Clinical trial NCT03361306
Conditions: Multiple Myeloma
Keywords: Relapsed
Sponsor: Wake Forest University Health Sciences
Start date: 2018-01-09; Completion date: 2025-02-14
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study drug elotuzumab, has been clinically shown to be effective in treating relapsed/refractory MM in combination with either bortezomib, or lenalidomide and dexamethasone. Elotuzumab in combination with lenalidomide and dexamethasone is currently approved by the Food and Drug Administration (FDA) for the treatment of patients with multiple myeloma. Carfilzomib is also FDA approved for treating multiple myeloma and frequently given in combination with lenalidomide and dexamethasone for treatment of relapsed/refractory MM. Based on these findings, this study will look at how subjects with relapsed/refractory MM respond to a combination treatment with the following drugs: elotuzumab, carfilzomib, lenalidomide and dexamethasone. The combination of these four drugs is not FDA approved and is experimental.

Detailed description:
This single arm, open-label phase II study is designed with the primary objective of evaluating the efficacy of induction therapy comprised of 4 cycles of carfilzomib, lenalidomide, dexamethasone and elotuzumab (KRd+elotuzumab) in terms of very good partial response or better (VGPR+) in subjects with relapsed and/or refractory MM, and comparing to relevant historical controls. Post induction, all subjects will undergo disease evaluation for assessment of the primary endpoint. Maintenance therapy comprised of elotuzumab and lenalidomide (R+elotuzumab) will start directly after induction and continue until relapse or progression.

Arms: arm 1: Induction (4 28-day cycles):

Carfilzomib (IV) @ 20 mg/m\^2, Day 1 of Cycle 1; @ 56 mg/m\^2, Day 8,15 of Cycle 1; @ 56 mg/m\^2, Day 1,8,15 of Cycles 2-4

Lenalidomide (Oral) @ 25 mg, once daily at bedtime on Days 1-21 of each cycle (Cycles 1-4)

Dexamethasone @ 28 mg orally OR 8 mg IV, once weekly on Day 1,8,15,22 of Cycles 1-2; @28 mg orally OR 8 mg IV on Day 1 of Cycles 3-4

Elotuzumab (IV) @ 10 mg/kg, once weekly on Day 1,8,15,22 of Cycles 1-2; @ 20 mg/kg on Day 1 of Cycles 3-4

Maintenance (28-day cycles):

Elotuzumab (IV) @ 20 mg/kg, Day 1 of each cycle (Cycles 1-n)

Lenalidomide (Oral) @ 15 mg (or last tolerated dose if \<15 mg), once daily at bedtime on Days 1-21 of each cycle (Cycles 1-n)
Interventions: intervention 1: Elotuzumab
Intervention descriptions: intervention 1: Experimental

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Number: LCI-HEM-MYE-CRD-002 
Version 7: 09/27/2021 
 
 
Protocol #: LCI-HEM-MYE-CRD-002  
 
TITLE: Phase II Study of Carfilzomib, Lenalidomide, Dexamethasone and Elotuzumab in 
Relapsed/Refractory Multiple Myeloma  
 
Coordinating Site: 
Levine Cancer Institute 
1021 Morehead Medical Drive 
Charlotte NC, 28204 
 
Sponsor-Investigator: 
Manisha Bhutani, MD 
Levine Cancer Institute 
1021 Morehead Medical Drive 
Charlotte NC, 28204 
 
Statistician: 
James Symanowski, PhD 
Levine Cancer Institute 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
 
 
Trial Supported by: 
Bristol-Myers Squibb 
CA204-211 
 
Investigational New Drug (IND): # 137121 
___________________________________________________________________________ 
The study will be conducted in compliance with the protocol, ICH/GCP and any applicable 
regulatory requirements. 
 
 
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed. 
Hence, the apperance of product names without these symbols does not imply that these names 
are not proprietary. 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation. Reproduction or disclosure of this document - whether in part 
or in full - to parties not associated with the clinical investigation, or its use for any other purpose, 
without the prior written consent of the Sponsor-Investigator is not permitted. 


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PROTOCOL SIGNATURE PAGE 
Phase II Study of Carfilzomib, Lenalidomide, Dexamethasone and Elotuzumab in 
Relapsed/Refractory Multiple Myeloma  
 
The signature below constitutes the approval of this protocol and the attachments, and, provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
 
 
 
 
___________________________________  
 
_____________________ 
 
 
Signature of Sponsor-Investigator 
 
 
 
Date 
 
 
Manisha Bhutani, MD


Protocol Number: LCI-HEM-MYE-CRD-002 
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I 
SYNOPSIS 
TITLE 
Phase II Study of Carfilzomib, Lenalidomide, Dexamethasone and 
Elotuzumab in Relapsed/Refractory Multiple Myeloma 
STUDY POPULATION 
Relapsed or Refractory Multiple Myeloma  
PHASE  
II 
SUMMARY OF STUDY 
RATIONALE 
Elotuzumab (BMS-901608, HuLuc63) is a first-in-class, 
immunostimulatory, humanized immunoglobulin G1 (IgG1) monoclonal 
antibody (mAb) targeted against Signaling Lymphocyte Activation 
Molecule Family 7 (SLAMF7, also called CS1), a glycoprotein highly 
expressed on myeloma cells independent of cytogenetic abnormalities. 
Elotuzumab is approved for the treatment of previously treated MM in 
combination with lenalidomide and dexamethasone (Rd). The regimen of 
carfilzomib (a proteasome inhibitor) with Rd (KRd) is a highly active 
regimen used in the treatment of relapsed and/or refractory MM. The 
immunomodulatory effects of KRd have a strong potential for synergy 
with those of elotuzumab, and data from elotuzumab in combination with 
the proteasome inhibitor bortezomib support the safety of combining 
elotuzumab with KRd.  
STUDY DESIGN  
This single arm, open-label phase II study is designed with the primary 
objective of evaluating the efficacy of induction therapy comprised of 4 
cycles of carfilzomib, lenalidomide, dexamethasone and elotuzumab 
(KRd+elotuzumab) in terms of very good partial response or better 
(VGPR+) in subjects with relapsed and/or refractory MM, and comparing 
to relevant historical controls. Post induction, all subjects will undergo 
disease evaluation for assessment of the primary endpoint. Maintenance 
therapy comprised of elotuzumab and lenalidomide (R+elotuzumab) will 
start directly after induction and continue until relapse or progression. 
OBJECTIVES 
Primary Objective:  
The primary objective is to evaluate the efficacy of elotuzumab when 
combined with KRd in terms of very good partial response or better 
(VGPR+) to induction therapy in subjects with relapsed or refractory 
multiple myeloma, and compare to relevant historical controls.  Response 
will be assessed based on the International Myeloma Working Group 
(IMWG) 2016 criteria. 
 
Secondary Objectives: 
Secondary objectives include evaluation of elotuzumab in combination 
with KRd by estimating the following: 
• Overall response rate (ORR) defined as the percent of subjects 
achieving a partial response or better per IMWG 2016 criteria. 
• Progression-free survival (PFS) defined as the time from treatment 
start (Cycle 1, Day 1) until disease progression or death. 
• Overall survival (OS) defined as the time from treatment start until 
death. 


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II
• Time to disease progression (TTP) defined as the time from 
treatment start until disease progression. 
• Duration of response (DoR) in subjects achieving a partial 
response or better defined as the time from achieving a partial 
response until disease progression or death. 
• Time to next treatment (TTNT) as defined by the time from 
treatment start until the start of the first subsequent anti-cancer 
therapy after all protocol directed therapy is completed.  
KEY INCLUSION 
CRITERIA  
• Documented history of relapsed and/or refractory multiple 
myeloma per IMWG 2016 criteria [22] (biochemical and/or 
clinical relapse per IMWG criteria) (subjects refractory to 
bortezomib and/or lenalidomide are eligible; subjects who 
previously received carfilzomib are eligible provided they 
experienced a response and relapsed >60 days after completion of 
treatment)  
• Prior treatment with one line (and no more than one line) of 
systemic therapy for MM 
• Age ≥ 18 years 
• ECOG ≤ 2 
• Measurable disease: 
o Serum M-protein > 0.5 g/dL OR 
o Urine M-protein ≥200 mg/24 h OR  
o Involved free light chain (FLC) level ≥10 mg/dL provided 
serum FLC ratio is abnormal  
• Recovered from any prior treatment-induced toxicities to ≤grade 1 
or baseline 
• Adequate organ and bone marrow function 
• Negative serum pregnancy test in females of childbearing potential 
(FCBP) 
• Willingness to use required birth control as applicable 
STATISTICAL 
CONSIDERATIONS 
 
The primary objective of this study is to evaluate the VGPR+ rate in 
subjects treated with elotuzumab in addition to the combination of 
carfilzomib, lenalidomde, and dexamethasone (KRd) in relapsed or 
refractory multiple myeloma subjects.  This will be evaluated in terms of 
the percent of subjects who achieve a VGPR+ to induction therapy.  
Wang [6] reported a VGPR+ rate of approximately 40% in this patient 
population treated with KRd. This study will be used to test the null 
hypothesis that the VGPR+ rate in subjects treated with elotuzumab+KRd 
is less than or equal to 40%.  Forty (40) response evaluable subjects will 
be enrolled, and if at least 21 of 40 subjects achieve a VGPR+, the null 
hypothesis will be rejected.  The design will provide 90% power with a 1-
sided alpha = 0.10 significance level, assuming the true VGPR+ rate is 
60%.  An improvement from 40% to 60% in the VGPR+ rate is 
considered clinically relevant.  


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III
TOTAL  
NUMBER OF 
SUBJECTS 
40 
 
 
 


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IV
 
SCHEMA  
 
 
 


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TABLE OF CONTENTS 
SYNOPSIS ...................................................................................................................................... I 
SCHEMA ..................................................................................................................................... IV 
1. 
BACKGROUND AND RATIONALE ............................................................................. 1 
1.1 
Multiple Myeloma (MM) ..................................................................................................... 1 
1.2 
Carfilzomib (Kyprolis®), Lenalidomide (Revlimid®), Dexamethasone (KRd) in 
Relapsed/Refractory MM................................................................................................................ 1 
1.3 
Elotuzumab .......................................................................................................................... 2 
1.4 
Study Rationale and Design ................................................................................................. 6 
2. 
OBJECTIVES .................................................................................................................... 8 
2.1 
Primary Objective ................................................................................................................ 8 
2.2 
Secondary Objectives........................................................................................................... 8 
2.3 
Safety Objectives ................................................................................................................. 9 
2.4 
Exploratory Objectives ........................................................................................................ 9 
3. 
SUBJECT SELECTION ................................................................................................... 9 
3.1 
Subject Recruitment ............................................................................................................. 9 
3.2 
Inclusion Criteria ............................................................................................................... 10 
3.3 
Exclusion Criteria .............................................................................................................. 13 
3.4 
Screen Failures ................................................................................................................... 14 
4. 
REGISTRATION ............................................................................................................ 14 
5. 
STUDY PLAN .................................................................................................................. 14 
5.1 
KRd+Elotuzumab Induction Regimen ............................................................................... 15 
5.2 
R+Elotuzumab Maintenance Regimen .............................................................................. 15 
6. 
TREATMENT DETAILS AND DOSE MODIFICATIONS/DELAYS ...................... 16 
6.1 
General Rules for Dose Modifications/Delays for KRd+Elotuzumab Induction .............. 16 
6.2 
General Rules for Dose Modifications/Delays for R+Elotuzumab Maintenance .............. 17 
6.3 
Carfilzomib ........................................................................................................................ 17 
6.4 
Elotuzumab ........................................................................................................................ 21 
6.5 
Lenalidomide ..................................................................................................................... 24 
6.6 
Dexamethasone .................................................................................................................. 26 
6.7 
Supportive Care ................................................................................................................. 28 
6.8 
Concomitant Medication .................................................................................................... 28 
7. 
STUDY CALENDAR ...................................................................................................... 31 
8. 
DETAILS ON STUDY PROCEDURES ........................................................................ 34 
8.1 
Screening Procedures ......................................................................................................... 34 
8.2 
Induction Procedures ......................................................................................................... 35 
8.3 
Maintenance Procedures .................................................................................................... 36 
8.4 
Time of CR ........................................................................................................................ 37 
8.5 
Time of Disease Relapse/Progression ................................................................................ 37 
8.6 
Safety Follow-up Visit ....................................................................................................... 37 
8.7 
Follow-up ........................................................................................................................... 38 
8.8 
Biospecimen Correlative Studies ....................................................................................... 39 


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9. 
DISCONTINUATION FROM TREATMENT AND STUDY WITHDRAWAL ...... 40 
9.1 
Treatment Discontinuation Criteria ................................................................................... 40 
9.2 
Off Study ............................................................................................................................ 40 
10. 
DRUG INFORMATION ................................................................................................. 41 
10.1 Elotuzumab ........................................................................................................................ 41 
10.2 Carfilzomib ........................................................................................................................ 44 
10.3 Lenalidomide ..................................................................................................................... 48 
10.4 Dexamethasone .................................................................................................................. 50 
11. 
DATA AND SAFETY MONITORING PLANS ........................................................... 51 
11.1 Safety Monitoring .............................................................................................................. 51 
11.2 Data Monitoring ................................................................................................................. 51 
12. 
SAFETY DATA COLLECTION, RECORDING AND REPORTING...................... 52 
12.1 Definitions.......................................................................................................................... 52 
12.2 Attribution .......................................................................................................................... 54 
12.3 Timing and Reporting ........................................................................................................ 55 
13. 
DISEASE EVALUATION .............................................................................................. 57 
13.1 IMWG 2016 Response Criteria ......................................................................................... 57 
14. 
STATISTICAL CONSIDERATIONS ........................................................................... 61 
14.1 Milestones .......................................................................................................................... 61 
14.2 Sample Size Determination................................................................................................ 61 
14.3 Endpoint Definitions .......................................................................................................... 61 
14.4 Analysis Populations .......................................................................................................... 62 
14.5 Analysis Methods............................................................................................................... 63 
15. 
STUDY COMPLETION OR TERMINATION ............................................................ 64 
15.1 Completion ......................................................................................................................... 64 
15.2 Termination ........................................................................................................................ 64 
16. 
STUDY MANAGEMENT ............................................................................................... 65 
16.1 IRB Approval ..................................................................................................................... 65 
16.2 Informed Consent............................................................................................................... 65 
16.3 Protocol Adherence ............................................................................................................ 65 
16.4 Changes to the Protocol and/or Informed Consent ............................................................ 65 
16.5 Other Protocol Deviations.................................................................................................. 65 
16.6 Retention of Records.......................................................................................................... 66 
16.7 Ethical and Legal Conduct of the Study ............................................................................ 66 
16.8 Confidentiality of Records ................................................................................................. 66 
16.9 Compliance with ClinicalTrials.gov .................................................................................. 67 
17. 
REFERENCES ................................................................................................................. 68 
18. 
APPENDICES .................................................................................................................. 71 
18.1 Appendix A: ECOG Performance Status ........................................................................... 71 
18.2 Appendix B: Cockcroft-Gault Equation ............................................................................ 72 
18.3 Appendix C: NYHA Classification ................................................................................... 73 


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1. BACKGROUND AND RATIONALE 
1.1 
Multiple Myeloma (MM) 
Multiple myeloma (MM) is a neoplasm of plasma cells that is characterized by osteolytic 
bone lesions and organ damage, such as hypercalcemia, anemia, and renal insufficiency.  
Despite major advances in therapy, MM is still considered an incurable malignancy.  The 
introduction of immunomodulatory agents (IMiDs; e.g., lenalidomide) and proteasome 
inhibitors (e.g., bortezomib, carfilzomib), coupled with advances in autologous stem cell 
transplant (ASCT) have improved progression free survival (PFS) and overall survival 
(OS) for MM patients. Unfortunately, the majority of patients still suffer relapses with 
progressively shorter disease free intervals with each relapse.  
 
A number of doublet and triplet regimens are available to treat patients who progress or 
relapse after initial therapy, with choice depending on what the patient has already 
received, and their initial response. Those who relapse > 6 months after discontinuation of 
initial therapy may be re-treated with the same regimen.  Common triplet regimens used 
for relapsed/refractory include bortezomib/lenalidomide/dexamethasone, and 
carfilzomib/lenalidomide/dexamethasone [1].  
 
Carfilzomib is an epoxomicin derivative with the ability to irreversibly inhibit 
proteosomes. It has been shown in preclinical and early clinical studies to have activity in 
MM [2]. 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 [3]. Pre/post carfilzomib in vivo 
pharmacogenomics gene expression profiling data from the University of Arkansas Car-
505 protocol (unpublished data) suggests that the use of carfilzomib may impact the more 
proliferative and high risk MM sub-clone in a given patient, whereas this effect was not 
seen with the proteasome inhibitor bortezomib [4]. The two agents share similar toxicity 
profiles, with intravenous bortezomib associated with a higher incidence of peripheral 
neuropathy. 
1.2 
Carfilzomib (Kyprolis®), Lenalidomide (Revlimid®), Dexamethasone (KRd) in 
Relapsed/Refractory MM 
The combination of carfilzomib (Kyprolis®) with lenalidomide (Revlimid®) and 
dexamethasone (a regimen termed “KRd”) initially exhibited excellent clinical activity in a 
phase Ib/II clinical trial in relapsed/refractory MM patients. In the dose escalation portion 
of the study (n=40), no maximally tolerated dose (MTD) was identified, and the maximum 
planned dose (MPD; 27mg/m2 of carfilzomib) was recommended for the phase II portion 
(with an initial dose of 20mg/m2 on days 1 and 2 of cycle 1, with the overall dosing 
regimen defined as 20/27 mg/m2). The overall response rate (ORR) across the dose 
escalating cohorts was 62.5% [5]. In the phase II portion, 52 patients were enrolled and 
treated with the combination at the MPD for carfilzomib. The ORR in this cohort was 
76.9% (the very good partial response or better [VGPR+] rate was 42.3%) and the median 
PFS was 15.4 months [6].  
 


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This trial was followed by the open-label phase III trial, ASPIRE, wherein KRd was 
compared to Rd in patients with relapsed/refractory MM (1-3 prior lines of therapy).  
Median PFS was significantly improved with the triplet (26.3 months compared to 17.6 
months, p=0.0001), as was the VGPR+ rate (69.9% compared to 40.4%). Median OS was 
not yet reached at the time of the analysis, but the OS rate at 24 months favored the triplet 
(73.3% versus 65%, p=0.04). Notably, patients in the KRd arm reported better quality of 
life as compared to the Rd arm [7]. This trial led to the Food and Drug Administration 
(FDA) approval of carfilzomib in combination with Rd for the treatment of patients with 
relapsed or refractory MM. 
1.3 
Elotuzumab 
Elotuzumab (BMS-901608, HuLuc63) is a first-in-class, immunostimulatory, humanized 
immunoglobulin G1 (IgG1) monoclonal antibody (mAb) targeted against Signaling 
Lymphocyte Activation Molecule Family 7 (SLAMF7, also called CS1), a glycoprotein 
highly expressed on myeloma cells independent of cytogenetic abnormalities. Elotuzumab 
was approved by the FDA in November 2015 for the treatment of previously treated MM 
in combination with lenalidomide and dexamethasone (Rd). This approval was based on an 
open label phase III randomized trial (ELOQUENT-2) of Rd versus elotuzumab+Rd in 
relapsed or refractory MM patients who had received 1-3 prior therapies.  
 
The function of the target of elotuzumab, SLAM7, is not well characterized, but it appears 
to play a critical role in interactions between MM cells and the bone marrow stromal cells. 
SLAMF7 is also expressed on natural killer (NK) cells and at significantly lower levels on 
specific immune cell subsets [8].  SLAMF7 has not been detected on hematopoietic stem 
cells nor on other normal solid organ tissues [8].     
 
Elotuzumab binding to SLAMF7 directly activates NK cells, but not myeloma cells. 
Elotuzumab bound to myeloma cells via SLAMF7 further activates NK cells via Fc 
receptors, thereby enabling selective killing of myeloma cells through antibody-dependent 
cellular cytotoxicity (ADCC) with minimal effects on normal tissue [9]. This dual 
mechanism of action (direct NK cell activation and NK cell-mediated ADCC) is illustrated 
in Figure 1[8, 10]. 
 
 
 


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Figure 1: Dual Mechanism of Action of Elotuzumab 
 
 
 
1.3.1 Elotuzumab Preclinical Summary 
Elotuzumab does not recognize nor bind to the SLAMF7 protein from species other than 
humans, and so the preclinical safety package was comprised of in vitro safety studies 
and in vivo biological evaluations. Elotuzumab (100 and 200 μg/mL) in vitro had no 
effect on lymphocytes, CD3, CD4, CD8 and B-cell counts in blood samples from healthy 
human donors. The NK cell counts were decreased on average by 20% at both doses of 
elotuzumab. Elotuzumab at concentrations up to 500 μg/mL did not adversely affect the 
ability of human bone marrow-derived hematopoietic stem cells to differentiate down the 
erythroid and myeloid pathways. Elotuzumab was also evaluated in a single-dose IV 
study in primates (rhesus monkeys) to explore for any potential off target effects. In this 
latter study, no elotuzumab-related effects were observed. 
 
Safety pharmacology studies were not considered relevant in view of the specificity of 
the interaction of elotuzumab with its target. In particular, elotuzumab is targeting a 
molecule/pathway that is not known to be involved in the functioning of the 3 main organ 
systems: central nervous system, respiratory system, and cardiovascular system. This 
specificity is confirmed by the observed lack of cross-reactivity in various human tissues. 
 
Experiments using an in vivo mouse xenograft model suggest that, while maximal 
antitumor activity is reached at elotuzumab serum levels of 70 to 430 μg/mL, minimal 
biological activity is seen at 2 to 13 μg/mL. In vitro experiments suggested that the 
elotuzumab concentration required to achieve saturation of SLAMF7 on peripheral blood 
mononuclear cells (PBMCs) from healthy donors was approximately 20 μg/mL. 
 
In nonclinical models, elotuzumab plus bortezomib, lenalidomide, or pomalidomide had 
greater antitumor activity than either agent alone.  Significant antibody-dependent killing 
of MM cells was observed when elotuzumab was incubated with L363 or OPM2 human 
MM cells in the presence of human PBMCs isolated from the blood of healthy donors or 
from the blood of MM subjects. No complement-dependent cytotoxicity was detected. 
Elotuzumab
Elotuzumab


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Elotuzumab treatment of mice bearing human xenograft MM tumors resulted in 
significant antitumor activity and eradication of tumors in many of the treated mice. See 
the latest version of the elotuzumab Investigator’s Brochure (IB) for additional details. 
1.3.2 Elotuzumab Pharmacodynamics 
The relationship between SLAMF7 saturation on MM cells and elotuzumab levels in 
blood was assessed in 3 phase I studies. At doses of 10 and 20 mg/kg of elotuzumab, 
SLAMF7 receptors on bone marrow-derived myeloma cells were consistently saturated. 
See the latest version of the elotuzumab IB for additional details. 
1.3.3 Elotuzumab Pharmacokinetics 
The pharmacokinetics (PK) of elotuzumab was evaluated in over 600 patients who 
received the drug as monotherapy or in combination with other agents. Elotuzumab 
exhibits nonlinear PK, resulting in greater than proportional increases in area under the 
concentration-time curve (AUC) indicative of target-mediated clearance.  
 
The multiple-dose PK of elotuzumab, given every week to every 4 weeks, was 
determined following IV administration of various doses.  Increase in exposure was more 
than dose proportional from 0.5 to 20 mg/kg. Following weekly or every 2 weeks’ 
administration of 10 mg/kg of elotuzumab in combination with 
lenalidomide/dexamethasone (Rd) or bortezomib/dexamethasone, mean trough 
concentrations (Cmin) were above the target threshold concentration (70 mcg/mL) 
associated with maximal efficacy observed in the nonclinical xenograft human MM 
mouse model. 
 
In the phase III trial combining elotuzumab with Rd (ELOQUENT-2), described in detail 
in Section 1.3.4.1), dosing elotuzumab weekly for the first 8 weeks of dosing followed by 
every 2-week dosing allows for attainment of steady-state exposure of elotuzumab 
approximately 6 weeks after the start of dosing. However, concentrations continued to 
rise for 3 more weeks. Once subjects were switched to every 2-week dosing, trough 
levels decreased to those reported at 6 weeks.  
 
Clinically significant differences were not observed in the pharmacokinetics of 
elotuzumab based on age, gender, race, baseline LDH, albumin, renal impairment ranging 
from mild to end-stage renal disease (creatinine clearance less than 15 mL/min) with or 
without hemodialysis, and mild hepatic impairment (defined as total bilirubin ≤ upper 
limit of normal (ULN) with AST > ULN or total bilirubin 1.0 to 1.5×ULN, and any 
AST). The pharmacokinetics of elotuzumab in patients with moderate to severe hepatic 
impairment is unknown. The clearance of elotuzumab increased with increasing body 
weight supporting a weight-based dose. See the latest versions of the elotuzumab IB and 
prescribing information for additional details. 
1.3.4 Elotuzumab Clinical Studies 
As of the May 15, 2016 IB, 13 clinical studies sponsored by the manufacturer of 
elotuzumab (1 as monotherapy and 12 in combination with other agents) in subjects with 


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MM were either ongoing or complete. One additional trial of monotherapy has been 
conducted in high risk smoldering myeloma. 
1.3.4.1 Combination with Lenalidomide and Dexamethasone 
Elotuzumab in combination with lenalidomide and dexamethasone has been evaluated in 
a number or clinical trials, including the ELOQUENT-2 trial [11]. In ELOQUENT-2, 
elotuzumab was dosed at 10 mg/kg every week for the first two cycles (8 weeks) 
followed by elotuzumab 10 mg/kg every 2 weeks. Lenalidomide was dosed at 25 mg 
orally daily on days 1-21 of each cycle. Dexamethasone was given weekly throughout 
treatment. On the days of elotuzumab administration, 36 mg of dexamethasone was given 
[28 mg orally and 8 mg IV]). On the weeks elotuzumab was not administered (i.e., weeks 
2 and 4 from cycle 3 on), subjects received 40 mg of oral dexamethasone. 
 
The trial was designed with two co-primary endpoints: ORR (partial response [PR] or 
better using the European Group for Blood and Marrow Transplantation) and PFS. The 
median PFS and ORR were significantly improved in the elotuzumab arm (19.4 months 
and 79% [33% VGPR+]) as compared to the Rd (control) arm (14.9 months and 66%).  
 
Serious adverse reactions were reported in 65.4% of patients treated on the elotuzumab 
arm and 56.5% of patients treated on the control arm. The most frequent serious adverse 
reactions (elotuzumab arm compared to the control arm) were: pneumonia (15.4% vs. 
11%), pyrexia (6.9% vs. 4.7%), respiratory tract infection (3.1% vs. 1.3%), anemia (2.8% 
vs. 1.9%), pulmonary embolism (3.1% vs. 2.5%), and acute renal failure (2.5% vs. 1.9%). 
Adverse reactions occurring at a frequency of at least 20% (all grades) in the elotuzumab 
arm and that are 5% or higher in the elotuzumab arm compared to the Rd arm included: 
fatigue, diarrhea, pyrexia, constipation, cough, peripheral neuropathy, nasopharyngitis, 
upper respiratory tract infection, decreased appetite and pneumonia. Of note, the 
incidence of grade 3 or 4 fatigue was 12.6% in the elotuzumab arm vs. 11.7% in the Rd 
arm and the incidence of grade 3 or 4 pneumonia was 14.2% in the elotuzumab arm vs. 
9.5% in the Rd arm. The rate of infusion related reactions (IRR) in the elotuzumab arm 
was 10% (n=33), with ≤ grade 2 in the large majority (n=29). Seventy percent of the 
IRRs occurred within the first cycle. No patient experienced a > grade 3 IRR [elotuzumab 
prescribing information and reference 11].  
 
Laboratory abnormalities worsening from baseline with a frequency of at least 10% (all 
grades) in the elotuzumab arm and that are 5% or higher in the elotuzumab arm compared 
to the Rd arm included (grade 3 or 4): lymphopenia (76.7%); leukopenia (32.4%); 
thrombocytopenia (19.2%); hypoalbuminemia (3.9%); elevated alkaline phosphatase 
(1.3%); hyperglycemia (17%); hypocalcemia (11.3%); low bicarbonate (0.4%); and 
hyperkalemia (6.6%). 
 
See the prescribing information and reference [11] for additional details on safety data 
from this trial. See the IB and Section Error! Reference source not found. for safety 
information across all clinical studies of elotuzumab to date. Section Error! Reference 
source not found.  also summarizes the warnings associated with elotuzumab 
administration: infections, second primary malignancies, IRR and hepatotoxicity. 


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1.3.4.2 Combination with Bortezomib 
Elotuzumab has been evaluated in combination with the proteasome inhibitor bortezomib 
in subjects with relapsed/refractory MM in a phase I [12] and subsequent randomized 
phase II study [13]. In the phase I trial, elotuzumab was administered from 2.5 to 20 
mg/kg on days 1 and 11 of each 21-day cycle in combination with bortezomib (1.3 mg/m2 
IV on days 1, 4, 8 and 11). The phase I subjects, who had received a median of 2 prior 
therapies, did not experience any DLTs during cycle 1 of the maximum planned dose of 
elotuzumab of 20mg/kg. The most common ≥ grade 3 adverse drug reactions were 
consistent with those reported previously for bortezomib and included lymphopenia 
(25%), fatigue (14%), and the following at 11% each (neutropenia, thrombocytopenia, 
peripheral neuropathy and hyperglycemia). Adverse reactions considered related to 
elotuzumab were primarily IRRs and resolved the same day of treatment. CS1 targets 
were saturated to a median of 80% at the 10 mg/kg dose of elotuzumab, and 95% at the 
20 mg/kg dose, and serum concentrations of ≥100 mcg/mL or greater at each of these 
doses was achieved [12].  
 
In the randomized phase II trial, elotuzumab, bortezomib and dexamethasone (EBd), or 
bortezomib and dexamethasone (Bd), were administered in 3 week cycles for the first 8 
cycles, followed by 4 week cycles until progression. Elotuzumab 10 mg/kg was 
administered weekly for cycles 1 and 2, on days 1 and 11 from cycles 3 to 8 and then 
every 2 weeks thereafter. Bortezomib 1.3 mg/m2 IV was administered on days 1, 4, 8 and 
11 for the first 8 cycles and days 1, 8 and 15 for all subsequent cycles. Dexamethasone 
was administered weekly as 20 mg orally on non-elotuzumab days or 8 mg orally plus 8 
mg IV on days elotuzumab was also administered. The median PFS was longer in the 
triplet arm as compared to Bd, with minimal differences in adverse events between the 
two arms. The incidence of ≥ grade 3 events were similar with the exception of infections 
(21% for the triplet versus 13% for Bd) and thrombocytopenia (9% for the triplet and 
17% for Bd) [13].  
1.4 
Study Rationale and Design 
Elotuzumab has demonstrated clinical efficacy in relapsed/refractory MM when combined 
with dexamethasone and lenalidomide [11] and has been shown to be safe and well 
tolerated when combined with the proteasome inhibitor bortezomib with or without 
dexamethasone [12, 13]. Further, the immunomodulatory effects of the KRd regimen, 
which incorporates the proteasome inhibitor carfilzomib, have a strong potential for 
synergy with those of elotuzumab (see Section 1.4.1). 
 
Given this, we propose a phase II trial designed to evaluate the efficacy (rate of VGPR+) 
after 4 cycles of KRd+elotuzumab in subjects with relapsed/refractory MM. The VGPR+ 
rate will be compared to a historical control rate of 40%, with the aim of improving the rate 
to 60% with the addition of elotuzumab. The 40% historical control rate for KRd comes 
from the MPD cohort from the phase Ib/II trial [6]. This rate of 40%, which is lower than 
the rate from the ASPIRE trial [7], was selected as the historical control for several 
reasons. In the present study, we will be evaluating our primary endpoint after 4 cycles of 
therapy. While both the phase Ib/II trial and the ASPIRE trial reported the best response 
over the full course of therapy, in ASPIRE, KRd was given at a fixed schedule until 


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progression, with the majority of patients receiving more than 18 cycles of therapy. On the 
other hand, in the phase Ib/II study the frequency of carfilzomib dosing was reduced after 
12 cycles from 6 times per month to 4, and the majority of patients received 12 cycles of 
therapy, making it more analogous to the present study. In addition, our trial includes 
subjects with light chain only disease, while these subjects were excluded from the 
ASPIRE study.  
 
We have incorporated identical doses of carfilzomib and lenalidomide as were used in 
previous trials of KRd as induction [14-15], and have maintained the same weekly dose of 
dexamethasone when administered with elotuzumab as was used in the elotuzumab+Rd 
regimen described in Section 1.3.4.1. The elotuzumab dose of 10 mg/kg during induction 
is identical to the approved dose of this agent when combined with Rd and is the dose that 
was utilized in the randomized phase II trial of elotuzumab+Bd [13]. We are maintaining 
the frequency of weekly elotuzumab dosing during induction for the first 2 cycles. Post-
induction, elotuzumab will be administered monthly in combination with lenalidomide, 
and dexamethasone will be omitted in an attempt to decrease long term toxicity. This is 
similar to an ongoing trial of elotuzumab in combination with lenalidomide as maintenance 
therapy after ASCT (NCT 02420860).  Also similar to this latter trial, and to several other 
ongoing trials of elotuzumab in MM (NCT 02654132; 02612779; 02272803), the 
elotuzumab dose will be increased to 20 mg/kg as the frequency decreases to once 
monthly. Safety will be carefully monitored in this study, and toxicity data reviewed 
regularly at all study team meetings. 
1.4.1 Correlatives 
Beyond a direct anti-MM plasma cell (PC) activity, proteasome inhibitor/IMiD drug 
combinations such as KRd have a potent effect on immune effector cells and overall 
inflammation. Carfilzomib and lenalidomide in particular can activate NK cells and 
enhance NK cell-mediated lysis [16]. Bortezomib and lenalidomide have also been 
shown to promote Type 1 T helper (TH1) inflammation triggering T helper and cytotoxic 
T cells expansion [17]. Noticeably, dexamethasone can potentiate these strong pro-
inflammatory stimuli by altering NK cell activating receptor expression [18] and sensitize 
T cells to anergy signaling [19].  
  
The aforementioned mechanisms of immune modulation by KRd present strong potential 
synergy with elotuzumab. While plasma cells (including MM-PC) express high levels of 
SLAMF7 (CS1), NK cells and activated T cells share this receptor expression [20]. 
Elotuzumab enhances NK activation and myeloma cell killing through TH1 
inflammation-dependent pathways [21]. 
 
In addition to exploring this synergy, correlative studies planned for this trial include 
evaluation of minimal residual disease (MRD). Relapse in MM, including in those who 
achieve a CR post treatment, is likely due to the presence of MRD undetectable by 
standard disease evaluation methods (i.e., assessment of monoclonal proteins in serum 
and urine and evaluation of bone marrow). MRD following therapy represents a state of 
immune equilibrium whereby detectable or undetectable low numbers of myeloma cells 
remain under surveillance as long as the immune environment continues to be 


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permissive, however after variable lengths of time, immune dormancy ends, leading to 
multiple myeloma progression. 
 
In order to characterize KRd+elotuzumab synergistic activity on antitumor immune 
function, and correlate this synergy with clinical response status (MRD, ORR, PFS or 
OS), blood will be collected serially across the study (see Section 7) for immune 
phenotyping by flow cytometry and multiplex protein assay. Further, peripheral blood 
mononuclear cells (PBMCs) will be isolated to assess T cell clonal expansion by next 
generation sequencing.   
 
Furthermore, changes in bone marrow microenvironment and bone marrow plasma cells 
from bone marrow biopsies/aspirates collected serially across the study (see Section 7) 
will be investigated at the cellular and molecular level. At each time point, MRD flow 
assay will be performed to quantify disease burden and/or assess MM-PC phenotype. In 
addition, CD138+ plasma cells and CD138- bone marrow microenvironment will be 
isolated for next generation sequencing (or microarray analysis) to assess plasma cell 
clonal distribution and T cell clonal expansion respectively. See Section 8.8 for additional 
details. 
 
Immune Response Analyses  
Monoclonal antibody therapy such as elotuzumab can be associated with IRRs such as 
cytokine release syndrome (CRS). CRS clinically manifests when large numbers of 
lymphocytes (B cells, T cells and or/ natural killer (NK) cells) become activated and 
release inflammatory cytokines. Patients can experience these reactions during 
monoclonal antibody infusion (uniphasic reaction) and/or within hours of an infusion 
(biphasic/delayed reaction). For subjects potentially experiencing grade ≥3 IRR 
(uniphasic or biphasic), we will conduct immune response analyses (with a particular 
emphasis on NK or T cell activation and polarization). These analyses may provide 
valuable insights regarding underlying immunological pathway(s) that could be applied 
to better prevention of management of such event.  
 
2. OBJECTIVES 
2.1 
Primary Objective 
The primary objective is to evaluate the efficacy of elotuzumab when combined with KRd 
in terms of very good partial response or better (VGPR+) after induction in subjects with 
relapsed or refractory multiple myeloma, and compare to relevant historical controls.  
Response will be assessed based on the International Myeloma Working Group (IMWG) 
2016 criteria [22]. 
2.2 
Secondary Objectives 
Secondary objectives include evaluation of elotuzumab in combination with KRd by 
estimating the following: 
• Overall response rate (ORR) defined as the percent of subjects achieving a partial 
response or better per IMWG 2016 criteria [22]. 


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• Progression-free survival (PFS) defined as the time from treatment start (Cycle 1, Day 1) 
until disease progression or death. 
• Overall survival (OS) defined as the time from treatment start until death. 
• Time to disease progression (TTP) defined as the time from treatment start until disease 
progression. 
• Duration of response (DoR) in subjects achieving a partial response or better defined as 
the time from achieving a partial response until disease progression or death. 
• Time to next treatment (TTNT) as defined by the time from treatment start until the start 
of the first subsequent anti-cancer therapy after all protocol directed therapy is 
completed.  
2.3 
Safety Objectives 
The safety objectives will include evaluation of study drug administration, adverse events 
assessed by NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.03, 
serious adverse events including deaths on study treatment.  
2.4 
Exploratory Objectives 
• Explore PET/CT response as an imaging correlate end-point. 
• Explore minimal residual disease (MRD) by: 
o Flow cytometry 
o NGS 
• Characterize KRd-Elotuzumab synergistic activity on NK and T cell function and 
polarization 
• Explore correlation of systemic immune profiling with measurements of clinical response 
such as MRD, ORR, PFS and OS by performing: 
o Cytokine profiling by multiplex protein assay 
o Blood immunotyping [including NK, NK-T and T cell subsets distribution and 
activation analyses] by flow cytometry 
o Bone marrow immunotyping by flow cytometry 
• Explore correlation of circulating T cell receptor (TCR) repertoire immuno-sequencing 
by NGS with parameters of clinical response such as MRD, ORR, PFS and OS. 
• Explore correlation of peripheral and medullar T cell clonal expansion with MM-PC 
clonal distribution 
• Examine changes in biology of BM and BM plasma cells before and after treatment(s) by 
B cell receptor (BCR) sequencing and global gene expression profiling 
• Explore immune response (with a particular emphasis on NK or T cell activation and 
polarization) in subjects who experience a grade ≥3 IRR 
3. SUBJECT SELECTION 
3.1 
Subject Recruitment 
Subjects will be recruited at Levine Cancer Institute (LCI) locations and potentially at 
other participating sites. 
 


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Because no dosing or adverse event data are currently available on the use of elotuzumab 
in combination with KRd in subjects <18 years of age, children are excluded from this 
study. In addition, MM is not a disease typically diagnosed in those <18 years of age. 
 
3.2 
Inclusion Criteria 
Subject must meet all of the following applicable inclusion criteria to participate in this 
study: 
 
1. Written informed consent and HIPAA authorization for release of personal health 
information signed by the subject or his/her legally authorized representative. 
 
2. Age ≥ 18 years at the time of consent.  
 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 (see Appendix 
A, Section 18.1). 
 
4. Documented history of relapsed and/or refractory multiple myeloma per IMWG 2016 
criteria [22] as defined below (biochemical and/or clinical relapse per IMWG criteria); 
(NOTE: subjects refractory to bortezomib and/or lenalidomide are eligible; subjects who 
previously received carfilzomib are eligible provided they experienced a minimal 
response or better and relapsed >60 days after completion of treatment [see exclusion 
criteria #2]): 
a. Relapse is defined as progression of disease after an initial response to previous 
treatment, more than 6 months after discontinuation of treatment. 
b. Refractory is defined as lack of response to previous treatment, progression of 
disease during treatment, or progression of disease within 6 months of 
discontinuation of treatment. 
 
5. Prior treatment with one line (and no more than one line) of systemic therapy for MM; 
NOTE: A new line of therapy is considered to start when a planned course of therapy is 
modified to include other treatment agents (alone or in combination) as a result of 
progressive disease (PD), relapse, or toxicity or when a planned period of observation off 
therapy is interrupted by a need for additional treatment for the disease. Induction therapy 
and stem cell transplant followed by planned maintenance therapy (provided there is no 
intervening PD) are considered to be a single line. 
 
6. Subject must have recovered from any treatment-induced toxicities to ≤grade 1 or 
baseline: 
 
7.  Adequate washout from previous therapy: 
a. Prior chemotherapy is completed >3 weeks prior to day 1 of treatment (6 weeks 
for melphalan, nitrosoureas or monoclonal antibodies). 
b. Autologous transplant completed (referring to day of stem cell infusion) >12 
weeks prior to day 1 of treatment; allogeneic transplant >16 weeks prior to day 1 
of treatment. 
c. Prior radiotherapy completed at least 2 weeks prior to day 1 of treatment. 


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d. Corticosteroid therapy at a dose equivalent to dexamethasone >4mg/day has been 
completed at least 2 weeks prior to day 1 of treatment. 
 
8. Measurable disease defined as: 
a. Serum M-protein > 0.5 g/dL OR   
b. Urine M-protein ≥200 mg/24 h OR  
c. Involved free light chain (FLC) level ≥10 mg/dL provided serum FLC ratio is 
abnormal.   
 
9. Demonstrate adequate organ function within 1 week of day 1 of treatment as defined in 
the table below:  
 
System 
Laboratory Value 
Hematological 
White Blood Cell (WBC)  
≥ 2,000/mm3 
Absolute Neutrophil Count (ANC) 
≥ 1,000/mm3 without growth factors 
within 1 week of day 1 of treatment 
Hemoglobin (Hgb) 
≥ 8 g/dL 
Platelet count  
≥ 70,000/mm3 if bone marrow 
plasmacytosis of <50%; otherwise ≥ 
50,000/mm3 
Renal 
Serum creatinine OR 
Creatinine clearance  
≤1.5 × upper limit of normal (ULN) OR 
≥ 40 mL/min as measured by a 24-hour 
urine collection or estimated by the 
Cockcroft and Gault formula1 
Hepatic 
Bilirubin 
≤2 × ULN; < 3.0 for subjects with 
Gilbert’s Syndrome  
Aspartate aminotransferase (AST) 
≤ 2.5× ULN 
Alanine aminotransferase (ALT) 
≤ 2.5 × ULN 
1See formula in Appendix B, Section 18.2  
 
10. Adequate cardiac function as defined by ≥45% Left Ventricular Ejection Fraction 
(LVEF) by ECHO or MUGA within 28 days prior to day 1 of treatment. 
 
11. Females of childbearing potential (FCBP) must have a negative serum pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to day 1 
of treatment, and be willing to undergo serial serum or urine pregnancy testing. NOTE: 
Females are considered of child bearing potential unless they are surgically sterile (have 
undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are 
postmenopausal (at least 12 consecutive months with no menses without an alternative 
medical cause). 
 
12. FCBP must be willing to use a highly effective contraceptive method (i.e., achieves a 
failure rate of <1% per year when used consistently and correctly) plus a second 


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contraceptive method (considered acceptable [failure rate of >1% per year] or highly 
effective) from the time of informed consent until 6 months after the last protocol 
prescribed therapy has been discontinued. NOTE: estrogens may further increase the 
risk of thrombosis (beyond that associated with lenalidomide) and their use should 
be based on a benefit-risk decision. For the highly effective contraceptive method, a 
method with low user dependency is preferable but not required (see tables, adapted 
from: http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf). 
 
Highly Effective Birth Control Methods  
• combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation 
o oral 
o intravaginal 
o transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation 
o oral 
o injectable 
o implantable1 
• intrauterine device (IUD) 1 
• intrauterine hormone-releasing system (IUS) 1 
• vasectomised partner 1,2 
• sexual abstinence 3 
 
1 Contraception methods considered to have low user dependency 
2 Vasectomised partner is a highly effective birth control method provided that partner is the 
sole sexual partner of the FCBP trial participant 
3 Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments 
 
Acceptable Birth Control Methods  
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action 
• Male or female condom with or without spermicide1 
• Cap, diaphragm or sponge with spermicide1 
1A combination of male condom with either cap, diaphragm or sponge with spermicide (double 
barrier methods) are also considered acceptable, but not highly effective, birth control methods. 
 
13. Male subjects (even those who have had a vasectomy) who are sexually active with a 
FCBP must be willing to use latex or synthetic condoms from the time of informed 
consent until 180 days after the last protocol prescribed therapy has been discontinued. 
The FCBP partner should also consider contraception recommendations (see inclusion 
#11). 
 
14. As determined by the enrolling physician, ability of the subject to understand and comply 
with study procedures for the entire length of the study. 


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3.3 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
 
1. Discontinuation of previous lenalidomide, carfilzomib or dexamethasone due to 
intolerance. 
 
2. If previously treated with carfilzomib, lack of response, progression during or relapsed 
within 60 days after completion of treatment. 
 
3. Any infection, at the time of screening, requiring systemic therapy (i.e. involving IV 
antibiotics) (NOTE: at discretion of investigator, subjects with uncomplicated urinary 
tract infections may be eligible). 
 
4. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the 
mother is being treated on study, and any female subject must agree not to donate eggs 
during the study and for 4 months after the last protocol prescribed therapy has been 
discontinued). 
 
5. Has a known additional malignancy that is active and/or progressive requiring treatment; 
exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder 
cancer, carcinoma of the prostate with a current PSA value of <0.5 ng/mL or other cancer 
for which the subject has completed treatment, been disease-free for at least five years, 
and is considered by Sponsor-Investigator to be at <30% risk of relapse, or on hormonal 
therapy for a history of either prostate cancer or breast cancer, provided that there has 
been no evidence of disease progression during the previous three years. 
 
6. Non-secretory MM. 
 
7. Active involvement of the central nervous system by MM. 
 
8. Prior cardiovascular cerebrovascular accident with persistent neurological deficit. 
 
9. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein, and skin changes). 
 
10. Had major surgery within 4 weeks prior to day 1 of treatment.  
 
11. Plasmapheresis within 4 weeks from day 1 of treatment. 
 
12. Treatment with any investigational drug within 4 weeks prior to day 1 of treatment. 
 
13. Uncontrolled clinically significant illness including, but not limited to, uncontrolled 
hypertension (as per the most updated Joint National Committee for the Management of 
Hypertension definitions), symptomatic congestive heart failure (as per New York Heart 
Association [NYHA] class III or IV [see Appendix C, Section 18.3], uncontrolled angina 


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pectoris, myocardial infarction within the past 6 months, known or suspected 
amyloidosis, uncontrolled cardiac arrhythmia, psychiatric illness/social situations that 
would limit compliance with study requirements as determined by the investigator, or any 
other condition (including laboratory abnormalities) that would, in the opinion of the 
Sponsor-Investigator, place the subject at unacceptable risk if he/she were to participate 
in the study. 
 
14. Known allergies, hypersensitivity, or intolerance to monoclonal antibodies or human 
proteins, elotuzumab or its excipients or known sensitivity to mammalian-derived 
products, carfilzomib or its excipients, lenalidomide or its excipients, or dexamethasone 
or its excipients. 
 
15. Known human immunodeficiency virus (HIV) infection or active hepatitis A, B and/or C 
infection.  
a. Subjects with resolved HBV infection (i.e. subjects who are HBsAg negative but 
positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to 
hepatitis B surface antigen [anti-HBs]) must be screened using real-time 
polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA 
levels. Subjects who are PCR positive will be excluded. Exception: subjects with 
serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only 
serologic marker) and a known history of prior HBV vaccination do not need to 
be tested for HBV DNA by PCR. 
3.4 
Screen Failures 
A subject who, for any reason (e.g., failure to satisfy the selection criteria or withdraws 
consent), terminates his/her study participation before receiving the first dose of study 
therapy is regarded as a “screen failure.” All screen failures will be tracked.  Enrollment 
will continue until the targeted sample size in the evaluable population (Section 14.4) is 
achieved. 
4. REGISTRATION  
Following informed consent, subjects will be registered by the Coordinating Site and 
assigned a Study ID number.  A subject is considered registered when they are assigned a 
Study ID number.  
5. STUDY PLAN  
See Schema (page III). 
 
This single arm, open-label phase II study is designed with the primary objective of 
evaluating the efficacy of induction therapy comprised of 4 cycles of carfilzomib, 
lenalidomide, dexamethasone and elotuzumab (KRd+elotuzumab) in terms of VGPR+ in 
subjects with relapsed or refractory multiple myeloma, and comparing to relevant historical 
controls. Post induction, all subjects will undergo disease evaluation for assessment of the 
primary endpoint. Maintenance therapy comprised of elotuzumab and lenalidomide 
(R+elotuzumab) will start directly after induction and continue until relapse or progression.  
 


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This study will initially open as a single center study at LCI and additional investigational 
site(s) may be added following activation at the coordinating center. We anticipate subjects 
will be accrued over 24 months. 
5.1 
KRd+Elotuzumab Induction Regimen  
All subjects enrolled will receive KRd+elotuzumab induction. See Section 6 for details on 
drug administration and dose modifications/delays. NOTE: Pre-hydration is required for 
carfilzomib as described in Section 6.3.2 and premedication is required prior to elotuzumab 
as described in Section 6.4.1. 
 
Table 1: KRd+Elotuzumab Induction Regimen  
 
Drug 
Dose 
Route 
Schedule 
4-Week 
(28D) Cycle 
Carfilzomiba,b 
20 mg/m2  
IV 
D1 
Cycle 1 
Carfilzomiba,b,c 
56 mg/m2 
IV 
D8, 15  
Cycle 1 
Carfilzomiba,b,c 
56 mg/m2 
IV 
D1, 8, 15  
Cycles 2-4 
Lenalidomide  
25 mgd 
Oral 
Once a day at bedtime on D1-21 
Cycles 1-4 
Dexamethasoneg 
28 mg 
Oral  
Once weeklye on D1, 8, 15, 22 
Cycles 1-2 
8 mg 
IV 
Dexamethasonee,g 
28 mg 
Oral  
D1 
Cycles 3-4 
8 mg 
IV 
Dexamethasonef, g 
40 mg 
PO 
Once weekly on D8, 15 and 22 
Cycles 3-4 
Elotuzumabb 
10 mg/kg 
IV  
Once weekly on D1, 8, 15, 22 
Cycles 1-2 
Elotuzumabb 
20 mg/kg 
IV 
D1 
Cycles 3-4 
a Calculate the dose using the subject’s actual body surface area (BSA) at baseline. For subjects with a BSA >2.2m2, calculate 
the dose based upon a BSA of 2.2m2.  
b If a subject’s weight changes by more than 10% from induction cycle 1 day 1 the dose of carfilzomib and elotuzumab 
should be recalculated. This re-calculated weight should be used as the new baseline weight. NOTE: use the subject’s actual 
(not ideal) body weight for dosing as per the American Society of Clinical Oncology (ASCO) guidelines in dosing of obese 
adult subjects. 
c NOTE: In subjects who enroll with a bilirubin and/or AST >1 x ULN, the starting dose of carfilzomib of 20mg/m2 should 
be maintained and not increased to 56mg/m2. The dose may be escalated to 56 mg/m2 if both bilirubin and AST resolve to ≤ 
ULN. 
d For subjects who enroll with a CrCl between 40-50 mL/min, the starting dose of lenalidomide may be reduced to 10mg at 
the discretion of the investigator. 
e On days when elotuzumab is administered: 28mg PO between 3-24 hours prior to start of elotuzumab OR as a split dose of 
12 mg 12-24 hours and 16 mg 3 hours prior to elotuzumab; 8 mg IV 45 to 90 minutes prior to elotuzumab infusion. NOTE: 
This will serve as the corticosteroid premedication for elotuzumab on days when elotuzumab is administered during induction 
f May administer 20 mg dexamethasone for subjects ≥ 75 years old 
g Oral dexamethasone may be reduced per investigator discretion. On days when elotuzumab is administered, this is allowable 
after C1 of induction has completed without an infusion-related reaction. 
5.2 
R+Elotuzumab Maintenance Regimen 
The first cycle of maintenance therapy will begin 4 weeks (28D) after the start of cycle 4 
of induction. NOTE: premedication (including dexamethasone) is required prior to 
elotuzumab as described in Section 6.4.1. 


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Table 2: R+Elotuzumab Maintenance Regimen 
 
Drug 
Dose 
Route 
Schedule 
4-Week 
(28D) Cycle 
Lenalidomide  
15 mg or LTD if 
<15mga 
Oral 
Once a day at bedtime on 
D1-21 
Cycles 1-n 
Elotuzumab 
20 mg/kgb 
IV  
D1 of each cycle 
Cycles 1-n 
aLTD=last tolerated dose 
bIf a subject’s weight changes by more than 10% from cycle 1 day 1 of induction the dose of elotuzumab should be 
recalculated. This re-calculated weight should be used as the new baseline weight. 
 
6. TREATMENT DETAILS AND DOSE MODIFICATIONS/DELAYS 
Any subject who receives treatment on this protocol will be evaluable for toxicity.  Each 
subject will be assessed periodically for the development of any toxicity according to the 
Study Calendar.  Toxicity will be assessed according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), v4.03. Dose adjustments 
should be made according to the system showing the greatest degree of toxicity.  
 
Note: In each dose modification table in Section 6, the Recommended Action is per 
investigator’s discretion. 
 
6.1 
General Rules for Dose Modifications/Delays for KRd+Elotuzumab Induction 
In the event of a possible drug-related toxicity, the investigator should, to the best of 
his/her ability, assess its relationship to each of the drugs within the regimen (carfilzomib, 
lenalidomide, dexamethasone, elotuzumab), or to the combination to the extent possible. 
Actions outlined in the sections below should be instituted for the agent(s) considered 
likely to be involved.  
 
If the dose of one drug in the KRd+elotuzumab regimen is delayed, interrupted, or 
discontinued, the treatment with the other drugs may continue as scheduled.  However, if 
elotuzumab is permanently discontinued, the subject should be removed from protocol-
mandated treatment, and followed up per protocol (KRd may continue off protocol at the 
discretion of the investigator).  If dexamethasone is delayed or discontinued during 
induction, the administration of elotuzumab should be at the discretion of the investigator 
and based on clinical judgment (i.e., risk of hypersensitivity). 
 
Subjects experiencing a 28-day delay in elotuzumab due to an elotuzumab-related AE must 
be discontinued from protocol-mandated treatment and followed up per protocol.  
 
While dose delays or interruptions are permitted, the start of each cycle cannot be delayed 
and is fixed relative to Cycle 1 Day 1 of induction. Adjustments to the Cycle 1 Day 1 
anchored schedule should not be performed. Missed doses should be skipped, not delayed, 
as detailed in the rules in the sections below. 


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6.2 
General Rules for Dose Modifications/Delays for R+Elotuzumab Maintenance 
In the event of a possible drug-related toxicity, the investigator should, to the best of 
his/her ability, assess its relationship to elotuzumab, lenalidomide, or to the combination to 
the extent possible. Actions outlined in the sections below should be instituted for the 
agent(s) considered likely to be involved.  
 
If the dose of elotuzumab is delayed or interrupted, treatment with lenalidomide may 
continue as scheduled. However, if elotuzumab is permanently discontinued, the subject 
should be removed from protocol-mandated treatment, and followed-up per protocol 
(lenalidomide may continue off protocol at the discretion of the investigator).  If 
lenalidomide is held or discontinued, treatment with elotuzumab may continue as 
scheduled. 
 
Subjects experiencing a 28-day delay in elotuzumab due to an elotuzumab-related AE must 
be discontinued from protocol-mandated treatment and followed up per protocol.  
 
While dose delays or interruptions are permitted, the start of each cycle cannot be delayed 
and is fixed relative to Cycle 1 Day 1 of maintenance. Adjustments to the Cycle 1 Day 1 
anchored schedule should not be performed. Missed doses should be skipped, not delayed, 
as detailed in the rules in the sections below. 
6.3 
Carfilzomib  
6.3.1 Administration 
Subjects with active or suspected infection of any kind that require systemic treatment 
should not be dosed with carfilzomib until the infection has resolved and if being treated 
with an anti-infective(s), the course of antibiotics has been completed.  
 
Subjects will receive carfilzomib as an intravenous (IV) infusion over approximately 30 
minutes as per the dose and schedule outlined in Table 1 for induction. 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 must be 
administered at a facility capable of managing IRRs.  
 
On the days both carfilzomib and elotuzumab are due to be administered, carfilzomib will 
be administered first.  
6.3.2 Pre- and Post-Dose Hydration and Monitoring Cycles 1 and 2 of Induction 
Starting at least 48 hours before Cycle 1 Day 1 of induction, subjects should be instructed 
to ingest oral hydration 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 tumor lysis syndrome (TLS; i.e., those with high tumor 
burden), oral hydration should be continued in Cycle 2 and beyond as required by the 


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subject’s medical condition and at the investigator’s discretion. See Section 6.8.1 for 
recommended concomitant medications. 
 
IV hydration will be given immediately prior to the first two doses of carfilzomib during 
Cycle 1 of induction.  This will consist of 250 to 500 mL normal saline or other 
appropriate IV fluid.   Subjects will remain at the clinic under observation for at least 1 
hour following the first 2 doses of carfilzomib in Cycle 1 of induction.  During these 
observation times, post dose IV hydration (between 250 mL and 500 mL normal saline or 
other appropriate IV fluid formulation) will be given.  Subjects should be monitored 
periodically during this period for evidence of fluid overload. After the second dose of 
Cycle 1, pre- and/or post-hydration may be administered at the discretion of the 
investigator. If, however, lactate dehydrogenase (LDH) or uric acid is elevated (and/or in 
subjects considered still at risk for TLS) after the second dose in Cycle 1of induction, 
then the recommended IV hydration should be given additionally before each remaining 
dose in Cycle 1.  The goal of 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.  
6.3.3 First Dose Effect for Carfilzomib during Induction 
A “first dose effect” has been seen with carfilzomib, 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.   Should a “first dose” effect occur at any point during 
Cycle 1 or 2 of induction, 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 and 
instituted, as medically indicated.  
6.3.4 Dose Modifications for Carfilzomib-Related Toxicities 
If a dose of carfilzomib is missed because of toxicities, the subject should not be 
administered an additional dose, but should be given the next usual prescribed dose.  
 
Refer to the following table for carfilzomib dose levels when dose reductions are required 
during induction: 
 
Table 3: Dose Levels for Carfilzomib during Induction 
 
Dose Level 
Dose 
0* 
56 mg/m2  
 
-1 
45 mg/m2  
 
-2 
36 mg/m2  
-3 
27 mg/m2 
*Dose level 0 is the starting dose. 


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If dose reductions of carfilzomib beyond those levels listed in Table 3 are required, this agent 
should be permanently discontinued. 
6.3.4.1 Hematologic Toxicities 
NOTE: Thrombocytopenia has been transient and typically resolves during the week 
between treatments.  
 
Table 4: Dose Modifications for Hematologic Toxicities 
 
Toxicity 
Recommended Action 
ANC < 500/mm3 
• First occurrence: Hold dose; resume at same dose 
level once ANC recovers to ≥ 500/mm3  
• For any recurrence: hold dose; resume with dose 
reduced by 1 level once ANC recovers to ≥ 
500/mm3  
ANC < 500/mm3 and 
temperature >38.5ºC or 2 
consecutive readings of >38.0ºC 
for 2 hours  
• Hold dose; resume at same dose level once ANC 
returns to baseline and fever resolves 
 
Platelets < 10,000/mm3 or 
evidence of bleeding with 
thrombocytopenia 
• First occurrence: Hold dose; resume at same dose 
level once platelets recover to ≥ 10,000/mm3 and/or 
bleeding is controlled 
• For any recurrence, hold dose; resume with dose 
reduced by 1 level once platelets recover to ≥ 
10,000/mm3 and/or bleeding is controlled 
6.3.4.2 Non-Hematologic Toxicities 
Creatinine clearance (CrCl) changes associated with carfilzomib are mostly transient, 
reversible, and non-cumulative. 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 on Day 1, 8, and 15 during 
induction. Creatinine clearance should be calculated on Day 1 of each cycle. 
 
Carfilzomib treatment can cause nausea, vomiting, diarrhea, or constipation sometimes 
requiring the use of antiemetics or antidiarrheals.  Fluid and electrolyte replacement 
should be administered as clinically indicated to prevent dehydration.   
 
Subjects with active or suspected infection of any kind that require systemic treatment 
should not be dosed with carfilzomib until the infection has resolved and if being treated 
with an anti-infective(s), the course of antibiotics has been completed.  
 
Subjects with a history of HBV should be closely monitored for signs and symptoms of 
active HBV infection throughout treatment with carfilzomib, including the 30-day safety 
monitoring follow-up period. 
 


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Subjects receiving carfilzomib should be monitored for any new or worsening neurologic, 
cognitive or behavioral signs and symptoms that may be suggestive of Progressive 
Multifocal Leukoencephalopathy (PML) as part of the differential diagnosis of central 
nervous system disorders. If PML is suspected, subjects should be referred to a specialist 
and appropriate diagnostic testing should be initiated. If a PML diagnosis is confirmed, 
carfilzomib should be permanently discontinued. 
 
 
Table 5: Dose Modifications for Non-hematologic Toxicities 
 
Toxicity 
Recommended Action 
Serum creatinine ≥ 2 X baseline 
or CrCl < 15mL/min, or CrCl 
decreases to ≤ 50% of baseline, 
or need for hemodialysis 
(Creatinine clearance only 
applicable for Day 1 of each cycle) 
• Hold dose and continue monitoring renal function  
• If attributable to carfilzomib, resume with dose 
reduced by 1 level once renal function has 
recovered to within 25% of baseline 
• If not attributable to carfilzomib, dosing may be 
resumed at discretion of investigator 
• If on hemodialysis, administer the dose after the 
hemodialysis procedure 
In subjects who enroll with 
bilirubin and AST <ULN at 
baseline, and bilirubin increases 
to >1 to 3 x ULN and/or AST 
increases to >ULN  
• Hold dose; resume with dose reduced by 1 level 
once resolved or returned to baseline 
In subjects who enroll with 
bilirubin and/or AST >ULN at 
baseline, and bilirubin and/or 
AST increases by 1 grade  
• Hold dose; resume with dose reduced by 1 level 
once resolved or returned to baseline 
≥ Grade 3 non-hematologic 
toxicitya 
• Hold dose; resume with dose reduced by 1 level 
once resolved or returned to baseline 
 
If Posterior Reversible 
Encephalopathy Syndrome (PRES) 
is suspected  
• 
Hold dose; consider evaluation with neuroradiological 
imaging, specifically MRI, for onset of visual or 
neurological symptoms suggestive of PRES. 
• 
If confirmed, permanently discontinue carfilzomib 
• 
If the diagnosis of PRES is excluded and if clinically 
appropriate, restart dose administration 
• 
If PRES recurs, permanently discontinue carfilzomib   
If thrombotic microangiopathy 
(TMA) (TTP/HUS) is suspected 
• 
Hold dose; and manage per standard of care including 
plasma exchange as clinically appropriate 
• 
If TMA is confirmed and related to carfilzomib, 
permanently discontinue 
• 
If diagnosis is excluded, carfilzomib can be re started at 
the previous dose 
• 
If the condition recurs, permanently discontinue 
carfilzomib   


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Hypertensive Urgency/emergency 
(defined as sustained or persistent 
SBO ≥ 180 mmHg or DBP ≥ 
110mmHg) 
 
• 
Hold dose until resolution to baseline and restart at 1 
dose decrement  
If Progressive Multifocal 
Leukoencephalopathy (PML) is 
suspected 
• 
Withhold carfilzomib; refer promptly to a specialist; 
appropriate diagnostic testing should be initiated 
• 
If a diagnosis of PML is confirmed, permanently 
discontinue carfilzomib 
Active HBV reactivation 
• 
Withhold carfilzomib until the infection is adequately 
controlled. If the benefits outweigh the risks, 
carfilzomib may be resumed with concomitant 
prophylaxis as per local standard of care. Consult a liver 
disease specialist as clinically indicated. 
Active or suspected infection of any 
kind that requires systemic 
treatment 
• 
Hold carfilzomib until the infection has resolved and the 
course of antibiotics has been completed, if being 
treated with an anti-infective(s) 
aOther than nausea, vomiting or diarrhea that responds to supportive care within 7 days, or Grade 3 fatigue or 
asthenia that lasts <7 days  
 
6.4 
Elotuzumab 
6.4.1 Premedication 
6.4.1.1 In Subjects Without a Prior Infusion-Related Reaction (IRR): 
1. Dexamethasone (if not already scheduled as part of induction): 
a. 28 mg PO (between 3 - 24 hours prior to the start of elotuzumab infusion OR as a 
split dose of 12 mg 12 – 24 hours and 16mg 3 hours prior to elotuzumab) AND 
b. 8 mg IV (45-90 minutes prior to the start of infusion) 
2. Note: Every attempt should be made to administer 8 mg IV dose of dexamethasone prior 
to each elotuzumab dose; oral dexamethasone may be reduced per investigator discretion. 
On days when elotuzumab is administered, this is allowable after C1 of induction has 
completed without an infusion-related reaction.H1 blocker: diphenhydramine (25 - 50 mg 
PO or IV) or equivalent 45-90 minutes prior to the start of infusion. Note: The 
diphenhydramine dose can be decreased or discontinued per investigator discretion after 
at least (3) doses of elotuzumab have been infused without infusion-related reaction. 
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 
6.4.1.2 In Subjects with a Prior Infusion-Related Reaction (IRR): 
1. Dexamethasone: see Table 6 below 
2. H1 blocker: diphenhydramine 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: 1000 mg PO 45-90 mins prior to the start of infusion 
 


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Table 6: Dexamethasone Premedication for Subjects with a Prior IRR 
 
Prior IRR 
Grade 
Dexamethasone Dose and Schedule 
≤ 1 
28 mg PO (between 3 - 24 hours prior to the start of elotuzumab infusion OR as a 
split dose of 12 mg 12 – 24 hours and 16 mg 3 hours prior to elotuzumab) AND  
8 mg IV (45-90 minutes prior to the start of infusion) 
 
2 
28 mg PO (between 3 - 24 hours prior to the start of elotuzumab infusion OR as a 
split dose of 12 mg 12 – 24 hours and 16 mg 3 hours prior to elotuzumab) AND  
10 mg IVa (45-90 minutes prior to the start of infusion) 
 
3 or recurrent 
Grade 2 
8 mg 12 – 24 hours and 8 mg 3 hours prior to elotuzumab AND  
18 mg IVa (45-90 minutes prior to the start of infusion) 
 
4 
Elotuzumab should not be given, see Section 6.4.2 
a If dose modification of dexamethasone is required in a subject with a prior grade 2 or 3 IRR, the dose of 
dexamethasone to be administered on the day of elotuzumab administration (45 to 90 minutes prior) should not 
be < 8mg IV. 
6.4.2 Administration 
See Section 10.1.2 for preparation of elotuzumab for administration. 
 
See Section 6.4.4 for management of any IRR. See below for elotuzumab infusion rates: 
 
Table 7 Infusion Rate for Elotuzumab 10 mg/kg 
 
Cycle 1 Day 1(first dose) 
Cycle 1 Day 8 (second dose) 
Cycle 1 Days 15&22 
and all subsequent 
doses 
Time Interval 
Rate 
Time Interval 
Rate 
Rate 
0-30 min 
0.5mL/min 
0-30 min 
3 mL/min 
5 mL/min 
30-60 min 
1 mL/min 
30 min or more 
4 mL/min 
60 min or more 
2 mL/min 
- 
- 
 
 
The first dose of elotuzumab will be administered following premedication 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). 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). 
If the subject does not have an IRR within 30 minutes, escalate the infusion rate by 0.5 
mL per minute. If the subject still does not have an IRR 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 IRR were reported with the first elotuzumab infusion. If the subject does not 


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experience an IRR during the first 30 minutes of the second dose of elotuzumab, escalate 
the infusion rate by 1 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 IRR were reported with previous elotuzumab infusions. 
 
Elotuzumab administered at the 20 mg/kg dose should be infused as indicated below. 
Subjects who have escalated to 5mL/min at the 10 mg/kg dose must decrease the rate to 3 
mL/min at the first infusion at 20 mg/kg. The infusion rate may be increased in a 
stepwise fashion as described in Table 8 if no infusion reactions develop. 
 
 
Table 8 Infusion Rate for Elotuzumab 20 mg/kg 
 
Dose 1 (at 20 mg/kg) 
 
Dose 2 and all 
subsequent doses 
Time Interval 
Rate 
Rate 
0-30 min 
3 mL/min 
5 mL/min 
30 min or more 
4 mL/min 
 
6.4.3 Dose Delays for Elotuzumab 
No dose reductions of elotuzumab are allowed.  
 
Table 9: Allowed Delays of Elotuzumab Based on Schedule 
 
 
Frequency 
If Dose Delay: 
Dosing Resumption 
Induction 
Weekly 
>2 days, miss dose 
next planned weekly dosing 
date  
Induction 
and 
Maintenance  
Every 4 weeks  
>14 days, miss dose 
next planned dosing date  
 
6.4.3.1 Infusion-Related Reaction (IRR) 
 
Table 10: Management of Elotuzumab IRR 
 
Grade  
Management 
1 
No intervention required, however, increased monitoring is recommended. 
2 or 3a  
during infusion 
Interrupt infusion. The subject should be treated as clinically indicated with one 
or more of the following medications or interventions: antiemetics, 
antihistamines, analgesics, corticosteroids, leukotriene inhibitors, oxygen 
inhalation, epinephrine, bronchodilators, or other supportive measures as 
indicated. 


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Once the IRR 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 IRR occurred. If no recurrence of the IRR, the escalation regimen can 
be resumed. Subjects who experience an IRR 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 IRR 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. 
 
Subjects 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 IRR 
occurred.  If no grade ≥2 IRR recurs, the escalation regimen may be resumed, and 
the next infusion may be initiated as planned per regimen. 
 
2 or 3a  
after completion 
of infusion 
Treat the subject as clinically indicated with 1 or more of the following 
medications or interventions: diphenhydramine, acetaminophen, hydrocortisone, 
H2 inhibitor, leukotriene inhibitor, oxygen inhalation, epinephrine, bronchodia-
lators, or other supportive measures as indicated. 
 
Subjects 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 IRR 
occurred.  If no grade ≥2 IRR recurs, the escalation regimen may be resumed, and 
the next infusion may be initiated as planned per regimen. 
 
4a 
Permanently discontinue elotuzumab infusion. 
a In the event of a grade ≥ 3 IRR, every attempt will be made to draw 15mL of blood, as soon as reasonably 
possible after the reaction if the subject is still in the infusion clinic. See Section 8.8.2 for additional information. 
 
 
6.4.3.2 Other Elotuzumab-Related Toxicities (Non-IRR) 
Delay elotuzumab for any  grade 3 toxicity (non-IRR) considered at least possibly 
related to elotuzumab. Treatment may resume once levels resume to baseline or  grade 
1. 
6.5 
Lenalidomide  
6.5.1 Administration 
Lenalidomide is self-administered and should be taken orally at about the same time each 
day (at bedtime) with water. It may be taken on a full or empty stomach. Subjects should 
not break, chew or open capsules. Missed doses of lenalidomide will not be made up. If a 
dose of lenalidomide is missed and it has been <12 hours since the subject’s regular 
dosing time, the subject should take the dose. If it has been ≥ 12 hours, the subject should 
skip that dose. The subject should not double up on the next dose.  
 


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6.5.2 Dose Modification for Lenalidomide-Related Toxicities 
 
Refer to the following table for lenalidomide dose levels when dose reductions are required 
during induction or maintenance: 
 
Table 11: Dose Levels for Lenalidomide* 
 
Dose Level 
Dose 
Schedule 
0** 
25 mg  
 
D1-21 
-1 
15mg  
 
D1-21 
-2 
10mg  
 
D1-21 
-3 
5mg  
 
D1-21 
-4 
2.5mg  
 
D1-21 
-5 
2.5mg  
 
Every other day during 
D1-21 
 
*If dose reduction required due to renal dysfunction, see Section 6.5.2.2 Table 11.  
**Dose level 0 is the starting dose.  
6.5.2.1 Hematologic Toxicities 
 
Table 12: Dose Modifications for Hematologic Toxicities 
 
 
Toxicity 
Recommended Action 
ANC < 1000/mm3 
• Interrupt lenalidomide 
• Resume at same dose level once ANC recovers to ≥ 
1000/mm3  
• For any recurrence, interrupt lenalidomide; resume 
with dose reduced by 1 level once ANC recovers to 
≥ 1000/mm3  
Platelets < 30,000/mm3 or 
evidence of bleeding with 
thrombocytopenia 
• Interrupt lenalidomide 
• Resume with dose reduced by 1 level once platelet 
count recovers to ≥ 30,000/mm3  
• For any recurrence, interrupt lenalidomide; resume 
with dose reduced by 1 level once platelets recover 
to ≥ 30,000/mm3 


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6.5.2.2 Dosing in Renal Impairment 
Because lenalidomide is primarily excreted unchanged by the kidney, adjustments to the 
dose of lenalidomide are recommended in subjects with renal impairment. The 
recommended doses for subjects with multiple myeloma and renal impairment are shown 
in the table below.  
 
Table 13: Dose Modifications for Renal Impairment 
Dose modifications related to creatinine clearance only apply to Day 1 of each cycle. 
 
 
 
Toxicity 
Recommended Action 
CrCl 30 to 50 mL/min 
• Ensure daily dose is no higher than 
10mg every 24 hours 
CrCl <30mL/min and not requiring dialysis 
• Ensure dose is no higher than 15 mg, 
and reduce frequency to every 48 
hours 
CrCl <30mL/min requiring dialysis 
• Ensure daily dose is no higher than 5 
mg every 24 hours; on dialysis days, 
administer the dose following dialysis. 
6.5.2.3 Other Non-Specified Non-Hematologic Toxicities 
 
Table 14: Dose Modifications for Non-Hematologic Toxicities 
 
Toxicity 
Recommended Action 
Other ≥ grade 3 non-hematologic 
toxicitya 
• Hold dose; resume with dose reduced by 1 level 
once resolved to ≤ grade 2 
aOther than nausea, vomiting or diarrhea that responds to supportive care within 7 days, or grade 3 fatigue or 
asthenia that lasts <7 days  
6.6 
Dexamethasone  
6.6.1 Administration 
For induction, the dexamethasone total oral dose of 28 mg may be given 3-24 hours prior 
to start of elotuzumab OR as a split dose of 12 mg 12-24 hours and 16 mg 3 hours prior 
to elotuzumab at the discretion of the investigator.  Forty-five to 90 minutes prior to 
elotuzumab infusion, administer 8 mg dexamethasone IV. Oral dexamethasone may be 
reduced per investigator discretion. On days when elotuzumab is administered, this is 
allowable after C1 of induction has completed without an infusion-related reaction. 
During maintenance when dexamethasone is administered as premedication only, any 
dose modifications required should be made at the discretion of the investigator. 
However, when using as a premedication, every attempt should be made to maintain the 8 
mg dexamethasone IV. 


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Refer to the following table for dexamethasone dose levels when dose reductions are 
required during induction: 
 
Table 15: Dose Levels for Dexamethasone during Induction on Elotuzumab Dosing Days 
 
Dose Level 
PO 
IV 
0 
 
28 mg 
8 mg 
-1 
12 mg 
8 mg 
-2 
0 mg 
8 mg 
 
If dose reductions of dexamethasone beyond those levels listed in Table 13, this agent 
should be permanently discontinued. 
 
Table 16: Dose Levels for Dexamethasone during Induction on NON-Elotuzumab Dosing 
Days 
 
Dose Level 
PO 
0 
 
40 mg 
-1 
20 mg 
-2 
12 mg 
 
6.6.2 Dose Modifications for Dexamethasone-Related Toxicities 
If a dose of dexamethasone is missed, the subject should not take an additional dose, but 
should take the next usual prescribed dose.  
 
Oral dexamethasone may be reduced per investigator discretion. On days when 
elotuzumab is administered, this is allowable after C1 of induction has completed without 
an infusion-related reaction. 
 
 
Table 17: Dose Modifications for non-Hematologic Toxicities 
 
Toxicity 
Recommendation Action 
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. 
 
≥Grade 3 (requiring hospitalization or surgery 
 
Hold dexamethasone until symptoms adequately 
controlled. Restart dexamethasone reduced by 1 dose 
level; consider concurrent therapy with H2 blockers, 
sucralfate, or omeprazole. If symptoms persist 


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despite above measures, discontinue dexamethasone 
permanently. 
Acute pancreatitis 
Discontinue dexamethasone permanently. 
Edema ≥ Grade 3 (limiting function and 
unresponsive to therapy or anasarca) 
Diuretics as needed, and restart dexamethasone 
reduced by 1 dose level; if edema persists despite 
above measures, decrease dose another level. 
Discontinue dexamethasone permanently if 
symptoms persist despite second reduction. 
Confusion or mood alteration ≥ Grade 2 
(interfering with function +/– interfering with 
activities of daily living) 
Hold dexamethasone until symptoms resolve. Restart 
dexamethasone reduced by 1 dose level. If symptoms 
persist despite above measures, reduce by another 
dose level. 
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. 
Hyperglycemia ≥ Grade 3 
Treatment with insulin or other hypoglycemic agents 
as needed. If uncontrolled despite above measures, 
decrease dose by 1 dose level until levels are 
satisfactory. 
Insomnia ≥ Grade 2 
Hold dexamethasone until symptoms resolve. Restart 
dexamethasone reduced by 1 dose level once 
symptoms resolve. 
Other non-hematologic toxicity ≥ Grade 3 felt 
related to dexamethasonea 
Hold dexamethasone dose. Resume dexamethasone 
reduced by 1 dose level when toxicity has resolved to 
≤Grade 2 or to baseline. If toxicity recurs, 
discontinue dexamethasone permanently. 
aOther than nausea, vomiting or diarrhea that responds to supportive care within 7 days, or Grade 3 fatigue or 
asthenia that was present at baseline or that lasts <7 days 
6.7 
Supportive Care 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Subjects may receive palliative radiation at the discretion of the Sponsor-
Investigator. 
6.8 
Concomitant Medication 
6.8.1 Recommended Medications 
6.8.1.1 Bisphosphonates 
For subjects who have not previously received bisphosphonates, bisphosphonates are 
recommended for all subjects. Bisphosphonate therapy is recommended to be continued per 
treatment guidelines. In addition, denosumab use is also permitted. 
6.8.1.2 Allopurinol 
It is recommended that subjects at high risk for TLS (i.e., those with a high tumor burden, high 
LDH and/or high uric acid level before the start of treatment) be treated prophylactically in 
accordance with local standards including allopurinol 300 mg daily. 


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6.8.1.3 Anti-Viral 
Acyclovir or equivalent antiviral should be given to all subjects to decrease the risk of herpes 
zoster reactivation, per institutional prophylaxis guidelines, unless contraindicated.  
 
Prophylaxis with antivirals should be considered in subjects who are carriers of HBV. 
 
6.8.1.4 Thromboprophylaxis 
Thromboprophylaxis is recommended for all subjects receiving the combination of carfilzomib, 
lenalidomide and dexamethasone. The regimen of thromboprophylaxis should be based on an 
assessment of the subject’s underlying risks. Instruct subjects to report immediately any signs 
and symptoms suggestive of thrombotic events.  
6.8.2 Prohibited Medications 
Concomitant administration of investigational agents, other than those mandated by the protocol, 
are prohibited.  
 
No investigational or commercial agents or therapies other than those described may be 
administered with the intent to treat the subject’s malignancy. 
6.8.3 Permitted Medications 
Subjects may receive antiemetics and antidiarrheal agents as necessary. Myeloid growth factors 
may be used if neutropenia occurs but should not be given prophylactically. Subjects may 
receive platelet transfusions if clinically indicated in accordance with institutional guidelines 
Subjects should have anemia treated in accordance with the institutional guidelines (however, 
see Section 6.8.3.1).  
 
All other treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. 
6.8.3.1 Precautionary Medications 
If an erythropoietic stimulating agents (ESAs) is given for anemia, keep in mind that there is an 
increased risk of thrombosis with lenalidomide and carfilzomib. Include all concomitant 
medications that are not specifically prohibited but require additional monitoring during study 
treatment. 
 
  
 
 
 
 
 
 
 
 


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7. STUDY CALENDAR 
Study Procedures 
Screening1 
Induction 
Cycles 1-22 
 
Induction Cycles 3-42 
Maintenance 
Cycles 1+4 
Safety 
Follow-up 
Visit5 
 Follow-up6 
Study Day 
D11 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
D13 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Physical exam7,22 
X 
X 
 
 
 
X 
 
 
 
X 
X 
ECOG Performance status 
22 
X 
X 
 
 
 
X 
 
 
 
X 
X 
Vital signs8 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
ECG 
X 
X 
 
 
 
X 
 
 
 
 
X 
ECHO or MUGA 
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis B virus (HBV) 
serology20 
X 
X 
Subjects with unknown HBV status who are currently receiving treatment with carfilzomib should be tested for 
HBV infection 
 
HBV DNA testing21 
X 
X 
Only required in subjects receiving carfilzomib not previously tested in screening who have serologic evidence of 
resolved HBV infection 
 
Serum chemistries9 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
CBCD10 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Pregnancy test11  
X 
See footnote #11 
 
AEs & concomitant meds 
X 
Monitor continuously (see Section 12.3 for timing of AE/SAE collection) 
Serum beta2-microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
Blood and urine for disease 
evaluation12 
X 
X 
 
 
 
X 
 
 
 
X3 
 
Bone marrow aspirate and 
biopsy13 
X 
 
 
 
 
 
 
 
 
X 
Post-induction 
and CR 
 
Skeletal Survey14 
X 
As clinically indicated 
 
Assess extramedullary 
plasmacytomas15  
X 
Assess at CR and/or if clinically indicated 
 
Carfilzomib16 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
Lenalidomide 
 
Days 1-21 (oral) each cycle 
 
Days 1-21 (oral) each cycle 
 
Days 1-21 (oral) 
each cycle 
 
Dexamethasone17 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Elotuzumab18 
 
X 
X 
X 
X 
X 
 
 
 
X 
 


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Blood sample for 
correlatives19 
 
X 
 
 
 
X 
 
 
 
X 
 
Key to Footnotes 
1 Within 28 days prior to induction cycle 1 day 1 (C1D1) unless otherwise noted; if screening hematology and serum chemistries were performed 
within 7 days of induction C1D1, these do not need to be repeated C1D1 of induction; if screening ECG was performed within 14 days of 
induction C1D1, an ECG does not need to be repeated C1D1 of induction. 
2 A window of +/- 2 days will be applied to all induction treatment study visits (includes treatment and required procedures). Every effort should 
be made to maintain consecutive dosing days.  
3 The post-induction disease evaluation (blood and urine collection and bone marrow biopsy/aspirate) should occur within 7 days prior to treatment 
on C1D1 of maintenance. The primary endpoint (VGPR or better post induction) will be assessed at this post-induction disease evaluation. See 
Section 13.1 for details on efficacy evaluations and note that all response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive 
assessments. 
4A window of +/- 14 days will be applied to all maintenance study visits (includes treatment and required procedures). 
5 This visit should occur in subjects 30 days (+/-10 days) after treatment stops for whatever reason (toxicity, progression, or at discretion of the 
investigator). NOTE: subjects who have ongoing Grade 4 AE or SAE at the time of the Safety Follow-up Visit will continue to be followed until 
the event is resolved or deemed irreversible by the investigator. 
6 For subjects who discontinue study treatment before relapse or PD, disease evaluations should continue to be performed until relapse or 
confirmed PD, death, start of a new anticancer treatment, withdrawal of consent to study participation, or end of the study, whichever occurs first. 
The schedule for disease evaluation should follow the schedule outlined during maintenance. Survival follow-up will occur every 3 months (+/- 30 
days) from the last administration of protocol-directed therapy or until death, and may be conducted via telephone. Any second primary 
malignancies discovered during long-term follow-up will be documented.  
7 Complete physical exam at screening with evaluation by body system, including height, weight and neurologic exam to detect peripheral 
neuropathy. Thereafter symptom-directed physical exam (to include weight) only. Subjects should also be monitored for second primary 
malignancies. If a subject’s weight changes by more than 10% from induction C1D1, the dose of carfilzomib and elotuzumab should be re-
calculated. This re-calculated weight should be used as the new baseline weight.  
8 Vital signs (to include temperature, heart rate, blood pressure and respiratory rate) should be recorded at screening, before each elotuzumab 
infusion, and at the Safety Follow-up Visit. 
9 Serum chemistries: BUN, creatinine, (with calculated creatinine clearance at screening and on Day 1 of each cycle), glucose, uric acid, calcium, 
chloride, phosphorus, potassium, sodium, LDH, albumin, total protein, magnesium, total bilirubin, alkaline phosphatase, AST and ALT. NOTE: 
calcium should also be corrected for albumin. Magnesium testing NOT required on C1D2  
10 CBCD: complete blood count with differential and platelets. 
11 If the screening serum B-HCG in FCBP is done within 24 hours prior to induction C1D1, it does not need to be repeated on C1D1. Pregnancy 
testing (serum or urine) must be repeated once a week (D1, 8, 15, 22) in induction cycle 1, and then monthly (D1 of each cycle) for subsequent 
cycles in FCBP. 
12 Tests to include: serum quantitative immunoglobulins (QIg; including IgA, IgM, IgG, IgD, IgE), serum protein electrophoresis (SPEP), urine 
protein electrophoresis (UPEP; 24-hr urine sample required), serum and urine immunofixation, and serum free light chain (FLC). If screening tests 
were performed within 14 days of induction C1D1, these do not need to be repeated C1D1 of induction. Testing for IgD and IgE will only be 


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performed for subjects with IgD and IgE-type myeloma. Serum FLC to be performed on D1 of each cycle for subjects with light chain only 
disease and for subjects where a CR is suspected or maintained. After screening assessments, subjects without measurable urine M-Protein at 
baseline will not be required to have UPEP or urine immunofixation repeated at subsequent disease assessment time-points, unless clinically 
indicated. Starting at maintenance cycle 14, disease evaluations should only be collected every 2 cycles (i.e., cycle 14, 16, 18, etc.) 
13 Bone marrow aspirate and biopsy collected for disease assessment and correlative analyses at screening (pre-induction), post-induction (within 7 
days prior to treatment on C1D1 of maintenance) and to confirm a CR. A bone marrow biopsy and aspirate will also be collected at 
relapse/progression for disease assessment and correlative studies at the discretion of the investigator. During maintenance, bone marrow biopsies 
and aspirates will be collected every 6 months (+/- 30 days) for disease evaluation per standard of care. See Section 8.8.3 for additional details.  
14 Acceptable for screening if performed as part of standard of care within 42 days prior to induction C1D1. 
15 Assess extramedullary plasmacytomas at screening using PET/CT and/or Whole Body (WB)-MRI for subjects with a history of plasmacytomas 
or if clinically indicated. Acceptable for screening if performed as part of standard of care within 42 days prior to induction C1D1.  
16 See Section 6.3 for required hydration and additional information regarding cycle 1 dosing. 
17 See Section 5.1 for dosing information. For maintenance, dexamethasone is given as a premedication for elotuzumab, but is not considered part 
of the regimen. 
18 See Section  6.4.1 for required premedication. Any time a grade 3 or higher IRR is observed during the study, every attempt should be made to 
draw an unscheduled blood sample (15) as soon as possible after the reaction for potential immune response analysis (see Section 6.4.4, Table 8) 
19 Peripheral blood (total of 15mL) will be collected before treatment on D1 of each induction cycle, before treatment on D1 of maintenance cycle 
1, cycle 3 and then every third maintenance cycle thereafter (i.e., cycle 6, 9, etc.), and at progression/relapse. See Section 8.8.1 for detailed 
information. 
20 Local testing for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (Anti-HBs), and hepatitis B core antibody (Anti-HBc) for all 
subjects in screening. Subjects not previously tested for HBV at screening with unknown HBV status currently receiving treatment with 
carfilzomib should be tested for HBV. For subjects currently receiving treatment with carfilzomib, every effort should be made to perform the 
HBV testing within 8 weeks of IRB approval Version 4 of protocol. 
21 For subjects with serologic evidence of resolved HBV infection (i.e. positive anti-HBs or positive anti-HBc) at Screening or for subjects with 
unknown HBV status currently on carfilzomib tested for HBV per Footnote #21. HBV DNA testing by PCR must be performed locally. Subjects 
with serologic findings suggestive of HBV vaccination (Anti-HBs positivity as the only serologic marker) and a known history of prior HBV 
vaccination do not need to be tested for HBV DNA by PCR. 
22 For office visits required during the COVID-19 pandemic, virtual visits will be allowed per investigator discretion starting with Cycle 2 Day 1 
induction.  This includes physical exam and performance status.


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8. DETAILS ON STUDY PROCEDURES 
Please also refer to the Study Calendar in Section 7.  
8.1 
Screening Procedures 
• Informed Consent: No protocol-related assessments may be performed prior to 
obtaining informed consent.  
• Medical History: A complete relevant medical history should be obtained, including 
documentation of any clinically significant pre-existing conditions.  
• Physical Examination: Evaluation by body system, including height, weight and 
neurologic exam to detect peripheral neuropathy.  
• Performance Status: ECOG performance status 
• Vital Signs: Vital signs should include temperature, heart rate, blood pressure and 
respiratory rate.  
• Cardiac Evaluation: ECG and MUGA or ECHO 
• Laboratory Assessments: 
o Serum chemistries: BUN, creatinine, (with calculated creatinine clearance on Day 
1 of each cycle), glucose, uric acid, calcium, chloride, phosphorus, potassium, 
sodium, LDH, albumin, total protein, magnesium, total bilirubin, alkaline 
phosphatase, AST and ALT. NOTE: calcium should also be corrected for 
albumin. 
o CBCD: complete blood count with differential and platelets 
o Serum pregnancy test for FCBP 
o HBV Serology: hepatitis B surface antigen (HBsAg), hepatitis B surface antibody 
(Anti-HBs), and hepatitis B core antibody. 
o HBV DNA testing (by PCR):  only for subjects positive for Anti-HBc or Anti-
HBs  
• Baseline Symptoms and Toxicities: Document pre-existing symptoms and any toxicities 
present (per NCI CTCAEv4.03) at the time of informed consent and prior to the first dose 
of study treatment 
• Concomitant Medications: Document any concomitant medications; concomitant 
medications include but are not limited to over the counter medications, supplements, and 
vitamins. 
• Disease Evaluation: 
o Serum beta2-microglobulin 
o Blood and urine tests: Serum QIg (including IgA, IgM, IgG, IgD, IgE), SPEP, 
UPEP (24-hr urine sample required), serum and urine immunofixation, and serum 
FLC. Testing for IgD and IgE will only be performed for subjects with IgD and 
IgE-type myeloma.  
o Bone marrow aspirate and biopsy (see Section 8.8.3). 
o Skeletal Survey 
o Assess extramedullary plasmacytomas: PET/CT and/or Whole Body (WB)-MRI; 
performed for subjects with history of plasmacytomas or if clinically indicated 


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8.2 
Induction Procedures 
NOTE: The sections below are focused on study procedures, and not drug administration 
Section 8.2.1 covers the non-laboratory assessments that are to be performed at each study visit. 
NOTE: serum or urine pregnancy testing is required weekly only during cycle 1 of induction in 
FCBP. Thereafter it is required on day 1 of each cycle. 
 
NOTE: Subjects with unknown HBV status not previously tested in screening and receiving 
carfilzomib should be tested for HBV as indicated in Section 7. 
8.2.1 Throughout the Induction Period 
• AEs: Record all AEs per the NCI CTCAEv4.03.   
• Concomitant Medications: Record any changes in concomitant medications. 
Concomitant medications include but are not limited to over the counter medications, 
supplements, and vitamins. 
• Disease Evaluation: 
o Skeletal Survey (if clinically indicated) 
o Assess extramedullary plasmacytomas (if clinically indicated): PET/CT and/or 
WB-MRI 
8.2.2 Day 1 Cycles 1-4 (unless otherwise noted) 
• Physical Exam: Symptom-directed physical exam (to include weight). Subjects should 
also be monitored for second primary malignancies. If a subject’s weight changes by 
more than 10% from induction C1D1, the dose of carfilzomib and elotuzumab should be 
re-calculated.   This re-calculated weight should be used as the new baseline weight. For 
office visits required during the COVID-19 pandemic, virtual visits will be allowed per 
investigator discretion starting with Cycle 2 Day 1 induction. 
• Performance Status: ECOG performance status. For required time-points during the 
COVID-19 pandemic, performance status may be performed virtually if the office visit is 
being performed virtually (starting with Cycle 2 Day 1 induction) 
• Vital Signs: Vital signs should include temperature, heart rate, blood pressure and 
respiratory rate. Measure prior to elotuzumab infusion. 
• Cardiac Evaluation: ECG 
• Laboratory Assessments 
o Serum chemistries: BUN, creatinine, (with calculated creatinine clearance on Day 
1 of each cycle), glucose, uric acid, calcium, chloride, phosphorus, potassium, 
sodium, LDH, albumin, total protein, magnesium, total bilirubin, alkaline 
phosphatase, AST and ALT. NOTE: calcium should also be corrected for 
albumin. 
o CBCD: complete blood count with differential and platelets 
o Pregnancy test (serum or urine) in FCBP; NOTE: if screening pregnancy was 
done within 24 hours of C1D1 it does not to be repeated on C1D1. 
  
• Disease Evaluation: 
o Blood and urine tests: Serum QIg (including IgA, IgM, IgG, IgD, IgE), SPEP, 
UPEP (24-hr urine sample required), serum and urine immunofixation, and serum 
FLC. Testing for IgD and IgE will only be performed for subjects with IgD and 


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IgE-type myeloma. Serum FLC to be performed for subjects with light chain only 
disease and for subjects where a CR is suspected or maintained. Subjects without 
measurable urine M-Protein at baseline will not be required to have UPEP or 
urine immunofixation repeated at subsequent disease assessment time-points, 
unless clinically indicated.  
 
• Blood sample for correlatives: See Section 8.8.1. 
 
8.2.3 Day 8, 15 and 22 Cycles 1-2 (unless otherwise noted) 
• Vital Signs: Vital signs should include temperature, heart rate, blood pressure and 
respiratory rate. Measure prior to elotuzumab infusion. Cycles 1-2 only 
• Laboratory Assessments 
o Serum chemistries: BUN, creatinine, glucose, uric acid, calcium, chloride, 
phosphorus, potassium, sodium, LDH, albumin, total protein, magnesium, total 
bilirubin, alkaline phosphatase, AST and ALT. NOTE: calcium should also be 
corrected for albumin. 
o CBCD: complete blood count with differential and platelets 
o Pregnancy test (serum or urine) in FCBP: Cycle 1 only 
8.3 
Maintenance Procedures 
NOTE: Subjects with unknown HBV status not previously tested in screening and receiving 
carfilzomib should be tested for HBV as indicated in Section 7. 
8.3.1 Throughout the Maintenance Period 
• AEs: Record all AEs per the NCI CTCAEv4.03.   
• Concomitant Medications: Record any changes in concomitant medications. 
Concomitant medications include but are not limited to over the counter medications, 
supplements, and vitamins. 
• Disease Evaluation: 
o Skeletal Survey (if clinically indicated) 
o Assess extramedullary plasmacytomas (if clinically indicated): PET/CT and/or 
WB-MRI 
8.3.2 Day 1 Cycles 1+ (unless otherwise noted) 
• Physical Exam: Symptom-directed physical exam (to include weight). Subjects should 
also be monitored for second primary malignancies. If a subject’s weight changes by 
more than 10% from induction C1D1, the dose of elotuzumab should be re-calculated.   
This re-calculated weight should be used as the new baseline weight. For office visits 
required during the COVID-19 pandemic, virtual visits will be allowed per investigator 
discretion. 
• Performance Status: ECOG performance status. For required time-points during the 
COVID-19 pandemic, performance status may be performed virtually if the office visit is 
being performed virtually  


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• Vital Signs: Vital signs should include temperature, heart rate, blood pressure and 
respiratory rate. Measure prior to elotuzumab infusion. 
• Laboratory Assessments 
o Serum chemistries: BUN, creatinine, (with calculated creatinine clearance on Day 
1 of each cycle), glucose, uric acid, calcium, chloride, phosphorus, potassium, 
sodium, LDH, albumin, total protein, magnesium, total bilirubin, alkaline 
phosphatase, AST and ALT. NOTE: calcium should also be corrected for 
albumin. 
o CBCD: complete blood count with differential and platelets 
o Pregnancy test (serum or urine) in FCBP. 
• Disease Evaluation: 
o Blood and urine tests: Serum QIg (including IgA, IgM, IgG, IgD, IgE), SPEP, 
UPEP (24-hr urine sample required), serum and urine immunofixation, and serum 
FLC. Testing for IgD and IgE will only be performed for subjects with IgD and 
IgE-type myeloma. Serum FLC to be performed for subjects with light chain only 
disease and for subjects where a CR is suspected or maintained.  Subjects without 
measurable urine M-Protein at baseline will not be required to have UPEP or 
urine immunofixation repeated at subsequent disease assessment time-points, 
unless clinically indicated.  
o Bone marrow aspirate and biopsy (see Section  8.8.3): Collected post-induction 
(within 7 days prior to treatment on C1D1 of maintenance) 
o Blood sample for correlatives: C1D1, C3D1, and then every third maintenance 
cycle thereafter (C6, C9, etc) See Section 8.8.1. 
8.3.3 Every 6 months for Cycles 1-n 
• Disease Evaluation: 
o Bone marrow aspirate and biopsy (see Sections 7 and 8.8.3 ): Disease evaluation 
per standard of care 
8.4 
Time of CR 
• Disease Evaluation: 
o Bone marrow aspirate and biopsy (see Section 8.8.3) 
o Assess extramedullary plasmacytomas: PET/CT and/or WB-MRI 
8.5 
Time of Disease Relapse/Progression 
• Disease Evaluation: 
o Bone marrow aspirate and biopsy (see Section 8.8.3): At discretion of investigator 
• Blood sample for correlatives: See Section 8.8.1. 
8.6 
Safety Follow-up Visit 
This visit should occur in subjects 30 days (+/-10 days) after treatment stops for whatever reason 
(toxicity, progression, or at discretion of the investigator). NOTE: this 30-day time period 
applies even if the subject is taken off study treatment and begins new anti-cancer treatment 
during this time period. 
 


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• Physical Exam: Symptom-directed physical exam (to include weight). Subjects should 
also be monitored for second primary malignancies.  For office visits required during the 
COVID-19 pandemic, virtual visits will be allowed per investigator discretion  
• Performance Status: ECOG performance status. For required time-points during the 
COVID-19 pandemic, performance status may be performed virtually if the office visit is 
being performed virtually  
• Vital Signs: Vital signs should include temperature, heart rate, blood pressure and 
respiratory rate.  
• Cardiac Evaluation: ECG 
• Laboratory Assessments 
o Serum chemistries: BUN, creatinine, glucose, uric acid, calcium, chloride, 
phosphorus, potassium, sodium, LDH, albumin, total protein, magnesium, total 
bilirubin, alkaline phosphatase, AST and ALT. NOTE: calcium should also be 
corrected for albumin. 
o CBCD: complete blood count with differential and platelets 
• AEs: Record all AEs; subjects who have ongoing Grade 4 AE or SAE at the time of 
discontinuation from treatment, and those who come off treatment prematurely for safety 
reasons will continue to be followed until the event is resolved or deemed irreversible by 
the investigator.  
• Concomitant Medications: Record any changes in concomitant medications. 
Concomitant medications include but are not limited to over the counter medications, 
supplements, and vitamins. 
 
8.7 
Follow-up  
For subjects who discontinue study treatment before relapse or PD, disease evaluations should 
continue to be performed until relapse or confirmed PD, death, start of a new anticancer 
treatment, withdrawal of consent to study participation, or until the criteria for the final analysis 
are met (Section 14.5.1) whichever occurs first. The schedule for disease evaluation should 
follow the schedule outlined during maintenance. Survival follow-up will occur every 3 months 
(+/- 30 days) from the last administration of protocol-directed therapy until death, lost to follow-
up, or until the criteria for the final analysis are met (Section 14.5.1) and may be conducted via 
telephone. Any second primary malignancies discovered during long-term follow-up will be 
documented. Follow-up clinical information may also be obtained through chart reviews or other 
data sources (e.g. death registries).   
 
The investigator is responsible for following the subject during the required follow-up period 
even if the subject lives elsewhere or has been released from his or her care and is being treated 
at another institution. 
 
If the subject cannot be contacted following three attempted telephone calls over a period of 10 
business days, the subject will be contacted in writing. Lost to follow-up is defined as four 
consecutive unsuccessful documented attempts (telephone and written) to contact the subject. 
 
NOTE: in the event the criteria for the final analysis are met, and there are subjects who have 
not yet been discontinued from study treatment, subjects in follow-up will continue to be 


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followed until all subjects have discontinued study treatment and completed the Safety Follow-
up Visit (see above). 
8.8 
Biospecimen Correlative Studies 
8.8.1 Blood Samples for Correlative Studies  
Blood (15mL) will be collected at each time-point for correlatives (characterization of 
immune cell subsets and flow cytometry) as outlined in the Study Calendar in Section 7. 
Comprehensive peripheral immune profiling techniques will be employed including: 
• Soluble immune analytes measurements combining cytokine, chemokine and growth 
factor profiling [15 cytokines (IL-1b. IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-12p70, 
IL-13, IL-15, IL-17, IL-22, TNFa, INFg); 5 chemokines (IL-8, MIP1a, MIP1b, MCP1, 
IP10); and 5 growth factors (VEGF, FGF, PDGF, EGF, HGF) together with 3 markers of 
hypoxia and bone remodeling (IGF-1, HIF, RANK-L)]. 
• Flow cytometry-based enumeration and characterization of circulating effector and 
functional memory T cell mobilization (T helper and cytotoxic T cell subsets) [23] as 
well as γδ T cells, NK cells, and inducible NK-T activation [23, 24]. 
• Circulating T cells (αβ and γδ subsets) clonal expansion assessment TCR-VD(J) 
rearrangement sequencing. 
• Immunoseq® T cell clonal expansion measurement: DNA will be extracted from PBMCs 
for Immunoseq® sequencing of TCR’s CRD3 region to be performed on a NGS Illumina® 
platform.  
8.8.2 Blood Samples for Exploration of IRR 
For subjects potentially experiencing grade ≥3 infusion-related adverse reaction 
(uniphasic or biphasic), we will conduct immune response analyses (with a particular 
emphasis on NK or T cell activation and polarization). In the event of a grade ≥ 3 IRR, 
every attempt will be made to drawa total of 15 mL of blood for immune response 
analyses, as soon as reasonably possible after the reaction if the subject is still in the 
infusion clinic. 
8.8.3 Bone Marrow Samples 
Bone marrow aspirates/biopsies will be collected at the time-points indicated in the Study 
Calendar in Section 7. In addition to routine clinical evaluation conducted on these 
samples (including flow cytometry, conventional cytogenetics and fluorescence in situ 
hybridization [FISH]), samples will also be evaluated for the following correlative 
studies: 
• 
Flow cytometry-based tumor microenvironment analysis: MRD status will be assessed 
for this study in part using a flow cytometry-based MM MRD assay developed by the 
Euroflow consortium utilizing 10 markers (CD138, CD38, CD45, CD19 CD56, CD27, 
CD117, CD81, κ / λ free light chains) to identify plasma cells, differentiate normal from 
MM-PC and well as PC clonality. Using alternative gating strategy, this flow cytometry 
panel will also allow identification and characterization of NK, T, B and myeloid cell 
subsets.  
• MRD assessment by NGS: MRD will be assessed via NGS which utilizes MM cell DNA 
from bone marrow samples. 


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• Micro-array / global gene expression analysis of isolated plasma cells.  
• Clonal evolution of PC (and MM-PC subpopulation) IgG VJ rearrangement sequencing. 
• Immunoseq® T cell clonal expansion measurement: DNA will be extracted from CD138- 
(plasma cell depleted) bone marrow fraction for Immunoseq® sequencing of TCR’s 
CRD3 region to be performed on a NGS Illumina® platform.  
 
In addition to the volumes required for routine clinical evaluation (if applicable), a 
minimum of9mL of bone marrow aspirate (1st pull or 1st technical pull after needle 
repositioning) will be collected for MRD assessment by flow cytometry and NGS. 
An additional 10mL of bone marrow aspirate will be collected for CD138+ plasma cell 
isolation (B cell receptor sequencing). 
8.8.4 Storage of Biospecimens 
Any specimens remaining after biospecimen-based studies are complete will be stored in 
the Atrium Health (AH) Immune Monitoring Core Laboratory for follow-up/validation 
studies. 
 
9. DISCONTINUATION FROM TREATMENT AND STUDY 
WITHDRAWAL 
9.1 
Treatment Discontinuation Criteria 
Study treatment will continue until one of the following criteria applies: 
• Disease relapse or progression 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Subject decides to withdraw study consent  
• General or specific changes in the subject’s condition render the subject unacceptable for 
further treatment in the judgment of the investigator 
• Study subject becomes pregnant 
 
NOTE: In the event the criteria for the final analysis are met, and there are subjects who 
have not yet been discontinued from study treatment, they will continue to receive therapy 
until one of the above criteria applies. 
9.2 
Off Study 
When subjects are removed from the study, the reason for study removal and date the 
subject was removed should be documented. Reasons a subject may be removed from 
study include, but are not limited to: 
• Subject non-compliance with study participation, in the opinion of the investigator 
• The subject or legal representative (such as a parent or legal guardian) withdraws study 
consent 
• The subject is lost to follow-up 
• Study completion 
• Investigator’s decision to withdraw the subject 


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• Subject death. 
 
Subjects that are Off Study will not participate in any study related procedures, including 
data collection. 
10. DRUG INFORMATION 
10.1 Elotuzumab 
10.1.1 Supplier/How Supplied  
Elotuzumab will be supplied free of charge to study subjects by the manufacturer, BMS 
as Elotuzumab for Injection, 400 mg/vials.  
10.1.2 Preparation  
The instructions will be found in the package insert and Investigator’s Brochure.  
 
10.1.3 Administration 
See Section 6.4.2 for details.   
 
10.1.4 Storage and Stability 
The instructions will be found in the BMS Investigator’s Brochure.  
 
10.1.5 Handling  
Elotuzumab should be handled using standard precautions for the safe handling of 
antineoplastic agents. Latex gloves are recommended. It must be dispensed only from 
official study sites by authorized personnel according to local regulations, and stored in a 
secure area according to local regulations.  It is the responsibility of the investigator to 
ensure that study drug is only dispensed to eligible study subjects. 
 
 
10.1.6 Accountability  
An adequate record of receipt, distribution, destruction, or return of this agent must be 
kept in the form of a Drug Accountability Form. The investigator, or responsible party 
designated by the investigator, will maintain a careful record of the inventory using the 
Drug Accountability Form. The investigational drug for this clinical trial shall only be 
dispensed by authorized personnel to subjects enrolled in this clinical trial. 
10.1.7 Destruction 
The investigator or designee is responsible for keeping accurate records of the clinical 
supplies received from BMS, including the amount remaining at the conclusion of the 
trial. Upon completion or termination of the study, all unused product will be destroyed at 
the site as dictated by the manufacturer. Any vials that are used during dose preparation 
may be destroyed immediately after preparation. It is the investigator’s responsibility to 
arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional 
guidelines and procedures, and provided that appropriate records of disposal are kept. 


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10.1.8 Drug Interactions 
Elotuzumab is an IgG1 monoclonal antibody, which is likely eliminated via several 
pathways similar to that of other antibodies, and therefore, unlikely to be impacted by 
other drugs. However, PK analysis showed that the combination of 
lenalidomide/dexamethasone or bortezomib/dexamethasone with elotuzumab decreased 
nonspecific clearance of elotuzumab by approximately 35% and 50%, respectively, thus 
increasing steady-state exposure of elotuzumab compared to patients receiving 
elotuzumab monotherapy. The effect seen can mainly be attributed to dexamethasone, an 
immunosuppressant that can potentially affect antibody clearance (see IB for additional 
information). 
 
10.1.9 Serious Adverse Reactions (SARs) 
To identify expected SARs from clinical studies, BMS performed a cumulative review of 
reported adverse reactions from completed and ongoing studies for elotuzumab. The 
overall frequency includes reported serious, life-threatening, and fatal SARs. Frequency 
is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10) or uncommon 
(≥ 1/1,000 to < 1/100). 
 
Serious Adverse Reactions for Elotuzumab Considered Expected 
 
SAR 
Frequency of all 
SARs 
Occurrence of 
Life-
Threatening 
SARs 
Herpes zoster 
Uncommon 
No 
Pneumonia 
Common 
No 
Pneumonia Pneumococcal 
Uncommon 
No 
Pyrexia 
Common 
No 
Upper respiratory tract infection 
Uncommon 
No 
 
Unexpected Life-Threatening and/or Fatal Serious Adverse Reactions with Elotuzumab 
 
SARs 
Frequency of Life-Threatening or Fatal 
SARs 
Atrial Fibrillation 
Uncommon 
Atrioventricular block complete  
Uncommon 
Cardiac arrest 
Uncommon 
Brain abscess 
Uncommon 
Gastroenteritis 
Uncommon 
Influenza 
Uncommon 
Pneumocystis Jurovecii 
Pneumonia 
Uncommon 
Pneumonia 
Uncommon 
Pneumonia Fungal 
Uncommon 
Pulmonary Sepsis 
Uncommon 


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Urinary Tract Infection 
Uncommon 
Urosepsis 
Uncommon 
Neutropenia 
Uncommon 
Thrombotic Thrombocytopenia 
Purpura 
Uncommon 
Sudden Death 
Uncommon 
Interstitial lung disease 
Uncommon 
Pulmonary embolism 
Uncommon 
Renal failure 
Uncommon 
 
 
The following warnings are associated with the use of elotuzumab (from the IB and/or the 
elotuzumab prescribing information): 
 
• IRR: Elotuzumab can cause IRR, the most common symptoms of which include fever, 
chills and hypertension. Bradycardia and hypotension also developed during infusions. 
The majority of IRRs occur during the first dose. Premedication with dexamethasone, an 
H1 and H2 blocker and acetaminophen is required prior to each dose. See Section 6.4.4 
for management of any IRR that occur during the study. 
• Infections: The incidence of infections, including pneumonia, was higher with 
elotuzumab treatment than with control. In the largest clinical study of patients with 
multiple myeloma (N = 635, the ELOQUENT-2 trial described in Section 1.3.4.1, 
infections were reported in 81% of patients in the elotuzumab combined with 
lenalidomide and dexamethasone arm and 74% in the lenalidomide and dexamethasone 
arm. Grade 3 to 4 infections were noted in 28% and 24% of the elotuzumab+Rd and Rd 
arms, respectively. Fatal infections were infrequent and were reported in 2.5% of 
elotuzumab+Rd and 2.2% of Rd treated patients.  
• Second Primary Malignancies: In ELOQUENT-2, invasive second primary 
malignancies have been observed in 9% of patients treated with elotuzumab+Rd and 6% 
of patients treated with Rd. Skin cancer was reported in 4.4% and 2.8% of patients treated 
with elotuzumab+Rd and Rd treated patients, respectively. 
• Hepatotoxicity: Elevations in liver enzymes (aspartate transaminase/alanine 
transaminase [AST/ALT] >3X UNL, total bilirubin >2 x UNL, and alkaline phosphatase 
<2 xULN) consistent with hepatotoxicity were reported in 2.5% and 0.6% of 
elotuzumab+Rd and Rd treated patients, respectively in the ELOQUENT-2 trial. Two 
patients experiencing hepatotoxicity were not able to continue treatment; however, 6 out 
of 8 patients had resolution and were able to continue treatment. 
• Interference with Determination of Complete Response: Elotuzumab is a humanized 
IgG kappa monoclonal antibody that can be detected on both the serum protein 
electrophoresis (SPEP) and immunofixation (IFE) assays used for the clinical monitoring 
of endogenous M-protein. This interference can impact the determination of complete 
response and possibly relapse from complete response in patients with IgG kappa 
myeloma protein. 


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10.2 Carfilzomib 
For complete information, please refer to the latest version of the prescribing information 
for carfilzomib, which can be found at www.kyprolis.com. 
 
Carfilzomib is proteasome inhibitor approved by the FDA in combination with 
lenalidomide and dexamethasone for the treatment of patients with relapsed or refractory 
multiple myeloma who have received one to three prior lines of therapy, or as 
monotherapy in patients with relapsed or refractory multiple myeloma who have received 
one or more lines of therapy. 
10.2.1 Supplier/How Supplied  
Commercial supplies of carfilzomib will be used and charged to the subject and or their 
insurance provider. Carfilzomib will be provided as a lyophilized powder which, when 
reconstituted, contains a 2 mg/mL isotonic solution of carfilzomib.  
10.2.2 Reconstitution and Preparation  
Refer to the latest version of the prescribing information for carfilzomib, which can be 
found at www.kyprolis.com, for instructions on reconstitution and preparation of 
carfilzomib. 
10.2.3 Storage and Stability 
Refer to the latest version of the prescribing information for carfilzomib, which can be 
found at www.kyprolis.com, for details on stability of unopened vials of carfilzomib, and 
on stability of carfilzomib once it is reconstituted. 
10.2.4 Handling  
Carfilzomb should be handled using standard precautions for the safe handling of 
antineoplastic agents. Latex gloves are recommended. It must be dispensed only from 
official study sites by authorized personnel according to local regulations, and stored in a 
secure area according to local regulations.  It is the responsibility of the investigator to 
ensure that study drug is only dispensed to eligible study subjects. 
10.2.5 Adverse Events Associated with Carfilzomib 
For complete information on safety, please refer to the latest version of the prescribing 
information for carfilzomib, which can be found at www.kyprolis.com. 
 
The safety of carfilzomib in combination with lenalidomide and dexamethasone (KRd) 
was evaluated in an open-label randomized study in patients with relapsed multiple 
myeloma. Adverse Reactions that occurred at a rate of ≥10% in the KRd arm (n=392) 
during the first 12 cycles of therapy are in the table below. 
 
 
KRd Arm 
n (%) 
Adverse Reaction 
Any Grade 
≥ Grade 3 
Anemia 
138 (35) 
53 (14) 
Asthenia 
54 (14) 
11 (3) 


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Back Pain 
41 (11) 
4 (1) 
Bronchitis 
55 (14) 
5 (1) 
Constipation 
68 (17) 
0 
Cough 
93 (24) 
2 (1) 
Diarrhea 
119 (30) 
8 (2) 
Dyspnea 
71 (18) 
8 (2) 
Fatigue 
113 (29) 
23 (6) 
Hyperglycemia 
43 (11) 
18 (5) 
Hypertension 
41 (11) 
12 (3) 
Hypocalcemia 
55 (14) 
10 (3) 
Hypokalemia 
78 (20) 
22 (6) 
Insomnia 
64 (16) 
6 (2) 
Muscle spasms 
92 (24) 
3 (1) 
Nausea 
63 (16) 
1 (0) 
Neutropenia 
124 (32) 
104 (27) 
Peripheral edema 
59 (15) 
3 (1) 
Peripheral neuropathies 
43 (11) 
7 (2) 
Pneumonia 
54 (14) 
35 (9) 
Pyrexia 
93 (24) 
5 (1) 
Rash 
45 (12) 
5 (1) 
Thrombocytopenia 
100 (26) 
58 (15) 
Upper Respiratory Tract Infection 
87 (22) 
7 (2) 
Venous Embolic and Thrombotic Events 
49 (13) 
16 (4) 
Viral upper respiratory tract infection 
55 (14) 
0 
 
 
Laboratory abnormalities ≥ Grade 3 reported at a rate of ≥ 10% in the KRd arm included 
decreases in the following (% of patients): lymphocytes (46%), ANC (39%), phosphorus 
(31%), platelets (26%), total WBC (25%), hemoglobin (15%) and potassium (11%). 
Increased glucose (14%) was also reported. 
 
The following warnings are associated with the use of carfilzomib (from the August 2020 
prescribing information): 
 
• Cardiac Toxicities: New onset or worsening of pre-existing cardiac failure (e.g., 
congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive 
cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have 
occurred following administration of carfilzomib. Some events occurred in patients with 
normal baseline ventricular function. In clinical studies with carfilzomib, these events 
occurred throughout the course of carfilzomib therapy. Death due to cardiac arrest has 
occurred within one day of carfilzomib administration. In randomized, open-label, 
multicenter trials for combination therapies, the incidence of cardiac failure events was 
8% and that of arrythmias was 8% (majority of which were atrial fibrillation and sinus 
tachycardia). In patients ≥ 75 years of age, the risk of cardiac failure is increased compared 
to younger patients.  


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• Acute Renal Failure: Cases of acute renal failure have occurred in patients receiving 
carfilzomib. Some of these events have been fatal. Renal insufficiency adverse events 
(including renal failure) have occurred in approximately 9% of patients treated with 
carfilzomib. Acute renal failure was reported more frequently in patients with advanced 
relapsed and refractory multiple myeloma who received carfilzomib monotherapy. This 
risk was greater in patients with a baseline reduced estimated creatinine clearance 
(calculated using Cockcroft and Gault equation). 
• Tumor Lysis Syndrome: Cases of TLS, including fatal outcomes, have been reported in 
patients who received carfilzomib. Patients with multiple myeloma and a high tumor 
burden should be considered to be at greater risk for TLS. 
• Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS), acute respiratory 
failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and 
interstitial lung disease have occurred in approximately 2% of patients receiving 
carfilzomib. Some events have been fatal. 
• Pulmonary Hypertension: Pulmonary arterial hypertension was reported in 
approximately 2% of patients treated with carfilzomib and was ≥Grade 3 in less than 1% 
of patients. 
• Dyspnea: Dyspnea was reported in 25% of patients treated with carfilzomib and was 
≥Grade 3 in 4% of patients. Evaluate dyspnea to exclude cardiopulmonary conditions 
including cardiac failure and pulmonary syndromes. 
• Hypertension: Hypertension, including hypertensive crisis and hypertensive emergency, 
has been observed with carfilzomib. In a randomized, open-label, multicenter trial 
evaluating carfilzomib in combination with KRd versus Rd, the incidence of hypertension 
events was 17% in the KRd arm versus 9% in the Rd arm. In a randomized, open-label, 
multicenter trial of Kd versus Vd, the incidence of hypertension events was 34% in the 
Kd arm versus 11% in the Vd arm. Some of these events have been fatal. Monitor blood 
pressure regularly in all patients. 
• Venous Thrombosis: Venous thromboembolic events (including deep venous 
thrombosis and pulmonary embolism) have been observed with carfilzomib. In a 
randomized, open-label, multicenter trial evaluating KRd versus Rd (with 
thromboprophylaxis used in both arms), the incidence of venous thromboembolic events 
in the first 12 cycles was 13% in the KRd arm versus 6% in the Rd arm. In a randomized, 
open-label, multicenter trial of Kd versus Vd, the incidence of venous thromboembolic 
events in months 1–6 was 9% in the Kd arm versus 2% in the Vd arm. With carfilzomib 
monotherapy, the incidence of venous thromboembolic events was 2%. 
• Infusion Reactions: Infusion reactions including life-threatening reactions, have 
occurred in patients receiving carfilzomib. Symptoms include fever, chills, arthralgia, 
myalgia, facial flushing, facial edema, laryngeal edema, vomiting, weakness, shortness of 
breath, hypotension, syncope, chest tightness, or angina. These reactions can occur 
immediately following or up to 24 hours after administration of carfilzomib. 
• Hemorrhage: Fatal or serious cases of hemorrhage have been reported in patients treated 
with carfilzomib. Hemorrhagic events have included gastrointestinal, pulmonary, and 
intracranial hemorrhage and epistaxis. The bleeding can be spontaneous, and intracranial 
hemorrhage has occurred without trauma. Hemorrhage has been reported in patients 
having either low or normal platelet counts. Hemorrhage has also been reported in 
patients who were not on antiplatelet therapy or anticoagulation. 


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• Thrombocytopenia: Carfilzomib causes thrombocytopenia with platelet nadirs observed 
between Day 8 and Day 15 of each 28-day cycle, with recovery to baseline platelet count 
usually by the start of the next cycle. Thrombocytopenia was reported in approximately 
32% of patients in clinical trials with carfilzomib. 
• Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, 
have been reported (2%) during treatment with carfilzomib. Carfilzomib can cause 
increased serum transaminases. 
• Thrombotic Microangiopathy: Cases of thrombotic microangiopathy, including 
thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have 
been reported in patients who received carfilzomib. Some of these events have been fatal. 
Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop 
carfilzomib and evaluate. If the diagnosis of TTP/HUS is excluded, carfilzomib may be 
restarted. The safety of reinitiating carfilzomib therapy in patients previously 
experiencing TTP/HUS is not known 
• Posterior Reversible Encephalopathy Syndrome: Cases of posterior reversible 
encephalopathy syndrome (PRES) have been reported in patients receiving carfilzomib. 
PRES, formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS), is 
a neurological disorder which can present with seizure, headache, lethargy, confusion, 
blindness, altered consciousness, and other visual and neurological disturbances, along 
with hypertension, and the diagnosis is confirmed by neuro-radiological imaging (MRI). 
Discontinue carfilzomib if PRES is suspected and evaluate. The safety of reinitiating 
carfilzomib therapy in patients previously experiencing PRES is not known. 
• Progressive Multifocal Leukoencephalopathy (PML): Progressive multifocal 
leukoencephalopathy (PML), which can be fatal, has been reported with Kyprolis. In 
addition to Kyprolis, other possible contributary factors include prior or concurrent 
immunosuppressive therapy that may cause immunosuppression. Consider PML in any 
patient with new onset of or changes in pre-existing neurological signs or symptoms. If 
PML is suspected, discontinue Kyprolis and initiate evaluation for PML including 
neurology consultation. 
• HBV Reactivation: Cases of HBV reactivation have been reported in the clinical trial 
and post-marketing setting in patients receiving treatment with carfilzomib.  Subjects 
should be tested for HBV infection before initiating treatment with carfilzomib. Subjects 
who are currently receiving treatment with carfilzomib and with unknown HBV status 
should be also be tested for HBV infection. For subjects who are carriers of HBV, 
prophylaxis with antivirals should be considered. Carriers of HBV who require treatment 
with carfilzomib should be closely monitored for signs and symptoms of active HBV 
infection throughout and following the end of treatment with carfilzomib. Consider 
consulting a specialist for subjects who test positive for HBV prior to or during treatment 
with carfilzomib. For subjects with active HBV reactivation, carfilzomib should be 
withheld until infection is adequately controlled. The safety of resuming carfilzomib after 
HBV reactivation is adequately controlled is not known. Therefore, investigators should 
weigh the risks and benefits when considering resumption of therapy in this situation. 
• Increased Fatal and Serious Toxicities in Combination with Melphalan and 
Prednisone in Newly Diagnosed Transplant-Ineligible Patients: In a clinical trial of 
955 transplant-ineligible patients with newly diagnosed multiple myeloma randomized to 
carfilzomib (20/36 mg/m2 by 30-minute infusion twice weekly for four of each six-week 


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cycle), melphalan and prednisone (KMP) or bortezomib, melphalan and prednisone 
(VMP), a higher incidence of fatal adverse reactions (7% versus 4%) and serious adverse 
reactions (50% versus 42%) were observed in the KMP arm compared to patients in the 
VMP arm, respectively. Patients in the KMP arm were observed to have a higher 
incidence of any grade adverse reactions involving cardiac failure (11% versus 4%), 
hypertension (25% versus 8%), acute renal failure (14% versus 6%), and dyspnea (18% 
versus 9%). This study did not meet its primary outcome measure of superiority in 
progression-free survival for the KMP arm. Carfilzomib in combination with melphalan 
and prednisone is not indicated for transplant-ineligible patients with newly diagnosed 
multiple myeloma 
• Embryo-fetal Toxicity: Carfilzomib can cause fetal harm when administered to a 
pregnant woman based on its mechanism of action and findings in animals.  Carfilzomib 
administered intravenously to pregnant rabbits during organogenesis at a dose 
approximately 40% of the clinical dose of 27 mg/m2 based on body surface area caused 
post-implantation loss and a decrease in fetal weight. Females of reproductive potential 
should avoid becoming pregnant while being treated with carfilzomib and must use 
contraception during treatment and for 6 months following the final dose. Males with 
female sexual partners of reproductive potential must use contraception during treatment 
with carfilzomib and for 3 months following the final dose. 
 
10.3 Lenalidomide 
For complete information, please refer to the latest version of the prescribing information 
for lenalidomide, which can be found at www.revlimid.com. 
 
Lenalidomide is a thalidomide analogue approved by the FDA in combination with 
dexamethasone for the treatment of patients with MM, and for use as maintenance therapy 
post ASCT. 
10.3.1 Supplier/How Supplied  
Commercial supplies of lenalidomide will be used and charged to the subject and or their 
insurance provider. However, subjects in the U.S. must be enrolled into the REVLIMID 
Risk Evaluation and Mitigation Strategy (REMS)™ program for the procurement of 
lenalidomide.  Lenalidomide is formulated in hard capsules containing 2.5 mg, 5 mg, 10 
mg, 15 mg, 20 mg, or 25 mg active drug for PO administration only.  
10.3.2 Storage and Stability 
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). 
10.3.3 Handling  
Lenalidomide should be handled using standard precautions for the safe handling of 
antineoplastic agents. Latex gloves are recommended. Lenalidomide capsules should not 
be opened or broken.  


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10.3.4 Adverse Events Associated with Lenalidomide 
For complete information on safety, please refer to the latest version of the prescribing 
information for lenalidomide, which can be found at www.revlimid.com. The most 
common adverse reactions (≥20%) when lenalidomide is used in MM include diarrhea, 
fatigue, anemia, constipation, neutropenia, leukopenia, peripheral edema, insomnia, 
muscle cramp/spasms, abdominal pain, back pain, nausea, asthenia, pyrexia, upper 
respiratory tract infection, bronchitis, nasopharyngitis, gastroenteritis, cough, rash, 
dyspnea, dizziness, decreased appetite, thrombocytopenia and tremor. 
 
The following warnings are associated with the use of lenalidomide in MM: 
 
• BLACK BOX WARNING: Embryo-fetal Toxicity: Lenalidomide, a thalidomide 
analogue, caused limb abnormalities in a developmental monkey study similar to birth 
defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it 
may cause birth defects or embryo-fetal death. Because of this, lenalidomide is only 
available through a restricted distribution program called the REVLIMID REMS™ 
program.  
• BLACK BOX WARNING: Hematologic Toxicity: Lenalidomide can cause significant 
neutropenia and thrombocytopenia. 
• BLACK BOX WARNING: Venous and Arterial Thromboembolism: There is a 
significantly increased risk of venous thromboembolic events (deep vein thrombosis and 
pulmonary embolism), as well as risk of arterial thromboembolic events (ATE, 
myocardial infarction and stroke) in patients with MM receiving lenalidomide in 
combination with dexamethasone. Anti-thrombotic prophylaxis is recommended. 
• Second Primary Malignancies: In clinical trials in patients with MM receiving 
lenalidomide an increase of invasive second primary malignancies notably AML and 
MDS have been observed. The increase of cases of AML and MDS occurred 
predominantly in NDMM patients receiving lenalidomide in combination with oral 
melphalan (frequency of 5.3%) or immediately following high dose intravenous 
melphalan and ASCT (frequency of 7.5%).  
• Increased Mortality in Patients with MM When Pembrolizumab Is Added to a 
Thalidomide Analogue and Dexamethasone: In two randomized clinical trials in 
patients with MM, the addition of pembrolizumab to a thalidomide analogue plus 
dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, 
resulted in increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 
blocking antibody in combination with a thalidomide analogue plus dexamethasone is not 
recommended outside of controlled clinical trials. 
• Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated 
with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients 
experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 
2% of patients with MM and 1% of patients with myelodysplasia had serious 
hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-
existing viral liver disease, elevated baseline liver enzymes, and concomitant medications 
may be risk factors. 
• Severe Cutaneous Reactions Including Hypersensitivity Reactions: Angioedema and 
serious dermatologic reactions including Stevens-Johnson syndrome (SJS), toxic 


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epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms 
(DRESS) have been reported. DRESS may present with a cutaneous reaction (such as 
rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with 
systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or 
pericarditis. These events can be fatal. 
• Tumor Lysis Syndrome: Fatal instances of TLS have been reported during treatment 
with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to 
treatment.  
• Impaired Stem Cell mobilization: A decrease in the number of CD34+ cells collected 
after treatment (> 4 cycles) with lenalidomide has been reported. 
• Thyroid Disorders: Both hypothyroidism and hyperthyroidism have been reported.  
• Hypersensitivity: Hypersensitivity, including angioedema, anaphylaxis, and 
anaphylactic reactions to lenalidomide has been reported. 
10.4 Dexamethasone 
Dexamethasone is a synthetic adrenoglucocorticoid. It is commercially available as a 
generic in tablet form for oral administration. It is indicated for a variety of medical 
conditions, including cancer. Commercial supplies of dexamethasone will be used for this 
study and charged to study subjects or their insurance company. 
10.4.1 Storage  
Dexamethasone is to be stored at controlled room temperature 20 to 25°C (68 to 77°F). 
Consult the package insert of the respective product for additional storage and usage 
instructions. 
10.4.2 Summary of Adverse Events Associated with Dexamethasone  
See Reference [25] for a more complete summary. Also see Section 6.6.2, Table 14. 
 
The side effects from systemic glucocorticoids are usually dose and duration dependent, 
and can impact virtually all body systems. Common side effects include thinning of the 
skin, purpura, Cushingoid appearance, weight gain, sleep disturbance and mood changes. 
Hyperglycemia is common if these agents are used in patients with pre-existing diabetes 
or those at risk of diabetes for other reasons. Cataracts are also common with prolonged 
(>1 year) of glucocorticoids. Other risks of concern with glucocorticoids include an 
increased risk of cardiovascular disease and hypertension (particularly when 
glucocorticoids are prescribed in patients with pre-existing cardiac or renal disease), 
increased risk of peptic ulcer disease and gastritis (especially when patients are also 
taking nonsteroidal anti-inflammatory agents), osteoporosis, increased fracture risk, 
osteonecrosis, myopathy, edema, and immunosuppression with an increased risk of 
infection. With the exception of cataracts and some of the cardiac and bone toxicities, 
adverse effects from glucocorticoids are at least partially reversible upon discontinuation. 


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11. DATA AND SAFETY MONITORING PLANS 
11.1 Safety Monitoring 
This protocol will be monitored according to the processes in effect for all LCI 
investigator-initiated studies and the protocol-specific monitoring plan, and will abide by 
standard operating procedures (SOPs) set forth by both AH Office of Clinical and 
Translational Research and the LCI Clinical Trials Office.  It is the responsibility of the 
Sponsor-Investigator to monitor the safety data for this study.  The Sponsor-Investigator, 
Statistician, and other team members as needed will meet regularly to monitor subject 
consents, enrollment and retention, safety data for all subjects (including AEs for all grades 
and attributions, SAEs), study drug administration, and validity/integrity of the data. 
Documentation of these meetings will be kept with study records. The Sponsor-
Investigator will submit data to the LCI Data and Safety Monitoring Committee according 
to the protocol-specific Data and Safety Monitoring Plan. 
 
The Sponsor-Investigator will monitor the study accrual data regularly.  
11.2 Data Monitoring 
This study will be organized, performed, and reported in compliance with the study 
protocol, SOPs of the LCI and AH Office of Clinical and Translational Research (and/or 
other participating institutional SOPs), the FDA, and other applicable regulations and 
guidelines (e.g. GCP).  
 
Subjects will be monitored by LCI Research /Data Monitors per the study-specific 
monitoring plan and LCI/AH SOPs for data quality. This monitoring will be done by 
comparing source documentation to the electronic case report forms (eCRFs). Any 
variation between the two data sets will be discussed with the investigator, Sponsor-
Investigator and/or other study team members as appropriate.  
 
The study database will be reviewed and checked for omissions, apparent errors, and 
values requiring further clarification using computerized and manual procedures. Data 
queries requiring clarification will be generated and addressed by the appropriate study 
team member. Only authorized personnel will make corrections to the study database and 
all corrections will be documented in an electronic audit trail. 
 
The trial site may also be subject to quality assurance audit by BMS or its designee as well 
as inspection by appropriate regulatory agencies. 
 
It is important for all investigators and their relevant personnel to be available during the 
monitoring visits and possible audits and for sufficient time to be devoted to the process. 
 


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12. SAFETY DATA COLLECTION, RECORDING AND REPORTING 
12.1 Definitions 
12.1.1 Adverse Event 
An adverse event is any untoward medical occurrence in a study subject who is 
administered any drug that does not necessarily have a causal relationship with this 
treatment.  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal 
product.  Pre-existing conditions that increase in frequency or severity or change in 
nature during or as a consequence of use of a drug in human clinical trials are also 
considered adverse events.  Adverse events may also include pre- or post-treatment 
complications that occur as a result of protocol mandated procedures (e.g., invasive 
procedures such as biopsies). 
 
An increase in grade to a pre-existing CTCAE toxicity grade present at the time of study 
treatment initiation will be recorded as an AE. Changes in vital signs, ECG, physical 
examination and laboratory test results will be recorded as an AE if they are judged 
clinically significant by the investigator and/or require a medical intervention or dose 
modification. 
 
Any continuing medical condition or clinically significant laboratory abnormality with an 
onset date before the first date of study treatment administration should be considered 
pre-existing and should be documented. 
 
An AE does not include: 
• relapse or progression of the underlying malignant disease;  
• medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion); 
NOTE: the condition that leads to the procedure may be an adverse event; 
• situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for elective surgery, social and/or convenience admissions); 
 
The severity of adverse events should be classified and recorded according to the CTCAE 
version 4.03. 
12.1.2 Suspected Adverse Reaction (SAR) 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable possibility 
that the drug is the cause.   Reasonable possibility means that there is evidence to suggest 
a causal relationship between the drug and the AE.  A suspected adverse reaction implies 
a lesser degree of certainty about causality than adverse reaction, which means any 
adverse event caused by a drug.   
 
Causality assessment to a study drug is a medical judgment made in consideration of the 
following factors: temporal relationship of the AE to study drug exposure, known 
mechanism of action or side effect profile of study treatment, other recent or concomitant 


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drug exposures, normal clinical course of the disease under investigation, and any other 
underlying or concurrent medical conditions.  Other factors to consider in considering 
drug as the cause of the AE: 
 
• Single occurrence of an uncommon event known to be strongly associated with drug 
exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome) 
• One or more occurrences of an event not commonly associated with drug exposure, but 
otherwise uncommon in the population (e.g., tendon rupture); often more than once 
occurrence from one or multiple studies would be needed before the Sponsor-Investigator 
could determine that there is reasonable possibility that the drug caused the event.   
• An aggregate analysis of specific events observed in a clinical trial that indicates the 
events occur more frequently in the drug treatment group than in a concurrent or 
historical control group 
12.1.3 Adverse Reaction 
An adverse reaction means any adverse event caused by a drug. Adverse reactions are a 
subset of all suspected adverse reactions where there is reason to conclude that the drug 
caused the event. 
12.1.4 Serious AE or SAR 
An AE or SAR is to be considered serious if the investigator deems it as such and the 
event results in any of the following outcomes: 
• Death (fatal); 
• Life-threatening situation (subject is at immediate risk of death); 
• Persistent or significant disability/incapacity; 
• Requires or prolongs inpatient hospitalization1; 
• A congenital anomaly/birth defect in the offspring of a subject who received study drug;  
• Based upon appropriate medical judgment, may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the afore listed outcomes from 
occurring (e.g. intensive treatment in an emergency room without hospitalization, blood 
dyscrasias or convulsions that do not result in hospitalization, development of drug 
dependency or drug abuse). NOTE: Potential drug induced liver injury (DILI2) is also 
considered an important medical event.  
• Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the 
study drug is an SAE.  
• Although pregnancy3, overdose4, and cancer are not always serious by regulatory 
definition, these events must be handled as SAEs. 
 
1Hospitalizations for study drug administration, protocol-related procedures, palliative or 
hospice care, or placement of an indwelling catheter, unless associated with other serious 
events, will not be recorded as SAEs. Other hospitalizations planned at the beginning of 
the trial also do not need to be reported as an SAE.  
 
2Potential 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 


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DILIs, meeting the defined criteria below must be reported as SAEs. Potential DILI is 
defined as 
1. ALT or AST elevation > 3 X ULN AND 
2. Total bilirubin > 2 X 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. 
 
3Pregnancy 
If, following initiation of study treatment, it is subsequently discovered that a study subject 
is pregnant or may have been pregnant at the time of study treatment exposure, including 
during at least 5 half-lives after product administration, the pregnancy must be reported as 
an SAE. 
 
4Overdose 
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. 
12.1.5 Unexpected AE (AE or SAE) or SAR 
An AE or SAR (whether serious or not) is considered unexpected if the specificity or 
severity of it is not consistent with the applicable product information (e.g., IB for an 
unapproved investigational product or package insert/summary of product characteristics 
for an approved product).  Unexpected also refers to AEs or SARs that are mentioned in 
the IB as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the particular 
drug under investigation.   
12.1.6 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 non-serious or 
serious AE, as appropriate, and reported accordingly. 
12.1.7 Unanticipated Problem (UAP) 
An UAP is any incidence, experience or outcome that is unexpected, given the 
information provided in research-related documentation (e.g., IB, informed consent) and 
the study population characteristics that is related or possibly related to participation in 
the research study and places the participant at an increased risk. By this definition, any 
event that meets the criteria defined in Section 12.1.5 would meet the criteria for a UAP. 
However other events may also meet the criteria for a UAP, e.g., a lost or stolen laptop 
computer that contains sensitive study information.  
12.2 Attribution 
The relationship to study treatment should be assessed using the following definitions: 


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Definite 
The AE is clearly related to the drug(s) under investigation 
Probable 
The AE is likely related to the drug(s) under investigation 
Possible 
The AE possibly related to the drug(s) under investigation 
Unlikely 
The AE is doubtfully related to the drug(s) under investigation 
Unrelated 
The AE is clearly not related to the drug(s) under investigation 
 
The investigator is responsible for verifying and providing source documentation for all 
AEs and assigning the attribution for each event for all subjects enrolled on the trial. 
12.3 Timing and Reporting  
12.3.1 Adverse Events 
All AEs, (including event name, grade, start/stop date and attribution) will be 
documented. AEs will be collected from the time of D1 of treatment until 90 days after 
last dose of study treatment. If the subject initiates subsequent anti-cancer therapy prior to 
90 days after cessation of study treatment, the reporting period is through 30 days 
following cessation of study treatment or until the start of the subsequent anti-cancer 
therapy, whichever is later. 
12.3.2 Pregnancy 
All initial reports of pregnancy must be reported as an SAE to BMS Worldwide Safety 
(see Section 12.3.3.2) by the Sponsor-Investigator or designee within 24 hours of 
becoming aware of the event using the BMS Pregnancy Surveillance Form (provided as a 
document separate from this protocol). Abnormal pregnancy outcomes (e.g. spontaneous 
abortion, fetal death, stillbirth, congenital anomaly, ectopic pregnancy) are considered 
SAEs and must be reported as such.  
 
Any subject who becomes pregnant during the study must be discontinued promptly from 
all protocol mandated treatment and followed up per protocol.   
 
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. 


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12.3.3 SAEs  
All SAEs, whether related to study treatment or not, including those thought to be 
associated with protocol-specified procedures, will be collected. SAEs will be reported  
after informed consent and continuing through 90 days after the discontinuation of all 
protocol mandated therapy. If the subject initiates subsequent anti-cancer therapy prior to 
90 days after cessation of study treatment, the reporting period is through 60 days 
following cessation of study treatment or until the start of the subsequent anti-cancer 
therapy, whichever is later. Any SAE occurring after these time periods that is believed to 
be related to study drug(s) or protocol-specified procedure should also be reported. 
 
It is the responsibility of the Sponsor-Investigator, investigators and the protocol team to 
ensure SAEs are reported according to the Code of Federal Regulations (CFR), GCP, the 
protocol guidelines, IRB, and FDA policy.  
 
SAEs will be followed until clinical recovery is complete and laboratory tests have 
returned to baseline, until progression has been stabilized, or until there has been 
acceptable resolution of the event.  This may at times cause the follow-up period for 
SAEs to be greater than 90 days.  Similarly, the Sponsor-Investigator is responsible for 
following the subject during the required follow-up period even if the subject lives 
elsewhere or has been released from his or her care and is being treated under another 
service at LCI. 
12.3.3.1 Reporting to Sponsor-Investigator 
 
All SAEs (whether considered related or not, expected or not) and pregnancies must be 
reported to the Sponsor-Investigator within 1 business day of awareness.  
 
When new significant information becomes available, a follow-up report must be 
reported to the Sponsor-Investigator within 1 business day of awareness. 
 
In the event of an unanticipated problem (UAP) as defined in Section 12.1.7 or life-
threatening complication the Sponsor-Investigator must be notified via email 
immediately after awareness. 
 
12.3.3.2 Reporting to BMS Worldwide Safety 
All SAEs whether considered related or not, expected or not, and pregnancies must be 
reported to BMS within 24 hours of Sponsor-Investigator awareness. SAEs are 
reportable to BMS from informed consent through 60 days after last dose of study 
treatment. SAEs must be recorded on a BMS approved form; pregnancies must be 
reported on a Pregnancy Surveillance Form. 
 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  609-818-3804 
 


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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.  
 
NOTE: if a report is submitted to the FDA (see Section 12.3.5), a simultaneous copy 
should be submitted to BMS. 
12.3.4 Reporting to the IRB 
All events occurring during the conduct of a protocol and meeting the definition of an 
SAE or UAP will be reported to the IRB per IRB reporting requirements. 
12.3.5 Reporting to the FDA 
According to CFR 312.32, the Sponsor-Investigator, or designee, will be responsible for 
notifying the FDA (via Form FDA 3500 (MedWatch Form)) and all participating 
investigators of any unexpected fatal or life-threatening events possibly related with 
the use of the study drug (drugs) as soon as possible, but in no case later than 7 calendar 
days after the Sponsor’s initial receipt of the information. For all other serious and 
unexpected safety events, the Sponsor-Investigator, or designee, will notify the FDA 
within 15 calendar days.   
 
It is the responsibility of the Sponsor-Investigator, investigators, and the Protocol Team 
to ensure SAEs are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, Institutional Review Board, and FDA policy. 
 
 
13. DISEASE EVALUATION 
 
13.1 IMWG 2016 Response Criteria 
Response 
IMWG Criteria* 
Abbreviations: NGF=next-generation flow. NGS=next-generation sequencing. FLC=free light chain. M-protein=myeloma 
protein. SPD=sum of the products of the maximal perpendicular diameters of measured lesions. CRAB features=calcium 
elevation, renal failure, anemia, lytic bone lesions. FCM=flow cytometry. SUVmax=maximum standardised uptake value. 
MFC=multiparameter flow cytometry. ⁸F-FDG PET=⁸F-fluorodeoxyglucose PET. ASCT=autologous stem cell 
transplantation. 
IMWG MRD Criteria (Requires a complete response as defined below)  
Sustained MRD-
negative 
MRD negativity in the marrow (NGF or NGS, or both) and by imaging as defined below, 
confirmed minimum of 1 year apart. Subsequent evaluations can be used to further specify 
the duration of negativity (e.g., MRD-negative at 5 years)† 


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Flow MRD-negative 
Absence of phenotypically aberrant clonal plasma cells by NGF‡ on bone marrow aspirates 
using the EuroFlow standard operation procedure for MRD detection in MM (or validated 
equivalent method) with a minimum sensitivity of 1 in 10⁵ nucleated cells or higher 
Sequencing MRD-
negative 
Absence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a 
clone is defined as less than two identical sequencing reads obtained after DNA sequencing 
of bone marrow aspirates using the LymphoSIGHT platform (or validated equivalent 
method) with a minimum sensitivity of 1 in 10⁵ nucleated cells§or higher 
Imaging-positive 
MRD-negative 
MRD negativity as defined by NGF or NGS plus disappearance of every area of increased 
tracer uptake found at baseline or a preceding PET/CT or decrease to less mediastinal blood 
pool SUV or decrease to less than that of surrounding normal tissue¶ 
Standard IMWG Response Criteria||; NOTE: see [22, 30 & 31] for additional details 
Stringent Complete 
Response 
(sCR) 
CR as defined below plus:  
• 
normal FLC ratio** and  
• 
absence of clonal cells in bone marrow by immunohistochemistry(κ/λ ratio ≤4:1 or 
≥1:2 for κ and λ patients, respectively, after counting ≥100 plasma cells)†† 
Complete Response 
(CR) 
• 
Negative immunofixation on the serum and urine ‡‡ and  
• 
disappearance of any soft tissue plasmacytomas and  
• 
< 5% plasma cells in bone marrow aspirates.   
Very Good Partial 
Response 
(VGPR) 
• 
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.   
Partial Response 
(PR) 
• 
≥ 50% reduction of serum M-protein plus reduction in 24 hour urinary M-protein 
by > 90% or to < 200 mg/24 h 
• 
If the serum and urine M-protein are unmeasurable, a > 50% decrease in the 
difference between involved and uninvolved FLC levels is required in place of the 
M-protein criteria 
• 
If serum and urine M-protein are not measurable, and serum free light assay is also 
not measurable, > 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 (SPD) §§of soft tissue plasmacytomas is also required 
Minimal Response 
• 
≥25% but ≤49% reduction of serum M-protein and  
• 
reduction in 24-h urine M-protein by 50–89%.  
In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size 
(SPD)§§ of soft tissue plasmacytomas is also required 
Stable Disease (SD) 
• 
Not meeting criteria for CR, VGPR, PR, minimal response, or PD 
Progressive disease 
(PD)¶¶,|||| 
Any one or more of the following criteria: 
• 
Increase of 25% from lowest confirmed response value in one or more of the 
following criteria: 


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o 
Serum M-protein (absolute increase must be > 0.5 g/dL)   
o 
Serum M-protein increase ≥ 1 g/dL, if the lowest M component was ≥ 5 g/dL; 
o 
Urine M-protein ( absolute increase must be > 200 mg/24 h);  
o 
In patients without measurable serum and urine M-protein levels, the difference 
between involved and uninvolved FLC levels. (absolute increase must be > 10 
mg/dL); 
o 
In patients without measurable serum and urine M-protein levels and without 
measurable involved  FLC levels, bone marrow plasma-cell percentage 
irrespective of baseline status (absolute increase must be ≥ 10%)  
o 
Appearance of a new lesion(s), ≥50% increase from nadir in SPD§§ of >1 lesion, 
or ≥50% increase in the longest diameter of a previous lesion >1 cm in short 
axis;  
o 
≥50% increase in circulating plasma cells (minimum of 200 cells per μL) if this 
is the only measure of disease= 
Clinical Relapse 
Clinical relapse requires one or more of the following criteria: 
• 
Direct indicators of increasing disease and/or end organ dysfunction (CRAB 
features) related to the underlying clonal plasma-cell proliferative disorder. It is not 
used in calculation of TTP or PFS but is listed as something that can be reported 
optionally or for use in clinical practice 
• 
Development of new soft tissue plasmacytomas or bone lesions (osteoporotic 
fractures do not constitute progression) 
• 
Definite increase in the size of existing plasmacytomas or bone lesions. A definite 
increase is defined as a 50% (and ≥1 cm) increase as measured serially by the SPD§§ 
of the measurable lesion 
• 
Hypercalcaemia (>11 mg/dL) 
• 
Decrease in hemoglobin of ≥2 g/dL not related to therapy or other non-myeloma-
related conditions 
• 
Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and 
attributable to myeloma; 
• 
Hyperviscosity related to serum paraprotein 
For MRD assessment, the first bone marrow aspirate should be sent to MRD (not for morphology) and this sample 
should be taken in one draw with a volume of minimally 2 mL (to obtain sufficient cells), 
but maximally 4–5 mL to avoid hemodilution. 
 
*All response categories  require two consecutive assessments made at any time before the institution of any new 
therapy; for MRD there is no need for two consecutive assessments, but information on MRD after each treatment 
stage is recommended (e.g. after induction, high-dose therapy/ASCT, consolidation, maintenance). MRD tests should 
be initiated only at the time of suspected complete response. All categories of response and MRD require no known 
evidence of progressive or new bone lesions or extra medullary plasmacytomas if radiographic studies were 
performed.  However, radiographic studies are not required to satisfy these response requirements except for the 
requirement of FDG PET if imaging MRD-negative status is reported.  
 
†Sustained MRD negativity when reported should also annotate the method used (e.g. sustained flow MRD-negative, 
sustained sequencing MRD-negative).  
 
‡Bone marrow MFC should follow NGF guidelines26. The reference NGF method is an eight-colour two-tube 
approach, which has been extensively validated. The two-tube approach improves reliability, consistency, and 
sensitivity because of the acquisition of a greater number of cells. The eight-colour technology is widely available 


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globally and the NGF method has already been adopted in many flow laboratories worldwide. The complete eight-
colour method is most efficient using a lyophilised mixture of antibodies which reduces errors, time, and costs. 5 
million cells should be assessed. The FCM method employed should have a sensitivity of detection of at least 1 in 10⁵ 
plasma cells.  
 
§DNA sequencing assay on bone marrow aspirate should use a validated assay such as LymphoSIGHT (Sequenta).  
 
¶Criteria used by Zamagni and colleagues27 and expert panel (IMPetUs; Italian Myeloma criteria for PET Use)28,29. 
Baseline positive lesions were identified by presence of focal areas of increased uptake within bones, with or without 
any underlying lesion identified by CT and present on at least two consecutive slices. Alternatively, an 
SUVmax=2.5 within osteolytic CT areas >1 cm in size, or SUVmax=1.5 within osteolytic CT areas ≤1 cm in size were 
considered positive. Imaging should be performed once MRD negativity is determined by MFC or NGS.  
 
||Derived from international uniform response criteria for multiple myeloma. 30Minor response definition and 
clarifications derived from Rajkumar and colleagues31. When the only method to measure disease is by serum FLC 
levels: complete response can be defined as a normal FLC ratio of 0.26 to 1.65 in addition to the complete response 
criteria listed previously. Very good partial response in such patients requires a ≥90% decrease in the difference 
between involved and uninvolved FLC levels. All response categories require two consecutive assessments made at 
any time before the institution of any new therapy; all categories also require no known evidence of progressive or 
new bone lesions or extramedullary plasmacytomas if radiographic studies were performed. Radiographic studies are 
not required to satisfy these response requirements. Bone marrow assessments do not need to be confirmed. Each 
category, except for stable disease, will be considered unconfirmed until the confirmatory test is performed. The date 
of the initial test is considered as the date of response for evaluation of time dependent outcomes such as duration of 
response.  
 
**All recommendations regarding clinical uses relating to serum FLC levels or FLC ratio are based on results obtained 
with the validated Freelite test (Binding Site, Birmingham, UK).  
 
††Presence/absence of clonal cells on immunohistochemistry is based upon the κ/λ/L ratio. An abnormal κ/λ ratio by 
immunohistochemistry requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of 
an abnormal clone is κ/λ of >4:1 or <1:2.  
 
‡‡Special attention should be given to the emergence of a different monoclonal protein following treatment, especially 
in the setting of patients having achieved a conventional complete response, often related to oligoclonal reconstitution 
of the immune system. These bands typically disappear over time and in some studies have been associated with a 
better outcome. Also, appearance of monoclonal IgG κ in patients receiving monoclonal antibodies should be 
differentiated from the therapeutic antibody.  
 
§§Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI scans, or dedicated CT 
scans where applicable. For patients with only skin involvement, skin lesions should be measured with a ruler. 
Measurement of tumor size will be determined by the SPD. 
 
¶¶Positive immunofixation alone in a patient previously classified as achieving a complete response will not be 
considered progression. For purposes of calculating time to progression and progression-free survival, patients who 
have achieved a complete response and are MRD-negative should be evaluated using criteria listed for progressive 
disease. Criteria for relapse from a complete response or relapse from MRD should be used only when calculating 
disease-free survival.  
 
||||In the case where a value is felt to be a spurious result per physician discretion (e.g. a possible laboratory error), that 
value will not be considered when determining the lowest value. 


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14. STATISTICAL CONSIDERATIONS 
14.1 Milestones 
14.1.1 Registration Date 
The date the subject signs the informed consent. 
14.1.2 Enrollment (On Study) Date 
The date of initiation of study treatment on Cycle 1, Day 1. 
14.1.3 Treatment Discontinuation Date 
The date the investigator makes the decision to discontinue elotuzumab. See Section 9 for 
criteria for discontinuation of treatment. 
14.2 Sample Size Determination 
The primary objective of this study is to evaluate the very good partial response or better 
(VGPR+) rate in subjects treated with elotuzumab in addition to the combination of carfilzomib, 
lenalidomde, and dexamethasone (KRd) in relapsed or refractory multiple myeloma subjects.  
This will be evaluated in terms of the percent of subjects who achieve a VGPR+ to induction 
therapy.  Wang [6] reported a VGPR+ rate of approximately 40% in this patient population 
treated with KRd. See Section 1.4 for the rationale for using this as the historical control. This 
study will be used to test the null hypothesis that the VGPR+ rate in subjects treated with 
elotuzumab+KRd is less than or equal to 40%.  Forty (40) response evaluable subjects will be 
enrolled, and if at least 21 of 40 subjects achieve a VGPR+, the null hypothesis will be rejected.  
The design will provide 90% power with a 1-sided alpha = 0.10 significance level, assuming the 
true VGPR+ rate is 60%.  An improvement from 40% to 60% in the VGPR+ rate is considered 
clinically relevant.  
14.3 Endpoint Definitions 
14.3.1 Very Good Partial Response or Better 
VGPR+ will be determined for each subject as a binary variable indicating whether or not 
the subject achieved a VGPR or better to induction, as determined by the IMWG 2016 
response criteria (see Section 13.1). 
14.3.2 Objective Response 
Objective response will be determined for each subject as a binary variable indicating 
whether or not the subject achieved a best overall response of PR or better as determined 
by the IMWG 2016 response criteria.   
14.3.3 Overall Survival 
Overall survival (OS) is defined as the duration from enrollment to the study (treatment 
start date) to the date of death from any cause.  Subjects who are alive or lost to follow-
up at the time of the analysis will be censored at the last known date they were alive. 


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14.3.4 Progression Free Survival  
Progression free survival (PFS) is defined as the duration of time from enrollment to the 
study (treatment start date) to first occurrence of either PD or death.  Disease progression 
must be objectively determined per IMWG 2016 criteria (see Section 13.1), where the 
date of progression is the date of the last assessment that identified PD.  If the subject 
died without documented disease progression, the date of progression will be the date of 
death.  For surviving subjects who do not have documented disease progression, PFS will 
be censored at the date of last disease assessment.  For subjects who receive subsequent 
anti-cancer therapy prior to documented disease progression, PFS will be censored at the 
date of last disease assessment prior to the commencement of subsequent therapy.  
Subjects who have an initial PFS event immediately following 2 or more consecutive 
missed disease assessments will be censored at the date of the last assessment prior to 
those missed assessments.  For participants with only one missed assessment, the 
documented PD status and assessment date will be used.  
14.3.5 Time to Disease Progression 
Time to disease progression (TTP) will be calculated in the same fashion as described for 
PFS with the exception that for subjects who die for causes other than disease 
progression, TTP will be censored at the date of the other cause mortality.  Otherwise, the 
censoring mechanism for TTP will be the same as previously described for PFS. 
14.3.6 Duration of Response  
Duration of response (DoR) will be calculated for each subject with response for the 
VGPR+ and overall response endpoints. The DoR intervals will be calculated from the 
time of the first assessment that identified response until disease progression or death.  
The censoring mechanism for DoR will be the same as described for PFS. 
14.3.7 Time to Next Treatment 
Time to next treatment (TTNT) will be calculated from the time of treatment start until 
the start of the first subsequent anti-cancer therapy after all protocol directed therapy is 
completed.  For surviving subjects who do not receive subsequent therapy, TTNT will be 
censored at the last contact date.  For subjects who die before beginning subsequent anti-
cancer therapy, TTNT will be censored at the date of death. 
14.3.8 Safety Endpoints 
Safety endpoints will include treatment administration (cumulative dose, dose intensity, 
and relative dose intensity—dose intensity as a percent of intended dose intensity), AEs, 
SAEs, and deaths while on study therapy.  
14.4 Analysis Populations 
Analyses of response endpoints (response evaluable population) will be conducted on the 
population of subjects who initiate treatment with elotuzumab and who have measurable 
disease at baseline.  Analyses of other efficacy and safety endpoints will be conducted on 
the population of subjects who initiate treatment with elotuzumab. Exploratory analyses 
will be conducted on the population of subjects who initiate treatment with elotuzumab 
treatment and who have available biomarker data.   


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14.5 Analysis Methods 
14.5.1 Timing of Analysis 
The primary analysis will occur after VGPR+ status (yes or no) has been determined for 
all subjects. Secondary endpoints will also be assessed at the time of the primary 
analyses. Updated analyses will be conducted after the PFS censoring rate reaches 20% 
or when all surviving subjects who are not lost to follow up or have not been withdrawn 
from the study have been on study for at least 3 years, whichever occurs first.  A final 
analysis will be conducted after the overall survival censoring rate reaches 20% or after 
all surviving subjects who are not lost to follow up or have not been withdrawn from the 
study have been on study for at least 5 years, whichever occurs first. 
14.5.2 Subject Disposition 
A disposition summary of all consenting subjects will be provided. This will include a 
summary of subjects who consented, were treated, discontinued treatment, died, and were 
lost to follow-up or withdrew consent.  
14.5.3 Baseline Subject and Disease Characteristics 
A summary of subject demographics and disease-related characteristics will be 
summarized and evaluated.  These results will be qualitatively compared to patient and 
disease characteristics in the same patient population that have been previously reported.    
14.5.4 Primary Analysis 
The frequency and proportion of subjects experiencing a VGPR+ will be calculated.  A 
corresponding 95% confidence interval will be estimated using the Clopper-Pearson 
method.  A one-sided test for binomial proportions using the rejection region described in 
the sample size section (Section 14.2) will be carried out, testing the null hypothesis that 
the VGPR+ rate is less than or equal to 40%.  Based on the design and corresponding 
sample size calculations described in Section 14.2, if at least 21 subjects experience a 
VGPR+, the null hypothesis can be rejected. 
 
Logistic regression techniques will be used to correlate VGRR+ rate with baseline subject 
and disease characteristics, and results from biomarker studies as previously described. 
This will include univariate and multivariable regression model techniques to identify 
individual and independent prognostic factors.    
14.5.5 Secondary Analysis 
The frequencies and proportions of overall response will be calculated.  Corresponding 
95% confidence intervals will be estimated using the Clopper-Pearson method.  OS, PFS, 
TTP, TTNT, and DoR endpoints will be analyzed using Kaplan Meier techniques.  
Selected landmarks will be estimated and reported.  Logistic regression models and Cox 
proportional hazards models will be used to analyze the treatment response endpoints as 
functions of baseline subject and disease characteristics, and results from biomarker 
studies as previously described. The percent of subjects achieving MRD negative status 
will be summarized.  Subgroup analyses will be conducted for selected efficacy 
endpoints on the subset of MRD negative subjects (i.e. time to event endpoints). 


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14.5.6 Safety Analysis 
Incident rates for treatment-emergent adverse events, adverse events leading to study 
drug discontinuation, SAEs and deaths while on study therapy will be summarized.  
Treatment-emergent adverse events are defined as follows: 
• An adverse event that occurs after treatment start that was not present at the time of 
treatment start; OR 
• An adverse event that increases in severity after treatment start if the event was present at 
the time of treatment start. 
 
Cumulative doses will be calculated for each subject (for elotuzumab, carfilzomib and 
lenalidomide) in both absolute terms and as a percent of expected cumulative dose (relative dose 
intensity).  Cumulative dose and relative dose intensity will then be summarized for the study 
arm. 
14.5.7 Interim Analysis 
No pre-specified interim analyses are planned for this study.   
15. STUDY COMPLETION OR TERMINATION 
15.1 Completion 
The study will be considered complete when one or more of the following conditions is 
met: 
• All subjects have died and/or are withdrawn from the study 
• All subjects have discontinued from the study 
• The IRB, FDA, LCI DSMC, or Sponsor-Investigator discontinues the study because of 
safety considerations 
• The Sponsor-Investigator defines an administrative or clinical cut-off date 
 
15.2 Termination 
The study will be terminated when one or more of the following conditions occur: 
• If risk-benefit ratio becomes unacceptable owing to, for example, 
o Safety findings from this study (e.g. SAEs) 
o Results of any interim analysis 
o Results of parallel clinical studies 
o Results of parallel animal studies (e.g. toxicity, teratogenicity, carcinogenicity or 
reproduction toxicity). 
o If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable 
time frame. 
• The Sponsor-Investigator has decided to close the trial at any site and at any time 
 
For any of the above closures, the following applies: 
• Closures should occur only after consultation between involved parties. 
• All affected institutions must be informed as applicable according to local law.   


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• In case of a partial study closure, ongoing subjects, including those in follow- up, must be 
taken care of in an ethical manner. 
16. STUDY MANAGEMENT 
16.1 IRB Approval  
The final study protocol and the final version of the informed consent form(s) must be 
approved in writing by the Sponsor IRB.  
 
The Sponsor-Investigator is responsible for informing the Sponsor IRB of any amendment 
to the protocol in accordance with local requirements. The protocol must be re-approved 
by the IRB annually, as local regulations require.  
16.2 Informed Consent 
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. 
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. 
16.3 Protocol Adherence 
Except for an emergency situation in which proper care for the protection, safety, and well-
being of the study subject requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol.   
16.4 Changes to the Protocol and/or Informed Consent 
16.4.1 Amendments to the Protocol 
If it is necessary for the study protocol to be amended and/or the informed consent 
revised, the amendment or a new version of the study protocol (amended protocol) and/or 
the revised informed consent must be approved by the Sponsor-Investigator, funding 
company(ies) (if required by the contract(s), the FDA and the Sponsor IRB. 
16.4.2 Emergency Modification 
The Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to the trial subjects without prior approval from 
applicable agencies.  As soon as possible, the implemented deviation or change, the 
reasons for it and if appropriate the proposed protocol amendment should be submitted to 
the appropriate agencies.  Any deviations from the protocol must be explained and 
documented by the investigator. 
16.5 Other Protocol Deviations 
If a deviation occurs, the event should be reported to the Sponsor-Investigator via entry in 
the CTMS no later than 10 business days after awareness.  


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Protocol deviations that, in the Investigator’s judgment, potentially caused harm to 
participants or others or indicates that the participants or others are at an increased risk of 
harm, or has adversely impacted data integrity will be reported promptly to the Sponsor-
Investigator and IRB per IRB reporting requirements. 
NOTE: Planned protocol deviations will be submitted to the FDA for prior approval only 
if the deviation affects the scientific validity of the study and/or the rights, safety, or 
welfare of subjects. 
16.6 Retention of Records 
Essential documentation (e.g. AEs, records of study drug receipt and dispensation), 
including all IRB correspondence, will be retained for at least 2 years after the 
investigation is completed.  Documentation will be readily available upon request. 
16.7 Ethical and Legal Conduct of the Study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Investigator abide by GCP 
guidelines.  The study will also be carried out in full conformity with Regulations for the 
Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 
CFR Part 56, and/or the ICH E6 and in keeping with applicable local law(s) and 
regulation(s). 
 
Documented approval from appropriate agencies (e.g. DSMC, IRB, FDA) will be obtained 
for all participating centers before the start of the study, according to GCP, local laws, 
regulations and organizations.  
 
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigators may not modify or alter the procedures described in this 
protocol.   
 
The Sponsor-Investigator is responsible for the conduct of the clinical trial at the sites in 
accordance with Title 21 of the CFR and/or the Declaration of Helsinki.  The Sponsor-
Investigator is responsible for overseeing the treatment of all study subjects.  The Sponsor-
Investigator must assure that all study site personnel, including sub-investigators and other 
study staff members, adhere to the study protocol and all applicable regulations and 
guidelines regarding clinical trials both during and after study completion. 
 
The Sponsor-Investigator will be responsible for assuring that all the required data will be 
collected and properly documented. 
16.8 Confidentiality of Records 
All records identifying the subject will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available. 


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16.9 Compliance with ClinicalTrials.gov 
The Sponsor-Investigator is solely responsible for determining whether the trial and its 
results are subject to the requirements for submission to ClinicalTrials.gov 
(http://www.clinicaltrials.gov).  
 
 


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17. REFERENCES 
 
1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Multiple Myeloma. 
Version 3.2017. 
2. Demo SD, Kirk CJ, Aujay MA et al. Anti-tumor activity of PR-171, a novel irreversible 
inhibitor of the proteasome. Cancer Res. 2007; 67(13):6383-91. 
3. Arastu-Kapur S, Shenk K, Parlati F et al. Non-proteasomal targets of proteasome inhibitors 
bortezomib and carfilzomib. Blood (ASH Annual Meeting Abstracts), Nov 2008; 112: 
abstract #2657. 
4. Shaughnessy J, Qu P, Usmani S, et al. Pharmacogenomics of bortezomib test-dosing 
identifies hyperexpression of proteasome genes, especially PSMD4, as novel high-risk 
feature in myeloma treated with Total Therapy 3. Blood 2011;118(13):3512-24. 
5. Niesvizky R, Martin TG 3rd, Bensinger WI, et al. Phase Ib dose-escalation study (PX-171-
006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive 
multiple myeloma. Clin Cancer Res. 2013;19(8):2248-2256.  
6. Wang M, Martin T, Bensinger W et al. Phase 2 dose-expansion study (PX-171-006) of 
carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple 
myeloma. Blood. 2013;122(18):3122-3128. 
7. Stewart AK, Rajkumar SV, Dimopoulos MA et al. Carfilzomib, lenalidomide, and 
dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142-152. 
8. Hsi ED, Steinle R, Balasa B, et al. CS1, a potential new therapeutic antibody target for the 
treatment of multiple myeloma. Clin Cancer Res. 14:2775–2784, 2008 
9. Elotuzumab: From mechanism to meaningful results in multiple myeloma. Bristol-Myers 
Squibb Company. Princeton, NJ. June 2015. Document Control No. 930089832.  
10. Tai YT, Dillon M, Song W, et. al. Anti-CS1 humanized monoclonal antibody HuLuc63 
inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the 
bone marrow milieu.  Blood. 2008;112:1329-1337. 
11. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzomab therapy for relapsed or refractory 
multiple myeloma. N Engl J Med. 2015;373:621-631. 
12. Jakubowiak AJ, Benson DM, Bensinger W et al. Phase I trial of anti-CS1 monoclonal 
antibody elotuzumab in combination with bortezomib in the treatment of relapsed/ refractory 
multiple myeloma. J Clin Oncol. 2012;30:1960-1965. 
13. Jakubowiak A, Offidani M, Pegourie B et al. Randomized phase 2 study: elotuzumab plus 
bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. 
Blood 2016;127:2833-2840.  
14. Landgren O, Hultcrantz M, Lesokhin AM, et al: Weekly carfilzomib, lenalidomide, 
dexamethasone, and daratumumab combination therapy provides unprecedented MRD 
negativity rates in newly diagnosed multiple myeloma: A clinical and correlative phase 2 
study. 2019 ASH Annual Meeting & Exposition. Abstract 862. Presented December 9, 2019.  


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15. Costa LJ, Chhabra S et al: Daratumumab, carfilzomib, lenalidomide and dexamethasone 
(Dara-KrdD) Induction, Autologous Transplantation and Post-Transplant, Response-
Adapted, Measurable Residual Disease (MRD)-Based Dara-Krd Consolidation in Patients 
with Newly Diagnosed Multiple Myeloma. 2019 ASH Annual Meeting & Exposition. 
Abstract 860. Presented December 9, 2019. 
 
16. Yang G, Gao M, Zhang Y et al. Carfilzomib enhances natural killer cell-mediated lysis of 
myeloma linked with decreasing expression of HLA class I. Oncotarget 2015:6(29):26982-
26994. 
17. Braga WMT, Atanackovic D, Colleoni GWB. The role of regulatory T cells and TH17 cells 
in multiple myeloma. Clin Dev Immunol 2012; 1-4. 
18. Hsu AK, Quach H, Tai T et al. The immunostimulatory effect of lenalidomide on NK-cell 
function is profoundly inhibited by concurrent dexamethasone therapy. Blood 
2011;117(5):1605-1613. 
19. Xing K, Gu B, Zhang P et al. Dexamethasone enhances programmed cell death 1 (PD-1) 
expression during T cell activation: an insight into the optimum application of 
glucocorticoids in anti-cancer therapy. BMC Immunology 2015:16:39, 1-9. 
20. Guo H, Cruz-Munoz ME, Wu N et al. Immune cell inhibition by SLAMF7 is mediated by a 
mechanism requiring SRC kinases, CD45, and SHIP-1 that is defective in multiple myeloma 
cells. Mol Cell Biol. 2015; 35(1):41-51. 
21. Balasa B, Yun R, Belmar NA et al. Elotuzumab enhances natural killer cell activation and 
myeloma cell killing through interleukin-2 and TNF-α pathways. Cancer Immunol 
Immunother. 2015;64(1):61-73. 
22. Kumar S, Paiva B, Anderson KC et al. International Myeloma Working Group consensus 
criteria for response and minimal residual disease assessment in multiple myeloma. Lancet 
Oncol. 2016 Aug;17(8):e328-46. 
23. Mahnke, Y. D., Beddall, M. H., Roederer, M. OMIP-017: Human CD4+helper T-cell subsets 
including follicular helper cells. Cytometry 2013; 83A: 439–440.  
24. Eller, M. A., Currier, J. R. OMIP-007: Phenotypic analysis of human natural killer cells. 
Cytometry 2012;81A: 447–449. 
25. Major side effects of systemic glucocorticoids. In. UpToDate, Matteson EL (Ed), UpToDate, 
Waltham, MA. (Accessed on February 8, 2017). 
26. Sarasquete ME, Garcia-Sanz R, Gonzalez D, et al. Minimal residual disease monitoring in 
multiple myeloma: a comparison between allelic-specific oligonucleotide real-time 
quantitative polymerase chain reaction and flow cytometry. Haematologica 2005; 90: 1365-
72 
27. Zamagni E, Nanni C, Mancuso K, et al. PET/CT improves the definition of complete 
response and allows to detect otherwise unidentifiable skeletal progression in multiple 
myeloma. Clin Cancer Res 2015; 21: 4384–90. 


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28. Usmani SZ, Mitchell A, Waheed S, et al. Prognostic implications of serial 18-fluoro-
deoxyglucose emission tomography in multiple myeloma treated with total therapy 3. Blood 
2013;121: 1819–23. 
29. Nanni C, Zamagni E, Versari A, et al. Image interpretation criteria for FDG PET/CT in 
multiple myeloma: a new proposal from an Italian expert panel. IMPeTUs (Italian Myeloma 
criteria for PET USe). Eur J Nucl Med Mol Imaging 2015; 43: 414–21. 
30. Durie BG, Harousseau JL, Miguel JS, et al, for the International Myeloma Working Group. 
International uniform response criteria for multiple myeloma. Leukemia 2006; 20: 1467–73. 
14/31 
31. Rajkumar SV, Harousseau JL, Durie B, et al, for the International Myeloma Workshop 
Consensus Panel 1. Consensus recommendations for the uniform reporting of clinical trials: 
report of the International Myeloma Workshop Consensus Panel 1. Blood 2011; 117: 4691–
95. 
 
 
 


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18. APPENDICES 
18.1 
Appendix A: ECOG Performance Status 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
Reference: Oken MM, Creech RH, Hormey RH et al. Toxicity and Response Criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5:649-655.  
 
 
 


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18.2 Appendix B: Cockcroft-Gault Equation 
 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
72 x serum creatinine in mg/dL 
 
Male CrCl = (140 - age in years) x weight in kg x 1.00  
72 x serum creatinine in mg/dL 
 
 
 


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18.3 
Appendix C: NYHA Classification 
 
Class 
Description 
I 
Subjects with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
II 
Subjects with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
III 
Subjects with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary 
physical activity causes fatigue, palpitation, dyspnea, or anginal pain. 
IV 
Subjects with cardiac disease resulting in inability to carry on 
physical activity without discomfort.  Symptoms of cardiac 
insufficiency or of the anginal syndrome may be present event at rest.  
If any physical activity is undertaken, discomfort is increased. 
Excerpt from Oxford Textbook of Medicine. Vol. 2, p.2228. Oxford Press. 1997. 
 
 
 

ICF_001.pdf: 
Official Title: LCI-HEM-MYE-CRD-002: A Phase II 
Study of Carfilzomib- Revlimid-Dexamethasone-
Elotuzumab in Relapsed/Refractory Multiple 
Myeloma 
NCT# 03361306
IRB-Approved Date: 09/15/2022