protocol # lci-hem-mye-crd-002
untitled h2

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
protocol # lci-hem-mye-crd-002
investigational new drug (ind) #

___________________________________________________________________________
The study will be conducted in compliance with the protocol, ICH/GCP and any applicable regulatory requirements.  
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.  
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.
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investigational new drug (ind) #

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  
| SYNOPSIS         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
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| 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 | Elotuzumab (BMS-901608, HuLuc63) is a first-in-class,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| RATIONALE        | 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. |  
I  
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| -                       | 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           | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Documented history of relapsed and/or refractory multiple |
| CRITERIA                | 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             | The primary objective of this study is to evaluate the VGPR+ rate in                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                           |
| CONSIDERATIONS          | 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. |                                                           |  
| TOTAL  NUMBER OF  SUBJECTS   | 40   |
|------------------------------|------|
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schema

then Q3  
  
Induction
Peripheral blood collection for correlatives  
| TABLE OF CONTENTS                                                                         |                                                                                                                                                                 |
|-------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|
| S SYNOPSIS .                                                                              |                                                                                                                                                                 |
| SCHEMA .                                                                                  |                                                                                                                                                                 |
| BACKGROUND AND RATIONALE .                                                                |                                                                                                                                                                 |
| 1.                                                                                        |                                                                                                                                                                 |
| 1.1                                                                                       | MM Multiple Myeloma (MM)                                                                                                                                        |
| 1.2                                                                                       | Carfilzomib (Kyprolis®), Lenalidomide (Revlimid®), Dexamethasone (KRd) in                                                                                       |
| Relapsed/Refractory MM                                                                    |                                                                                                                                                                 |
| 1.3                                                                                       | Elotuzumab .                                                                                                                                                    |
| 1.4                                                                                       | Study Rationale and Design                                                                                                                                      |
| 2.                                                                                        | OBJECTIVES .                                                                                                                                                    |
| 2.1                                                                                       | Primary Objective                                                                                                                                               |
| 2.2                                                                                       | Secondary Objectives                                                                                                                                            |
| 2.3                                                                                       | Safety Objectives ........................................................................................................................................ 9    |
| 2.4                                                                                       | Exploratory Objectives .............................................................................................................................. 9         |
| 3.                                                                                        | SUBJECT SELECTION ........................................................................................................................................... 9 |
| Subject Recruitment                                                                       |                                                                                                                                                                 |
| 3.1                                                                                       |                                                                                                                                                                 |
| 3.2                                                                                       | Inclusion Criteria .                                                                                                                                            |
| 3.3                                                                                       | Exclusion Criteria .                                                                                                                                            |
| 3.4                                                                                       | Screen Failures                                                                                                                                                 |
| 4.                                                                                        | REGISTRATION .                                                                                                                                                  |
| 5.                                                                                        | STUDY PLAN .                                                                                                                                                    |
| 5.1                                                                                       | KRd+Elotuzumab Induction Regimen                                                                                                                                |
| 5.2                                                                                       | R+Elotuzumab Maintenance Regimen .............................................................................................................. 15              |
| 6.                                                                                        | TREATMENT DETAILS AND DOSE MODIFICATIONS/DELAYS                                                                                                                 |
| General Rules for Dose Modifications/Delays for KRd+Elotuzumab Induction ............. 16 |                                                                                                                                                                 |
| 6.1                                                                                       |                                                                                                                                                                 |
| 6.2                                                                                       | General Rules for Dose Modifications/Delays for R+Elotuzumab Maintenance............. 17                                                                        |
| 6.3                                                                                       | Carfilzomib                                                                                                                                                     |
| 6.4                                                                                       | Elotuzumab .                                                                                                                                                    |
| 6.5                                                                                       | LENALIDOMIDE .                                                                                                                                                  |
| 6.6                                                                                       | DEXAMETHASONE                                                                                                                                                   |
| 6.7                                                                                       | Supportive Care                                                                                                                                                 |
| 6.8                                                                                       | Concomitant Medication                                                                                                                                          |
| 7.                                                                                        | STUDY CALENDAR .                                                                                                                                                |
| 8.                                                                                        | DETAILS ON STUDY PROCEDURES                                                                                                                                     |
| 8.1                                                                                       | Screening Procedures                                                                                                                                            |
| 8.2                                                                                       | Induction Procedures .                                                                                                                                          |
| 8.3                                                                                       | Maintenance Procedures .                                                                                                                                        |
| 8.4                                                                                       | Time of CR .                                                                                                                                                    |
| 8.5                                                                                       | Time of Disease Relapse/Progression                                                                                                                             |
| 8.6                                                                                       | Safety Follow-up Visit                                                                                                                                          |
| 8.7                                                                                       | Follow-up                                                                                                                                                       |
| 8.8                                                                                       | Biospecimen Correlative Studies                                                                                                                                 |  
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| 9.                                   | DISCONTINUATION FROM TREATMENT AND STUDY WITHDRAWAL ..... 40                                                                          |
| 9.1                                  | Treatment Discontinuation Criteria .                                                                                                  |
| 9.2                                  | Off Study.                                                                                                                            |
| 10.                                  | DRUG INFORMATION .                                                                                                                    |
| 10.1                                 | E Elotuzumab .                                                                                                                        |
| 10.2                                 | Carfilzomib                                                                                                                           |
| 10.3                                 | LENALIDOMIDE .                                                                                                                        |
| 10.4                                 | DEXAMETHASONE                                                                                                                         |
| 1.                                   | DATA AND SAFETY MONITORING PLANS .                                                                                                    |
| 11.1                                 | Safety Monitoring                                                                                                                     |
| DATA MONITORING                      |                                                                                                                                       |
| 11.2                                 | SAFETY DATA COLLECTION, RECORDING AND REPORTING.......................... 52                                                          |
| 12.                                  |                                                                                                                                       |
| 12.1                                 | DEFINITIONS                                                                                                                           |
| 12.2                                 | A Attribution                                                                                                                         |
| 12.3                                 | Timing and Reporting .                                                                                                                |
| 13.                                  | DISEASE EVALUATION .                                                                                                                  |
| 13.1                                 | IMWG 2016 Response Criteria                                                                                                           |
| 14.                                  | STATISTICAL CONSIDERATIONS .                                                                                                          |
| 14.1                                 | Milestones .                                                                                                                          |
| 14.2                                 | Sample Size Determination                                                                                                             |
| 14.3                                 | Endpoint Definitions .                                                                                                                |
| 14.4                                 | Analysis Populations                                                                                                                  |
| 14.5                                 | Analysis Methods                                                                                                                      |
| STUDY COMPLETION OR TERMINATION      |                                                                                                                                       |
| 15.                                  |                                                                                                                                       |
| 15.1                                 | COMPLETION                                                                                                                            |
| 15.2                                 | Termination                                                                                                                           |
| 16.                                  | STUDY MANAGEMENT .                                                                                                                    |
| 16.1                                 | IRB Approval                                                                                                                          |
| 16.2                                 | Informed Consent                                                                                                                      |
| Protocol Adherence                   |                                                                                                                                       |
| 16.3                                 |                                                                                                                                       |
| 16.4                                 | Changes to the Protocol and/or Informed Consent .................................................................................. 65 |
| 16.5                                 | Other Protocol Deviations                                                                                                             |
| Retention of Records                 |                                                                                                                                       |
| 16.6                                 |                                                                                                                                       |
| 16.7                                 | Ethical and Legal Conduct of the Study .                                                                                              |
| 16.8                                 | Confidentiality of Records .                                                                                                          |
| Compliance with ClinicalTrials.gov . |                                                                                                                                       |
| 16.9                                 | REFERENCES                                                                                                                            |
| 17.                                  |                                                                                                                                       |
| 18.                                  | APPENDICES .                                                                                                                          |
| 18.1                                 | Appendix A: ECOG Performance Status                                                                                                   |
| 18.2                                 | Appendix B: Cockcroft-Gault Equation .                                                                                                |
| 18.3                                 | Appendix C: NYHA Classification                                                                                                       |
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1. background and rationale 1.1

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 nonproteasomal proteases when compared to bortezomib [3]. Pre/post carfilzomib in vivo pharmacogenomics gene expression profiling data from the University of Arkansas Car505 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.
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1.2 carfilzomib (kyprolis) lenalidomide (revlimid)

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/m2of carfilzomib) was recommended for the phase II portion
(with an initial dose of 20mg/m2on 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].  
1 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].  
2
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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 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.
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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.
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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.
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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 MM were either ongoing or complete. One additional trial of monotherapy has been conducted in high risk smoldering myeloma.
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1.3.4.1 combination with lenalidomide and

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/m2IV 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].
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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 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. Postinduction, 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 proinflammatory 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 7 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.
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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.
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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].
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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].  
- 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.
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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.
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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
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3. subject selection

3.1 **Subject Recruitment**
Subjects will be recruited at Levine Cancer Institute (LCI) locations and potentially at other participating sites. 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.
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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.  
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                | ≤1.5 × upper limit of normal (ULN) OR                                                                    |
| Creatinine clearance                     | ≥ 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 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).
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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
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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
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.
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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.
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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.
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5. study plan see schema

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. 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.
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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.  
| 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 |
| 28 mg                                                                                                                           | Oral     | Once weeklye on D1, 8, 15, 22 | Cycles 1-2                     |            |
| Dexamethasoneg                                                                                                                  | 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 |          |                               |                                |            |  
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  
Elotuzumabb20 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.  
bIf 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/m2should  
be maintained and not increased to 56mg/m2. The dose may be escalated to 56 mg/m2if 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.
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table 1 krd+elotuzumab induction 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.  
| Drug                     | Dose            | Route   | Schedule                 | 4-Week     |
|--------------------------|-----------------|---------|--------------------------|------------|
| (28D) Cycle              |                 |         |                          |            |
| Lenalidomide             | 15 mg or LTD if | Oral    | Once a day at bedtime on | Cycles 1-n |
| <15mga                   | D1-21           |         |                          |            |
| Elotuzumab               | 20 mg/kgb       | IV      | D1 of each cycle         | Cycles 1-n |
| aLTD=last tolerated dose |                 |         |                          |            |  
Elotuzumab 20 mg/kgbIV 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.
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table 2 r+elotuzumab maintenance regimen

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.
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note in each dose modification

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 protocolmandated 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

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.
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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.
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6.3.2 pre- and post-dose hydration

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 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.
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6.3.3 first dose effect for

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.
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6.3.4 dose modifications for carfilzomib-related

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:  
| 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. |          |  
If dose reductions of carfilzomib beyond those levels listed in Table 3 are required, this agent should be permanently discontinued.
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6.3.4.1 hematologic toxicities

NOTE: Thrombocytopenia has been transient and typically resolves during the week between treatments.  
| 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 |                                                                                                                               |  
Table 4: Dose Modifications for Hematologic Toxicities
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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. 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.  
| 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                                                                                                                                                               | -                                                                                                                                 | Hold dose; resume with dose reduced by 1 level                                                                                                      |
| toxicitya                                                                                                                                                                               | 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                                                                                                                                                           | -                                                                                                                                 | Hold dose; and manage per standard of care including                                                                                                |
| (TMA) (TTP/HUS) is suspected                                                                                                                                                            | 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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table 5 dose modifications for

| 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 |                                                                          |                                                                                                                                                                                                                                                               |
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6.4 elotuzumab 6.4.1 premedication 6.4.1.1

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
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6.4.1.2 in subjects with a

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  
| Prior IRR                                                                                                                                                                                                                               | Dexamethasone Dose and Schedule                                                                                                                                                                                          |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade ≤ 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                                                                                                                                                                                                                          | 8 mg 12 - 24 hours and 8 mg 3 hours prior to elotuzumab AND                                                                                                                                                              |
| Grade 2                                                                                                                                                                                                                                 | 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. |                                                                                                                                                                                                                          |
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table 6 dexamethasone premedication for

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:  
| 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                      | -                                               | -        |          |
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table 7 infusion rate for

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 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.  
| 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         |          |
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6.4.3 dose delays for elotuzumab

No dose reductions of elotuzumab are allowed.  
| 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         |
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table 9 allowed delays of

| Grade           | Management                                                                                                                                                                                                                              |
|-----------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 1               | No intervention required, however, increased monitoring is recommended.                                                                                                                                                                 |
| 2 or 3a         | Interrupt infusion. The subject should be treated as clinically indicated with one                                                                                                                                                      |
| during infusion | or more of the following medications or interventions: antiemetics,  antihistamines, analgesics, corticosteroids, leukotriene inhibitors, oxygen  inhalation, epinephrine, bronchodilators, or other supportive measures as  indicated. |  
| 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, bronchodialators, 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.                                              |
| 4 a                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | 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.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                              |
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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.
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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

Refer to the following table for lenalidomide dose levels when dose reductions are required during induction or maintenance:  
| 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 |
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table 11 dose levels for

*If dose reduction required due to renal dysfunction, see Section 6.5.2.2 Table 11. **Dose level 0 is the starting dose.
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6.5.2.1 hematologic toxicities table 12

| 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.
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table 13 dose modifications for

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. |
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6.5.2.3 other non-specified non-hematologic toxicities

| Toxicity                                                                                                                                    | Recommended Action         |                                                |
|---------------------------------------------------------------------------------------------------------------------------------------------|----------------------------|------------------------------------------------|
| Other ≥ grade 3 non-hematologic                                                                                                             | -                          | Hold dose; resume with dose reduced by 1 level |
| toxicitya                                                                                                                                   | 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 |                            |                                                |
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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. Refer to the following table for dexamethasone dose levels when dose reductions are required during induction:  
Dose **Level** PO IV  
0 28 mg 8 mg  
-1 12 mg 8 mg -2 0 mg 8 mg  
Table 15: Dose Levels for Dexamethasone during Induction on Elotuzumab Dosing Days 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
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6.6.2 dose modifications for dexamethasone-related

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.  
| Dose Level   | PO    |
|--------------|-------|
| 0            | 40 mg |
| -1           | 20 mg |
| -2           | 12 mg |
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table 17 dose modifications for

| 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 |  
| despite above measures, discontinue dexamethasone  permanently.                                                                                                             |                                                                                                                                                                                      |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Acute pancreatitis                                                                                                                                                          | Discontinue dexamethasone permanently.                                                                                                                                               |
| Edema ≥ Grade 3 (limiting function and                                                                                                                                      | Diuretics as needed, and restart dexamethasone                                                                                                                                       |
| unresponsive to therapy or anasarca)                                                                                                                                        | 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                                                                                                                               | Hold dexamethasone dose. Resume dexamethasone                                                                                                                                        |
| related to dexamethasonea                                                                                                                                                   | 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 |                                                                                                                                                                                      |
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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 SponsorInvestigator.
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6.8 concomitant medication 6.8.1 recommended

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.
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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.
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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.
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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.
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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.
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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                                                               | Induction Cycles 3-4 2       | Maintenance   | Safety   |    |     |     |     |    |
|-------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------|------------------------------|---------------|----------|----|-----|-----|-----|----|
| Cycles 1-2 2                                                                                                                              | Cycles 1+4                                                                                                                 | 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                                                                                                                   | X                                                                                                                          | X                                                                       | X                            | X             | X        |    |     |     |     |    |
| 22 Vital signs8                                                                                                                           | X                                                                                                                          | X                                                                       | X                            | X             | X        | X  | X   | X   |     |    |
| ECG                                                                                                                                       | X                                                                                                                          | X                                                                       | X                            | X             |          |    |     |     |     |    |
| ECHO or MUGA                                                                                                                              | X                                                                                                                          |                                                                         |                              |               |          |    |     |     |     |    |
| Hepatitis B virus (HBV)                                                                                                                   | X                                                                                                                          | X                                                                       |                              |               |          |    |     |     |     |    |
| serology20                                                                                                                                | 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                                                                                                               | X                                                                                                                          | X                                                                       | X                            | X3            |          |    |     |     |     |    |
| evaluation12 Bone marrow aspirate and                                                                                                     | X                                                                                                                          | X                                                                       |                              |               |          |    |     |     |     |    |
| biopsy13                                                                                                                                  | Post-induction  and CR                                                                                                     |                                                                         |                              |               |          |    |     |     |     |    |
| Skeletal Survey14                                                                                                                         | X                                                                                                                          | As clinically indicated                                                 |                              |               |          |    |     |     |     |    |
| Assess extramedullary                                                                                                                     | X                                                                                                                          | Assess at CR and/or if clinically indicated                             |                              |               |          |    |     |     |     |    |
| plasmacytomas15 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  |     |     |     |    |  
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 recalculated. 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 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

- **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 AntiHBs
- **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.
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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
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8.2.2 day 1 cycles 1-4

- **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
- **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
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- 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. 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.
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- blood sample for correlatives

- **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
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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.
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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
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8.3.2 day 1 cycles 1+

- **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
- **Vital Signs:** Vital signs should include temperature, heart rate, blood pressure and respiratory rate. Measure prior to elotuzumab infusion.
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- 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.
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8.3.3 every 6 months for

o Bone marrow aspirate and biopsy (see Sections 7 and 8.8.3 ): Disease evaluation per standard of care
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8.4 time of cr -

o Bone marrow aspirate and biopsy (see Section 8.8.3) o Assess extramedullary plasmacytomas: PET/CT and/or WB-MRI
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8.5 time of disease relapse/progression

o Bone marrow aspirate and biopsy (see Section 8.8.3): At discretion of investigator
- **Blood sample for correlatives:** See Section 8.8.1.
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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.  
- **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
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- 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.
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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 followup, 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 followed until all subjects have discontinued study treatment and completed the Safety Followup Visit (see above).
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8.8 biospecimen correlative studies 8.8.1

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.
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8.8.2 blood samples for exploration

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.  
- 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).
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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.
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9. discontinuation from treatment and

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.
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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  
- Subject death.
Subjects that are Off Study will not participate in any study related procedures, including data collection.
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10. drug information 10.1 elotuzumab

Elotuzumab will be supplied free of charge to study subjects by the manufacturer, BMS as Elotuzumab for Injection, 400 mg/vials.
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10.1.2 preparation

The instructions will be found in the package insert and Investigator's Brochure.
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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.
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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.
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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).
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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).  
| SAR                               | Frequency of all   | Occurrence of   |
|-----------------------------------|--------------------|-----------------|
| SARs                              | LifeThreatening  SARs                    |                 |
| Herpes zoster                     | Uncommon           | No              |
| Pneumonia                         | Common             | No              |
| Pneumonia Pneumococcal            | Uncommon           | No              |
| Pyrexia                           | Common             | No              |
| Upper respiratory tract infection | Uncommon           | No              |  
Serious Adverse Reactions for Elotuzumab Considered Expected 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          | Uncommon                                       |
| Pneumonia Pneumonia             | Uncommon                                       |
| Pneumonia Fungal                | Uncommon                                       |
| Pulmonary Sepsis                | Uncommon                                       |  
| Urinary Tract Infection     | Uncommon   |
|-----------------------------|------------|
| Urosepsis                   | Uncommon   |
| Neutropenia                 | Uncommon   |
| Thrombotic Thrombocytopenia | Uncommon   |
| Purpura 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.
protocol signature page phase ii
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.
protocol signature page phase ii
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.
protocol signature page phase ii
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.
protocol signature page phase ii
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.
protocol signature page phase ii
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.