 
11. 
DATA REPORTING ....................................................................................................................................... 82 
12. 
REGULATORY OBLIGATIONS .................................................................................................................. 82 
12.1. 
Informed Consent .............................................................................................................................. 83 

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12.2. 
Compliance with Laws and Regulations .................................................................................. 83 
12.3. 
Subject Confidentiality .................................................................................................................... 84 
12.4. 
Multicenter Guidelines .................................................................................................................... 84 
13. 
ADMINISTRATION AND LEGAL OBLIGATIONS ............................................................................... 84 
13.1. 
Institutional Review Board (IRB) Approval and Consent ................................................. 84 
13.1.1. 
Annual IRB Renewals, Continuing Review and Final Reports..................................... 85 
13.2. 
Food and Drug Administration (FDA) Approval .................................................................. 85 
13.3. 
Required Documentation ............................................................................................................... 85 
13.4. 
Protocol Amendments and Study Termination .................................................................... 86 
13.5. 
Study Documentation and Archive............................................................................................. 86 
13.5.1. 
Source Documents ...................................................................................................................... 86 
13.5.2. 
Record Retention ........................................................................................................................ 87 
13.5.3. 
Case Report Form Completion............................................................................................... 87 
13.5.4. 
Archival of Records .................................................................................................................... 87 
13.6. 
Clinical Monitoring Procedures ................................................................................................... 87 
13.6.1. 
Obligations of Study Site Investigators .............................................................................. 88 
13.6.2. 
Protocol Deviations .................................................................................................................... 88 
13.7. 
Data Safety and Monitoring ........................................................................................................... 88 
13.8. 
Quality Assurance & Auditing ...................................................................................................... 89 
REFERENCES ............................................................................................................................................................. 90 
APPENDIX 1: MULTIPLE MYELOMA STAGING ........................................................................................... 93 
APPENDIX 2: ECOG PERFORMANCE STATUS .............................................................................................. 94 
APPENDIX 3: NCI CTCAE VERSION 4.0 ........................................................................................................... 95 
APPENDIX 4: RESPONSE CRITERIA FOR MULTIPLE MYELOMA ......................................................... 96 
APPENDIX 5: Revlimid Prescribing and REMS information .................................................................. 99 
APPENDIX 6: SCHEDULE OF EVENTS .......................................................................................................... 100 
 
 

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SYNOPSIS 
Study Title 
Open-label, Single-arm, Phase 2 Study of Initial Treatment with 
Elotuzumab, Carfilzomib (Kyprolis), Lenalidomide (Revlimid) and 
Low dose Dexamethasone (E-KRd) in Newly Diagnosed, Multiple 
Myeloma Requiring Systemic Chemotherapy. 
Objectives 
Primary Objective 
• 
The primary efficacy endpoint will be the rate of sCR and/or the rate 
of negative MRD by next generation gene sequencing (NGS) by 
clonoSEQ (Adaptive Biotechnologies) at the end of 8 cycles among 
non-transplant candidates and transplant candidates who agreed to 
defer transplant.    
 
Secondary Objectives 
• 
To evaluate the safety and tolerability of elotuzumab in combination 
with KRd, when administered to subjects with newly diagnosed 
multiple myeloma. 
• 
To determine the rate of MRD by next generation gene sequencing 
(NGS) by clonoSEQ (Adaptive Biotechnologies) and by multi-color 
flow cytometry (MFC) at the end of Cycle 4, 8,and 12 for all 
subjects, and end of C18 (for subjects who are MRD+ at the end of 
C8 but MRD- at the end of C12 only), 24 months after C1D1, and 
yearly after that. 
• 
To estimate time to event, including duration of response (DOR), 
progression-free survival (PFS), time to progression (TTP), and 
overall survival (OS). 
 
Exploratory Objectives 
∗ 
GEP, proteomics, and gene sequencing to evaluate the correlation 
between treatment outcome and pre-treatment subject profile.  
∗ 
Immunologic correlative studies including FcγRIIIa V genotype.   
Sample Size 
40 - 55 
Study Design 
This study will be a multi-center, open-label, Phase 2 study. Those newly 
diagnosed with MM requiring systemic chemotherapy will be eligible 
for enrollment. 
Dose Schedule and Dose Levels in 28-day cycles 
Subjects will be tested for Minimal Residual Disease (MRD) by Next 
Generation Sequencing (NGS) and flow cytometry after cycles 8 and 12. 
A treatment decision will be made after cycle 12 based on these results. 
There are three possible outcomes based on the IFM trial (Avet-Loiseau 
et al., 2015): 1) if the subject is MRD-negative by NGS after cycle 8 and 
12, the subject will be go on E-Rd maintenance until disease progression. 
2) If the subject is MRD-positive after cycle 8 but MRD-negative after 
cycle 12, 6 more cycles of E-KRd will be given and at the end of 18 

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cycles, the subject will go on E-Rd maintenance until disease 
progression. 3) Finally, if the subject is MRD-positive at both instances, 
12 additional cycles of E-KRd will be given and at the end of 24 cycles 
total, the subject will go on E-Rd maintenance until disease progression. 
For subjects for whom NGS evaluation is not successful because of 
inadequate calibration specimen or not-evaluable follow-up specimen, 
the results of MRD testing by flow will be used for treatment decisions. 
Elotuzumab  
Cycle 1-2 Days 1, 8, 15, 22 
Cycle 3+ Days 1 and 15 
10 mg/kg IV infusion weekly 
starting Cycle 1 day 1 
10 mg/kg IV infusion every 2 
weeks starting Cycle 3 day 1 
* On days when elotuzumab and carfilzomib coincide, carfilzomib will be 
infused first followed by elotuzumab infusion 
Carfilzomib  
Cycle 1* 
Cycle 2-8 
Cycle 9+ 
IV infusion 
Day 1: 20 mg/m2 
Day 8 & 15: 56 
mg/m2 
IV infusion 
70 mg/m2: Days 1, 8, 
and 15 
IV infusion 
Last tolerated dose on 
Days 1 and 15 
*Dose escalation may need to be modified based on toxicities in the prior 
week. Please see dose modifications section. 
Lenalidomide 
Cycle 1-8 
Cycle 9+ 
PO at 25 mg per dose on Days 1- 
21 
PO at last tolerated dose for days 
1-21 
Dexamethasone  
Cycle 1-2 
Tx Days 1, 8, 15 
Tx Days 2, 9, 16 
Tx Day 22 
20 mg IV no more 
than 3 hrs prior to 
elotuzumab infusion 
20 mg PO the day 
after elotuzumab 
infusion 
40mg IV (C1 only) or 
PO, no more than 3 
hrs prior to 
elotuzumab infusion 
Cycle 3-4 
Tx Days 1, 8, 15, 22 
40mg PO weekly. On days when dexamethasone and elotuzumab 
coincide, dexamethasone should be taken no more than 3 hours prior to 
elotuzumab infusion 
Cycle 5+ 
Tx Days 1, 8, 15, 22 
20mg PO weekly. On days when dexamethasone and elotuzumab 
coincide, dexamethasone should be taken no more than 3 hours prior to 
elotuzumab infusion 

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Duration of Treatment 
Cycles 1 through 4 are considered E-KRd induction cycles, cycle 5-8 E-
KRd consolidation, and cycles 9+ E-KRd maintenance cycles.  After 
Cycle 4, subjects who are deemed candidates for ASCT will proceed to 
stem cell harvest as per institutional guidelines.  However, the study 
design recommends a “delayed” transplant for ASCT candidates as in 
completed frontline KRd study with delayed transplant for transplant 
candidates (Jakubowiak et al., 2012b). After completion of stem cell 
harvest, subjects will resume protocol treatment. Subjects who will 
proceed to transplant will be discontinued from the trial. Intention to go 
on ASCT will be required at the time of enrollment with 15 subjects 
planned in this category per study design. Subjects who were assigned to 
the ‘non-ASCT’ or ‘deferred ASCT’ category, who proceed to ASCT for 
reasons other than disease progression or toxicity, will be replaced (up to 
5 subjects).  
Subjects who will continue E-KRd protocol treatment until the end of 
study or toxicity, will then proceed to maintenance treatment with E-Rd, 
i.e. with elotuzumab (every 4 weeks), lenalidomide (days 1-21), and low 
dose dexamethasone (weekly) at last tolerated doses in 28-day cycles 
until subject reaches PD. 
Inclusion / Exclusion 
Criteria 
Inclusion criteria: 
Subjects must meet all of the following inclusion criteria to be eligible to 
enroll in this study. No enrollment waivers will be granted. 
1. Newly diagnosed, previously untreated myeloma requiring 
systemic chemotherapy 
a. Prior treatment of hypercalcemia or spinal cord 
compression or active and/or aggressively progressing 
myeloma with corticosteroids and/or lenalidomide 
and/or bortezomib/PI-based regimens does not disqualify 
the subject. The corticosteroid treatment dose should not 
exceed the equivalent of 160 mg of dexamethasone in a 
4 week period or not more than 1 cycle of lenalidomide 
and/or PI-based therapy. A higher total dose of 
corticosteroid is allowed for the management of cord 
compression at the discretion of the PI, as long as the 
subject does not exhibit any steroid related toxicities at 
the initiation of study treatment. 
2. Both transplant and non-transplant candidates are eligible. 
3. Diagnosis of symptomatic multiple myeloma as per current 
IMWG uniform criteria prior to initial treatment 
4. Monoclonal plasma cells in the BM 10% or presence of a 
biopsy-proven plasmacytoma 
5. Measurable disease, prior to initial treatment as indicated by one 
or more of the following: 
a. Serum M-protein ≥ 1 g/dL  
b. Urine M-protein ≥ 200 mg/24 hours 

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c. If serum protein electrophoresis is felt to be unreliable 
for routine M-protein measurement, then quantitative 
immunoglobulin levels are acceptable (≥ 1 g/dL) 
d. Involved serum free light chains ≥ 10 mg/dL 
provided that free light chain ratio is abnormal 
 
6. Screening laboratory values must meet the following criteria and 
should be obtained within 21 days prior to enrollment 
 
WBC   
≥ 2000/μL 
 
Platelets 
 ≥ 75 x103/μL 
 
ANC 
 
>1000/μL 
 
Hemoglobin  
> 8.0 g/dL 
 
Serum creatinine ≤ 1.5 x ULN or creatinine 
clearance (CrCl) ≥ 50 mL/min  
a) Use the Cockcroft-Gault formula 
below): 
o Female CrCl = (140 - age in 
years) x weight in kg x 0.85 
• 
72 x serum 
creatinine in 
mg/dL 
 
o Male CrCl = (140 - age in years) 
x weight in kg x 1.00  
• 
72 x serum 
creatinine in 
mg/dL 
b) Alternatively to Cockcroft-Gault 
formula of CrCl, 24hr urine CrCl can be 
used 
 
AST/ALT  
≤ 3 x ULN  
 
Total Bilirubin ≤ 1.5 x ULN (except subjects 
with Gilbert Syndrome, who can have total 
bilirubin < 3.0 mg/dL) or ≤ 2 x ULN if 
lenalidomide is being prescribed.  
7. Males and females ≥ 18 years of age  
8. ECOG performance status of 0-1 
9. Females of childbearing potential (FCBP) must have 2 negative 
pregnancy tests (sensitivity of at least 50 mIU/mL) prior to 
initiating lenalidomide. The first pregnancy test must be 
performed within 10-14 days before and the second pregnancy 
test must be performed within 24 hours before lenalidomide is 
prescribed for Cycle 1 (prescriptions must be filled within 7 
days). 
10. FCBP must agree to use 2 reliable forms of contraception 
simultaneously or to practice complete abstinence from 
heterosexual intercourse during the following time periods 
related to this study: 1) for at least 28 days before starting 
lenalidomide; 2) while participating in the study; and 3) for at 
least 28 days after discontinuation from the study. 

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11. Male subjects must agree to use a latex condom during sexual 
contact with females of childbearing potential while participating 
in the study and for at least 28 days following discontinuation 
from the study even if he has undergone a successful vasectomy. 
12. All study participants in the US must be consented to and 
registered into the mandatory Revlimid REMS® program and be 
willing and able to comply with the requirements of Revlimid 
REMS®. 
13. Voluntary written informed consent 
 
Exclusion Criteria: 
Subjects meeting any of the following exclusion criteria are not eligible 
to enroll in this study. No enrollment waivers will be granted. 
1. Non-secretory or hyposecretory multiple myeloma, prior to 
initial treatment defined as <1.0 g/dL M-protein in serum, <200 
mg/24 hr urine M-protein, and no measurable disease as per 
IMWG by Freelite. 
2. POEMS syndrome (polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein, and skin changes) 
3. Geriatric assessment score of ≥2 as defined by Palumbo et al. 
4. Known or suspected Amyloidosis 
5. Plasma cell leukemia 
6. Within 4 weeks since any plasmapheresis 
7. Within 3 weeks of any corticosteroids except per inclusion 
criteria #1.a. 
8. Waldenström’s macroglobulinemia or IgM myeloma 
9. Participation in an investigational therapeutic study within 3 
weeks or within 5 drug half-lives (t1/2) prior to first dose, 
whichever time is greater 
10. Subjects not able to tolerate elotuzumab, lenalidomide, 
carfilzomib, or dexamethasone 
11. Peripheral neuropathy ≥ Grade 2 at screening 
12. Prior CVA with persistent neurological deficit 
13. Diarrhea > Grade 1 in the absence of antidiarrheals 
14. CNS involvement 
15.  Corrected calcium ≥ 11.5 mg/dL within 2 weeks of 
randomization 
16. Pregnant or lactating females 
17. Radiotherapy within 14 days before randomization. Seven days 
may be considered if to single area  
18. Major surgery within 3 weeks prior to first dose 
19. Subject has clinically significant cardiac disease, including: 

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• 
myocardial infarction within 1 year before Cycle 1 Day 
1, or an unstable or uncontrolled disease/condition 
related to or affecting cardiac function (eg, unstable 
angina, congestive heart failure, New York Heart 
Association Class III-IV 
• 
uncontrolled cardiac arrhythmia (NCI CTCAE Version 
4 Grade 2:2) or clinically significant ECG 
abnormalities 
• 
screening 12-lead ECG showing a baseline QT interval 
as corrected by Fridericia’s formula (QTcF) >470 msec 
20. Uncontrolled HTN 14 days prior to enrollment  
21. Prior or concurrent deep vein thrombosis or pulmonary 
embolism 
22. Rate-corrected QT interval of electrocardiograph (QTc) > 470 
msec on a 12-lead ECG during screening 
23. Uncontrolled hypertension (defined as average systolic blood 
pressure  ≥140 or average diastolic blood pressure  ≥90, with 
blood pressure measured ≥3 times in the two weeks prior to 
enrollment ) or diabetes 
24. Acute infection requiring systemic antibiotics, antivirals, or 
antifungals within two weeks prior to first dose 
25. Active infection 
26. Known seropositive for or active viral infection with human 
immunodeficiency virus (HIV), hepatitis B virus (HBV) or 
hepatitis C virus (HCV). Subjects who are seropositive because 
of hepatitis B virus vaccine are eligible. 
27. Non-hematologic malignancy or non-myeloma hematologic 
malignancy within the past 3 years except a) adequately treated 
basal cell, squamous cell skin cancer, thyroid cancer, carcinoma 
in situ of the cervix, or prostate cancer < Gleason Grade 6 with 
stable prostate specific antigen levels or cancer considered cured 
by surgical resection alone 
28. Any clinically significant medical disease or condition that, in 
the Treating Investigator’s opinion, may interfere with protocol 
adherence or a subject’s ability to give informed consent 
Response 
M-protein determination: 
• 
Serum Protein Electrophoresis (SPEP) and immunofixation 
• 
Urine Protein Electrophoresis (UPEP) and immunofixation 
• 
Serum Free Light Chains  
• 
Serum quantitative immunoglobulins (Igs), only used if SPEP 
and IFIX are felt to be unreliable. In this case, the same 
magnitude of decrease of involved heavy chain immunoglobulin 
as defined in IMWG response criteria for M-spike will be used 
for assigning specific response level. 
Bone marrow biopsy is required to confirm response at time of suspected 
nCR or better (if nCR determination is not possible, then VGPR will be 
used to trigger a bone marrow biopsy. A Bone Marrow Biopsy to 
confirm nCR or VGPR will not be required if the subject is within 2 

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months of a landmark BMBX timepoint), or if PD in marrow is 
suspected. 
MRD by gene sequencing and flow cytometry 
Plasmacytoma evaluation should be completed if clinically indicated 
Safety Variables & 
Analysis 
The safety and tolerability of elotuzumab, lenalidomide, and carfilzomib 
will be evaluated by means of drug related AE reports, physical 
examinations, and laboratory safety evaluations. Common Terminology 
Criteria for Adverse Events (CTCAE) V 4.0 will be used for grading of 
AEs.  Treating Investigators will provide their assessment of causality as 
1) unrelated, 2) unlikely related 3) possibly related, or 4) probably or 5) 
definitely related for all AEs.   
Statistical Analysis 
A total of 55 subjects will be enrolled in a single-stage Phase II design. 
Time to progression or death will be calculated from the date of first 
treatment on protocol until the date of disease progression or death from 
any cause.  Subjects at the time of analysis not having either endpoint 
will be censored as of the last negative exam (tumor 
assessment).  Adherence to protocol and ability to follow subjects in 
follow-up is expected to be excellent; however, if any subject revokes 
consent for further follow-up not due to disease progression, they will be 
censored as of the last negative exam.  Likewise, subjects in follow-up 
that are lost or that refuse or revoke further study participation will be 
censored as of the last negative exam. 
 

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U C M I R B 1 6 -1 1 3 8  
 
El o -K R d V ersi o n  8 0 3 / 2 6 / 2 0 2 0  
P a g e 1 7  
 
 
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  
  
C  
de grees Ce nti gra de  
F  
de grees Fa hre n heit  
A E  
A d verse e ve nt  
A L T  
Ala ni ne a mi n otra nsferase  
A N C  
A bs ol ute ne utr o p hil c o u nt  
A M L  
a P T T 
Ac ute m y el oi d le u ke mia 
Acti vate d partial t hr o m b o plasti n ti me (als o P T T)  
A Sa T  
All S u bjects as Treate d  
A S C T  
A S T  
A S O -P C R  
A ut ol o g o us Ste m Cell Tra ns pla nt  
As partate a mi n otra nsferase  
Allele -S pecific Oli g o n ucle oti de P ol y merase C hai n Reacti o n  
bi d  
T wice dail y  
B S A  
B o d y s urface area  
B U N  
Bl o o d urea nitr o ge n  
C B C  
C o m plete bl o o d c o u nt  
C F R  
C o de of Fe deral Re g ulati o ns  
C H F  
C o n gesti ve heart fail ure 
C K  
C N S  
C R  
Creati ni ne ki nase  
Ce ntral ner v o us s yste m  
C o m plete res p o nse  
Cr Cl  
Creati ni ne Cleara nce  
C R F  
Case re p ort f or m(s)  
C R M 1  
C R O  
C hr o m os o me re gi o n mai nte na nce pr otei n 1  
Cli nical researc h or ga nizati o n  
C S R  
Cli nical St u d y Re p ort  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
C T Sca n  
C V  
C o m p ute d T o m o gra p h y Sca n  
C urric ul u m vitae  
C Y P 4 5 0  
d L  
C yt oc hr o m e P 4 5 0  
Deciliter  
D L T  
D ose -li miti n g t o xicit y 
D N A  
D O R  
De o x yri b o n ucleic aci d  
D urati o n of res p o nse  
D V T  
E C  
Dee p ve n o us t hr o m b osis  
Et hical C o m mittee  
E C G  
Electr ocar di o gra m  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
E O T  
F A S  
E n d of Treat me nt  
F ull A nal ysis Set  
F C B P  
Fe males of c hil d beari n g p ote ntial  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
FI S H  
Fl u oresce nt i n sit u h y bri dizati o n  
F L C  
F PI  
Free li g ht c hai n 
First S u bject  I n 

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FU 
G-CSF 
Follow-up 
Granulocyte colony stimulating factor 
GCP 
Good Clinical Practice  
GI 
GLP 
Gastrointestinal 
Good Laboratory Practice  
GM-CSF 
Granulocyte macrophage colony stimulating factor 
GSH 
h 
Glutathione 
Hour(s) 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
HL 
Human immunodeficiency virus 
Hodgkin’s Lymphoma 
IA 
IB 
ICF 
Interim analysis 
Investigator Brochure 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Igs 
IMWG 
IMiD® 
Independent Ethics Committee 
Immunoglobulins 
International Myeloma Working Group 
Immunomodulatory 
IND 
Investigational New Drug (Application) 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram(s) 
KRAS 
KRd (CRd) 
LDH 
MFC 
Kirsten Rat sarcoma 
Kyprolis (Carfilzomib), Revlimid, Dexamethasone 
Lactate dehydrogenase 
Multiparameter Flow Cytometry 
mg 
Milligram(s) 
min 
Minute(s) 
mIU 
Milli International Units 
mL 
Milliliter(s) 
MM 
Multiple myeloma 
mm2 
Millimeter(s) squared 
mm3 
Millimeter cubed 
MR 
MRD 
Minimal response 
Minimal Residual Disease 
MRI 
MTD 
Magnetic Resonance Imaging 
Maximum tolerated dose 
NCI 
nCR 
National Cancer Institute 
Near Complete Response 
NCT 
NHL 
National Center for Tumor Diseases 
Non-Hodgkin’s lymphoma 
NYHA 
ORR 
New York heart association 
Overall response rate 
OS 
PBMC 
Overall survival 
Peripheral blood mononuclear cells 
PBSCT 
PCCC 
Peripheral Blood Stem Cell Transplant 
Personal Cancer Care Consortium (of the University of Chicago) 

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PD 
Progressive disease 
PDn 
PFS 
PI 
PIS 
Pharmacodynamics 
Progression-free survival 
Proteasome Inhibitor 
Subject Information Sheet 
PK 
Pharmacokinetics 
PO 
Per os (oral) 
PR 
Partial response 
PSA 
Prostate-specific antigen 
PT 
Pt 
Prothrombin time 
Subject 
PTT 
Partial thromboplastin time 
QDx5 
Daily dosing for five days 
QI 
Qualified Investigator Undertaking Form 
RBC 
Red blood cell 
RECIST 
SAE 
Response Evaluation Criteria in Solid Tumors 
Serious adverse event 
SAP 
Statistical Analysis Plan 
sCR 
Stringent complete response 
SD 
Stable disease 
SEER 
SFLCs 
Surveillance, Epidemiology, and End Results 
Serum Free Light Chains 
SINE 
SOC 
SPEP 
SPM 
Selective Inhibitor of Nuclear Export 
System Organ Class 
Serum protein electrophoresis 
Second Primary Malignancies 
STD10 
Severely toxic dose in 10% of animals 
SUSAR 
TK 
TLS 
Suspected unexpected serious adverse reaction 
Toxicokinetics 
Tumor lysis syndrome 
TSH 
TSP 
TTP 
Thyroid Stimulating Hormone 
Tumor Suppressor Protein 
Time to tumor progression 
UCM 
UPEP 
VGPR 
 
 
 
University of Chicago Medicine 
Urine Protein Electrophoresis 
Very Good Partial Response 
 
 
 

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1. 
INTRODUCTION 
1.1. Overview of Multiple Myeloma 
Multiple myeloma is a clonal neoplastic proliferation of plasma cells affecting 19,900 US subjects 
each year (Ries LAG, 2007). Multiple myeloma is characterized by anemia, bone destruction, 
monoclonal gammopathy, renal failure, hypercalcemia and increased susceptibility to infections. 
The disease is systemic, and chemotherapy is indicated for management of symptomatic myeloma. 
Current front-line treatments include combination chemotherapy with regimens using melphalan 
(Alkeran®), bortezomib (Velcade®), thalidomide (Thalomid®), and lenalidomide (Revlimid®) and 
their combinations with and without corticosteroids. In addition, Carfilzomib (Kyprolis®), 
Pomalidomide (Pomalyst®), daratumumab (Darzalex®), elotuzumab (Empliciti®), and ixazomib 
(Ninlaro®) have been approved in the treatment of relapsed disease. Younger subjects are 
consolidated with high-dose therapy (ablative chemotherapy or radiation) with autologous stem cell 
transplantation (ASCT). Although improvements in progression free survival and overall survival 
have occurred in the past 5 years, even with the best available approved agents, 10-30% of subjects 
fail to respond to the primary therapy, and almost all subjects eventually relapse, with a median 
overall survival of 44.8 months (Kumar et al., 2008). 
1.2. Proteasome Background 
The proteasome is a multicatalytic proteinase complex that is responsible for degradation of a wide 
variety of protein substrates within normal and transformed cells.  Intracellular proteins targeted for 
degradation by the proteasome are first ubiquitinated via the ubiquitin conjugation system.  
Ubiquitinated proteins are cleaved within the proteasome by one or more of three separate threonine 
protease activities: a chymotrypsin-like activity, a trypsin-like activity, and a caspase-like activity.   
1.3. Carfilzomib Background 
Carfilzomib (PR-171, Kyprolis®) is a tetrapeptide ketoepoxide-based inhibitor specific for the 
chymotrypsin-like active site of the 20S proteasome.  Carfilzomib is structurally and mechanistically 
distinct from the dipeptide boronic acid proteasome inhibitor bortezomib (Velcade®).  In addition, 
when measured against a broad panel of proteases including metallo, aspartyl, and serine proteases, 
carfilzomib demonstrated less reactivity against non-proteasomal proteases when compared to 
bortezomib (Arastu-Kapur S, Nov 2008; Demo et al., 2007). 
Indications and Usage: Carfilzomib (Kyprolis®) is a proteasome inhibitor indicated for the 
treatment of subjects with multiple myeloma who have received at least two prior therapies including 
bortezomib and an immunomodulatory agent and have demonstrated disease progression on or 
within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, 
such as improvement in survival or symptoms, has not been verified. More details can be found on 
the package insert and in the Investigator Brochure. 
Adverse Events: Most commonly reported adverse reactions (incidence ≥ 30%) are fatigue, anemia, 
nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia.Complete and updated adverse events are 
available in the Investigator Brochure and the IND Safety Letters. 
1.4. Lenalidomide Background 
Lenalidomide (Revlimid®) is a proprietary IMiD® compound of Celgene Corporation.  IMiD® 
compounds have both immunomodulatory and anti-angiogenic properties which could confer 
antitumor and antimetastatic effects.  Lenalidomide has been demonstrated to possess anti-
angiogenic activity through inhibition of bFGF, VEGF and TNF-alpha induced endothelial cell 
migration, due at least in part to inhibition of Akt phosphorylation response to bFGF (Dredge et al., 
2005). In addition, lenalidomide has a variety of immunomodulatory effects.  Lenalidomide 

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stimulates T cell proliferation, and the production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 beta 
and IL-6 and modulates IL-12 production (Dredge et al., 2005). Upregulation of T cell derived IL-
2 production is achieved at least in part through increased AP-1 activity (Corral et al., 1999). 
Although the exact antitumor mechanism of action of lenalidomide is unknown, a number of 
mechanisms are postulated to be responsible for lenalidomide’s activity against multiple myeloma.  
Lenalidomide has been shown to increase T cell proliferation, which leads to an increase in IL-2 and 
IFN-gamma secretion.  The increased level of these circulating cytokines augment natural killer cell 
number and function, and enhance natural killer cell activity to yield an increase in multiple 
myeloma cell lysis (Schafer et al., 2003). In addition, lenalidomide has direct activity against 
multiple myeloma and induces apoptosis or G1growth arrest in multiple myeloma cell lines and in 
multiple myeloma cells of subjects resistant to melphalan, doxorubicin and dexamethasone (Davies 
et al., 2001). 
Indications and Usage: REVLIMID is a thalidomide analogue indicated for the treatment of 
subjects with: 
• 
Multiple myeloma (MM), in combination with dexamethasone  
• 
Transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic 
syndromes (MDS) associated with a deletion 5q abnormality with or without additional 
cytogenetic abnormalities  
• 
Mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior 
therapies, one of which included bortezomib  
Adverse Events: Most common adverse reactions (≥20%) include diarrhea, fatigue, anemia, 
constipation, neutropenia, peripheral edema, insomnia, muscle cramp/spasms, back pain, nausea, 
asthenia, pyrexia, upper respiratory tract infection, cough, rash, dyspnea, dizziness, decreased 
appetite, thrombocytopenia, and tremor (6.1). 
Complete and updated adverse events are available in the package insert. 
1.4.1. Dose Rationale 
1.4.1.1. 
Carfilzomib Dose Rationale 
Data suggest that carfilzomib as a single agent can produce substantial response rates in myeloma 
subjects across a variety of dosing cohorts.  Responses were seen over a wide therapeutic window, 
from 15 to 70 mg/m2.  Maximum proteasome inhibition was seen at doses 11 mg/m2 and higher in 
whole blood samples taken 1 hour after the first dose.   Carfilzomib is rapidly cleared from plasma 
with an elimination half-life of < 60 minutes at the 20 mg/m2 dose.  Large, single arm studies of the 
27 mg/m2 dose have demonstrated that this dose is very well tolerated with subjects being treated 
for >10 cycles without cumulative toxicities. 
Carfilzomib is currently approved by the FDA in combination with lenalidomide and 
dexamethasone for the treatment of subjects with relapsed multiple myeloma who have received one 
to three prior lines of therapy. The recommended dose is 20mg/m2 on cycle 1 day 1 and can be 
escalated to 27mg/m2 on day 8 of cycle 1 on twice weekly schedule, i.e. on days 1, 2, 8, 9, 15, 16 in 
28-day cycles. At this time, the MTD had not been defined but the dose of 36 mg/m2 on the same 
schedule was established as tolerated in newly diagnosed myeloma (Jakubowiak et al., 2012b; 
Jakubowiak, 2016; Korde et al., 2015).  
In the past year, an alternative schedule of carfilzomib with weekly infusion on days 1, 8, 15 in 28-
days cycles was evaluated in several studies. A number of already published as well as ongoing 

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evaluations reported the MTD of carfilzomib at 70mg/m2 given once weekly in combinations 
(Berenson et al., 2016). Additionally, this weekly dose of carfilzomib was formally evaluated versus 
original twice-weekly schedule in the randomized ARROW trial, which completed enrollment with 
results still pending. Finally, the KRd+Daratumumab arm of the ongoing Janssen MMY1001 trial 
completed enrollment using weekly dosing of carfilzomib with 70mg/m2 per dose in combination 
with lenalidomide, dexamethasone, and daratumumab. 
1.5. Elotuzumab Background 
Elotuzumab (HuLuc63/BMS-901608) is a humanized monoclonal IgG1 antibody product directed 
to human CS1 (CD2 subset-1, also known as CRACC and SLAMF7), a cell surface glycoprotein 
with homology to the CD2 family of cell surface proteins (Boles and Mathew, 2001; Tassi and 
Colonna, 2005). Originally, CS1 was identified as a natural killer cell (NK) marker and was shown 
to be expressed in a subset of circulating leukocytes (Boles et al., 2001). Blood analysis confirmed 
expression of CS1 on the cell surface of NK, NK-like T-cells (NKT), activated monocytes, CD8 
positive T cells, and on tissue plasma cells (Hsi et al., 2008). High CS1 expression was seen in 
plasma cells obtained from normal healthy donors and from subjects with MGUS, SMM, and 
active MM. More than 90% of MM bone marrow samples, irrespective of cytogenetic 
abnormalities, express CS1. In addition CS1 expression is maintained in MM subjects after relapse 
from therapy. A paired analysis of a subset of subjects with MM showed that CS1 gene expression 
is detectable in subjects both at diagnosis and at relapse. 
 
In agreement with the gene chip data, flow cytometry analysis demonstrated that CD138+ plasma 
cells from MM bone marrow stained strongly positive for elotuzumab binding. In addition, 
immunohistochemistry (IHC) using anti-CS1 antibodies showed strong staining of MM cells in 9/9 
plasmacytoma tissue samples and in 20/20 myeloma bone marrow cores tested (Hsi et al., 2008) 
The proposed mechanism of action of elotuzumab involves natural killer (NK) cell mediated 
antibody dependent cell-mediated cytotoxicity (ADCC). Elotuzumab monotherapy can kill MM 
cell lines and primary myeloma cells in vitro in the presence of peripheral blood mononuclear cells 
(PBMCs) or purified NK cells. In addition, elotuzumab exhibits significant in vivo monotherapy 
anti-tumor activity against human myeloma xenograft models grown in severe combined 
immunodeficient (SCID) mice (Hsi et al., 2008; Tai et al., 2008). This in vivo anti-tumor activity 
of elotuzumab appears to be largely dependent on the presence of active NK cells. Experiments 
using an in vivo mouse xenograft model suggest that maximal antitumor activity is reached at 
elotuzumab serum levels of 70 to 430 mcg/mL. 
 
Indications and Usage: Elotuzumab (EMPLICITI®) is a SLAMF7-directed immunostimulatory 
antibody indicated in combination with lenalidomide and dexamethasone for the treatment of 
subjects with multiple myeloma who have received one to three prior therapies. More details can 
be found on the package insert and in the Investigator Brochure. 
 
Dosage and Administration:  
• 
With lenalidomide and dexamethasone: 10 mg/kg administered intravenously every week 
for the first two cycles and every 2 weeks thereafter until disease progression or 
unacceptable toxicity.   
• 
Pre-medicate with dexamethasone, diphenhydramine, ranitidine and acetaminophen 
 
Adverse Reactions: Most common adverse reactions (20% or higher) are fatigue, diarrhea, 
pyrexia, constipation, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract 
infection, decreased appetite, pneumonia. 
Complete and updated adverse events are available in the package insert. 

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1.5.1.1. 
Infusion Reactions 
Elotuzumab can cause infusion reactions. Infusion reactions were reported in approximately 10% 
of subjects treated with elotuzumab with lenalidomide and dexamethasone in the randomized trial 
in multiple myeloma. All reports of infusion reaction were Grade 3 or lower. Grade 3 infusion 
reactions occurred in 1% of subjects. The most common symptoms of an infusion reaction 
included fever, chills, and hypertension. Bradycardia and hypotension also developed during 
infusions. 
In the trial, 5% of subjects required interruption of the administration of elotuzumab for a median 
of 25 minutes due to infusion reactions, and 1% of subjects discontinued due to infusion reactions. 
Of the subjects who experienced an infusion reaction, 70% (23/33) had them during the first dose.  
Administer premedication consisting of dexamethasone, antihistamines (H1 and H2 blockers) and 
acetaminophen prior to elotuzumab infusion (See section 6.5.2) 
Interrupt elotuzumab infusion for Grade 2 or higher infusion reactions and institute appropriate 
medical management (See section 6.5.2).  
1.5.1.2. 
Overall Risk/Benefit Assessment 
Elotuzumab is a humanized monoclonal IgG1 antibody directed to human CS1, a cell surface 
glycoprotein. CS1 is expressed on plasma cells and a subset of circulating leukocytes. Since 
elotuzumab does not recognize non-human CS1, minimal animal toxicology has been performed. 
Non-clinical activity as monotherapy as well as in combination led to human trials. Although as 
monotherapy in heavily pretreated subject the best responses were SD, elotuzumab showed high 
response rates in combination with bortezomib or lenalidomide. 
Elotuzumab was approved in November of 2015 for treatment of relapsed MM subjects with prior 
1-3 lines of therapy. Please refer to the package insert and Investigator’s Brochure for more 
information. 
1.6. Study Rationale 
Previous studies have indicated that the KRd combination (formerly CRd) is highly active in new 
myeloma; best response for all subjects on ITT (N=53) 98% PR, 87% VGPR, 72% >nCR, 64% CR, 
55% sCR, and 51% MRD-negative rate, 3-year PFS of 79% (Jakubowiak, 2016) and is well tolerated 
in both new myeloma (Jakubowiak, 2016) as well is in relapsed myeloma (Stewart et al., 2015). 
Additionally, the combination of elotuzumab with lenalidomide and dexamethasone is more active 
than Rd and well tolerated in relapsed MM with no significant added or overlapping toxicity after 
an addition of elotuzumab (Lonial et al., 2015; Moreau, 2012; Moreau et al., 2012). Finally, the 
combination of elotuzumab with proteasome inhibitor (bortezomib) shows encouraging activity 
suggestive of additive effect and no significant overlapping toxicity (Jakubowiak et al., 2012a). We 
hypothesize that an addition of elotuzumab to KRd combination (E-KRd combination), which 
includes both proteasome inhibitor (carfilzomib), and immunomodulatory drug (lenalidomide) will 
further improve treatment outcome, including the rate of CR/sCR and rate of MRD-negative disease.   
As recently reported, incorporation of autologous stem cell transplant into KRd treatment of newly 
diagnosed myeloma improves rates of CR and MRD-negative disease, and appears to further 
improve PFS (Jakubowiak, 2016) providing, as a proof of concept, evidence that KRd results can 
further be improved. Since the achievement of CR and MRD negative status is associated with 
improved long term-control of the disease (Dytfeld et al., 2011; Harousseau et al., 2010), and 
elotuzumab in particular improves time to event in combination with IMiD and PI, this regimen may 
further improve overall treatment outcome in myeloma.  

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We hypothesize that treatment with E-KRd will improve the rate of sCR and/or the rate of negative 
MRD by  next generation gene sequencing (NGS) by clonoSEQ (Adaptive Biotechnologies)  at the 
end of 8 cycles among non-transplant candidates or transplant candidates who agreed to defer 
transplant compared to historical results of KRd alone. We would like to investigate this in the 
proposed study, in subjects who are newly diagnosed and who are transplant ineligible or those who 
are transplant-eligible, and choose to delay transplant. The primary efficacy endpoint will be the rate 
of sCR and/or the rate of negative MRD by NGS at the end of 8 cycles among non-transplant 
candidates and/or transplant candidates who agreed to defer transplant.  
Among secondary objectives, we propose to evaluate the status of MRD disease at established 
landmark time-points, and to use MRD status to determine the duration of E-KRd treatment. We 
anticipate that E-KRd treatment will result in a statistically improved rate of MRD-negative disease 
compared to the MRD rate observed in subjects who were treated with KRd in the historical trial. 
Based on the results from the IMF study (Avet-Loiseau et al., 2015) we propose to use different 
durations of E-KRd treatment using MRD status as the modifying criteria. There will be 3 possible 
outcomes: 
1) Subjects who have MRD-negative disease at the completion of 8 and 12 cycles of E-KRd 
will receive a shorter duration of E-KRd treatment (for a total of 12 cycles) and continue on 
E-Rd maintenance until disease progression.  
2) Subjects that are MRD-positive after cycle 8 but transform to MRD-negative after 12 cycles 
of E-KRd will receive an additional 6 cycles of E-KRd and then continue on E-Rd 
maintenance until disease progression.  
3) Subjects that are MRD-positive after 8 and 12 cycles, will receive an additional 12 cycles 
of E-KRd and then continue on E-Rd maintenance until disease progression.   
To make safety the highest priority, the protocol will (1) incorporate scheduled dose reductions of 
dexamethasone and will (2) provide aggressive required dose modifications with the emergence of 
any treatment related toxicities greater than G1. 
1.7. Study Population and Sample Size  
A total of 40, non-transplant candidates, and/or transplant candidates who agreed to defer transplant 
will be enrolled. Since the study does not plan to exclude transplant candidates who do not wish to 
defer transplant, additional 15 subjects who discontinue E-KRd treatment and proceed to transplant 
are planned to be enrolled to generate additional tolerability and toxicity data, bringing the total 
number of subjects to be enrolled to 55. Subjects that continue to transplant will be removed from 
the study and censored at the end of 4 cycles. These subjects will not be followed up or further 
analyzed. Intention to go on ASCT will be required at the time of enrollment with 15 subjects 
planned in this category per study design. Subjects who were assigned to the ‘non-ASCT’ or 
‘deferred ASCT’ category who proceed to ASCT for reasons other than disease progression or 
toxicity, will be replaced (up to 5 subjects). 
For 40 non-transplant candidates and/or transplant candidates who agreed to defer transplant, we 
hypothesize that treatment with E-KRd will improve the rate of sCR at the end of 8 cycles among 
non-transplant candidates or transplant candidates who agreed to defer transplant compared to 
historical results of KRd alone.  
1.8. Assessment for Response  
Response will be determined according to the IMWG response criteria for multiple myeloma (2006). 
Disease assessment for response will include Serum Protein Electrophoresis (SPEP), Urine Protein 
Electrophoresis (UPEP), Serum Free Light Chains (SFLC) and Immunoglobulins (Igs). Bone 
marrow procedures should be completed at the time of suspected near complete response (or very 

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good partial response when nCR cannot be determined). A serum sample from blood at landmark 
timepoints (after C4, 8, 12, and 18, 24 months after C1D1, and yearly after) will be required for 
banking at the University of Chicago for later M-spike analysis with a new elotuzumab interference 
assay. This assay will use mass spectrometry and is not commercially available. This assay is 
proprietary to BMS, which will receive banked samples and perform this assay. Assay results will 
not be used for clinical decision-making, but rather to assess and confirm the primary endpoint of 
stringent CR.  
 
Additionally, for subjects who have a plasmacytoma or disease measured by imaging at baseline, 
plasmacytoma evaluations and radiographic imaging should be completed as per standard of care 
and in accordance with IMWG response criteria for multiple myeloma. Subjects who achieve SD, 
PR, or CR will continue therapy until disease progression. Subjects with disease progression will 
discontinue the treatment regimen and be removed from protocol. 
2. 
OBJECTIVES 
2.1. Primary Objective 
• 
The primary efficacy endpoint will be the rate of sCR and/or the rate of negative MRD by  
next generation gene sequencing (NGS) by clonoSEQ (Adaptive Biotechnologies) at the 
end of 8 cycles among non-transplant candidates and transplant candidates who agreed to 
defer transplant    
2.2. Secondary Objectives 
• 
To evaluate the safety and tolerability of elotuzumab in combination with KRd, when 
administered to subjects with newly diagnosed multiple myeloma. 
• 
Determine the rate of MRD by next generation gene sequencing (NGS) by clonoSEQ 
(Adaptive Biotechnologies) and by multi-color flow cytometry (MFC) at the end of Cycle 
4, 8,and 12 for all subjects, and end of C18 (for subjects who are MRD+ at the end of C8 
but MRD- at the end of C12 only), 24 months after C1D1, and yearly after that. 
• 
Estimate time to event, including duration of response (DOR), progression-free survival 
(PFS), time to progression (TTP), and overall survival (OS). 
2.3. Exploratory Objectives 
• 
GEP, proteomics, and gene sequencing to evaluate the correlation between treatment 
outcome and pre-treatment subject profile.  
• 
Immunologic correlative studies including FcγRIIIa V genotype.   
3. 
STUDY ENDPOINTS 
 
3.1. Primary Endpoints 
• 
To determine the rate of sCR and/or the rate of negative MRD by NGS at the end of 8 cycles 
per IMWG criteria. 

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3.2. Secondary Endpoints 
• 
Evaluate the safety and tolerability of elotuzumab in combination with KRd by monitoring 
AE rate, classification, and relation to study drug 
• 
Compare rates of MRD between MFC and NGS at the end of cycles 4, 8,and 12 for all 
subjects, and end of C18 (for subjects who are MRD+ at the end of C8 but MRD- at the end 
of C12 only), 24 months after C1D1, and yearly after that. 
• 
Estimate the time to event including duration of response (DOR), progression-free survival 
(PFS), time to progression (TTP), and overall survival (OS) 
3.3. Tertiary/Exploratory Endpoints 
• 
Conduct GEP, Proteomic, and gene sequencing studies to evaluate the correlation between 
treatment outcome and pre-treatment subject profile 
• 
Conduct immunologic correlative studies including FcγRIIIa V genotype 
4. 
INVESTIGATIONAL PLAN 
4.1. Overview of Study Design and Dosing Regimen 
 
This is a Phase 2, open-label, multicenter study studying the safety and tolerability to the 
combination therapy of elotuzumab, lenalidomide, carfilzomib, and dexamethasone for newly 
diagnosed subjects with multiple myeloma requiring systemic chemotherapy.  
Subjects will receive treatment until disease progression or unacceptable toxicity (whichever 
occurs first). The primary endpoint of this Phase 2 study is to determine the rate of sCR and/or the 
rate of negative MRD by NGS at the end of 8 cycles per IMWG criteria and to evaluate the safety 
and tolerability of elotuzumab in combination with KRd, when administered to subjects with 
newly diagnosed multiple myeloma. 
4.2. Study Procedures 
On cycles 1 and 2, subjects will receive elotuzumab weekly on days 1, 8, 15, and 22 of a 28-day 
cycle at 10mg/kg. From cycle 3 onward, elotuzumab will be dosed every other week on days 1 and 
15 at 10mg/kg..  
Carfilzomib will be dose escalated on cycle 1 as follows: 20 mg/m2 on day 1, 56mg/m2 on day 8, 
and 56mg/m2 on day 15. Between cycles 2-8, carfilzomib will be given on days 1, 8, and 15 of a 28-
day cycle at 70 mg/m2. From cycle 9 onward, carfilzomib will be given at the best-tolerated dose on 
days 1 and 15 of a 28-day cycle. Splitting carfilzomib dose to 27 mg/m2 on days 8, 9 and 36 mg/m2 
on days 15, 16, and in subsequent cycles on days 1, 2, 8, 9, 15, 16 – as in the original KRd 2-day 
weekly schedule – will be allowed based on discussion with the lead PI.  
Lenalidomide will be given initially at 25mg per dose daily on days 1-21 of a 28-day cycle for cycles 
1-8. From cycle 9 onward, lenalidomide will be dosed at last tolerated dose daily on days 1-21 of a 
28-day cycle.  
Dexamethasone will initially be give 40 mg weekly (cycles 1-4), which in the first cycle will be split 
into two doses as follows: 20mg of dexamethasone will be given IV on days 1, 8, and 15 no more 
than 3 hours prior to elotuzumab infusion and 20mg on days 2, 9, and 16 will be taken PO. If in the 
course of dose modification carfilzomib is split, dex will be given prior to carfilzomib. 
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40mg dexamethasone will be given IV no longer than 3 hours prior to elotuzumab. In cycles 2-4 
40mg dexamethasone will be taken PO (or IV) on days 1, 8, 15, and 22. On days when 
dexamethasone coincides with elotuzumab, dexamethasone will be taken no longer than 3 hours 
prior to elotuzumab infusion. For cycles 5+ dexamethasone will be reduced to 20 mg PO or IV 
weekly. 
Dose modifications will be mandated based on aggressive schedule of dose modification for 
toxicities as per specific guidelines. Otherwise, subjects will continue at their best tolerated dose of 
lenalidomide on days 1-21 and their best tolerated dose of carfilzomib on days 1, 8, 15 in cycles 1-
8 and days 1, 15, in cycles 9-12 (in subjects with MRD- disease at the end of cycle 8 and 12) or 
cycles 9-18 (in subjects with MRD+ disease at the end of cycle 8 but MRD- at the end of cycle 12) 
or cycles 9-24 (in subjects with MRD+ disease at the end of cycle 8 and 12). See section 1.7. 
All subjects will have weekly visits for toxicity assessments in the first cycle and then monthly from 
cycles 2+. Disease assessments will start on Cycle 1 Day 15 and then will be done on clinic visits 
on day 1 of each cycle. Treatment will continue on protocol for up to 24 months or if elotuzumab, 
carfilzomib and lenalidomide are permanently discontinued. Toxicity will be graded using the 
National Cancer Institute Common Terminology Criteria for Adverse Events version 4. Subject who 
complete 12 cycles (who are MRD-negative at the end of cycle 8 and 12), 18 cycles (who were 
MRD-positive at the end of cycle 8 but MRD-negative at the end of cycle 12), or 24 cycles (who 
were MRD-positive after cycle 8 and 12) of E-KRd, will then continue elotuzumab, lenalidomide, 
dexamethasone (E-Rd) maintenance.. This regimen will continue until there is progression of the 
disease or the toxicities require discontinuation of the drug. 
Minimal residual disease analysis will be performed at the end of cycle 8 and 12 to determine the 
course of treatment (either move to ERd maintenance at the end of 12, 18, or 24 cycles of E-KRd. 
See section 1.7). MRD analysis will be performed using the most recent Spanish protocol by 
multiparameter flow cytometry (10-color) and by Next Generation Sequencing (NGS). MRD will 
be assessed in all bone marrow samples at the beginning of the study, after cycles 4, 8, 12, and 18 
(when applicable), 24 months after C1D1, yearly after that, and at any time a bone marrow biopsy 
is completed to assess response for suspected nCR (or VGPR when nCR assessment is not possible). 
From the time nCR (or VGPR) is established, MRD analysis should continue at 12-month intervals 
from randomization up to 6 years in subjects with ongoing sCR. If a confirmatory BM for nCR is 
scheduled within 2 months of a hallmark BM, it is acceptable to wait until the hallmark timepoint. 
All flow cytometry analysis will be performed at the University of Chicago, based on a consensus 
for the most recent technical guidelines and flow cytometry (current EuroFlow technique) 
parameters as outlined by Orfeo et al. (MRD IMWG meeting New York, NY 2014). The same 
samples will be evaluated by Adaptive Biotechnologies using clonoSEQ® platform after processing 
at the University of Chicago site. For this purpose, sites will be required to provide a fresh screening 
BM sample at all timepoints. At screening only, alternatively, non-decalcified slides from the BM 
aspirate, or FFPE clot slides can be used to establish a baseline for MRD samples analyzed by 
Adaptive Biotechnologies. Decisions to change treatment at indicated time points will be based 
primarily on MRD results by NGS. Only if NGS testing is not successful (i.e. either at the calibration 
or measurement step), flow-based results will be used for decision about duration of E-KRd 
treatment. 
Treatment responses will be assessed by serum and urine monoclonal protein electrophoresis and 
immunofixation and serum free light chains (SFLC) and where needed by serum protein 
immonglobulins at Cycle 1 Day 15, then at Cycle 2 Day 1 and then at the beginning of each 
subsequent cycle. A serum sample from blood at landmark timepoints (after C4, 8, 12, and 18, 24 
months after C1D1, and yearly after) will be required for banking at the University of Chicago for 
later M-spike analysis with a new elotuzumab interference assay. The analysis of banked samples 
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Subjects with stable disease or better will continue treatment until disease progression or the 
development of unacceptable toxicities. All subjects will then undergo a final visit (end of treatment 
visit) within 30 (+/-7) days of last dose of study medication. 
4.2.1. MRD Detection Methods 
The tests used Minimal Residual Disease (MRD) after cycles 8 and 12 is considered experimental 
and has not been approved by the US Food & Drug Administration (FDA) for use in evaluating 
MRD disease in multiple myeloma.  
The flow cytometry analysis procedure used to determine MRD is performed on a NAVIOS 
FLOW CYTOMETER SYSTEM manufactured by BECKMAN COULTER, INC., using a 
laboratory developed assay. The Premarket Notification 510(k) (Number K130373) for the device 
can be found using the following link. 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K130373.  
4.2.2. Number of Centers 
A total of 5 centers in the US will participate. 
4.2.3. Definition of Treatment Cycle and Duration 
Each treatment cycle is 28 days. The study is planned to start in Q4 2016 with respect to first subject 
in (FSI). With an expected accrual rate of 2-4 subjects per month across 5 centers, and a total number 
of 40-55 subjects planned, the anticipated enrolment period is 12 -18 months. Hence the last subject 
in will be included not prior to Q4 2017. The length of treatment period will be up to 24 months. 
Subjects will be followed for survival for up to 6 years since their enrollment or until death, 
whichever occurs first. 
4.2.4. Treatment Phase  
Treatment will be continued until progression of disease according to IMWG criteria, until the 
subject goes into transplant, unacceptable toxicities occur in individual subjects, or consent is 
withdrawn.  
4.2.5. End of Treatment Visit  
Subjects that discontinue from treatment will undergo an end of treatment visit, regardless of the 
reason of discontinuation, 30 (+/-7) days after the last dose of study medication. 
4.2.6. Long Term Follow Up 
Subjects will be followed up every 3 months for progression and survival after the end of 
treatment. Subjects will be followed for survival for up to 6 years after enrollment or until death, 
whichever occurs first.  The follow up will be done over the phone. 
5. 
SUBJECT SELECTION 
5.1. Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible to enroll in this study. No 
enrollment waivers will be granted. 
1. Newly diagnosed, previously untreated myeloma requiring systemic chemotherapy 

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a. Prior treatment of hypercalcemia or spinal cord compression or active and/or 
aggressively progressing myeloma with corticosteroids and/or lenalidomide and/or 
bortezomib/PI-based regimens does not disqualify the subject. The corticosteroid 
treatment dose should not exceed the equivalent of 160 mg of dexamethasone in a 
4 week period or not more than 1 cycle of lenalidomide and/or PI-based therapy. 
A higher total dose of corticosteroid is allowed for the management of cord 
compression at the discretion of the PI, as long as the subject does not exhibit any 
steroid related toxicities at the initiation of study treatment. 
2. Both transplant and non-transplant candidates are eligible. 
3. Diagnosis of symptomatic multiple myeloma as per current IMWG uniform criteria prior to 
initial treatment 
4. Monoclonal plasma cells in the BM 10% or presence of a biopsy-proven plasmacytoma 
5. Measurable disease, prior to initial treatment as indicated by one or more of the following: 
a. Serum M-protein ≥ 1 g/dL  
b. Urine M-protein ≥ 200 mg/24 hours 
c. If serum protein electrophoresis is felt to be unreliable for routine M-protein 
measurement, then quantitative immunoglobulin levels are acceptable (≥ 1 g/dL) 
d. Involved serum free light chains ≥ 10 mg/dL provided that free light chain 
ratio is abnormal 
 
 
6. Screening laboratory values must meet the following criteria and should be obtained within 
21 days prior to enrollment 
i. WBC   
≥ 2000/μL 
ii. Platelets 
 ≥ 75 x103/μL 
iii. ANC  
>1000/μL 
iv. Hemoglobin  > 8.0 g/dL 
v. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) 
≥ 50 mL/min  
a) Use the Cockcroft-Gault formula below): 
o Female CrCl = (140 - age in years) x weight in kg x 
0.85 
• 72 x serum creatinine in mg/dL 
 
o Male CrCl = (140 - age in years) x weight in kg x 1.00  
1. 72 x serum creatinine in mg/dL 

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b) Alternatively to Cockroft-Gault formula of CrCl, 24hr urine 
CrCl can be used 
vi. AST/ALT  
≤ 3 x ULN  
vii. Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, 
who can have total bilirubin < 3.0 mg/dL) or ≤ 2 x ULN if 
lenalidomide is being prescribed.  
7. Males and females ≥ 18 years of age  
8. ECOG performance status of 0-1 
9. Females of childbearing potential (FCBP) must have 2 negative pregnancy tests (sensitivity 
of at least 25 mIU/mL) prior to initiating lenalidomide. The first pregnancy test must be 
performed within 10-14 days before and the second pregnancy test must be performed 
within 24 hours before lenalidomide is prescribed for Cycle 1 (prescriptions must be filled 
within 7 days). 
10. FCBP must agree to use 2 reliable forms of contraception simultaneously or to practice 
complete abstinence from heterosexual intercourse during the following time periods related 
to this study: 1) for at least 28 days before starting lenalidomide; 2) while participating in 
the study; and 3) for at least 28 days after discontinuation from the study. 
11. Male subjects must agree to use a latex condom during sexual contact with females of 
childbearing potential while participating in the study and for at least 28 days following 
discontinuation from the study even if he has undergone a successful vasectomy. 
12. All study participants in the US must be consented to and registered into the mandatory 
Revlimid REMS® program and be willing and able to comply with the requirements of 
Revlimid REMS®. 
13. Voluntary written informed consent 
 
5.2. Exclusion Criteria 
Subjects meeting any of the following exclusion criteria are not eligible to enroll in this study. No 
enrollment waivers will be granted. 
1. Non-secretory or hyposecretory multiple myeloma, prior to initial treatment defined as <1.0 
g/dL M-protein in serum, <200 mg/24 hr urine M-protein, and no measurable disease as per 
IMWG by Freelite. 
2. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, 
and skin changes) 
3. Geriatric assessment score of ≥2 as defined by Palumbo et al. 
4. Known or suspected Amyloidosis 
5. Plasma cell leukemia 
6. Within 4 weeks since any plasmapheresis 
7. Within 3 weeks of any corticosteroids except per inclusion criteria #2 
8. Waldenström’s macroglobulinemia or IgM myeloma 
9. Participation in an investigational therapeutic study within 3 weeks or within 5 drug half-
lives (t1/2) prior to first dose, whichever time is greater 
10. Subjects not able to tolerate elotuzumab, lenalidomide, carfilzomib, or dexamethasone 
11. Peripheral neuropathy ≥ Grade 2 at screening 
12. Prior CVA with persistent neurological deficit 

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13. Diarrhea > Grade 1 in the absence of antidiarrheals 
14. Corrected calcium ≥ 11.5 mg/dL within 2 weeks of randomization 
15. CNS involvement 
16. Pregnant or lactating females 
17. Radiotherapy within 14 days before randomization. Seven days may be considered if to 
single area  
18. Major surgery within 3 weeks prior to first dose 
19. Subject has clinically significant cardiac disease, including: 
• 
myocardial infarction within 1 year before Cycle 1 Day 1, or an unstable or 
uncontrolled disease/condition related to or affecting cardiac function (eg, 
unstable angina, congestive heart failure, New York Heart Association Class III-
IV 
• 
uncontrolled cardiac arrhythmia (NCI CTCAE Version 4 Grade 2:2) or clinically 
significant ECG abnormalities 
• 
screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s 
formula (QTcF) >470 msec 
20. Uncontrolled HTN 14 days prior to enrollment 
21. Prior or concurrent deep vein thrombosis or pulmonary embolism 
22. Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead ECG 
during screening 
23. Uncontrolled hypertension (defined as average systolic blood pressure  ≥140 or average 
diastolic blood pressure  ≥90, with blood pressure measured ≥3 times in the two weeks prior 
to enrollment ) or diabetes 
24. Acute infection requiring systemic antibiotics, antivirals, or antifungals within two weeks 
prior to first dose 
25. Active infection 
26. Known seropositive for or active viral infection with human immunodeficiency virus (HIV), 
hepatitis B virus (HBV) or hepatitis C virus (HCV). Subjects who are seropositive because 
of hepatitis B virus vaccine are eligible. 
27. Non-hematologic malignancy or non-myeloma hematologic malignancy within the past 3 
years except a) adequately treated basal cell, squamous cell skin cancer, thyroid cancer, 
carcinoma in situ of the cervix, or prostate cancer < Gleason Grade 6 with stable prostate 
specific antigen levels or cancer considered cured by surgical resection alone 
28. Any clinically significant medical disease or condition that, in the Treating Investigator’s 
opinion, may interfere with protocol adherence or a subject’s ability to give informed 
consent 
5.3 SUBJECT ENROLLMENT AND REGISTRATION 
5.3.1 
Registration Process 
 
Prior to registration and any study-specific evaluations being performed, all subjects must have 
given written informed consent for the study and must have completed the pre-treatment evaluations.  
Subjects must meet all of the eligibility requirements listed in Section 5.  
Registration will be done centrally at University of Chicago. All subjects who have signed consent, 
regardless of if they are enrolled or not, will be entered into the University of Chicago Clinical Trials 
Management database, eVelos, within 24 hours of signing consent. Subjects will be assigned a 
unique subject number that will remain consistent for the duration of the study. Sites should make 

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all enrollment requests at least 72 hours before the anticipated start date of Cycle 1 Day 1. Screening 
and on-treatment assessments are expected to be entered into eVelos within two weeks of study-
required visits. 
The Lead PI or designee will be responsible for approving the eligibility of all subjects. Specifically, 
once all required screening assessments have been performed, the information will have to be 
reviewed by the Lead Principal Investigator or designee. When the subject’s study eligibility has 
been confirmed by the Lead Principal Investigator or designee, they or an authorised site staff, will 
finalize data entry into eVelos. Treatment may not start until the approved enrollment form, 
including the designated treatment arm, is sent back to the site. 
When a potential subject has been identified, notify the University of Chicago CRA via phone or 
email to ensure a reservation on the study:  (773) 702-2052 and/or 
PhaseIICRA@medicine.bsd.uchicago.edu. Reservations for potential subjects will only be held for 
subjects who have signed consent for that particular study. 
When registering a subject, the following must occur:  
• 
Confirm that the institution has a current IRB approval letter for the correct version of 
protocol/consent and has an annual update on file, if appropriate.  
• 
Submit all required materials (Eligibility Checklist, Source documentation, & full copy of the signed 
informed consent form) to confirm eligibility and required pre-study procedures to the CRA a 
minimum of 48 hours prior to the subject’s scheduled therapy start date.  
• 
Source documentation includes copies of all original documents that support each 
inclusion/exclusion criteria.  The eligibility checklist does not serve as source documentation but 
rather as a checklist that original source documentation exists for each criterion. 
• 
Communicate with the CRA to ensure all necessary supporting source documents are received and 
the potential subject is eligible to start treatment on schedule. If there are questions about eligibility, 
the CRA will discuss it with the PI. PI may clarify, but not overturn, eligibility criteria.  
• 
Affiliate sites must confirm registration of subjects by obtaining a subject study ID number from the 
CRA via phone, fax or email.  
• 
If a subject does not start on the scheduled day 1 treatment date, promptly inform the CRA as the 
delay in start may deem the subject ineligible and/or require further or repeat testing to ensure 
eligibility.  
• 
The date the subject’s eligibility is confirmed by the CRA will be considered the subject’s 
“Enrolled/On Study Date.” The subject’s subject ID will be assigned and a confirmation of 
registration will be issued by the Lead Site CRA on this date. Subjects that sign consent and do not 
go “On Study” will be recorded in the database as “Not Enrolled” with the date they signed consent 
and the reason they were not enrolled (e.g., Ineligible, Screen Failure or Withdrawn Consent).  
6. 
TREATMENT PLAN 
Please refer to the Study Calendar (Appendix 6 for an overview). 
After screening, eligibility determination and enrollment, subjects will receive elotuzumab, 
carfilzomib, lenalidomide, and dexamethasone, in 28-day cycles until progression, unacceptable 
toxicity or subject withdraws consent. 

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A subject is considered to be off-treatment following a 30-day safety follow-up period after the last 
treatment. Long-term follow-up for survival will be 6 years total from the time of enrollment. 
6.1. Treatment Regimen 
Please refer to the Study Calendar (Appendix 6 for an overview). 
After screening, eligibility determination and enrollment, subjects will receive elotuzumab, 
carfilzomib, lenalidomide, and dexamethasone, in 28 day cycles until progression, 
unacceptable toxicity or subject withdraws consent. 
A subject is considered to be off-treatment following a 30-day safety follow-up period after 
the last treatment. Long-term follow-up for survival will be 6 years total from the time of 
enrollment. 
 
Cycles 1 – 2  
Agent 
Premedication and 
Precautions 
Schedule 
Dose 
Route 
Elotuzumab 
Please refer to Section 6.3 
Days 1, 8, 15, 
22 
10 mg/kg 
Intravenous-See 
appendix B for 
more details 
Carfilzomib 
Please refer to Section 6.3 
 
 
 
Lenalidomide 
None 
Days 1-21 of 
each cycle 
25 mg 
Oral 
Dexamethasone 
Take with food; 
recommended to be taken 
in the morning 
Days 1, 8, 15 
 
Days 2,9, 16 
 20 mg 
20 mg  
IV 
 
Oral  
Day 22 
 40 mg 
Oral 
 
 
Cycles 3 – 4  

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Agent 
Premedication and 
Precautions 
Schedule 
Dose 
Route 
Elotuzumab 
Please refer to Section 6.3 
Days 1 and 15 10 mg/kg 
Intravenous-See 
appendix B for 
more details 
Carfilzomib 
Please refer to Section 6.3 
 
 
 
Lenalidomide 
None 
Days 1-21 
ofeach 
cycle 
25 mg 
Oral 
Dexamethasone 
Take with 
food;recommende
d to be taken in the 
morning 
Days 1, 8,15, 
22 
  
40 mg 
Oral 
 
 
 
 
Cycles 5+  
Agent 
Premedicationand 
Precautions 
Schedule 
Dose 
Route 
Dexamethasone 
Takewithfood;  
recommended to be taken in 
the morning 
Days1, 
8,15,22 
20 mg 
Oral 
 
6.2. Study Procedures 
6.2.1. Screening Procedures 
The screening period is 21 days in length. The screening period starts on the date that the subject 
signs the Informed Consent Form. Refer to the study calendar (Appendix 6) 
Signed written informed consent 
Obtained prior to any study specific assessments 
Demographics and medical history 
 
 
 
 
 
• 
Age, gender, ethnic background 
• 
Details on myeloma diagnosis 
• 
Previous and concurrent relevant diseases 
• 
Current symptoms and/ or residual toxicities from 
prior therapies 

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Skeletal Survey 
May be within 3 months of planned treatment start (does 
not need to be repeated if within 3 months). Includes: 
lateral radiograph of the skull, anteroposterior and lateral 
views of the spine, and anteroposterior views of the pelvis, 
ribs, femora, and humeri, whole body MRI, or whole body 
CT. 
 
Cardiac evaluation  
12-lead ECG  
Echocardiogram 
Required  
 
Physical examination and vital 
signs  
• 
Body height and weight 
• 
BSA 
• 
ECOG Performance Status (Appendix 2) 
• 
Blood pressure, pulse, temperature, respiration 
• 
Physical examination 
 
Hematology (CBC)  
Hemoglobin, WBC with complete differential, RBCs, 
platelet count, absolute neutrophil and lymphocyte counts. 
WBC differential may be automated or manual as per 
institutional standards.  
Serum chemistry  
Sodium, potassium, chloride, creatinine, glucose, uric 
acid, phosphorus, magnesium, LDH, total bilirubin, CRP 
Pregnancy test (if applicable) 
FCBP must have two negative pregnancy tests (sensitivity 
of at least 50 mIU/mL) prior to starting study treatment. 
The first pregnancy test must be performed within 10-14 
days prior to the start of study treatment and the second 
pregnancy test must be performed 24 hours before 
lenalidomide is prescribed. 
β2 microglobulin 
Required  

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Myeloma Disease Assessment –
laboratory 
M-protein determination: 
• 
Serum Protein Electrophoresis (SPEP) and 
immunofixation 
• 
Urine Protein Electrophoresis (UPEP) and 
immunofixation 
• 
24hr Urine 
• 
Serum Free Light Chains (SFLC) 
• 
Serum quantitative immunoglobulins (IgGs) 
All of the above assessments are required at screening 
regardless of the disease classification.  
Bone Marrow Biopsy 
The Screening BM aspirate and biopsy is SOC. Quantify 
percent myeloma cell involvement, and obtain bone 
marrow aspirate for MRD analysis by flow and NGS, 
conventional cytogenetics, and fluorescent in situ 
hybridization. A BM aspirate sample at screening is 
required for calibration for NGS analysis. For subjects 
who sign consent for correlative samples, an additional 
aspirate sample should be collected at screening.  
CT-PET 
A CT-PET must be performed at screening. 
Correlative Samples 
For subjects who sign additional consent: peripheral blood 
and Buccal mucosa swab (screening only) will be 
collected  
Adverse Events  
AEs will be collected from the time of first study drug 
treatment through 30-days after end of study treatment 
Only SAEs considered related to study procedure need to 
be reported.  
6.2.2. Treatment Phase Procedures 
The following assessments should be performed on Day 1 of each cycle before administering drug 
unless otherwise noted. Please refer to Appendix 4 for details of response evaluation to be completed 
at any time throughout the trial when a nCR (or VGPR when nCR determination is not possible) or 
better is suspected. Hematology and Chemistry labs are required per SOC before Carfilzomib 
infusion on day 1, 8, and 15 of cycles 1-8, and  on days 1, and 15 of cycles 9+. On cycles 9+ this 
evaluation should be done as clinically indicated . 
Complete Physical examination 
and vital signs on Day 1 
 
 
 
Symptom-directed Physical Exam 
Days 8, 15, (and 22 on cycles 1-2) 
• 
Body weight 
• 
BSA 
• 
ECOG Performance Status 
• 
Blood pressure, pulse, temperature, respiration 
• 
Physical examination 
• 
Pulse oximetry to investigator discretion 

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Vital signs on each treatment day 
with Carfilzomib and/or 
elotuzumab 
 
 
Hematology 
(Day 1,8 and 15 on cycles 1-8before 
infusion required. On cycles 9+ days 
1 and 15 before infusion and as 
clinically indicated) 
 
 
Hemoglobin, WBC with complete differential, RBCs, 
platelet count, absolute neutrophil and lymphocyte counts. 
WBC differential may be automated or manual as per 
institutional standards. Results must be reviewed before 
dosing.  
Complete clinical chemistry  
(Day 1, 8, and 15 on cycles 1-8  
before infusion required. On cycles 
9+ days 8 and 15 before infusion and 
as clinically indicated) 
Sodium, potassium, chloride, creatinine, glucose, uric 
acid, phosphorus, magnesium, LDH, total bilirubin, CRP 
Results must be reviewed before dosing in Cycles 1 and 2.  
Pregnancy Test 
FCBP with regular or no menstrual cycles must agree to 
have pregnancy tests every 7 days (weekly) for the first 28 
days of study participation and then every 28 days while 
on study. If menstrual cycles are irregular, the pregnancy 
testing must occur weekly for the first 28 days and then 
every 14 days while on study.  
Myeloma Disease Assessment –
laboratory 
(Cycle 1 Day 15 and on Day 1 of 
every cycle from cycle 2+) 
M-protein determination: 
• 
Serum Protein Electrophoresis (SPEP) and 
immunofixation 
• 
Urine Protein Electrophoresis (UPEP) and 
immunofixation 
• 
24hr Urine 
• 
Serum Free Light Chains  
• 
Serum quantitative immunoglobulins (Igs) 
Only those assessments used to follow the myeloma 
disease are required past screening. All assessments are 
required for confirmation of response. A serum sample 
from blood at landmark timepoints (after C4, 8, 12, and 18, 
24 months after C1D1, and yearly after) will be required 
for banking at the University of Chicago for later M-spike 
analysis with a new elotuzumab interference assay. 
Analysis of banked samples via elotuzumab interference 
assay will be performed using Mass Spectrometry by 
BMS. 
Bone Marrow Aspirate/biopsy  
 
All BM aspirates and biopsies are SOC except the end of 
cycle 4 sample, which will only be SOC for subjects who 
proceed to transplant. Quantify percent myeloma cell 
involvement, and obtain bone marrow aspirate for MRD 
analysis by flow and NGS. This is required at end of Cycle 

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8 and end of cycle 12 for treatment decision making. 
Additionally, a BM aspirate and biopsy will be collected 
at the end of cycle 4. For subjects who sign consent for 
correlative samples, an additional aspirate sample should 
be collected at the time of the SOC BMA  
 
CT-PET 
A CT-PET must be performed to confirm MRD-negative 
disease per Standard of Care. Subjects who are MRD-
positive do not need PET scans until suspected CR. If there 
is clinical need for assessment at cycles 8 and 12, a CT-
PET should be performed at these timepoints as well. 
Correlative samples 
For subjects who sign additional consent: peripheral blood 
will be collected every time a Bone Marrow biopsy is 
performed as SOC 
Adverse events  
Assessed on an ongoing basis 
Study Treatment 
Section 6 and Appendix 6 
 
6.2.3. End of Treatment Procedures and Long-Term Follow-Up 
Subjects who discontinue therapy for any reason must have and end of treatment (EOT) visit 
completed 30 days (± 7 days) after the last application of study drug. Following the end of treatment, 
subjects will be followed for survival for 6 years total since enrollment. 
At the EOT visit, the subjects will undergo the following assessments: 
Physical examination and vital 
signs 
• 
Body weight 
• 
ECOG 
• 
Blood pressure, pulse, temperature, respiration 
• 
Physical examination 
Pulse oximetry to investigator discretion 
Hematology  
Hemoglobin, WBC with complete differential, RBCs, 
platelet count, absolute neutrophil and lymphocyte counts. 
WBC differential may be automated or manual as per 
institutional standards.  
Clinical chemistry  
Sodium, potassium, chloride, creatinine, glucose, uric 
acid, phosphorus, magnesium, LDH, total bilirubin, CRP  
Pregnancy test (if applicable) 
FCBP 
pregnancy 
testing 
required 
at 
treatment 
discontinuation and at 28-days following treatment 
discontinuation. If menstrual cycles are irregular, 
additional 
testing 
14-days 
following 
treatment 
discontinuation is required 
Myeloma Disease Assessment–
laboratory 
M-protein determination: 
• 
Serum Protein Electrophoresis (SPEP) and 
immunofixation 

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• 
Urine Protein Electrophoresis (UPEP) and 
immunofixation 
• 
24hr Urine 
• 
Serum Free Light Chains  
• 
Serum quantitative immunoglobulins (Igs) 
Bone Marrow Aspirate/biopsy  
 
All BM aspirates and biopsies are SOC, except the end of 
cycle 4 sample, which will only be SOC for subjects who 
proceed to transplant. Quantify percent myeloma cell 
involvement, and obtain bone marrow aspirate for MRD 
analysis by flow and NGS. This is required at EOT (C12, 
C18 or C24), 24 months after C1D1, and yearly after that 
(for up to 6 years after enrollment). Additionally, a BM 
aspirate and biopsy is required at any time nCR is 
suspected and MRD will be tested at this time. If nCR (If 
nCR determination is not possible, then VGPR will be 
used to trigger a bone marrow biopsy. A Bone Marrow 
Biopsy to confirm nCR or VGPR will not be required if 
the subject is within 2 months of a landmark Bone Marrow 
Biopsy timepoint) is suspected within 3 months of EOT, it 
is acceptable to wait for the EOT BM biopsy.  
For subjects who sign consent for correlative samples, an 
additional aspirate sample should be collected at EOT 
 
CT-PET 
MRD-negative subjects will undergo a yearly PET until 
progression.  
Correlative samples 
For subjects who sign additional consent: peripheral blood 
will be collected every time a Bone Marrow biopsy is 
performed as SOC 
 
Adverse events  
Record through 30-days after last treatment. All SAEs 
considered related to treatment must be followed until 
resolution. 
 
6.3. Pretreatment Preparation 
6.3.1. Hydration 
At least 48 hours before Cycle 1 Day 1, oral hydration should be given as follows:  30 mL/kg/day 
(approximately 6 to 8 cups of liquid per day) continuing up to the time of treatment.  Subject 
compliance must be assessed before initiating treatment, which is to be delayed if oral hydration is 
not adequate.  In subjects considered at risk for TLS, oral hydration should be continued in Cycle 2 
and beyond as required by the subject’s medical condition and at the Treating Investigator’s 
discretion. 
IV hydration will be given immediately prior to carfilzomib during Cycle 1.  This will consist of 
250 to 500 mL normal saline or other appropriate IV fluid.  If lactate dehydrogenase (LDH) or uric 
acid is elevated (and/or in subjects considered still at risk for TLS) at Cycle 2 Day 1, then the 
recommended IV hydration should be given additionally before each dose in Cycle 2.  The goal of 

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the hydration program is to maintain robust urine output (e.g., ≥ 2 L/day).  Subjects should be 
monitored periodically during this period for evidence of fluid overload. 
6.3.2. Concomitant Medications 
The following are required concomitant medications to be started on Cycle 1 Day 1 or up to 24 
hours prior to Cycle 1 Day 1: 
• 
Valacyclovir 500 mg PO QD or equivalent HZV prophylaxis, continuing for the duration of 
treatment. Additional prophylaxis is at the Treating Investigator's discretion.  
• 
  
Patients receiving multi-agent chemotherapy are inherently at greater risk of thrombosis and should 
follow the anticoagulation recommendations from International Myeloma Working Group (IMWG) 
guidelines. This includes LMWH 40 mg subcutaneously daily or warfarin target INR 2-3. As an 
alternative to LMWH or warfarin, we would accept prophylactic doses of direct oral anticoagulants 
(apixaban 2.5 mg twice daily or rivaroxaban 10 mg daily). If patient is unable to receive any of the 
previously listed options and has not risk of thrombosis/no prior thrombosis the patient may proceed 
with aspirin, preferably 325 mg, after discussing with the study overall PI. 
The following are recommended medications to be started on Cycle 1 Day 1 or up to 24 hours prior 
to Cycle 1 Day 1: 
• 
Lansoprazole (Prevacid) 15 mg PO QD, or other PO proton-pump inhibitor or H1 blocker 
to prevent peptic disease for the duration of treatment. Note that this is a recommended 
(optional) treatment. 
• 
Mycostatin or Nystatin to prevent oral thrush. Note that this is a recommended (optional) 
treatment. 
• 
Allopurinol (or other approved uric acid-lowering agent) in subjects at high risk for tumor 
lysis syndrome due to high tumor burden may be prescribed at the Treating investigator’s 
discretion. Allopurinol should be prescribed according to the package insert.  
6.3.2.1. 
Contraception 
Females of childbearing potential (FCBP) must: 
• 
Avoid pregnancy for at least 4 weeks before beginning lenalidomide 
• 
Have 2 negative pregnancy tests prior to starting treatment, the first test within 10 to 14 days 
and the second test 24 hours before prescribing lenalidomide. 
• 
Pregnancy tests weekly for the first month of treatment 
• 
Pregnancy tests monthly during treatment after the first month or semimonthly for women 
of childbearing potential with irregular menstruation 
• 
Agree to abstain from heterosexual sexual intercourse or to use 2 methods of effective 
contraception beginning 4 weeks prior to initiating treatment with lenalidomide, during 
therapy, during dose interruptions and for 3 months following the last dose of drug (more 
frequent pregnancy tests may be conducted if required per local regulations) 
• 
The contraceptive requirement for Carfilzomib in Females of childbearing potential is at 
least 30 days after the last dose.  Carfilzomib is prohibited in breast-feeding women. 

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An FCBP is defined as a sexually mature female who: 1) has not undergone a hysterectomy or 
bilateral oophorectomy, or 2) has not been naturally postmenopausal for at least 24 consecutive 
months (i.e., no menses at any time in the preceding 24 consecutive months). Amenorrhea following 
cancer therapy does not rule out childbearing potential. 
Male subjects and their partners must use 1 highly effective method of birth control plus 1 additional 
effective method of birth control (contraception) at the SAME TIME during treatment and for 3 
months following the last dose of drug, even if they have undergone a successful vasectomy. Male 
subjects must not donate sperm while taking lenalidomide and for 30 days after stopping 
lenalidomide. 
Highly effective methods of contraception include: 
• 
Intrauterine device (IUD) 
• 
Hormonal therapy (birth control pills, injections, implants) 
• 
Tubal ligation 
• 
Vasectomy 
Additional effective methods include: 
• 
Latex condom 
• 
Diaphragm 
• 
Cervical Cap 
 
6.3.3. Prohibited Concomitant Medications 
Concurrent therapy with a marketed or investigational anticancer therapeutic is not allowed.  
Corticosteroids for non-malignant conditions (e.g., asthma, inflammatory bowel disease) equivalent 
to a dexamethasone dose ≥ 4mg/day or prednisone > 20 mg/day are not permitted. Other 
investigational agents are not to be used during the study. 
6.3.4. Use of Blood Products 
Subjects may receive red blood cell (RBC) or platelet transfusions, if clinically indicated, per 
institutional guidelines. Subjects who require repeated transfusion support should be discussed with 
the Lead Principal Investigator. 
Appropriate anti-coagulation is allowed during the study (eg: LMW heparin, direct factor Xa 
inhibitors, etc). Warfarin is allowed during the study provided that subjects are monitored for INR 
twice a week during the first two cycles of therapy, then weekly to biweekly thereafter.  
Subjects may receive supportive care with bisphosphonates, erythropoietin, darbepoetin, G-CSF or 
GM-CSF, pegylated growth factors, and platelet stimulatory factors, in accordance with clinical 
practice or institutional guidelines prior to entry and throughout the study. 
6.3.5. Radiation Treatment 
If clinically indicated, palliative radiation therapy to non-target lesions is permitted but study drugs 
should be held for 3-5 days before the start of palliative radiation therapy and 3-5 days after palliative 
radiation therapy.  

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6.4. Study Drug Administration 
6.4.1. Elotuzumab Administration 
Elotuzumab for Injection is supplied as a lyophilized product in single-use 400mg and 300mg 
vials. Each vial of Elotuzumab for Injection, 400 mg/Vial and Elotuzumab for Injection, 300 
mg/Vial should be reconstituted with sterile water for injection (SWFI) at the clinical 
compounding site. Once the reconstitution is completed, dilution with 0.9% sodium chloride 
injection (NS) is necessary to result in an elotuzumab concentration from 1.0 mg/mL to no higher 
than 6.0 mg/mL. The dose for C1D1 will be calculated using the screening weight. Dose 
adjustments do not need to be made for weight gains/losses of ≤ 10%. 
Elotuzumab will be given as an IV infusion and should be initiated at a rate of 0.5mL/min. If well 
tolerated, the infusion rate may be increased in a stepwise fashion as described in the table below. 
The maximum infusion rate should not exceed 5mL/min.  
• 
Cycle 1-2: 10mg/kg on days 1, 8, 15, and 22 of a 28-day cycle 
• 
Cycles 3+: 10mg/kg on days 1 and 15 of a 28-day cycle 
 
Infusion Rate for Elotuzumab 
Cycle 1, Dose 1 
Cycle 1, Dose 2 
Cycle 1, Dose 3 and 4  
And all subsequent Cycles 
Time 
Interval 
Rate 
Time 
Interval 
Rate 
Rate 
0 - 30 min 
0.5 mL/min 
0 - 30 min 
3 mL/min 
 
5 mL/mina 
 
30 - 60 min 
1 mL/min 
≥30 min  
4 mL/mina 
≥60 min 
2 mL/mina 
- 
- 
 
All subjects should have vital signs monitored at the start and end of the infusion. If a subject 
experiences any significant medical event, then the investigator should assess whether the subject 
should stay overnight for observation. If the subject has not experienced a significant medical 
event but is hospitalized overnight only for observation, then the hospitalization should not be 
reported as a serious adverse event. 
The sponsor may modify the infusion rates or the preinfusion medications (Section 6.1.3.1) 
prospectively based upon the information collected to date from this and other studies. Additional 
details for administration times and rates, as well as preinfusion medications, will be provided in 
the administration guidelines. 

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6.4.2. Carfilzomib Administration 
Carfilzomib for Injection is supplied as a lyophilized parenteral product in single-use vials. The 
lyophilized product is reconstituted with Water for Injection to a final carfilzomib concentration of 
2.0 mg/mL prior to administration.  The dose will be calculated using the subject’s actual BSA at 
baseline.  Subjects with a BSA > 2.2 m2 will receive a dose based upon a 2.2 m2 BSA. Dose 
adjustments do not need to be made for weight gains/losses of ≤ 10%.  Subjects with a Body Surface 
Area (BSA) of greater than 2.2 m2 will receive a capped dose of 44 mg of carfilzomib (at the 
20mg/m2 dose level), 123.2mg of carfilzomib (at the 56mg/m2 dose level), or 154 (at the 70mg/m2 
dose level). 
Carfilzomib will be given as an IV infusion over 30 minutes on Days 1, 8, and 15 of a 28-day cycle.  
If the subject has a dedicated line for carfilzomib administration, the line must be flushed with a 
minimum of 20 mL of normal saline prior to and after drug administration.  The dose will be 
administered at a facility capable of managing hypersensitivity reactions. Subjects will be pre-
hydrated with 250mL normal saline or other appropriate IV fluid formulation on cycle 1 Day 1. 
Other hydration procedures will be optional and per the discretion of the treating physician. Subjects 
will remain at the clinic under observation for at least 1 hour following each dose of carfilzomib in 
Cycle 1 and following the dose on Cycle 2 Day 1. Subjects should be monitored periodically during 
this period for evidence of fluid overload. Serum chemistry values, including creatinine, must be 
obtained and reviewed prior to each dose of carfilzomib during Cycles 1 and 2. Refer to Table 6-1 
for guidance regarding dose reduction in subjects with compromised renal function.  
Doses of carfilzomib may be rescheduled up to 2 days if the scheduled day falls upon a holiday or 
with approval from the Lead Principal Investigator. Missed doses will not be replaced during a cycle. 
Carfilzomib will be escalated from 20mg/m2 (Cycle 1 Day 1) to 56mg/m2 (Cycle 1 Day 8 and 15 - 
see below) and then further escalated to 70mg/m2 (Cycle 2 Day 1) as long as the subject does not 
present with cytokine release symptoms (fever, rash, dyspnea, etc) after Cycle 1 Day 2.  
• 
Cycle 1: 20 mg/m2 Day 1; 56 mg/m2 Day 8; 56mg/m2 Day 15.  
• 
Cycles 2 - 8: 70mg/m2 if tolerated Days 1, 8, and 15 
• 
Cycles 9+ (for up to 24 cycles max): 70mg/m2 if tolerated Days 1 and 15 
Subjects will continue on E-KRd regimen for 12 cycles. MRD results after cycles 8 and 12 will 
determine the course of action after C12 with 3 possible outcomes: 1) subjects who are MRD- at 
both instances will end E-KRd and will continue on E-Rd maintenance until disease progression. 2) 
Subjects who are MRD+ after cycle 8 but MRD- after cycle 12 will receive 6 additional E-KRd 
cycles (for a total of 18) and then continue on E-Rd maintenance until disease progression. 3) 
Subjects who are MRD+ at both instances will receive 12 additional E-KRd cycles (for a total of 
24) and continue on E-Rd maintenance until disease progression. 
6.4.3. Lenalidomide Administration 
Lenalidomide will be provided in accordance with the Revlimid REMS® program of Celgene 
Corporation.  Per standard Revlimid REMS® requirements, all physicians who prescribe 
lenalidomide for research subjects enrolled into this trial must be registered and must comply with 
all requirements of the Revlimid REMS® program.  Prescriptions must be filled within 7 days.  
Subjects will receive lenalidomide as follows in 28-day cycles: 
• 
Cycle 1-8: 25 mg days 1-21 
• 
Cycles 9+: best tolerated dose days 1-21 

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Lenalidomide should be taken each evening at approximately the same time.  Lenalidomide is taken 
with water on a full or empty stomach.  Subjects should not break, chew or open capsules.  Late 
doses of Lenalidomide should if possible be taken on the assigned day but should not be made up 
the next day. Vomited doses will not be made up. Subjects should be instructed to never take 
Lenalidomide past Day 21 of each cycle. 
 
 
 
 
 
6.4.4. Dexamethasone Administration 
Dexamethasone will be administered no longer than 3 hours preceding elotuzumab and between 30 
min and 4 hours prior to carfilzomib (on days that they coincide). When dexamethasone, carfilzomib 
and elotuzumab coincide, dexamethasone will be given first, followed by carfilzomib and finally 
elotuzumab will be infused:  
• 
Cycle 1-2: 20 mg IV not longer than 3 hours prior to elotuzumab infusion and between 30 
min and 4 hours prior to carfilzomib on Days 1, 8, and 15. 20mg PO will be taken on Days 
2, 9, and 16 and 40mg PO will be taken as a single dose on Day 22 not longer than 3 hours 
prior to elotuzumab infusion. 
 
• 
Cycles 3-4: 40 mg PO Days 1, 8, 15, 22. On days when dexamethasone coincides with 
elotuzumab, dexamethasone will be taken no longer than 3 hours prior to elotuzumab 
infusion. On days when carfilzomib is given, dexamethasone will be dosed between 30 min 
and 4 hours prior to carfilzomib 
 
• 
Cycles 5+: 20mg PO Days 1, 8, 15, 22. On days when dexamethasone coincides with 
elotuzumab, dexamethasone will be taken not longer than 3 hours prior to elotuzumab 
infusion. On days when carfilzomib is given, dexamethasone will be dosed between 30 min 
and 4 hours prior to carfilzomib 
 
Split weekly dosing on cycles other than cycle 1 (e.g. 10mg on Day 1 and 10mg on Day 2, etc.) is 
permitted with approval from Lead Principal Investigator  
Dexamethasone given on days without elotuzumab or carfilzomib (on cycles 3+ day 22) may be 
self-administered by the subject on an outsubject basis. 
Missed doses of dexamethasone will not be made up.  
6.4.5. Maintenance treatment  
Subjects that complete 12 cycles (who were MRD-negative after cycles 8 and 12), 18 cycles (who 
were MRD-positive after cycle 8 but MRD-negative after cycle 12), or 24 cycles (who were MRD-
positive after cycle 8 and 12) of E-KRd, will continue a regimen of E-Rd until disease progression. 
This regimen will have elotuzumab every four weeks, lenalidomide at best-tolerated dose (days 1-
21), and low dose dexamethasone (weekly) in 28-day cycles until disease progression. 

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6.4.6. Treatment Compliance 
Research center personnel will review the dosing instructions with subjects. Subjects will be asked 
to maintain a diary to record drug administration. Subjects will be asked to bring empty drug 
containers to the research center at their next visit for destruction.  
6.5. Instructions for Initiation of a New Cycle 
A new course of treatment may begin on the scheduled Day 1 of a new cycle if all of the following 
are met:  
• 
ANC ≥ 1.0 x 109/L  
• 
Platelet count ≥ 30 x 109/L  
• 
Any other study drug-related adverse event must have resolved to grade 1 or baseline (see 
Appendix 2)  
• 
Serum uric acid and creatinine concentrations must return to baseline prior to carfilzomib 
doses during Cycles 1 and 2  
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated weekly, and a 
new treatment cycle will not be initiated until the toxicity has resolved, as described above.  
If elotuzumab, carfilzomib or lenalidomide are held for the remainder of the previous cycle or the 
new cycle is delayed due to residual toxicity on the planned Day 1 of the next cycle, then the new 
cycle will be started at 1 dose decrement. 
If a delay of starting a new cycle is greater than 21 days, the subject should be discontinued from 
treatment, unless continuing treatment is mutually agreed upon by the site Lead Principal 
Investigator at the University of Chicago and the Co-Investigator at the treating institution. 
6.6. Dose-Modification Guidelines 
The following sections and tables summarize dosing modifications of elotuzumab, carfilzomib, 
lenalidomide, and dexamethasone to manage possible toxicity.  Dose modifications different from 
those stated in the protocol should be discussed with the Lead Principal Investigator.  Administration 
of carfilzomib and lenalidomide will be discontinued in the event of any other toxicity that, in the 
opinion of the Lead, Secondary Site, or Treating Investigator, warrants discontinuation.   
In addition to dose reductions, administration of elotuzumab, carfilzomib and lenalidomide will be 
held temporarily in the event of a treatment-related toxicity at the Treating Investigator's discretion.  
Study treatment may be reintroduced if resolution of the event to the baseline value or to ≤ Grade 1 
within 21 days; otherwise study drug will be permanently discontinued. Any deviations from this 
plan must be approved by the Lead Principal Investigator. 
If a subject’s elotuzumab administration is delayed on day 1 of a cycle, carfilzomib, lenalidomide, 
and dexamethasone will also be delayed until the elotuzumab is resumed, which would then 
become the new day 1 of that cycle. 
If a subject’s elotuzumab is held in the middle of a cycle, carfilzomib, dexamethasone, and 
lenalidomide dosing will continue as scheduled. If the subject’s elotuzumab is delayed during the 
cycle and is resumed within the designated window, (+/-3 days Cycles 1 and 2; +/-7 days Cycles 3 
and beyond) the subject may receive the scheduled dose. If the elotuzumab is not resumed within 
the given window (+/-3 days Cycles 1 and 2; +/-7 days Cycles 3 and beyond), the subject is to 
omit that dose, and resume dosing at the next dosing time point. 
 
If a study drug (except dexamethasone) is discontinued, the subject may continue on trial. 
However, if the discontinuation happens prior to the end of cycle 8 (1ary endpoint), the subjects will 

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continue to be treated and will only be included on the intent to treat analysis. 
All clinically-significant non-hematologic toxicities must be resolved to Grade 1 or baseline. 
Dose reduction levels of elotuzumab, carfilzomib, lenalidomide, and dexamethasone for toxicity 
management of individual subjects are provided below: 
 
 
 

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Table 6-1 Carfilzomib Dose Adjustments 
Nominal 
carfilzomib dose 
Dose -1 
Dose -2 
Dose -3 
Dose -4 
70 mg/m2 
56 mg/m2 
45 mg/m2 
36 mg/m2 
27 mg/m2 
         Table 6-1 Lenalidomide Dose Adjustments 
Nominal 
Lenalidomide 
Dose 
Dose -1 
Dose -2 
Dose -3 
25 mg Days 1-21  
15 mg 
10 mg 
5 mg 
 
Table 6-3 Dexamethasone Dose Adjustments 
Nominal 
Dexamethasone 
Dose 
Dose -1 
Dose -2 
Dose -3 
40mg or 20 mg 
Reduce dexamethasone by 50% 
from starting dose; however, 
the 
20-mg 
IV 
dose 
of 
dexamethasone given before 
the infusion on the day of 
elotuzumab infusions must not 
be decreased. 
Discontinue 
dexamethasone 
on the day when 
elotuzumab 
is 
not given. 
Discontinue 
dexamethasone 
*Split dosing of dexamethasone on days 1,2, 8,9, 15,16, 22,23 may be implemented to 
control toxicities that do not require a dose reduction. Split dosing requires the approval 
of the Lead Principal Investigator  
 
          6-4 Elotuzumab Dose Adjustments 
No dose reductions for elotuzumab are allowed. If Elotuzumab is held on Day 1 of a new cycle, 
treatment with carfilzomib/lenalidomide/dexamethasone will also be delayed. If elotuzumab is 
held during any cycle on days 8, 15, or 22, the treating investigator will decide if lenalidomide, 
carfilzominb, and/or dexamethasone will be held using recommended guidance for retreatment 
below. Treatment may be delayed for a maximum of 21 days (see section 6.5.2.1 for details). 
6.6.1. Toxicity Management Guidelines 
Treatment guidelines for specific hematologic toxicities are outlined in Section 7.5.1.1 and 
nonhematologic toxicities in Section 7.5.1.2. In addition to dose reductions, administration of 
carfilzomib and/or lenalidomide may be held temporarily in the event of a treatment-related toxicity 
at the Treating Investigator’s discretion. 
 
 

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6.6.1.1. 
Hematologic Toxicity 
Table 6-5 Dose Modification Guidelines for Hematologic Toxicities 
 
When 
Platelets: 
Lenalidomide 
Carfilzomib 
Elotuzumab 
Fall to < 30 x 
109/L 
• Hold dose, follow 
CBC weekly 
• Hold prophylactic 
anticoagulation until 
platelets return to ≥ 
30 × 109/L 
• Then resume at 1 
dose decrement 
If platelets 10-30 
x109/L without 
evidence of 
bleeding 
• Hold 
• With resolution 
restart at previous 
dose 
• Hold 
• Upon resolution elotuzumab 
can be restarted at the treating 
physician’s discretion 
 
 
If evidence of 
bleeding or platelets 
< 10 x109/L 
• Hold 
• With resolution 
restart at previous 
dose 
• Hold 
• Upon resolution elotuzumab 
can be restarted at the treating 
physician’s discretion 
For 
each 
subsequent 
drop to < 30 x 
109/L 
• Hold dose, follow 
CBC weekly 
• Hold prophylactic 
anticoagulation until 
platelets return to ≥ 
30 × 109/L 
• Then resume at 
additional dose 
decrement 
If platelets 10-30 x 
109/L without 
evidence of 
bleeding 
• Hold 
• With resolution 
restart at previous 
dose 
• Hold 
• Upon resolution elotuzumab 
can be restarted at the treating 
physician’s discretion 
 
 
If evidence of 
bleeding or platelets 
< 10 x109/L 
• Hold 
• With resolution 
restart at 1 dose 
decrement 
• Hold 
• Upon resolution elotuzumab 
can be restarted at the treating 
physician’s discretion 
Grade 4 thrombocytopenia without evidence of bleeding, carfilzomib dosing may occur at the discretion of the Treating 
Investigator. However, subjects should receive supportive measures in accordance with institutional guidelines. 
 
 
 

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Table 6-5 Dose Modification Guidelines for Hematologic Toxicities 
 
When 
ANC: 
Lenalidomide 
Carfilzomib 
Elotuzumab 
Fall to < 
0.75 
x 
109/L 
• Hold dose, 
administer myeloid 
growth factor 
• Follow CBC weekly 
• Resume at full dose 
when ANC ≥ 0.75 x 
109/L 
If ANC 0.5-0.75 x 
109/L 
• Continue at full 
dose 
• Continue at full dose 
 
 
If ANC < 0.5 x109/L 
• Hold 
• Resume at 1 dose 
decrement when 
ANC returns to ≥ 
0.5 x109/L 
• Hold 
• Upon resolution elotuzumab 
can be restarted at the 
treating physician’s 
discretion 
For 
each 
subsequent 
drop to < 
0.75 
x 
109/L 
• Hold dose, 
administer myeloid 
growth factor 
• Follow CBC weekly 
• Resume at 1 dose 
decrement when 
ANC ≥ 0.75 x 109/L 
If ANC 0.5-0.75 x 
109/L 
• Continue at full 
dose 
• Hold 
• Upon resolution elotuzumab 
can be restarted at the 
treating physician’s 
discretion 
 
 
If ANC < 0.5 x109/L 
• Hold 
• Resume at 1 dose 
decrement 
when 
ANC returns to ≥ 
0.5 x109/L 
• Hold 
• Upon resolution elotuzumab 
can be restarted at the 
treating physician’s 
discretion 
 
6.6.1.2. 
Non-hematologic Toxicity 
Table 6-6 Dose Modifications for Non-hematologic Toxicity 
 
Recommended Action 
 Non-heme toxicity 
Lenalidomide 
Carfilzomib 
Elotuzumab 
Non-Blistering Rash 
 
 
 
Grade 3 
Hold lenalidomide dose; 
follow weekly 
If the toxicity resolves to 
≤ Grade 1 prior to Day 21 
of the current cycle, 
restart at 1 dose 
decrement and continue 
the cycle until Day 21 of 
the current cycle. 
Hold (if Treating 
Investigator’s opinion is 
possibly related to 
Carfilzomib) until ≤ Grade 
1, reinstitute at current 
dose 
Hold 
Upon resolution 
elotuzumab can be 
restarted at the treating 
physician’s discretion 
Grade 4 
Discontinue 
lenalidomide study drug. 
Hold until ≤ Grade 1, 
reinstitute at current dose. 
Hold 
Upon resolution 
elotuzumab can be 
restarted at the treating 
physician’s discretion 

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Table 6-6 Dose Modifications for Non-hematologic Toxicity 
 
Recommended Action 
 Non-heme toxicity 
Lenalidomide 
Carfilzomib 
Elotuzumab 
Desquamating (blistering) 
rash  
– any grade 
Discontinue 
lenalidomide study drug. 
Hold until ≤ Grade 1, 
reinstitute at current dose. 
Hold 
Upon resolution 
elotuzumab can be 
restarted at the treating 
physician’s discretion 
Erythema multiforme ≥ 
Grade 3 
Discontinue 
lenalidomide study drug. 
Hold until ≤ Grade 1, 
reinstitute at current dose. 
Hold 
Upon resolution 
elotuzumab can be 
restarted at the treating 
physician’s discretion 
Sinus bradycardia/ other 
cardiac arrhythmia 
 
 
 
≤ Grade 2 
Hold lenalidomide dose. 
Follow at least weekly. 
If the toxicity resolves to 
≤ Grade 1 prior to Day 
21, restart at 1 dose 
decrement and continue 
the cycle until Day 21. 
Hold until ≤ Grade 1, 
reinstitute at current dose. 
Hold 
Upon resolution 
elotuzumab can be 
restarted at the treating 
physician’s discretion 
≥ Grade 3 
Discontinue 
lenalidomide study drug 
Hold until ≤ Grade 1, 
reinstitute at current dose. 
Hold 
Upon resolution 
elotuzumab can be 
restarted at the treating 
physician’s discretion 
Allergic 
reaction/hypersensitivity 
 
 
 
Grade 2 – 3 
Hold lenalidomide dose. 
Follow at least weekly. 
If the toxicity resolves to 
≤ Grade 1 prior to Day 
21, restart at 1 dose 
decrement and continue 
the cycle until Day 21. 
Hold until ≤ Grade 1, 
reinstitute at current dose. 
Discontinue 
Grade 4 
Discontinue 
Discontinue 
Discontinue 

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Table 6-6 Dose Modifications for Non-hematologic Toxicity 
 
Recommended Action 
 Non-heme toxicity 
Lenalidomide 
Carfilzomib 
Elotuzumab 
Tumor lysis syndrome 
(≥ 3 of the following: ≥ 50% 
increase in creatinine, uric 
acid, or phosphate;≥ 30% 
increase in potassium;≥ 
20% decrease in calcium; 
or ≥ 2-fold increase in LDH 
Hold lenalidomide until 
all abnormalities in 
serum chemistries have 
resolved. 
Reinstitute at full doses. 
Hold carfilzomib until all 
abnormalities in serum 
chemistries have resolved. 
Reinstitute at full doses. 
Hold 
Upon resolution 
elotuzumab can be 
restarted at the treating 
physician’s discretion 
Infection Grade 3 or 4 
Hold lenalidomide until 
systemic treatment for 
infection is completed. If 
no neutropenia, restart 
lenalidomide at full 
dose.  If neutropenic, 
follow neutropenic 
instructions. 
Hold carfilzomib until 
systemic treatment for 
infection is completed If 
no neutropenia, restart 
carfilzomib at full dose.  If 
neutropenic, follow 
neutropenic instructions. 
Hold 
Upon resolution 
elotuzumab can be 
restarted at the treating 
physician’s discretion 
Herpes zoster or simplex of 
any grade 
Hold lenalidomide until 
lesions are dry. 
Reinstitute at full doses. 
Hold carfilzomib until 
lesions are dry. 
Reinstitute at full doses. 
Hold 
When lesions are dry 
elotuzumab can be 
restarted at the treating 
physician’s discretion 
Grade 2 neuropathy with pain 
or any Grade 3 neuropathy 
Hold until ≤ Grade 2.  
Then restart 
lenalidomide at 1 dose 
decrement 
Withhold until toxicity is 
resolved or returned to 
baseline After resolution, 
consider if restarting CFZ 
at the same dose or at a 
reduced dose is 
appropriate. If tolerated, 
the reduced dose may be 
escalated to the previous 
dose at the discretion of 
the physician 
Hold 
Upon resolution 
elotuzumab can be 
restarted at the treating 
physician’s discretion 
Grade 4 neuropathy 
Discontinue 
Discontinue 
Hold 
Upon resolution 
elotuzumab can be 
restarted at the treating 
physician’s discretion 
Renal dysfunction 
 
 
 
Serum creatinine > 2 mg/dL 
Base dose reduction on 
calculated GFR (below) 
Base dose reduction on 
calculated GFR (below) 
Hold 
Upon resolution 
elotuzumab can be 

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Table 6-6 Dose Modifications for Non-hematologic Toxicity 
 
Recommended Action 
 Non-heme toxicity 
Lenalidomide 
Carfilzomib 
Elotuzumab 
restarted at the treating 
physician’s discretion 
CrCl>60 mL/min  
Full dose 
Full dose 
Full dose 
CrCl <60 mL/min 
> 30 mL/min 
Reduce lenalidomide to 
10 mg every 24 h; may 
reinstate prior dose if, 
after 2 cycles, CrCl 
normalizes 
Full dose 
Full dose 
CrCl< 30 mL/min 
Reduce lenalidomide to 
15 mg every 48 h  
Hold carfilzomib until 
CrCl> 30 mL/min. If 
attributed to carfilzomib, 
restart at 1 dose 
decrement. If tolerated, the 
reduced dose may be 
escalated to the previous 
dose at the discretion of 
the physician. If not 
attributed to carfilzomib, 
restart at dose used prior to 
the event. Frequent 
monitoring of renal 
function should then be 
implemented 
 
Full Dose 
CrCl< 30 mL/min requiring 
dialysis 
5 mg once daily. On 
dialysis days the dose 
should be administered 
following dialysis. 
Hold until resolved to ≤ 
Grade 2. Then restart 
carfilzomib at  1 dose 
decrement 
Full Dose 

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Table 6-6 Dose Modifications for Non-hematologic Toxicity 
 
Recommended Action 
 Non-heme toxicity 
Lenalidomide 
Carfilzomib 
Elotuzumab 
Venous thrombosis/embolism 
≥ Grade 3 
Hold lenalidomide dose 
and adjust 
anticoagulation regimen; 
re-start at Treating 
Investigator’s discretion 
at full dose 
No adjustment required 
No adjustment required 
Hyperthyroidism or 
hypothyroidism 
Omit lenalidomide for 
remainder of cycle, 
evaluate, and initiate 
appropriate therapy. 
Restart lenalidomide 
next cycle at 1 dose 
decrement 
No adjustment required 
No adjustment required 
Congestive heart failure 
(CHF) 
Any subject with 
symptoms of CHF, 
whether or not 
lenalidomide related, 
must have the dose held 
until resolution or return 
to baseline.  If CHF was 
felt to be lenalidomide 
related, reinstate by one 
dose decrement after 
return to baseline. If no 
resolution of CHF after 
2 weeks, the subject will 
be withdrawn from the 
study. 
Any subject with 
symptoms of CHF, 
whether or not carfilzomib 
related, must have the dose 
held until resolution or 
return to baseline.  If CHF 
was felt to be carfilzomib 
related, reinstate by one 
dose decrement after return 
to baseline. If tolerated, the 
reduced dose may be 
escalated to the previous 
dose at the discretion of 
the physician. If no 
resolution of CHF after 2 
weeks, the subject will be 
withdrawn from the study. 
Hold 
Upon resolution 
elotuzumab can be 
restarted at the treating 
physician’s discretion 
Hypertension including 
Hypertensive Crises 
NA 
≥ Grade 3: Carfilzomib 
attribution, hold drug until 
resolved to ≤ Grade 2.  
Resume at one level dose 
reduction 
NA 

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Table 6-6 Dose Modifications for Non-hematologic Toxicity 
 
Recommended Action 
 Non-heme toxicity 
Lenalidomide 
Carfilzomib 
Elotuzumab 
Heart problems, including 
rapid, strong, or irregular 
heartbeat, heart attack, 
reduced blood flow to the 
heart, abnormal amount of 
fluid to the lining around the 
heart, and swelling/irritation 
of the lining around the heart 
NA 
≥ Grade 3: Carfilzomib 
attribution, hold drug until 
resolved to ≤ Grade 1.  
Resume at one level dose 
reduction 
NA 
Pericardial Effusion 
NA 
≥ Grade 3: Carfilzomib 
attribution, hold drug until 
resolved to Grade 1.  
Resume at one level dose 
reduction 
NA 
Pericarditis 
NA 
≥ Grade 3: Carfilzomib 
attribution, hold drug until 
resolved to Grade 1.  
Resume at one level dose 
reduction 
NA 
Pulmonary Hypertension 
 
 
NA 
≥ Grade 3: Carfilzomib 
attribution, hold drug until 
resolved to baseline.  After 
resolution consider if 
restarting CFZ at the same 
dose or reduced dose is 
appropriate. If tolerated, 
the reduced dose may be 
escalated to the previous 
dose at the discretion of 
the physician. 
NA 
Pulmonary Toxicities: 
Interstitial Lung Disease (inc. 
pneumonitis), Acute 
Respiratory Failure, and 
Adult Respiratory Distress 
Syndrome (ARDS), cough and 
cough with phlegm 
 
 
NA 
≥ Grade 2 for Pneumonitis 
≥ Grade 3 for ARDS 
≥ Grade 4 for Respiratory 
Failure 
 
Carfilzomib attribution, 
hold drug until resolved to 
≤Grade 1. Resume at one 
level dose reduction 
NA 

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Table 6-6 Dose Modifications for Non-hematologic Toxicity 
 
Recommended Action 
 Non-heme toxicity 
Lenalidomide 
Carfilzomib 
Elotuzumab 
Blood clot in the lungs, fluid 
in the lungs, bleeding in the 
lungs 
NA 
≥ Grade 3: Carfilzomib 
attribution, hold drug until 
resolved to ≤ Grade 1.  
Resume at one level dose 
reduction 
NA 
Gastrointestinal Perforation 
NA 
≥ Grade 3: Carfilzomib 
attribution, hold drug until 
resolved to Grade 1.  
Resume at one level dose 
reduction 
NA 
Hepatic Toxicities (≥ Grade 3 
elevation of AST or ALT, 
Bilirrubin, or other ≥ Grade 3 
liver abnormalities) 
Hold drug until resolved 
to ≤Grade 1 or baseline. 
Resume at the same dose 
or reduced dose as 
appropriate. If tolerated, 
the reduced dose may be 
escalated to the previous 
dose at the discretion of 
the physician. Frequent 
monitoring of liver 
function should then be 
implemented. 
Hold drug until resolved to 
≤Grade 1 or baseline. 
Resume at the same dose 
or reduced dose as 
appropriate. If tolerated, 
the reduced dose may be 
escalated to the previous 
dose at the discretion of 
the physician. Frequent 
monitoring of liver 
function should then be 
implemented. 
Hold treatment and restart 
when toxicity has resolved 
to ≤ Grade 1 or baseline 
Other non-hematologic 
toxicity assessed as 
lenalidomide-related ≥ Grade 
3 
Hold lenalidomide dose. 
Follow at least weekly. 
If the toxicity ≤ Grade 1 
before Day 21 of the 
current cycle, restart at 1 
dose decrement and 
continue until Day 21 of 
the current cycle 
Full dose 
Full dose 

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Table 6-6 Dose Modifications for Non-hematologic Toxicity 
 
Recommended Action 
 Non-heme toxicity 
Lenalidomide 
Carfilzomib 
Elotuzumab 
Other non-hematologic 
toxicity assessed as 
carfilzomib-related ≥ Grade 3 
Full dose 
Hold carfilzomib dose 
until toxicity resolves to 
≤ Grade 1 or baseline. 
After resolution, consider 
if restarting CFZ at the 
same dose or at a reduced 
dose as appropriate. If 
tolerated, the reduced dose 
may be escalated to the 
previous dose at the 
discretion of the physician. 
Full dose 
Other non-hematologic 
toxicity assessed as 
elotuzumab-related ≥ Grade 3 
Full dose 
Full dose 
Hold  
Upon resolution, restart 
at the treating physician’s 
discretion 
Other non-hematologic 
toxicity assessed as drug-
related ≥ Grade 3 
Hold treatment and 
restart at 1 dose 
decrement when toxicity 
has resolved to ≤ Grade 
1 or baseline 
Hold treatment and restart 
at 1 dose decrement when 
toxicity has resolved to ≤ 
Grade 1 or baseline 
Hold treatment and restart 
when toxicity has resolved 
to ≤ Grade 1 or baseline 
 
Table 6-8 Dose Modification Guidelines for Toxicity Related to Dexamethasone 
BODY SYSTEM  
SYMPTOM 
RECOMMENDED ACTION 
Gastrointestinal 
Dyspepsia, gastric or duodenal ulcer, 
gastritis 
Grade 1-2 (requiring medical 
management) 
Treat with H2 blockers, sucralfate, or 
omeprazole. If symptoms persist despite above 
measures, decrease dexamethasone dose by 
1 dose level. 
Gastrointestinal 
≥ Grade 3 (requiring hospitalization or 
surgery) 
Hold 
dexamethasone 
until 
symptoms 
adequately controlled. Restart at 1 dose 
decrement along with concurrent therapy with 
H2 blockers, sucralfate, or omeprazole. If 
symptoms persist despite above measures, 
discontinue dexamethasone permanently. 
Gastrointestinal 
Acute pancreatitis 
Discontinue dexamethasone permanently. 
Cardiovascular 
Edema ≥ Grade 3 (limiting function and 
unresponsive to therapy or anasarca) 
Diuretics as needed, and restart dexamethasone 
at 1 dose decrement; if edema persists despite 
above measures, decrease dose another level. 
Discontinue dexamethasone permanently if 
symptoms persist despite second reduction. 
 
Neurology 
Confusion or mood alteration 
Hold dexamethasone until symptoms resolve. 
Restart at 1 dose decrement. If symptoms 

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> Grade 2 (interfering with function +/- 
interfering with activities of daily 
living) 
persist despite above measures, discontinue 
dexamethasone permanently. 
Musculoskeletal 
Muscle weakness > Grade 2 
(symptomatic and interfering with 
function +/- interfering with activities 
of daily living) 
Decrease dexamethasone by 1 dose level. If 
weakness persists, decrease dose by 1 more 
dose 
level. 
Discontinue 
dexamethasone 
permanently if symptoms persist. 
Metabolic 
Hyperglycemia ≥ Grade 3 
Treatment with insulin or PO hypoglycemic 
agents as needed. If uncontrolled despite above 
measures, decrease dose by 1 dose level until 
levels are satisfactory. 
 
 
 

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6.6.2. Guidelines for Elotuzumab Infusion and pre-medication in Subjects with 
Infusion Reactions 
 
Required Treatments 
Dexamethasone 
On weeks without elotuzumab administer the weekly dose of 40 mg (Cycles 3-4) or 20mg (Cycles 
5+) dexamethasone orally 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. 
At the discretion of the investigator, the oral dexamethasone component may be given as a split 
dose 12 – 24 hours and 3 hours prior to elotuzumab. 
Premedication Before Elotuzumab: 
1. Dexamethasone 20 mg IV (C1 and 2), 40mg PO (C3-4), or 20mg (C5+)  not longer than 3 
hours prior to the start of elotuzumab infusion when they coincide, and 20mg PO the day 
after elotuzumab infusion (C1-2 only). 
AND 
2. H1 blocker: diphenhydramine (25 - 50 mg PO or IV) or equivalent (45-90 minutes prior to 
the start of infusion) 
3. H2 blocker: ranitidine (50 mg IV) or equivalent (45-90 mins prior to the start of infusion) 
4. Acetaminophen (650 - 1000 mg PO), (45-90 mins prior to the start of infusion 
Premedication Regimen in Subjects With a Prior Infusion Reaction  
Subjects with prior infusion reaction must receive H1, H2 blockers and acetaminophen at 
maximum doses specified above. 
 
Table 6-9 Elotuzumab infusion in subjects with infusion reactions 
Prior Infusion Reaction  
Corticosteroid premedication prior to elotuzumab 
None or 
Only Grade 1 infusion reaction 
no change 
Prior Grade 2 infusion reaction 
Split dexamethasone dose on days of elotuzumab; e.g. for dose level 40 mg 
to 28 mg prior to carfilzomib and 12 mg 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 
24 mg IV dexamethasone at least 45-90 min prior to elotuzumab 
 

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At the discretion of the investigator, the 40 mg oral dexamethasone component may be given as a 
split dose: 20 mg PO (12–24 hours prior to elotuzumab) AND 20 mg PO (3 hours prior to 
elotuzumab). 
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). 
Subjects with a Grade 4 elotuzumab infusion reaction must have elotuzumab permanently 
discontinued. Additionally, subjects who have a recurrence of ≥ Grade 2 infusion reactions with 
subsequent doses and subjects who have a true hypersensitivity reaction at ≥ Grade 2 should 
have elotuzumab permanently discontinued (but may continue on KRd). 
 
6.6.2.1. 
Elotuzumab Dose Delay or Interruption 
If toxicity is considered to be related to elotuzumab, elotuzumab should delayed, interrupted, or 
discontinued (please refer to tables 6-5 and 6-6 for further guidelines). However, if dexamethasone 
is delayed or discontinued, the administration of elotuzumab should be based on clinical judgment 
(ie, risk of hypersensitivity). 
If a ≥Grade 2 infusion reaction occurs during elotuzumab administration, the infusion must be 
interrupted. Upon resolution to ≤Grade 1, elotuzumab should be restarted at 0.5 mL/min and may 
be gradually increased at a rate of 0.5 mL/min every 30 minutes as tolerated to the rate at which the 
infusion reaction occurred. If there is no recurrence of the infusion reaction, the escalation regimen 
can be resumed (Table 6-9). 
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 infusion reaction recurs, the elotuzumab 
infusion must be stopped and not restarted on that day. Very severe infusion reactions may require 
permanent discontinuation of elotuzumab therapy and emergency treatment. 
If a subject’s elotuzumab administration is delayed on day 1 of a cycle, carfilzomib, lenalidomide, 
and dexamethasone will also be delayed until the elotuzumab is resumed, which would then 
become the new day 1 of that cycle. 
If a subject’s elotuzumab is held in the middle of a cycle, carfilzomib, dexamethasone, and 
lenalidomide dosing will continue as scheduled. If the subject’s elotuzumab is delayed during the 
cycle and is resumed within the designated window, (+/-3 days Cycles 1 and 2; +/-7 days Cycles 3 
and beyond) the subject may receive the scheduled dose. If the elotuzumab is not resumed within 
the given window (+/-3 days Cycles 1 and 2; +/-7 days Cycles 3 and beyond), the subject is to 
omit that dose, and resume dosing at the next dosing time point. 
6.7. Response Evaluation 
The first response assessment should be completed at Cycle 1 Day 15. If at any time throughout the 
treatment a complete response or better is suspected, a complete disease assessment should be 
performed to confirm response according to IMWG criteria: 
Myeloma Disease Assessment –
laboratory 
M-protein determination: 
• 
Serum Protein Electrophoresis (SPEP) and 
immunofixation 
• 
Urine Protein Electrophoresis (UPEP) and 
immunofixation 
• 
24hr Urine 

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• 
Serum Free Light Chains  
• 
Serum quantitative immunoglobulins (Igs) 
A serum sample from blood at landmark timepoints (after 
C4, 8, 12, and 18, 24 months after C1D1, and yearly after) 
will be required for banking at the University of Chicago 
for later M-spike analysis with a new elotuzumab 
interference assay. The analysis of banked samples by 
elotuzumab interference assay will be performed using 
Mass Spectrometry by BMS.  
Bone Marrow Biopsy 
Quantify percent myeloma cell involvement, and obtain 
bone marrow aspirate for conventional cytogenetics and 
fluorescent in situ hybridization. For subjects who give 
consent for correlative samples, an additional aspirate 
sample should be collected at screening, at time of 
complete response (if applicable), at the end of cycles 8 
and 12, EOT, and time of progression.  
Radiographic Imaging 
As per standard of care  
Progressive disease requires 2 consecutive assessments made at any time before classification 
of relapse or progression and/or institution of new therapy when clinically possible.  
6.8. Study Termination 
Any Grade 5 toxicity related to study treatment will prompt stopping of the trial until further 
review is completed. Additionally, development of Grade 4 of non-hematologic toxicities in 2 or 
more patients will prompt the DSMB to stop the study for review to  determine whether the trial 
should be terminated due to excessive toxicity. 
6.9. Treatment Discontinuation 
Subjects will be free to discontinue treatment or withdraw from the study at any time, for any reason, 
or they may be withdrawn/ removed if necessary in order to protect their health (see reasons for 
withdrawal below).  
Subjects will be removed from further treatment for the following reasons: 
• 
Disease Progression 
• 
Non-compliance with study procedures 
• 
Subject no longer consents to participate in the study 
• 
Intercurrent illness that interferes with study assessments  
• 
Treatment-related toxicity requiring treatment discontinuation 
• 
Incidence or severity of AEs that indicates a potential health hazard to the subject 
• 
For the fourth occurrence of the same Grade ≥ 3 non-hematological toxicity 
• 
A delay in treatment > 21 days unless approved by the Lead Principal Investigator as well 
that due to Congestive Heart Failure unresolved for > 28 days the treatment shall be 
discontinued (see table 6-7) 
• 
Treating Investigator discretion 
• 
Requirement for alternative therapy 
• 
Suspected or positive pregnancy 

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• 
Termination of the study by the sponsor 
The Lead Principal Investigator should be contacted regarding any impending discontinuation of a 
study subject. If the reason for withdrawal is the occurrence of an AE, the subject will be followed 
until such events resolve, stabilize, and, according to the Treating Investigator’s judgment, there is 
no need for further follow-up. The reason for withdrawal from study must be documented in the 
case report form. 
In case of premature discontinuation of the study treatment, the investigations scheduled for the 
EOT should be performed, if possible. Should a subject decide to withdraw, every effort will be 
made to complete and report the observations as thoroughly as possible. The Treating Investigator 
should contact the subject to determine as completely as possible the reason for the withdrawal. A 
complete final evaluation at the time of the subject’s withdrawal should be made, with an 
explanation of why the subject is withdrawing from the study. 
6.9.1. Duration of Follow Up 
Long-term follow up will include an assessment for disease progression in subjects who did not 
progress during treatment.  This should occur every 3 months (+/- 30 days) for up to 6 years from 
enrollment. 
6.10. 
Safety Considerations & Supportive Care 
Supportive measures for optimal medical care shall be provided during participation in this clinical 
trial. Supportive care including anti-nausea / anti-emetic therapy, acid suppression (proton pump 
inhibitors and/or H2-blockers), glucocorticoids, and other standard treatments may be administered 
as per institutional guidelines for symptomatic subjects. As needed and per individual study site 
institutional guidelines, prophylactic therapies, including antivirals, antifungals, and antibiotics, 
may be administered to ameliorate risks associated with non-malignant disorders or of immune 
system compromise. 
6.10.1. Elotuzumab Infusion Reactions 
The first dose of elotuzumab will be administered following pre-medications to each subject as an 
IV infusion, using an automated infusion pump set at an initial rate of 0.5mL per minute (30 
mL/hour). If the subject does not have an infusion reaction within 30 minutes, escalate the infusion 
rate by 0.5 mL per minute. If the subject still does not have an infusion reaction within 30 minutes, 
escalate the infusion rate to a maximum of 2 mL per minute (120 mL/hour).  
The second dose of elotuzumab should be initiated at an infusion rate of 3 mL per minute if no 
infusion reactions were reported with the first elotuzumab infusion. If the subject does not 
experience an infusion reaction during the first 30 minutes of the second dose of elotuzumab, 
escalate the infusion rate by 1.0 mL per minute to a maximum infusion rate of 4 mL per minute. 
The third and fourth dose of elotuzumab should be initiated at an infusion rate of 5 mL per minute 
if no infusion reactions were reported with previous elotuzumab infusions. 
Guidelines for Elotuzumab Infusion in Subjects with Infusion Reactions 
Grade 1 Infusion Reaction: Grade 1 elotuzumab infusion-related reactions by definition do not 
require intervention; however, increased monitoring is recommended 
Grade 2 or 3 Infusion Reaction: Infusion reactions during the elotuzumab infusion:  For a 
Grade 2 or 3 elotuzumab infusion-related reactions, the infusion must be interrupted. The subject 
should be treated as clinically indicated with one or more of the following medications or 

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interventions: antiemetics, antihistamines, analgesics, corticosteroids, leukotriene inhibitors, 
oxygen inhalation, epinephrine, bronchodilators, or other supportive measures as indicated. 
Once the elotuzumab infusion-related reaction has resolved to Grade ≤ 1, the infusion can be 
restarted at 0.5 mL/minute. If symptoms do not recur after 30 minutes, the infusion rate may be 
increased in a stepwise fashion (0.5 mL/minute every 30 minutes) to the rate at which the infusion 
reaction occurred. If no recurrence of the infusion reaction, the escalation regimen can be resumed. 
Subjects who experience an infusion reaction require vital signs to be monitored every 30 minutes 
for 1 or 2 hours after the end of the elotuzumab infusion (as clinically indicated). 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. 
Infusion reactions after the completion of elotuzumab infusion: Should a Grade 2 or 3 infusion 
reaction occur following the 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, bronchodialators, or other supportive measures as indicated. 
Elotuzumab infusions on subsequent weeks after a prior Grade 2 or 3 infusion reaction: 
Subjects with a prior Grade 2 or 3 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 the rate 
at which the infusion reaction occurred.  If no Grade ≥2 infusion reaction occurs, the escalation 
regimen may be resumed, and the next infusion may be initiated as planned per regimen. 
Grade 4 Infusion Reaction: Subjects with a Grade 4 elotuzumab infusion reaction must have 
elotuzumab permanently discontinued. 
6.10.2. First Dose Effect (Carfilzomib) 
A “first dose effect” has been seen, which is notable for fever, chills, rigors, and/or dyspnea 
occurring during the evening following the first day of infusion and an increase in creatinine on Day 
2, which may be the clinical sequelae of rapid tumor lysis and/or cytokine release. 
All subjects should be well hydrated (Section 6.3.2). Clinically significant electrolyte abnormalities 
should be corrected prior to dosing with carfilzomib. Renal function must be monitored closely 
during treatment. 
Should a “first dose” effect occur at any point during Cycle 1 or 2, treatment with high dose 
glucocorticoids (e.g. methylprednisolone 50–100 mg) is recommended.  In addition, intravenous 
fluids, vasopressors, oxygen, bronchodilators, and acetaminophen should be available for immediate 
use and instituted, as medically indicated.   
6.10.3. Tumor Lysis Syndrome 
TLS, which may be associated with multi-organ failure, has been observed in treatment Cycles 1 
and 2 in some subjects with MM who have been treated with carfilzomib. All subjects should follow 
the hydration guidelines outlined in Section 6.3.2. If subjects are considered to be at risk for TLS, 
hydration should be continued into Cycle 2 if clinically indicated. 

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MM subjects with high tumor burden (e.g., Durie-Salmon or ISS Stage II/III), rapidly increasing M-
protein or light chains, or compromised renal function (CrCl < 50 mL/min) should be considered to 
be at particularly high risk. 
During Cycles 1 and 2, serum electrolytes and chemistries are closely monitored. Subjects with 
laboratory abnormalities consistent with lysis of tumor cells  (e.g. serum creatinine ≥ 50% increase, 
LDH ≥ 2-fold increase, uric acid ≥ 50% increase, phosphate ≥ 50% increase, potassium ≥ 30% 
increase, calcium ≥ 20% decrease) prior to dosing should not receive the scheduled dose. Subjects 
with such abnormalities should be re-evaluated as clinically indicated. The Lead Principal 
Investigator should be consulted if there are further delays. 
If TLS occurs, cardiac rhythm, fluid, and serial laboratory monitoring should be instituted.  Correct 
electrolyte abnormalities, monitor renal function and fluid balance, and administer therapeutic and 
supportive care, including dialysis, as clinically indicated. 
All cases of TLS must be reported to the Lead Principal Investigator (who will, in turn be responsible 
for distributing this information to all sites) and to Amgen as a Serious Adverse Event (SAE) through 
the normal process within 24 hours of the clinical site becoming aware of the event. 
6.10.4. Renal Function 
Carfilzomib has not been fully characterized in subjects with creatinine clearance < 30 mL/min. It 
is critical that the subject’s renal function is known at the time of dosing. Renal function, serum 
creatinine, and serum uric acid should be monitored closely during treatment with carfilzomib. Renal 
function must be monitored closely during treatment with carfilzomib.  Serum chemistry values, 
including creatinine, must be obtained and reviewed prior to each dose of carfilzomib during Cycles 
1 and 2. Refer to Table 6-7 for guidance regarding dose reduction in subjects with compromised 
renal function. 
7. 
SAMPLES FOR MRD EVALUATION AND CORRELATIVE STUDIES 
Bone marrow samples for MRD evaluation are required and as per the standard of care and will be 
collected prior to initiation of treatment (screening), at the completion of 4 (non-SOC for subjects 
who do not continue to ASCT), 8, 12, and 18 (for subjects who are MRD+ at the end of C8 but 
MRD- at the end of C12 only) cycles of E-KRd, 24 months after C1D1 for all subjects, and then 
yearly or at the time of near complete response (nCR determination is not possible, then VGPR will 
be used to trigger a bone marrow biopsy. A Bone Marrow Biopsy to confirm nCR or VGPR will not 
be required if the subject is within 2 months of a landmark BMBX timepoint ) if more than 2-3 
months from scheduled evaluation, and/or progression/relapse.  
MRD evaluation will be done centrally at the University of Chicago (by Flow) and at Adaptive 
Biotechnologies (by NGS). For this purpose, two BM samples must be shipped at each timepoint. 
Additionally, provided that the subject consents, correlative samples will be collected and banked 
for further research studies. 
Shipping locations will be as follows: 
 
Samples Shipped to University of Chicago Hematology Lab: 
- 
Screening, cycle 4, cycle 8, cycle 12, cycle 18 (when applicable), 24 months after C1D1, 
yearly after that, and at the time of nCR (or VGPR if nCR determination is not possible) 
Samples Shipped to Adaptive Biotechnologies directly: 

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- 
End of cycle 12 for quick turnaround for treatment decision 
Samples Shipped to University of Chicago MM lab: 
- 
Screening, cycle 4, cycle 8, cycle 18 (when applicable), 24 months after C1D1, yearly after 
that,, and the time of nCR, or VGPR when nCR determination is not possible (MRD only 
for batch shipping to Adaptive) 
- 
Screening, cycle 4, cycle 8, cycle 12, cycle 18 (when applicable), 24 months after C1D1, 
and at the time of nCR, or VGPR when nCR determination is not possible (all correlative 
samples) 
 
 

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Shipment time points are outlined below.  
Table 7-1 MRD and correlative sample shipment schema 
MRD sample 
Correlative Sample 
Time Points 
Bone Marrow Aspirate 
Bone Marrow Aspirate 
Screening/Pre-treatment, after 
4, 8 and 12, and 18 (when 
applicable) cycles, 24 months 
after C1D1,, yearly after that, 
and at the time of near 
complete response (or VGPR if 
nCR determination is not 
possible) 
Progression/Relapse* 
 
Peripheral Blood 
 
Plasma/Serum 
 
Buccal Swab 
Screening only 
* Correlative sample only 
All bone marrow procedures, except end of cycle 4 for subjects who do not go into ASCT (including 
those performed at screening, response and/or progression/relapse) are considered standard of care 
and a subject may give consent to have extra research samples collected at these visits.   
Please refer to the Laboratory Manual for detailed processing and shipping instructions.  
Label all specimens with the following:  
1. Subject initials  
2. Subject study number (will include protocol number) and MRN 
3. Visit at which sample was drawn (i.e. C1D4)  
4. Date sample drawn (i.e. mm/dd/yyyy)  
5. Time sample drawn (24 hour clock)  
6. Sample type (eg. plasma, serum, bone marrow cells, tumor cells)  
 
Shipping Instructions to the University of Chicago Hematology lab (for MRD by flow) 
1. Specimens should be delivered to the Hematology Laboratory within 24 hours of 
collection.  
2. The delivery information should be on the outside of package.  
3. Specimens cannot be accepted on Saturday or Sunday. NO FRIDAY 
SHIPMENTS PLEASE 
4. Packages should be delivered to: 
 
Julie Leanse, MS, MT (ASCP) 
Hematology Laboratory 
Room TW-051 / MC0008 
5841 S. Maryland Ave. 
Chicago, IL  60637            
Phone: 773-702-1314  
 

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Shipping Instructions to the University of Chicago MM lab (for batch shipping to Adaptive and 
correlative samples):  
1. An inventory sheet including a complete list of samples shipped (subject number 
and MRN, timepoint, study #) must accompany each shipment.  
2. An electronic copy (Word or Excel) of the sample list must also be sent via email. 
The listing must also include a contact name, address and phone number of the 
person who is responsible for the shipment. They should sign and date the form.  
3. Please contact lab technician to alert him/her of an incoming shipment by email: 
myeloma-lab@bsd.uchicago.edu  
4. Please ship Monday, Tuesday, Wednesday or Thursday, as shipments cannot be 
received on weekends and/or on holidays.  
Andrzej J Jakubowiak, MD, PhD  
Attention: Myeloma Laboratory  
900 E 57th St  
KCBD 7240 LB17  
Chicago, IL 60637  
Business Phone (773) 702-1345 or 773-834-1592  
Business Fax 773-702-9268 
Email: myeloma-lab@bsd.uchicago.edu 
 
Note: Please follow your institution’s policy regarding destruction of subject samples upon 
withdrawal of informed consent.  
8. 
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 an investigational 
(medicinal) product and that does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of investigational product, whether or not 
considered related to the investigational product. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) 
NONSERIOUS ADVERSE EVENT 
• 
Nonserious Adverse Events are to be provided to BMS in aggregate via interim or final 
study reports as specified in the agreement or, if a regulatory requirement [e.g. IND US trial] 
as part of an annual reporting requirement.  
• 
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.  
A nonserious adverse event is an AE not classified as serious.  
Nonserious Adverse Event Collection and Reporting 

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The collection of nonserious AE information should begin at initiation of study drug. All nonserious 
adverse events deemed to be related to study drug combination should be collected continuously 
during the treatment period and for a minimum of 30 days following the last dose of study treatment.  
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. 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.  
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported as such. 
The following laboratory abnormalities should be documented and reported appropriately: 
• 
any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
any laboratory abnormality that required the subject to have study drug discontinued or 
interrupted 
• 
any laboratory abnormality that required the subject to receive specific corrective therapy.  
 
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. Potential drug induced liver injury is 
defined as: 
1) 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 AST/ALT 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. 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be reported 
as an SAE. 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, 
x-rays, and any other potential safety assessments, whether or not these procedures are required by 
the protocol, should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly. 
Unexpected AEs 

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An unexpected AE is any adverse drug event, the specificity or severity of which is not consistent 
with the current IB or prescribing information for a marketed compound.  Also, reports which add 
significant information on specificity or severity of a known, already documented AE constitute 
unexpected AEs.  For example, an event more specific or more severe than described in the IB would 
be considered “unexpected”.    
Whenever possible, the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
should be used to describe the event and for assessing the severity of AEs (see Appendix 3).  Any 
events representing a change in the CTCAE Grade need to be reported on the AE case report form.  
This includes any change in laboratory values.   
For AEs not adequately addressed in the CTCAE, the severity table below may be used: 
Severity 
Description 
GRADE 1 – Mild 
Transient or mild discomfort; no limitation in 
activity; no medical intervention/therapy required. 
GRADE 2 – Moderate 
Mild to moderate limitation in activity—some 
assistance may be needed; no or minimal medical 
intervention/therapy required. 
GRADE 3 – Severe 
Marked limitation in activity, some assistance 
usually 
required; 
medical 
intervention/therapy 
required, hospitalizations possible. 
GRADE 4 – Life-threatening 
Extreme limitation in activity, significant assistance 
required; life-threatening (immediate risk of death); 
significant medical intervention/therapy required, 
hospitalization or hospice care probable. 
GRADE 5 – Fatal 
Death 
 
Any condition, laboratory abnormality, or physical finding with an onset date prior to the subject 
signing consent for study participation is considered to be pre-existing in nature and part of the 
subject’s medical history. 
8.1. Causality 
Using the following criteria, the relationship of the AE to the study drug should be assessed as 
follows:  
Definite (5) – The AE is clearly related to the study treatment. 
Probable (4) – The AE is likely related to the study treatment. 
Possible (3) – The AE may be related to the study treatment. 
Unlikely (2) – The AE is doubtfully related to the study treatment. 
Unrelated (1) – The AE is clearly NOT related to the study treatment. 
All AEs will be considered for dose-limiting toxicity evaluation unless the event can clearly be 
determined to be unrelated to the drug.  
8.2. Adverse Event Reporting Procedures 
Information about all AEs, whether volunteered by the subject, discovered by the Treating 
Investigator questioning, or detected through physical examination, laboratory tests or other means, 
will be collected and recorded in eVelos and followed as appropriate.  

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All Adverse Events must be reported in routine study data submissions to the lead PI who will 
review and will be responsible for alerting all participating sites about the AE as required.  AEs 
reported using the Serious Event Reporting Form and/or MedWatch Form discussed below 
must also be reported in routine study data submissions in eVelos.  Details of the event must 
include severity, relationship to study drug, duration, action taken, and outcome as shown on the 
eCRF in eVelos. All AEs must be followed to resolution or stabilization regardless of relationship 
to study drug. 
All AEs that are considered related to study regimen must be followed to resolution or stabilization 
if improvement is not expected.  
AEs must be reported from the date of the first dose of treatment through 30 days post-last dose of 
study treatment or initiation of a new anti-cancer therapy, whichever occurs first. If a subject is 
enrolled but discontinues study prior to receiving any study drug, only SAEs that are considered 
related to study procedures must be reported through the end-of-study visit. AEs that completely 
resolve and then recur should be recorded as a new AE. For subjects who complete the end of study 
visit less than 30 days following their last dose of study drug, a follow up of ongoing AEs should be 
attempted by telephone, and documented in the subject’s source. AEs continuing at 30 days post-
last dose should have a comment in the source by the Treating Investigator that the event has 
stabilized or is not expected to improve. SAEs continuing at 30 days post-last dose should be 
followed until resolution or stabilization. 
The Treating Investigator is responsible for evaluating all AEs for relationship to study drug and for 
seriousness, obtaining supporting documents, and determining that documentation of the event is 
adequate. Adverse events will be assigned a severity grade using the NCI-CTCAE grading scale 
v4.0. The Treating Investigator must assess all abnormal laboratory results for their clinical 
significance. Only grade 1 & 2 abnormal laboratory values considered clinically significant, related 
to study treatment, and/or requiring concomitant medication will be recorded. If any abnormal 
laboratory result is considered clinically significant, the Treating Investigator must provide details 
about the action taken with respect to the test drug and about the subject’s outcome. All Grade 3 and 
4 laboratory abnormalities must be recorded as AEs on the CRF. Grade 1 and 2 abnormalities should 
only be recorded if they require treatment or are otherwise considered clinically significant by the 
Treating Investigator.  
The Lead Principal Investigator may delegate these duties to Sub-investigators and must ensure that 
these Sub-investigators are qualified to perform these duties under the supervision of the Lead 
Principal Investigator, and that they are listed on the delegation log. 
8.3. Serious Adverse Events 
All SAEs will be collected by the UC CRA and reviewed by the Lead Principal Investigator. Only 
those determined to be SUSARs by the Lead Principal Investigator will be distributed to all 
participating sites (using the completed MedWatch 3500 form). To ensure subject safety, each 
serious adverse event must be reported to the Lead Principal Investigator and the University of 
Chicago Comprehensive Cancer Center via paper submission via fax or email within 24 hours of 
learning of its occurrence. A paper SAE form is provided for this study and may be used and sent 
via fax or email. 
The Lead Principal Investigator is responsible for notifying the investigators of any expedited, 
annual, or other periodic safety reports in accordance with applicable regulations.  
The Site Investigator is also responsible for notifying the local IRB in accordance with local 
regulations. Additionally, the Lead Principal Investigator is responsible for reporting SAEs to BMS 
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8.3.1. Serious Adverse Event Definition 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
● Results in death 
● Life threatening experience defined as any adverse experience that places the subject, in the 
view of the Treating Investigator, at immediate risk of death at the time of occurrence; i.e., 
it does not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
● Requires insubject hospitalization or prolongation of an existing hospitalization (except 
scheduled hospitalizations for non-acute, unrelated cause such as an elective surgery) 
● Results in persistent or significant disability/incapacity or any other medicinal product 
effects, which the doctor by his state of knowledge deemed serious 
● Is a congenital anomaly/birth defect in the offspring of an exposed subject 
● Important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered an SAE, when, based upon appropriate medical 
judgment, it jeopardizes the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
● Potential drug induced liver injury (DILI) is also considered an important medical event.  
● Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the 
study drug is an SAE.  
Although pregnancy, overdose, and cancer are not always serious by regulatory definition, these 
events must be handled as SAEs. 
Any death occurring within 30 days of the subject receiving study drug, regardless of the subject 
having discontinued from the study must be reported to the Lead Principal Investigator as an SAE.  
ALL Serious Adverse Events MUST be reported to the Lead Principal Investigator and to the 
University of Chicago Comprehensive Cancer Center (UC CCC), via paper submission via fax or 
email. This is whether or not they are considered related to the study agent. Refer to Section 8.3.3 
for reporting guidelines. 
8.3.2.  Serious and Unexpected Suspected Adverse Reaction (SUSAR) 
A serious adverse event is considered to be a suspected adverse reaction if there is evidence to 
suggest a causal relationship to the study agent. This may include a single occurrence of an event 
strongly associated with drug exposure (e.g. Stevens Johnson Syndrome), one or more occurrence 
of an event otherwise uncommon in the study population, or an aggregate analysis of specific events 
occurring at greater frequency than expected from historical controls.  
Unexpected events are those not listed at the observed specificity or severity in the protocol, consent, 
Investigator brochure, or FDA-approved package insert. This includes adverse events listed in the 
protocol or consent as occurring within the class of drugs or otherwise expected from the drug’s 
pharmacological properties but which have not been previously observed with this agent.  
The lead institution (University of Chicago) is responsible for notifying all participating 
investigators, when required, and in accordance with applicable laws and regulations of any 
Expedited Safety Reports that are determined by the Lead Principal Investigator to be Unexpected.  

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8.3.3. Serious Adverse Event Reporting and Documentation Requirements 
 
8.3.3.1. 
Serious Adverse Event Reporting to the University of Chicago 
 
Use the UC CCC protocol number and the protocol-specific subject ID assigned during trial 
registration on all reports. 
All  serious adverse events (as defined above) occurring on this study require expedited 
reporting to the University of Chicago Comprehensive Cancer Center (UC CCC). 
SAEs occurring at the University of Chicago as well as other sites, will be reviewed by the Lead 
Principal Investigator, who will determine whether they are SUSARs. The Lead Principal 
Investigator or designee will report all SUSARs to the UC CRA and UC CCC, who will report 
simultaneously to the UC IRB and other US sites, according to regulations (see below).  
The responsible Research Nurse or other designated individual at the treating site should 
report the SAE to the Study Lead Investigator, the University of Chicago CRA and the UC 
CCC CCTO by the end of the business day when s/he becomes aware of the event.  Events 
occurring after business hours should be reported to the CCTO by 12pm (noon) the next business 
day.  Reports should be made using the ‘Serious Event Report’ Form.  Please scan and send via 
email (preferred) or fax to the following: 
 
University of Chicago Phase II CRA General: 
PhaseIICRA@medicine.bsd.uchicago.edu 
Phone: 773-834-1746 
Fax: 773-702-4889 
 
UC CCC Cancer Clinical Trials Office Quality Assurance: 
qaccto@bsd.uchicago.edu 
 
All unexpected adverse reactions must be reported to the IND holder so that the University of 
Chicago CCTO can inform the FDA.  The responsible Research Nurse or other designated 
individual at the treating site should provide a complete written report using the FDA MedWatch 
3500A form.  The completed form should be sent to the CCTO at qaccto@bsd.uchicago.edu and to 
the Phase II CRA at PhaseIICRA@medicine.bsd.uchicago.edu within the specified timelines 
below regardless of whether all information regarding the event is available.  If applicable, a 
follow-up report should be provided to the CCTO if additional information on the event becomes 
available.   
Fatal or Life-threatening Events: within 4 calendar days from treating investigator knowledge of 
the event 
All Other Reportable Events: within 10 calendar days of treating investigator knowledge of the 
event. 
All serious adverse events should also be reported to the local IRB of record according to 
their policies and procedures.   
 

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8.3.3.2. 
Serious and Unexpected Adverse Event reporting by the University of 
Chicago 
The designated UC CCC Regulatory Manager will notify all participating sites of all SUSARs that 
occur on this clinical trial and which are reported to the UC Institutional Review Board (IRB). A 
copy of the completed Form 3500 (MedWatch) will be distributed to all participating sites. 
8.4. Expedited Reporting by the Lead Principal Investigator to BMS and Amgen 
The University of Chicago CRA will inform BMS and Amgen in writing by email or facsimile of 
any SAE occurring to US subjects within 24 hours of being aware of the event using a completed 
MedWatch3500 Form.  
The date of awareness should be noted on the report. The initial report must be as complete as 
possible, including details of the current illness and (serious) adverse event, and an assessment of 
the causal relationship between the event and the investigational product(s). A final report to 
document resolution of the SAE is required.  
 
SAE Reporting to Bristol-Myers Squibb (BMS) 
The Overall PI, as study sponsor, will be responsible for all communications with the BMS. With 
the exception of any serious adverse event that meets the FDA’s criteria for expedited reporting 
following the reporting requirements and timelines set by the FDA. The written report must be 
completed and supplied to BMS by facsimile or e-mail within 24 hours of Lead Principal 
Investigator knowledge of the event 
 
• 
The BMS SAE form should be used to report SAEs. If the BMS form cannot be used, 
another acceptable form (ie, CIOMS or Medwatch) must be reviewed and approved by 
BMS. The BMS protocol ID number must be included on whatever form is submitted by 
the Sponsor/Investigator. 
• 
Following the subject’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, are collected, including those thought to be associated with 
protocol-specified procedures. The investigator should report any SAE occurring after these 
time periods that is believed to be related to study drug or protocol-specified procedure. For 
drugs with potential for delayed SAEs (eg, delayed excretion of the parent or active 
metabolites), a longer follow-up period may be warranted to allow collection of these SAEs, 
laboratory tests, and other assessments. 
• 
The Investigator will reconcile the clinical database SAE cases transmitted to BMS Global 
Pharmacovigilance (worldwide.safety@bms). Frequency of reconcilliation should be on a 
quarterly basis and prior to the database lock or final data summary.  BMS GPV&E will 
email upon request from the Investigator, the GPV&E reconcilliaton report. Requests for 
reconcilliation should be sent to aebusinessprocess@bms.com.  The data elements listed on 
the GPV&E reconcilliation report will be used for case identification purposes. If the 
Investigator determines a case was not transmitted to BMS GPV&E, the case should be sent 
immediately to BMS. 
• 
In accordance with local regulations, BMS will notify investigators of all reported SAEs 
that are suspected (related to the investigational product) and unexpected (ie, not previously 
described in the IB). In the European Union (EU), an event meeting these criteria is termed 
a Suspected, Unexpected Serious Adverse Reaction (SUSAR). Investigator notification of 
these events will be in the form of an expedited safety report (ESR).  

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o Other important findings which may be reported by the as an ESR include: 
increased frequency of a clinically significant expected SAE, an SAE considered 
associated with study procedures that could modify the conduct of the study, lack 
of efficacy that poses significant hazard to study subjects, clinically significant 
safety finding from a nonclinical (eg, animal) study, important safety 
recommendations from a study data monitoring committee, or sponsor decision to 
end or temporarily halt a clinical study for safety reasons. 
o Upon receiving an ESR from BMS, the investigator must review and retain the ESR 
with the IB. Where required by local regulations or when there is a central IRB/IEC 
for the study, the sponsor will submit the ESR to the appropriate IRB/IEC. The 
investigator and IRB/IEC will determine if the informed consent requires revision. 
The investigator should also comply with the IRB/IEC procedures for reporting any 
other safety information.  
o In addition, suspected serious adverse reactions (whether expected or unexpected) 
shall be reported by BMS to the relevant competent health authorities in all 
concerned countries according to local regulations (either as expedited and/or in 
aggregate reports). 
• 
An SAE report should be completed for any event where doubt exists regarding its 
seriousness.  
• 
For studies with long-term follow-up periods in which safety data are being reported, 
include the timing of SAE collection in the protocol. 
• 
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. 
• 
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 BMS using 
the same procedure used for transmitting the initial SAE report. All SAEs should be 
followed to resolution or stabilization. All SAEs should be followed to resolution or 
stabilization. 
 
All Serious Adverse Events (SAEs) that occur following the subject’s written consent to 
participate in the study through 60 days of discontinuation of dosing must be reported to BMS 
Worldwide Safety. SAEs, whether related or not related to study drug, and pregnancies must be 
reported to BMS within 24 hours. SAEs must be recorded on BMS or an approved form; 
pregnancies must be reported on a Pregnancy Surveillance Form. 
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.  

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All SAEs should be followed to resolution or stabilization. 
SAE Reporting to Amgen 
The Lead Principal Investigator must inform Amgen in writing by e-mail or fax at the contact 
information listed below for all SUSARs that are judged as reasonably related to the Amgen study 
drug. Site will transmit the final MedWatch form of that event to Amgen within twenty-four (24) 
hours of Lead Principal Investigator knowledge of the event.  
For regulatory reporting purposes, an event of “Death, Cause Unknown” from the study shall be 
processed as a SUSAR.  All forms must be completed and provided to Amgen in English.  
The Individual Case Safety Report (ICSR) may be referred to as an individual safety report or SAE 
Report, including Pregnancy Exposure Reports and Follow up Reports. The ICSR must be as 
complete as possible, at a minimum including event reference number, protocol name and number, 
investigator contact information, specific subject identifiers (e.g., initials, subject number, date of 
birth or age, or gender), the name of the suspect Study Drug, the date and dosage(s) of exposure, 
event, the date(s) of event, country of event, “Serious” Criteria, Relationship/causality of Study 
Drug, Hospitalization history for the event, Event status/outcome, Relevant history (including 
diagnostics, laboratory values, radiographs, concomitant medications, and event treatment, and 
narrative summary.  
The Lead Principal Investigator shall be responsible for collecting all SAEs and Pregnancy and 
Lactation Exposure Reports and will exercise commercially reasonable due diligence to obtain 
follow-up information on incomplete SAE or Pregnancy and Lactation Exposure Reports. In the 
event that the Company requires clarification or further information on individual SAE or Pregnancy 
and Lactation Exposure Reports, Amgen will not contact non-party investigators directly, but will 
route all such inquiries through the Lead Principal Investigator for forwarding to such 
investigator(s). The Lead Principal Investigator will be responsible to ensure such inquiries are 
completed and timely provided to Amgen.  
Information not available at the time of the initial report (e.g., an end date for the SAE, discharge 
summaries, lot numbers, relevant laboratory values, scan data and autopsy reports) which are 
received after the initial report must be documented on a follow-up form, and submitted to Amgen 
in the same timelines as outlined above. The Lead Principal Investigator shall be responsible for 
obtaining follow-up information for the SAEs and demonstrate diligence in attempting to obtain 
such information by, among other things, maintaining written records of such attempts. 
Other aggregate analysis including reports containing safety data generated during the course of the 
study is to be submitted to Amgen at the time the Lead Principal Investigator submits to anybody 
governing research conduct i.e. IRB etc. Final study report and reports of unauthorized use of a 
marketed product to be submitted to Amgen at the time the Lead Principal Investigator ISS submits 
to anybody governing research conduct i.e. IRB etc. but not later than one calendar year of study 
completion. 
Reports containing safety data generated during the course of the study is to be submitted to Amgen 
at the time the Lead Principal Investigator submits to anybody governing research conduct, i.e. IRBs.   
The Lead Principal Investigator will support reconciliation of all ICSRs at the end of the study at a 
minimum. 

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The Amgen protocol number (ISS # 20167383) and the institutional protocol number should be 
included on SAE reports to Amgen.  
 
Amgen Safety Contact Information: 
 
Fax: Toll-free US  888-814-8653 
+1 805-480-9205 (toll, global)    
Drug Safety Reporting by secure e-mail can be established upon request. 
8.4.1. Pregnancy Reporting 
Pregnancy of a female subject or the female partner of a male subject occurring while the subject is 
on treatment or within 4 weeks after the subject’s last dose of study drug are considered expedited 
reportable events. Study drugs—Lenalidomide, dexamethasone, and carfilzomib—are to be 
discontinued immediately. The pregnancy must be reported within 24 hours of the Treating 
Investigator’s knowledge of the pregnancy by phone and facsimile using the SAE form to the 
University of Chicago CRA either by fax or by email. The Treating Investigator must inform the 
University of Chicago in writing by email or facsimile of any pregnancy within 24 hours / 1 business 
day at the latest on the following workday of being aware of the event. The University of Chicago 
must report pregnancy as an SAE directly to BMS and Amgen using expedited reporting procedures 
listed in Section 8.4 and 8.4.1. 
Pregnancy Reporting by Lead Principal Investigator to BMS 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 5 half lives after product administration, the investigational product will be 
permanently discontinued in an appropriate manner (e.g. dose tapering if necessary for subject 
safety).  
The investigator must immediately notify Worldwide.safety@bms.com of this event via the 
Pregnancy Surveillance Form in accordance with SAE reporting procedures.  
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 [provided upon request from BMS] 
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. 
 
 
Pregnancy Reporting by Lead Principal Investigator to Amgen 
Report Pregnancy and potential infant exposure including Lactation, within ten (10) calendar days 
of the Lead Principal Investigator awareness. Provide to Amgen the SAE reports associated with 
pregnancy.   
Subjects, spouses, or partners will be followed through the outcome of the pregnancy.   
If the outcome of the pregnancy meets a criterion for immediate classification as an SAE—
spontaneous abortion (any congenital anomaly detected in an aborted fetus is to be documented), 

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stillbirth, neonatal death, or congenital anomaly—the Treating Investigator should repeat the 
procedures for expedited reporting of SAEs as outlined above. 
9. 
INVESTIGATIONAL MEDICINAL PRODUCT 
9.1. Elotuzumab 
9.1.1. Description  
Elotuzumab (BMS- 901608; formerly known as HuLuc63) is a humanized recombinant 
monoclonal IgG1 antibody product directed to human CS1 (CD2-subset-1, also known as CRACC 
and SLAMF7), a cell surface glycoprotein that is highly expressed in MM cells. 
9.1.2. Form  
Elotuzumab for injection has been developed to be used as an intravenous (IV) infusion for the 
clinical studies. The drug product will be reconstituted prior to administration. 
 
 
Product Description 
/ Class and Dosage 
Form 
Potency 
Blinded or Open 
Label 
Packaging / 
Appearance 
Storage Conditions 
(per label) 
Elotuzumab Powder 
for Solution for 
Infusion 
400 mg/vial or 
300mg/vial 
Open Label 
20 mL Vial/ Sterile, 
white to off-white, 
preservative-free, 
lyophilized cake 
Store at 2°C - 8°C 
 
9.1.3. Storage and Stability  
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the sponsor. If 
concerns regarding the quality or appearance of the study drug arise, do not dispense the study 
drug and contact the sponsor immediately. 
 
The lyophilized elotuzumab drug product should be stored at 2° to 8° C. Prior to administration the 
drug product must be reconstituted with Sterile Water for Injection, USP, and then further diluted 
in 0.9% sodium chloride normal saline, USP, as per the instructions in section 9.1.6. After the dose 
is diluted in normal saline, it must be administered within 8 hours if stored at room temperature. If 
a delay is anticipated, the prepared dose may be refrigerated at 2° to 8° C for up to 24 hours. If 
stored under refrigerated conditions, the prepared study drug solution should be equilibrated to 
room temperature (process takes 2 - 2.5 hours) and the container must be gently inverted to mix 
well before administration. Do not use the accelerated warming method. If administration is 
delayed beyond the specified time, the prepared dose solution must be discarded, and the reason 
documented by the pharmacist in study drug accountability records. 
The dose of elotuzumab to be administered to a subject will be calculated by multiplying the 
subject’s weight (kg) by 10 mg/kg. The subject’s pre-dose weight at screening will be used to 
calculate the dose for each cycle, unless there is a change in weight of ≥10%. Each dose should be 
infused as per instructions in Section 6.3. 

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9.1.4. Handling 
The lyophilized elotuzumab drug product should be stored at 2° to 8°C. Prior to administration the 
drug product must be reconstituted with Sterile Water for Injection, USP, and then further diluted 
in 0.9% sodium chloride normal saline, USP, as per the instructions in Section 9.1.6. 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the 
environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 
9.1.5. Availability 
Bristol-Myers Squibb will supply elotuzumab. Elotuzumab is an investigational agent and will be 
supplied free-of- charge. Drug will be shipped to the pharmacy at the study site. 
9.1.6. Preparation 
Elotuzumab for Injection, 400 mg/vial and Elotuzumab for Injection, 300 mg/vial.  
Each vial of Elotuzumab for Injection, 400 mg/Vial and Elotuzumab for Injection, 300 mg/Vial 
should be reconstituted with sterile water for injection (SWFI) at the clinical compounding site. The 
lyophilized powder should dissolve in less than 10 minutes. Once the reconstitution is completed, 
withdraw 16 mL from the 400 mg/vial presentation or 12 mL from the 300 mg/vial presentation for 
dilution with 0.9% sodium chloride injection (NS) to result in an elotuzumab concentration from 1.0 
mg/mL to no higher than 6.0 mg/mL in a polyvinyl chloride or polyolefin infusion bag. Five percent 
(5%) Dextrose injection (D5W) may be used as a diluent in place of 0.9% sodium chloride injection. 
During drug product preparation, vigorous mixing or shaking is to be avoided. The infusion is to be 
administered through a sterile, non-pyrogenic, low protein binding in line filter (with a pore size of 
0.2-µm to 1.2-µm) using an automated infusion pump. Additionally, care must be taken to ensure 
the sterility of the prepared solution, as the drug product does not contain anti-microbial 
preservatives or bacteriostatic agents. A sufficient excess of drug product is included in each vial to 
account for withdrawal losses.  
The infusion of the reconstituted and diluted solution of elotuzumab for injection prepared for dosing 
must be completed within 24 hours of reconstitution. If not used immediately, the infusion solution 
may be stored under refrigeration conditions, 2ºC to 8ºC (36ºF to 46ºF), and protected from light for 
up to 24 hours (a maximum of 8 hours of the total 24 hours can be at room temperature, 20ºC to 
25ºC (68ºF to 77ºF), and room light). The drug solution should be equilibrated to room temperature 
and the container must be gently inverted to mix well before administration. 
9.1.7. Administration 
Elotuzumab will be given cycle 1 & 2 at 10 mg/kg IV once a week (days, 1, 8, 15, and 22) in 28-
day cycles. 
From cycle 3 and beyond, elotuzumab will be given at 10mg/kg IV every two weeks (days 1 and 
15) in 28-day cycles. 
Elotuzumab should be initiated at an infusion rate of 0.5 mL per minute. If well tolerated, the 
infusion rate may be increased in a stepwise fashion as described in Table 5. The maximum 
infusion rate should not exceed 5 mL per minute. Please refer to section 6.3.1 for full infusion rate 
details for elotuzumab. 

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9.1.8. Ordering 
The investigator or designee will order drug from Bristol-Myers Squibb, according to the ordering 
instructions provided by company. 
9.1.9. Accountability 
The investigator, or designee, is responsible for taking an inventory of each shipment of 
elotuzumab received, and comparing it with the accompanying accountability form. The 
Investigator, or designee, will verify the accuracy of the information on the form, sign and date it, 
retain a copy in the study fill. Accurate records will be kept in the source documentation of all 
drug administration (including dispensing and dosing). 
9.1.10. Destruction and Return 
IMP (those supplied by the sponsor or sourced by the site/investigator) are ideally to be destroyed 
on site. It is the Investigator’s responsibility to ensure that arrangements have been made for the 
destruction, procedures for proper destruction have been established according to applicable 
regulations, guidelines and institutional procedures, and appropriate records of the destruction 
have been documented. The unused IMPs can only be destroyed after being inspected and 
reconciled by the responsible site monitor.  
 
Ideally used IMP should not be returned to the Sponsor but destroyed on site. All unused and/or 
partially used IMP may be destroyed on site providing the site has an appropriate standard 
operating procedure on file.  
 
If required by local country/hospital regulations IMP can be returned to a BMS off-site IMP 
destruction vendor, but this should only be arranged by your site monitor. All IMP destruction 
must be documented. If on-site destruction occurs, then a Confirmation of Destruction must be 
available at the site, in accordance with the local laws, regulations and institutional requirements. 
If IMP is returned for destruction off site, the Investigational Product Return Form acts as the 
destruction certificate. All related documentation must be filed. 
9.2. Carfilzomib 
9.2.1. Description 
Carfilzomib is a synthetic small molecule peptide bearing the chemical name (2S)-N-((S)-1-((S)-4-
methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-
morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide.  The molecular formula is 
C40H57N5O7 and the molecular weight is 719.91.  It specifically functions as an inhibitor of the 
chymotrypsin-like activity of the 20S proteasome, which leads to the accumulation of protein 
substrates within the cell and induction of apoptosis. 
9.2.2. Formulation 
Carfilzomib for Injection will be provided as a lyophilized powder which, when reconstituted, 
contains 2 mg/mL isotonic solution of carfilzomib Free Base in 10 mM sodium citrate buffer 
(pH 3.5) containing 10% (w/v) sulfobutylether--cyclodextrin (SBE--CD, Captisol®). 
9.2.3. Storage 
Lyophilized Carfilzomib for Injection must be stored at 2–8ºC under the conditions outlined in the 
separate Pharmacy Manual, in a securely locked area to which access is limited to appropriate study 
personnel. 

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9.2.4. Accountability 
Amgen, Inc. and the Site Investigator will maintain records of each shipment of investigational 
product.  The records will document shipment dates, method of shipment, batch numbers, and 
quantity of vials contained in the shipment.  Upon receipt of the investigational product, the 
designated recipient at the study site will inspect the shipment, verify the number and condition of 
the vials, and prepare an inventory or drug accountability record.  
Drug accountability records must be readily available for inspection.  
Empty and partially used vials should be accounted for and destroyed at the study site in accordance 
with the internal standard operating procedures.  Drug destruction records must be readily available 
for inspection.  
Only sites that cannot destroy unused drug on-site will be required to return their unused supply of 
investigational product. 
9.3. Lenalidomide 
9.3.1. Description 
Lenalidomide, a thalidomide analogue, is an immunomodulatory agent with anti-angiogenic and 
anti-neoplastic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) 
piperidine-2,6-dione. The empirical formula for lenalidomide is C13H13N3O3, and the gram 
molecular weight is 259.3. 
Lenalidomide is off-white to pale-yellow solid powder.  It is soluble in organic solvent/ water 
mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and low 
pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 0.4 to 0.5 
mg/mL.  Lenalidomide has an asymmetric carbon atom and can exist as the optically active forms 
S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of zero.  Lenalidomide 
is available in 5 mg, 10 mg, 15 mg and 25 mg capsules for PO administration.  Each capsule contains 
lenalidomide as the active ingredient and the following inactive ingredients: lactose anhydrous, 
microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.  The 5 mg and 25 mg 
capsule shell contains gelatin, titanium dioxide and black ink.  The 10 mg capsule shell contains 
gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink.  The 15 mg capsule shell 
contains gelatin, FD&C blue #2, titanium dioxide and black ink.  
9.3.2. Supply 
Commercially available REVLIMID® (lenalidomide) capsules are supplied through the Revlimid 
REMS® program as the drug is approved for indications in this study. Lenalidomide is for PO (oral) 
administration only. 
9.3.3. Storage Conditions 
Store lenalidomide at 25°C (77 °F) away from direct sunlight; excursions permitted to 15-30°C (59-
86 °F). 
9.3.4. Accountability 
Bottles of lenalidomide will contain a sufficient number of capsules to last for one cycle of dosing.  
Sites will be required to record and document subject compliance regarding lenalidomide dosing. 

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9.3.5. Prescribing Information 
Lenalidomide will be provided in accordance with the Revlimid REMS® program of Celgene 
Corporation.  Per standard Revlimid REMS® requirements, all physicians who prescribe 
lenalidomide for research subjects enrolled into this trial must be registered in must comply with all 
requirements of the Revlimid REMS® program.  Prescriptions must be filled within 7 days.  Only 
enough lenalidomide for one cycle of therapy will be supplied to the subject each cycle.  
9.3.6. Special Handling Instructions 
Females of child-bearing potential should not handle or administer lenalidomide unless they are 
wearing gloves. 
9.4. Dexamethasone 
Dexamethasone may be given IV or PO 
9.4.1. Description 
Dexamethasone, a synthetic adrenocortical steroid, is a white to practically white, odorless, 
crystalline powder.  It is stable in air.  It is practically insoluble in water. 
9.4.2. Formulation 
Dexamethasone is a commercially available PO drug, supplied as 2 and 4 mg tablets. 
9.4.3. Storage conditions 
Store dexamethasone at controlled room temperature 20 to 25ºC (68 to 77ºF) 
9.4.4. Accountability 
Sites will be required to record and document subject compliance regarding dexamethasone dosing. 
10. 
STATISTICAL CONSIDERATIONS 
10.1. Objectives 
10.1.1. Primary Objective  
• 
The primary efficacy endpoint will be the rate of sCR and/or the rate of negative MRD by  
next generation gene sequencing (NGS) by clonoSEQ (Adaptive Biotechnologies) at the 
end of 8 cycles among non-transplant candidates and transplant candidates who agreed to 
defer transplant    
10.1.2. Secondary Objectives 
• 
To evaluate the safety and tolerability of elotuzumab in combination with KRd, when 
administered to subjects with newly diagnosed multiple myeloma 
• 
Rate of MRD by next generation gene sequencing (NGS) by clonoSEQ (Adaptive 
Biotechnologies) and by multi-color flow cytometry (MFC) at the end of Cycles 4, 8, 12, 
and 18 (for subjects who are MRD+ at the end of C8 but MRD- at the end of C12), 24 
months after C1D1, and yearly after that. 
• 
Estimate time to event, including duration of response (DOR), progression-free survival 
(PFS), time to progression (TTP), and overall survival (OS). 

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10.1.3. Exploratory Objectives 
• 
GEP, proteomics, and gene sequencing to evaluate the correlation between treatment 
outcome and pre-treatment subject profile.  
• 
Immunologic correlative studies including FcγRIIIa V genotype.   
10.2. Sample Size Justification & Analysis Plan   
A total of 40, non-transplant candidates, and/or transplant candidates who agreed to defer transplant 
will be enrolled. Since the study does not plan to exclude transplant candidates who do not wish to 
defer transplant, an additional 15 subjects who discontinue E-KRd treatment and proceed to 
transplant are planned to be enrolled to generate additional tolerability and toxicity data, which will 
bring a total number of subjects to be enrolled to 55. Subjects that continue to transplant will be 
removed from the study and censored at the end of 4 cycles. These subjects will not be followed up 
or further analyzed 
10.2.1. Primary Objective Sample Size Justification 
The primary endpoint is the sCR rate and/or the rate of MRD-negativity after 8 cycles of therapy. 
The rate of sCR for KRd treatment is established as the primary reference endpoint for statistical 
considerations by robust data (Jakubowiak et al., 2012b) Recognizing that the measurement of 
sCR has technical challenges when involving elotuzumab – which are anticipated to be resolved 
by the time it is needed – a co-primary endpoint of MRD-negative status by NGS is included in the 
primary efficacy assessment. This is based on the close correlation between MRD-negative status 
and sCR rate established in the ongoing KRd+transplant study (Jakubowiak et al. EHA 2016, 
Zimmerman et al. ASH 2016, both oral presentations). This primary endpoint incorporates also the 
new definition of MRD status, which requires sCR to confirm MRD negativity (Kumar et al., 
2016). Therefore, an improvement from historical 30% (which is the sCR rate and the estimated 
MRD-negative rate by NGS in the KRd study without elotuzumab (Jakubowiak, 2016)) to 50% or 
higher sCR and/or MRD-negative status at the completion of 8 cycles, would be considered 
promising.  
 For 40 non-transplant candidates and/or transplant candidates who agreed to defer transplant, we 
will test the null hypothesis that the sCR and/or negative MRD status by NGS rate after 8 cycles 
is,≤30% against the alternative that it is,>30% using an exact one-sided binomial test at the 
alpha=0.10 significance level.  The null hypothesis will be rejected if 17 or more sCR’s and/or 
MRD-negative’s responses are observed (>42.5%). The sample size of n=40 response evaluable 
subjects provides a little over 85% power if the true sCR and/or negative MRD status rate by NGS 
is 50%.  The sample size is selected to also allow for collection of sufficient data for toxicity and 
tolerability evaluation of the E-KRd regimen. The frequency of adverse events will be summarized 
by type, grade, and attribution to the study drugs. 
10.2.2. Secondary Objective Sample Size Justification 
Since the rate of MRD-negative disease by NGS methodology at the end of 8 cycles is not 
established at this time, based on the ongoing evaluations, a rate of NGS MRD-negative disease of 
50% or higher after 8 cycles will be considered promising.  The rate of successful MRD testing at 
landmark time points (i.e, after cycles 4, 8, 12, 18 –when applicable- 24 months after C1D1, yearly 
after that, and/or when nCR is suspected), the rate of VGPR or better, and the rate of near 
complete responses or better will be estimated along with 90% confidence intervals.  DOR, PFS, 
TTP, and OS will be estimated by the Kaplan-Meier method (Kaplan and Meier, 1958).  DOR will 
be defined as the length of the interval from response to disease progression among responders.  
PFS will be defined as the time from first dose until disease progression or death from any cause.  
Subjects alive and without progression will be censored as of the date of the last negative exam.  

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TTP analyses will be similar to PFS except that subjects who die without a prior disease 
progression will be censored at the time of death.  OS will be calculated as the time from first dose 
until date of death or date last known alive.  In addition to the Kaplan-Meier curves, we will 
estimate the median time to event and 90% confidence intervals using the method of Brookmeyer 
and Crowley (Brookmeyer and Crowley, 1982).  The study population for PFS, TTP, and OS will 
be all subjects who receive at least one dose of study drug.  The study population for DOR will be 
subjects who have responded to therapy. 
Among all 55 subjects enrolled in the trial, including those who proceed to transplant, we will test 
the hypothesis that the sCR rate at the end of 4 cycles improves from a historical 8% rate to a 
higher value, using an exact binomial test at the 0.10 one-sided significance level.  The total 
sample size of n=55 subjects will provide 85% power if the true rate is 19%, and the null 
hypothesis (≤8% rate) will be rejected if 8 or more of the 55 subjects respond. However, any 
subject who undergoes transplant prior to 4 cycles will be excluded, and the corresponding exact 
binomial test performed on the reduced sample size.  (Thus, for example, if 6 subjects undergo 
transplant prior to 4 cycles, only 7 responders among the 49 would be needed to reject the null 
hypothesis.)   
10.2.3. Exploratory Objectives 
The association of exploratory biomarkers (GEP, proteomics, gene sequencing, and immunologic 
correlates) with outcomes will be analyzed using logistic regression for binary outcomes and Cox 
regression modeling for time-to-event endpoints (Cox, 1972).   
11. 
DATA REPORTING 
 
Data reporting will be performed utilizing the eVelos electronic data capture system for all 
subjects. The University of Chicago CRA will provide the applicable user registration information 
for all sub-sites. 
All required data must be recorded in the eVelos database within two weeks of the completion of 
each cycle.  AEs and SAEs are to be entered in eVelos in real time. SAEs are also to be recorded 
on the paper Serious Adverse Event Form within 24 hours of the site’s knowledge of the event and 
sent via email (preferred) or fax to the University of Chicago 
(PhaseIICRA@medicine.bsd.uchicago.edu or qaccto@bsd.uchicago.edu; Fax: 773-702-4889).  
All case report forms must be completed by designated study personnel. Each screened subject 
(signed informed consent) is to be entered into eVelos within 48 hours of subject registration. In 
addition to direct data entry, providing supporting documentation is required as per Subject 
Enrollment and Registration policies. Source records are original documents, data, and records 
(e.g., medical records, raw data collection forms, pharmacy dispensing records, recorded data from 
automated instruments, laboratory data) that are relevant to the clinical trial. Each site will 
prepare and maintain adequate and accurate source documents. These documents are 
designed to record all observations and other pertinent data for each subject enrolled in this clinical 
trial. Source records must be adequate to reconstruct all data transcribed onto the case report form. 
12. 
REGULATORY OBLIGATIONS 
 

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12.1. Informed Consent 
No Investigator may involve a human being as a subject in research unless the Investigator has 
obtained the legally effective informed consent of the subject or the subject’s legally authorized 
representative. An Investigator shall seek such consent only under circumstances that provide the 
prospective subject or the subject’s legally authorized representative sufficient opportunity to 
consider whether or not to participate, and that minimize the possibility of coercion or undue 
influence. The information that is given to the subject or the representative shall be in a language 
understandable to the subject or representative.  
The Lead PI will provide all Site Investigators with an Informed Consent Form (ICF) developed by 
the Lead PI. Local and/or institutional requirements may require disclosure of additional information 
in the ICF. Any changes to this document must be submitted to the University of Chicago CCTO 
for approval, prior to submission to the participating site IRB. The IRB will review the Informed 
Consent Form for approval. A copy of the IRB approval form must be submitted to the University 
of Chicago CCTO prior to initiation of the study at the participating site. 
Before implementing any study procedure, informed consent shall be documented by the use of a 
written consent form approved by the IRB. A copy of signed ICF will be given to the subject or 
subject’s legally authorized representative. The original signed consent must be maintained by the 
Site Investigator and available for inspection by the designated Lead Principal Investigator 
representative at any time. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study.  
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and investigational 
therapies. In addition, subjects will be offered an option of supportive care for therapeutic 
studies.) 
4. The name of the Investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time.  
12.2. Compliance with Laws and Regulations 
The study will be conducted in accordance with U.S. Food and Drug Administration (FDA) and 
International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), the 
Declaration of Helsinki, and applicable local health law and authority, and Institutional Review 
Board (IRB) requirements.  
This study must have the approval of a properly constituted IRB. Before the investigational drug is 
shipped to the Site Investigator, the Lead Principal Investigator or designee will provide BMS and 
Amgen with a copy of the IRB approval letter stating that the study protocol and any subsequent 
amendments and informed consent form have been reviewed and approved.  
The Lead Principal Investigator and Site Investigator or designee will be responsible for obtaining 
annual IRB re-approval throughout the duration of the study, when necessary.  
The Lead Principal Investigator and Site Investigator are also responsible for notifying their IRB of 
any significant adverse events that are serious and unexpected as per their policies.  
BMS will provide the Lead Principal Investigator with any expedited safety reports generated from 
any ongoing studies with elotuzumab, changes to the Investigator’s Brochure, and any other safety 

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information which changes the risk/benefit profile of elotuzumab during the conduct of the study, 
to allow him/her to fulfill his/her obligation for timely reporting to the IRB, participating sites, and 
other Investigators participating in the study, when necessary.  
Amgen will provide the Lead Principal Investigator with any expedited safety reports generated 
from any ongoing studies with carfilzomib, changes to the Investigator’s Brochure, and any other 
safety information which changes the risk/benefit profile of carfilzomib during the conduct of the 
study, to allow him/her to fulfill his/her obligation for timely reporting to the IRB, participating 
sites, and other Investigators participating in the study, when necessary.  
Upon completion of the trial, the Lead Principal Investigator must provide the IRB, BMS and 
Amgen with a summary of the trial’s outcome. 
12.3. Subject Confidentiality 
Subject medical information obtained as part of this study is confidential, and must not be disclosed 
to third parties, except as noted below. The subject may request in writing that medical information 
be given to his/her personal physician.  
The Investigator/Institution will permit direct access to source data and documents by the FDA 
and/or other applicable regulatory authority. The access may consist of trial-related monitoring, 
audits, IRB reviews, and FDA inspections. Identifiable data will be shared by the following 
collaborator: Adaptive Biotechnologies (to allow an IDE annual report to FDA). 
Release of research results should preserve the privacy of medical information and must be carried 
out in accordance with the Department of Health and Human Services Standards for Privacy of 
Individually Identifiable Health Information, 45 CFR 164.508.  
12.4. Multicenter Guidelines 
Clinical studies coordinated by The University of Chicago must be conducted in accordance with 
the ethical principles that are consistent with Good Clinical Practices (GCP) and in compliance 
with other applicable regulatory requirements 
The Study Lead PI or designee are responsible for distributing all official protocols, amendments, 
and Unexpected Event Safety Reports to all participating institutions for submission to their 
applicable local IRBs as required.   
13. ADMINISTRATION AND LEGAL OBLIGATIONS 
13.1. Institutional Review Board (IRB) Approval and Consent 
The investigator-sponsor will obtain, from the University of Chicago Institutional Review Board 
(IRB), prospective approval of the clinical protocol and corresponding informed consent form(s); 
modifications to the clinical protocol and corresponding informed consent forms, and 
advertisements (i.e., directed at potential research subjects) for study recruitment.    
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent form(s) may be initiated in the absence of prospective IRB approval is to 
eliminate an apparent immediate hazard to the research subject(s).  In such circumstances, the 
investigator-sponsor will promptly notify the University of Chicago IRB of the deviation.  

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The University of Chicago IRB operates in compliance with FDA regulations at 21 CFR Parts 50 
and 21 CFR 56, and in conformance with applicable International Conference on Harmonization 
(ICH) Guidelines on Good Clinical Practice (CGP).  
Unless otherwise specified, each participating institution must obtain approval from a valid IRB 
before enrolling subjects on this study. It is expected that the IRB will have the proper 
representation and function in accordance with valid mandated regulations.  The IRB should 
approve the consent form and protocol. 
In obtaining and documenting informed consent, the Treating Investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
Before recruitment and enrollment onto this study, the subject will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA regulations and local or state 
regulations. Once this essential information has been provided to the subject and the Treating 
Investigator is assured that the subject understands the implications of participating in the study, 
the subject will be asked to give consent to participate in the study by signing an IRB-approved 
consent form. 
Prior to a subject’s participation in the trial, the written informed consent form should be signed 
and personally dated by the subject and by the person who conducted the informed consent 
discussion. 
13.1.1. Annual IRB Renewals, Continuing Review and Final Reports 
A continuing review of the protocol will be completed by the University of Chicago IRB and the 
participating institutions’ IRBs at least once a year for the duration of the study. The annual 
IRB renewal approvals for participating institutions should be forwarded promptly to the 
University of Chicago’s Regulatory Manager. If the institution’s IRB requires a new version of 
the consent form with the annual renewal, the consent form should be included with the 
renewal letter. 
Final Reports will be provided to IRBs and the Lead Principal Investigator within 1 year since the 
end of long-term follow up. 
13.2. Food and Drug Administration (FDA) Approval 
This study will be conducted under an IND held by Dr. Andrzej Jakubowiak at the University of 
Chicago.  The University of Chicago CCTO will be responsible for facilitating all communications 
with the FDA on behalf of the IND holder.   Participating sites should not communicate directly 
with the FDA. 
13.3. Required Documentation 
Before the study can be initiated at any site, the following documentation must be provided to the 
Cancer Clinical Trials Office (CCTO) at the University of Chicago Comprehensive Cancer Center. 
• 
A copy of the official IRB approval letter for the protocol and informed consent 
• 
IRB membership list 
• 
CVs and medical licensure for the Site Investigator and any sub-investigators who will be 
involved in the study. 
• 
Form FDA 1572 appropriately filled out and signed with appropriate documentation 

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• 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
• 
Investigational drug accountability standard operating procedures 
• 
Additionally, before the study can be initiated at any site, the required executed research 
contract/subcontract must be on file with the University of Chicago. 
13.4. Protocol Amendments and Study Termination 
All protocol amendments will be implemented by the Lead PI and must receive IRB, approval before 
implementation, except where necessary to eliminate an immediate hazard to subjects. Amendments 
should only be submitted to the IRB after consideration of BMS and Amgen. 
 
All modifications to the protocol, consent form, and/or questionnaires will be submitted to the 
University of Chicago IRB for review and approval. A list of the proposed modifications or 
amendments to the protocol and/or an explanation of the need of these modifications will be 
submitted, along with a revised protocol incorporating the modifications.  
Only the Study Lead PI can authorize any modifications, amendments, or termination of the 
protocol. 
13.4.1. Amendments to the Protocol at sub-Sites 
Once a protocol amendment has been approved by the University of Chicago IRB, the Regulatory 
Manager will send the amended protocol and consent form (if applicable) to the affiliate 
institutions electronically. Upon receipt of the packet the affiliate institution is expected to do the 
following: 
• 
The affiliate must reply to the email from the Regulatory Manager indicating that the 
amendment was received by the institution and that it will be submitted to the local IRB.  
• 
The amendment should be submitted to the affiliate institution’s IRB as soon as 
possible after receipt. The amendment must be IRB approved by the institution 
within 3 months from the date that it was received.  
• 
The  University  of  Chicago  version  date  and/or  amendment  number  must  
appear  on  the  affiliate consent form and on the affiliate IRB approval letter.  
The version dates can be found on the header and/or footer of every page of the protocol 
and consent form.  The amendment number can be found on the University of Chicago 
IRB amendment approval letter that is sent with the protocol/amendment mailing.  
• 
The IRB approval for the amendment and the amended consent form (if amended 
consent is necessary) for the affiliate institution must be sent to the designated UC 
Regulatory Manager as soon as it is received.  
 
13.5. Study Documentation and Archive 
13.5.1. Source Documents 
Source records are original documents, data, and records (e.g., medical records, raw data collection 
forms, pharmacy dispensing records, recorded data from automated instruments, laboratory data) 
that are relevant to the clinical trial. The Lead Principal Investigator will prepare and maintain 
adequate and accurate source documents. These documents are designed to record all observations 
and other pertinent data for each subject enrolled in this clinical trial. Source records must be 
adequate to reconstruct all data transcribed onto the case report forms. 

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13.5.2. Record Retention 
Study documentation includes all CRFs, data correction forms or queries, source documents, Lead 
PI-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol 
and amendments, IRB correspondence and approval, signed subject consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
Government agency regulations and directives require that all study documentation pertaining to the 
conduct of a clinical trial must be retained by the Study Lead Principal Investigator. Study 
documents should be kept on file until three years after the completion and final study report of this 
investigational study or five years after a marketing application is approved for the drug for the 
indications for which it is being investigated (see 13.5.4), whichever is longer. 
13.5.3. Case Report Form Completion 
The data collected for this study will be entered into a secure database eCRF. The Lead PI will 
provide the applicable user registration information. Source documentation must be available to 
support the computerized subject record. Source records are original documents, data, and records 
(e.g., medical records, raw data collection forms, pharmacy dispensing records, recorded data from 
automated instruments, laboratory data) that are relevant to the clinical trial. Each site will prepare 
and maintain adequate and accurate source documents. These documents are designed to record all 
observations and other pertinent data for each subject enrolled in this clinical trial. Source records 
must be adequate to reconstruct all data transcribed onto the case report form. Upon registration, 
source documentation including demographics, screening labs, subject demographics, physician’s 
notes for confirmation of concurrent conditions, and confirmation of disease status and treatment 
history. Additional information may be requested on a case-by case basis. 
AEs are to be entered in real time. SAEs are to be entered in eCRF on the SAE reporting form within 
24 hours of the site’s knowledge of the event (in addition to the paper SAE form). All other data is 
to be entered within 5 days of source acquisition. 
The University of Chicago CRA is responsible for training US affiliate sites on eCRF completion. 
This will be done over a teleconference (see section 13.7 on Data Safety and Monitoring). 
13.5.4. Archival of Records 
According to 21 CFR 312.62I, the Lead Principal Investigator shall retain records required to be 
maintained under this part for a period of 5 years following the date a marketing application is 
approved for the drug for the indication for which it is being investigated. If no application is to be 
filed or if the application is not approved for such indication, it is suggested that the Lead Principal 
Investigator retain these records until 15 years after the investigation is discontinued and the FDA 
or applicable regulatory authorities are notified.  
The Lead Principal Investigator must retain protocols, amendments, IRB approvals, copies of the 
FDA forms, signed and dated consent forms, medical records, case report forms, drug accountability 
records, all correspondence, and any other documents pertaining to the conduct of the study. 
13.6. Clinical Monitoring Procedures 
This study will be remotely monitored by the designated University of Chicago Clinical 
Research Associate (CRA) in accordance with the University of Chicago, Section of 
Hematology/Oncology standard operating procedure titled Monitoring of Multi-Institutional 
Investigator Initiated Clinical Trials.  

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University of Chicago will be responsible for monitoring all sites and it will be conducted to verify 
the following: 
• 
Adherence to the protocol 
• 
Completeness and accuracy of study data and samples collected 
• 
Compliance with regulations 
• 
Submission of required source documents  
13.6.1. Obligations of Study Site Investigators 
The Study Site Investigator is responsible for the conduct of the clinical trial at the site in accordance 
with Title 21 of the Code of Federal Regulations, valid local regulations and the Declaration of 
Helsinki.  The Study Site Investigator is responsible for personally overseeing the treatment of all 
study subjects.  He/she must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI/local regulations and 
guidelines regarding clinical trials both during and after study completion. 
The Study Site Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered into the CRFs. If monitoring visits or audits are 
conducted, he/she must provide access to original records to permit verification of proper entry of 
data. 
13.6.2. Protocol Deviations 
Protocol deviations are to be documented using the Protocol Deviation Form and sent via email 
to PhaseIICRA@medicine.bsd.uchicago.edu.  
Deviations that are considered major because they impact subject safety or alter the risk/benefit 
ratio, compromise the integrity of the study data, and/or affect subjects’ willingness to participate in 
the study must be reported within 7 days. Please contact the University of Chicago CRA 
(PhaseIICRA@medicine.bsd.uchicago.edu) if you have questions about how to report deviations.  
All major protocol deviations should also be reported to the local IRB according to their policies 
and procedures. 
13.7. Data Safety and Monitoring 
Prior to subject recruitment, and unless otherwise specified, any participating site will undergo a Site 
Initiation Teleconference to be conducted by the designated University of Chicago research team. 
The site’s principal investigator and his or her study staff must attend the site initiation meeting. 
Participating sites will also undergo a site close-out teleconference upon completion, termination or 
cancellation of a study to ensure fulfillment of study obligations during the conduct of the study, and 
to ensure that the Site Investigator is aware of his/her ongoing responsibilities. 
Unless otherwise specified, this protocol will undergo bi-weekly review at the multi-institutional 
data and safety monitoring teleconference as per procedures specified by the UC CCC NCI- 
approved Data and Safety Monitoring Plan. The conference will review: 
• 
Enrollment rate relative to expectations, characteristics of participants 
• 
Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
• 
Adherence to protocol (protocol deviations) 
• 
Completeness, validity and integrity of study data 
• 
Retention of study participants 

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13.8. Quality Assurance & Auditing 
In addition to the clinical monitoring procedures, the University of Chicago Comprehensive Cancer 
Center will perform routine Quality Assurance Audits of Investigator-initiated clinical trials at the 
University of Chicago as described in the NCI-approved UC CCC DSM Plan. Audits provide 
assurance that trials are conducted and study data are collected, documented and reported in 
compliance with the protocol. Further, quality assurance audits ensure that study data are collected, 
documented and reported in compliance with Good Clinical Practices (GCP) Guidelines and 
regulatory requirements. The audit will review subjects enrolled at the University of Chicago in 
accordance with audit procedures specified in the UC CCC Data and Safety Monitoring plan. For 
institutions who are formal members of the Personalized Cancer Care Consortium (PCCC), the UC 
CCC will conduct on site quality assurance audits on average every two years during the enrollment 
and treatment phase of the study.  
Auditing procedures for participating sites that are not full members of the PCCC must be specified 
and approved by the UC CCC Clinical Research Advisory Committee.  In general, for sites that are 
not full members of the PCCC, auditing responsibility will be delegated to the participating center, 
with the annual audit report forwarded to the University of Chicago for review.   
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its 
conduct or even after its completion. If an inspection has been requested by a regulatory authority, 
the Site Investigator must immediately inform the University of Chicago Cancer Clinical Trials 
Office and Regulatory Manager that such a request has been made.  
 
 

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Gentil, C., Arnulf, B., Belhadj, K., et al. (2015). Evaluation of Minimal Residual Disease (MRD) 
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Boles, K. S., and Mathew, P. A. (2001). Molecular cloning of CS1, a novel human natural killer 
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D., Chauhan, D., et al. (2001). Thalidomide and immunomodulatory derivatives augment 
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Lewis, E. R., Parlati, F., et al. (2007). Antitumor activity of PR-171, a novel irreversible inhibitor 
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Kropff, M., Kentos, A., Cavo, M., Golenkov, A., et al. (2010). Superior outcomes associated with 
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Hsi, E. D., Steinle, R., Balasa, B., Szmania, S., Draksharapu, A., Shum, B. P., Huseni, M., Powers, 
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Anderson, T., Nordgren, B., Detweiler-Short, K., et al. (2012b). A phase 1/2 study of carfilzomib 
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Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or 
Newly Diagnosed Multiple Myeloma. JAMA Oncol 1, 746-754. 
Kumar, S., Paiva, B., Anderson, K. C., Durie, B., Landgren, O., Moreau, P., Munshi, N., Lonial, S., 
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Kumar, S. K., Rajkumar, S. V., Dispenzieri, A., Lacy, M. Q., Hayman, S. R., Buadi, F. K., Zeldenrust, 
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Moreau, P., Mateos, M. V., Magen, H., et al. (2015). Elotuzumab Therapy for Relapsed or 
Refractory Multiple Myeloma. N Engl J Med 373, 621-631. 
Moreau, P. (2012). A randomized phase II study of elotuzumab with lenalidomide and low-
dose dexamethasone in patients with relapsed/refractory multiple myeloma. J Clin Oncol 30. 
Moreau, P., Richardson, P. G. G., Jakubowiak, A. J., Jagannath, S., Raab, M., Facon, T., Vij, R., Reece, 
D. E., White, D., Benboubker, L., et al. (2012). A randomized phase II study of elotuzumab with 
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National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975-2004/, based on 
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Rice, A. G., et al. (2008). Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma 
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APPENDIX 1: MULTIPLE MYELOMA STAGING 
A. Durie-Salmon Staging 
Stage I  
All of the following must be present: 
● Hemoglobin > 10.5 g/dL or hematocrit >32%  
● Serum calcium level normal (≤12 mg/dL) 
● Low serum myeloma protein production rates as evidenced by all of the following:  
o 
IgG peak < 5g/dL  
o 
IgA peak < 3g/dL  
o 
Bence Jones protein < 4g/24 h  
● No bone lesions  
Stage II 
All subjects who do not meet criteria for Stage I or III are considered Stage II. 
Stage III 
One of the following abnormalities must be present: 
● Hemoglobin < 8.5 g/dL, hematocrit < 25%  
● Serum calcium >12 mg/dL  
● Very high serum or urine myeloma protein production rates as evidenced by one or 
more of the following:  
● 
IgG peak > 7g/dL  
● 
IgA peak > 5g/dL  
● 
Bence Jones protein > 12g/24 h  
● 
> 3 lytic bone lesion on bone survey (bone scan not acceptable)  
Sub-classification 
a. Serum creatinine <2.0 mg/dL 
b. Serum creatinine >2.0 mg/dL 
 
B. International Myeloma Working Group International Staging System (ISS) 
1. 
Stage I: B2M < 3.5 plus serum albumin >3.5 (med S 62m) 
2. 
Stage II: B2M < 3.5 but serum alb. < 3.5 OR B2M 3.5 - < 5.5 (med S 44m) 
3. 
Stage III: B2M > 5.5 (med S 29m) 
4. 
Subclassify stages 1+2 according to cr< or > 2 and stage 3 according to low platelets 
(< 130k) or high LDH 
 
IMWG criteria for symptomatic myeloma: 
All three criteria must be met:  
1. Clonal bone marrow plasma cells and/or documented clonal plasmacytoma 
2. Presence of serum and/or urinary monoclonal protein 
3. Evidence of end-organ damage that can be attributed to the underlying plasma cell 
proliferative disorder, specifically:  
a. Hypercalcemia: serum calcium ≥11.5 mg/dL or 
b. Renal insufficiency: serum creatinine >2mg/dL or 
c. Anemia: hemoglobin at least 2 g/dL below the lower limit of normal or a 
hemoglobin <10 g/dL or 
Bone lesions: lytic lesions, osteopenia or pathologic fractures 
 

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APPENDIX 2: ECOG PERFORMANCE STATUS 
 
Grade 
Description 
0 
Normal activity, fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but fully ambulatory, restricted in physically strenuous but 
ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined 
to bed or chair. 
5 
Dead 
 
 
 

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APPENDIX 3: NCI CTCAE VERSION 4.0 
 
Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute 
(NCI) v4.0 
 
Publish Date:  September 15, 2009 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
 

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APPENDIX 4: RESPONSE CRITERIA FOR MULTIPLE MYELOMA 
 
IMWG Criteria 
Response 
IMWG criteria1,2 
sCR 
Stringent 
Complete 
Response 
CR as defined below plus:  
● normal FLC ratio and  
● absence of clonal cells in bone marrow by immunohistochemistry 
or 2 – 4 color flow cytometry 
CR 
Complete 
Response 
● Negative immunofixation on the serum and urine and  
● disappearance of any soft tissue plasmacytomas and  
● < 5% plasma cells in bone marrow.   
● In subjects with only FLC disease, a normal FLC ratio of 0.26–1.65 
is required. 
VGPR 
Very Good 
Partial 
Response 
● Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or 
● > 90% reduction in serum M-protein plus urine M-protein level < 
100 mg/24 h.   
● In subjects with only FLC disease, >90% decrease in the difference 
between involved and uninvolved FLC levels is required. 
PR 
Partial 
Response 
● 50% reduction of serum M-protein and reduction in 24 hours urinary 
M-protein by >90% or to < 200 mg/24 h 
● If the serum and urine M-protein are unmeasurable,3 a > 50% 
decrease in the difference between involved and uninvolved FLC 
levels is required in place of the M-protein criteria 
● If serum and urine M-protein are not measurable, and serum free 
light assay is also not measureable, > 50% reduction in plasma cells 
is required in place of M-protein, provided baseline bone marrow 
plasma cell percentage was > 30% 
● In addition to the above listed criteria, if present at baseline, a > 50% 
reduction in the size of soft tissue plasmacytomas is also required 
Stable 
Disease 
● Not meeting criteria for CR, VGPR, PR or progressive disease 

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Progressive 
disease 
Increase of > 25% from lowest response value in any one of the following: 
● Serum M-component (the absolute increase must be > 0.5 g/dL)4and/or  
● Urine M-component (the absolute increase must be > 200 mg/24 
h)and/or  
● Only in subjects without measurable serum and urine M-protein, the 
difference between involved and uninvolved FLC levels. The absolute 
increase must be > 10 mg/dL 
● Only in subjects without measurable serum and urine M-protein and 
without measurable disease by FLC levels, bone marrow plasma cell 
percentage (absolute % must be ≥ 10%)  
● Definite development of new bone lesions or soft tissue plasmacytomas 
or definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas 
● Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) 
that can be attributed solely to the plasma cell proliferative disorder 
 
All relapse categories (CR, sCR, VGPR, and PD) require two consecutive assessments made at 
anytime before the institution of any new therapy; complete response and PR and SD categories also 
require no known evidence of progressive or new bone lesions if radiographic studies were 
performed.  VGPR and CR categories require serum and urine studies regardless of whether disease 
at baseline was measurable in serum, urine both or either.  Radiographic studies are not required to 
satisfy these response requirements. Bone marrow assessments need not be confirmed.  For 
progressive disease, serum M-component increases of ≥ I gm/dl are sufficient to define response if 
starting M-component is ≥ 5 g/dl.    
 
IMWG clarification for coding PD:   
● clarified that bone marrow criteria for PD are to be used only in subjects without measurable 
disease by M protein and by FLC levels.   
● clarified that 25% increase refers to M protein, FLC, and bone marrow results and does not refer 
to bone lesions, soft tissue plasmacytomas or hypercalcemia.  Note the lowest response value 
does not need to be a confirmed value. 
 
Additional response criteria for specific disease states1,2,3,4 
Minor response in subjects with relapsed and 
refractory myeloma adapted from the EMBT 
criteria3 
≥ 25% but < 49% reduction of serum M protein and 
reduction in 24 hour urine M protein by 50 – 89%, 
which still exceeds 200 mg/24hrs. 
In addition to above; if present at baseline, 25-49% 
reduction in the size of soft tissue plasmacytomas is 
also required 
 
No increase in size or number of lytic bone lesions 
(development of compression fractures does not 
exclude response) 

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Near Complete Response nCR 
The absence of myeloma protein on electrophoresis, 
with positive immunofixation, stable bone disease, and 
a normal serum calcium concentration 
Immunophenotypic CR 
Stringent CR plus 
Absence of phenotypic abarrent PC (clonal) in bone 
marrow with a minimum of one million of total BM 
cells analyzed by multiparametric flow cytometry 
(with ≥4 colors) 
Molecular CR 
Stringent CR plus negative ASO-PCR (sensitivity 10-
5) 
1. Durie et al. International uniform response criteria for multiple myeloma. Leukemia 
2006;20:1467-73 
2. S. Vincent Rajkumar, Jean-Luc Harousseau, Brian Durie, Kenneth C. Anderson, Meletios 
Dimopoulos, Robert Kyle, Joan Blade, Paul Richardson, Robert Orlowski, David Siegel, 
Sundar Jagannath, Thierry Facon, Hervé Avet-Loiseau, Sagar Lonial, Antonio Palumbo, 
Jeffrey Zonder, Heinz Ludwig, David Vesole, Orhan Sezer, Nikhil C. Munshi, and Jesus 
San Miguel. Consensus recommendations for the uniform reporting of clinical trials: report 
of the International Myeloma Workshop Consensus Panel 1 . Blood First Edition Paper, 
prepublished online February 3, 2011;DOI 10.1182/blood-2010-10-299487 
3. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, 
Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee 
S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A 
Phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609, June 
2, 2003. 
4. Richardson et al. Bortezomib or High-Dose Dexamethasone for Relapsed Multiple 
Myeloma. N Eng J Med. 352:2487-98, 2005 
 
 
 

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APPENDIX 5: Revlimid Prescribing and REMS information 
 
Revlimid Risk Evaluation and Mitigation Strategy (REMS)™ Program 
http://www.revlimidrems.com/pdf/REV_Prescriber_Guide.pdf 
 
Revlimid Prescribing Information 2013 
http://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=5fa97bf5-28a2-48f1-8955-
f56012d296be&type=pdf&name=5fa97bf5-28a2-48f1-8955-f56012d296be 
 
 
 

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APPENDIX 6: SCHEDULE OF EVENTS 
 
Assessment 
Screeni
ng 
Cycles 1-2 
Cycles 3-8 
Cycles 9-12, 9-18 
or    9-24 
End 
of 
Cycle 
4 
End 
of 
Cycle 
8 
End 
of 
Cycle 
12 
24 mo 
after 
C1D1 
and 
yearly 
x4 
Cycles 13+, 19+, 
or 25+ (after end 
of E-KRd) 
E
O
T
25 
LTFU 
26,27 
Day 
-21 to -1 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
 
 
 
 
1 
8 
15 
22 
 
 
Informed Consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
and 
Medical History2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skeletal Survey3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/PET28 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
(X) 
X 
 
 
 
 
X 
 
ECG4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam/ 
ECOG6 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Vital Signs7 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Hematology8 
X 
X 
X8 
X8 
 
X 
X 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Serum Chemistry9 
X 
X 
X9 
X9 
 
X 
X 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 

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Assessment 
Screeni
ng 
Cycles 1-2 
Cycles 3-8 
Cycles 9-12, 9-18 
or    9-24 
End 
of 
Cycle 
4 
End 
of 
Cycle 
8 
End 
of 
Cycle 
12 
24 mo 
after 
C1D1 
and 
yearly 
x4 
Cycles 13+, 19+, 
or 25+ (after end 
of E-KRd) 
E
O
T
25 
LTFU 
26,27 
Day 
-21 to -1 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
 
 
 
 
1 
8 
15 
22 
 
 
Pregnancy Test10 
 
 
X 
X 
 
(X) 
10 
(X)
10 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Disease 
Assessment11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
β2-microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPEP and IFIX12  
X 
X 
 
X 
12,13 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
24 hour Urine: UPEP 
and IFIX13;14 
X 
X 
 
X 14 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
SFLC 
X 
X 
 
X  
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Quantitative IgGs 
X 
X 
 
X  
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
BM Aspirate/ biopsy, 
cytogenetics, FISH15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
BM aspirate sample 
for MRD analysis16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
Correlative 
Samples17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
 

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Assessment 
Screeni
ng 
Cycles 1-2 
Cycles 3-8 
Cycles 9-12, 9-18 
or    9-24 
End 
of 
Cycle 
4 
End 
of 
Cycle 
8 
End 
of 
Cycle 
12 
24 mo 
after 
C1D1 
and 
yearly 
x4 
Cycles 13+, 19+, 
or 25+ (after end 
of E-KRd) 
E
O
T
25 
LTFU 
26,27 
Day 
-21 to -1 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
 
 
 
 
1 
8 
15 
22 
 
 
Adverse Events18 
 
X 
 
Treatment Schedule 
Elotuzumab19 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Carfilzomib20 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Lenalidomide21,22 
 
Days 1-21 
 
Dexamethasone23,24 
 
X
23 
X   
23 
X  
23 
X  
23 
X
24 
X  
24 
X  
24 
X 
24 
X
24 
X 
24 
X  
24 
X 
24 
 
 
 
 
X 
2
4 
X 
24 
X 
24 
X 
24 
 
 
(X) As clinically indicated  
1. Informed consent may be obtained within 30 days of start of treatment but must be obtained prior to any research-related 
activity 
2. Includes baseline symptoms, neuropathy history and documentation of the CTCAE grade if peripheral neuropathy is present 
at baseline. 
3. May be within 3 months of planned start. Includes: lateral radiograph of skull, anteroposterior and lateral views of the spine, 
and anteroposterior views of the pelvis, ribs, femora, and humeri. Skeletal surveys performed outside of the 30-day window 
may be considered for inclusion after discussion with the Lead Principal Investigator. Skeletal survey only needs to be repeated 
throughout the trial if clinically indicated. 
4. 12-Lead ECG including QTc interval. ECG should be performed throughout the study only as clinically indicated 
5. Echocardiogram must be completed at screening to demonstrate LVEF ≥ 50%. ECHO may be performed throughout the study 
if clinically indicated. 

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6. For Day 1 of cycle 1, screening results may be used if within 7 days of treatment start. Complete physical exam (including 
vital signs, [systolic and diastolic blood pressure, respiration, pulse, oral temperature], height, weight, calculation of body 
surface area [BSA]) and ECOG score required at screening at Day 1 of each cycle (height only required at screening). 
Symptom-directed Physical Exam on Days 8, 15, (and 22 on cycles 1-2) 
7. Systolic and diastolic blood pressure, pulse, respiration, temperature before and after elotuzumab infusion and approximately 
1 hour before carfilzomib dosing on days where only carfilzomib is dosed. 
8. Hemoglobin, WBC with complete differential, RBCs, platelet count, absolute neutrophil and lymphocyte counts.  Results must 
be reviewed before dosing. On cycles 1-8, these tests will be required on days 1, 8, and 15 prior to infusion and on cycles 9+ 
they will be required on days 1 and 15 prior to infusion. 
9. Full serum chemistry panel at screening, days 1, 8, and 15, and EoT for all subjects: sodium, potassium, chloride, creatinine, 
glucose, uric acid, phosphorus, magnesium, LDH, total bilirubin, C-Reactive Protein.  Results must be reviewed before dosing. 
On cycles 1-8, these tests will be required on days 1, 8, and 15 prior to infusion and on cycles 9+ they will be required on days 
1 and 15 prior to infusion. 
10. Pregnancy tests must occur within 10-14 days and again within 24 hours prior to prescribing lenalidomide (prescriptions must 
be filled within 7 days.  FCBP with regular or no menstruation must have a pregnancy test weekly for the first 28 days and 
then every 28 days while on therapy (including breaks in therapy); at discontinuation of lenalidomide and at Day 28 post the 
last dose of lenalidomide.  Females with irregular menstruation must have a pregnancy test weekly for the first 28 days and 
then every 14 days while on therapy (including breaks in therapy), at discontinuation of lenalidomide and at Day 14 and Day 
28 post the last dose of lenalidomide. When applicable, females must have a pregnancy test at the EoT.   
11. Disease assessment including bone marrow biopsy (as indicated), SPEP, UPEP, SFLC to be done at any point during treatment 
when response is suspected. The first response assessment should be completed on Cycle 1 Day 15 and on D1 of every cycle 
onwards.  
12. Obtain blood for M-protein levels measured by SPEP or quantitative immunoglobulins for those subjects in whom SPEP/UPEP 
are felt to be unreliable (IgA type multiple myeloma), depending upon which studies were positive at baseline. SPEP is required 
on Cycle 1 Day 15 for all subjects. A serum sample from blood at landmark timepoints (after C4, 8, 12, and 18, 24 months 
after C1D1, and yearly after) will be required for banking at the University of Chicago for later M-spike analysis with a new 
elotuzumab interference assay. BMS will perform this assay on banked samples, using using Mass Spectrometry.  
13. Urine protein electrophoresis (UPEP), and urine protein immunofixation (only for those whose disease is being followed by 
UPEP).  Subjects with baseline urine protein greater than 200 mg/24 hours must have a UPEP to confirm VGPR or better. For 
subjects whose disease is being monitored through UPEP, additional post baseline 24-hour urine collections are required as 
indicated. UPEP is required on Cycle 1 Day 15 for all subjects. 

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14. 24 hour urine is required on Cycle 1 Day 15 for all subjects. 
15. Bone marrow aspirate and biopsy - quantify % myeloma cell involvement; bone marrow sample for cytogenetics and 
fluorescent in situ hybridization (FISH).  Repeat bone marrow biopsy/aspirate if nCR (or VGPR when nCR determination is 
not possible) is suspected and as appropriate to confirm achievement of sCR, CR, or nCR.  Bone marrow biopsy/aspirate 
performed outside of the 30-day window may be considered for inclusion.  Please contact the Lead Principal Investigator at 
the coordinating site on a case-by-case basis. Cytogenetics and FISH are required at screening only. If cytogenetics/FISH are 
completed at a time point other than screening, the results should be captured in eCRF.  
16. All subjects are required to have a sample for MRD collected at screening, end of cycles 4, 8 12, 18 (if MRD+ at C8 but MRD- 
at C12),  24 months after C1D1, yearly after that, and at any other time a Bone Marrow biopsy/aspirate is collected as SOC.  
If nCR (or VGPR if nCR determination is not possible) is recorded between screening and EoT, a Bone Marrow Biopsy can 
be indicated. However, if nCR (or VGPR when nCR is not possible) is suspected within 2 months of a scheduled BM per 
protocol, it is acceptable to wait for the scheduled BM biopsy. Refer to lab manual for collection and shipping instructions. 
Central analysis includes MRD by multiparameter flow cytometry and MRD by gene sequencing.  Non-decalcified FFPE or 
BMA slides from the subject at screening can be provided alternatively to fresh BM for calibration of MRD by gene 
sequencing. 
17. For subjects who sign additional consent: peripheral blood and bone marrow aspirate samples collected at screening, end of 
cycle 4, 8, 12, and 18, 24 months after C1D1, yearly after that, and any time after enrollment that nCR or better is suspected 
or a BM is performed per protocol. Buccal mucosa swab will be collected at screening only. Please see the lab manual for 
specific instructions 
18. AEs will be collected from the time of first study drug treatment through 30-days after end of study treatment. 
19. Elotuzumab will be given IV at 10mg/kg weekly in 28-day cycles in cycles 1 and 2 starting on cycle 1 day 1. In cycles 3+, 
elotuzumab will dosed IV at 10mg/kg every two weeks in 28-day cycles starting on cycle 3 day 1. Refer to section 6.3.1 for 
elotuzumab infusion rates. 
20. Carfilzomib days 1, 8, and 15 of cycles 1-8 and 1 and 15 of cycles 9+ at assigned dose. Cycle 1 step-up dosing is required: 
20mg/m2 Day 1; 56mg/m2 Day 8; 56mg/m2 Day 15. On Cycle 2 day 1, the dose of carfilzomib will be escalated to 70mg/m2 
and will continue to be dosed at this level. Hydration directions from section 6.3.2 must be followed 
21. Lenalidomide must be prescribed through and in compliance with the RevlimidREMS™ program of Celgene Corporation.  
Prescriptions must be filled within 7 days.  Consideration should be given to prescribing lenalidomide 5 to 7 days in advance 
of Day 1 of each cycle to allow time for required subject and prescriber surveys, and drug shipment to subject.  

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22. Lenalidomide dosing Days 1-21. Cycles 1-8 Lenalidomide will be administered at 25 mg. From cycle 9+ Lenalidomide will 
be administered at best tolerated dose on days 1-21 of a 28-day cycle. Lenalidomide should be taken in the evening at 
approximately the same time each day.  
23. On cycles 1-2, dexamethasone will be split into two doses as follows: 20mg of dexamethasone will be given IV on days 1, 8, 
and 15 no more than 3 hours prior to elotuzumab infusion and between 30min and 4 hours prior to carfilzomib, and 20mg will 
be taken PO on days 2, 9, and 16. On Day 22 of cycle 1, 40mg dexamethasone will be taken PO no longer than 3 hours prior 
to elotuzumab. When dexamethasone, carfilzomib and elotuzumab coincide, dexamethasone will be dosed first, followed by 
carfilzomib infusion, and finally elotuzumab will be infused. 
24. On cycles 3-4 40mg dexamethasone will be taken PO on days 1, 8, 15, and 22. On days when dexamethasone coincides with 
elotuzumab, dexamethasone will be taken no longer than 3 hours prior to elotuzumab infusion. On days when dexamethasone 
coincides with carfilzomib, dexamethasone will be taken between 30min and 4 hours prior to carfilzomib infusion. When 
dexamethasone, carfilzomib and elotuzumab coincide, dexamethasone will be dosed first, followed by carfilzomib infusion, 
and finally elotuzumab will be infused.On cycles 5+ 20mg dexamethasone will be taken PO on days 1, 8, 15, and 22. On days 
when dexamethasone coincides with elotuzumab, dexamethasone will be taken no longer than 3 hours prior to elotuzumab 
infusion. On days when dexamethasone coincides with carfilzomib, dexamethasone will be taken between 30min and 4 hours 
prior to carfilzomib infusion. When dexamethasone, carfilzomib and elotuzumab coincide, dexamethasone will be dosed first, 
followed by carfilzomib infusion, and finally elotuzumab will be infused. 
25. End of treatment will vary depending on MRD results post cycle 8 and 12. Subjects that are MRD negative after cycle 8 and 
12, will go on E-Rd maintenance until disease progression, subjects that are MRD+ after cycle 8 but MRD- after cycle 12, will 
get another 6 cycles of Elo-KRd and go on E-Rd maintenance until disease progression; and subjects that are MRD+ at both 
instances will be given another 12 cycles of Elo-KRd and go on E-Rd maintenance until disease progression 
26. Subjects will be followed for survival and development of any new cancers, at least every 3 months for up to 6 years from start 
of treatment.  Reports of any death should include date of death and specific cause (disease under study or specify other cause). 
27. Assessment for disease progression in subjects who did not progress during treatment.  Every 3 months (+/- 30 days) from 
safety follow-up visit (28 days post-last study treatment or ASCT, if applicable) for up to 6 years from enrollment. 
28. A CT-PET must be performed to confirm MRD-negative disease per Standard of Care. Subjects who are MRD-positive do not 
need PET scans until suspected CR. MRD-negative subjects will undergo a yearly PET until progression. If there is clinical 
need for assessment at cycles 8 and 12, a CT-PET should be performed at these timepoints as well.