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protocol title

E- PRISM (Precision Intervention Smoldering Myeloma): A Phase II Trial of Combination of Elotuzumab, Lenalidomide and Dexamethasone in High-Risk Smoldering Multiple Myeloma NCT \#: NCT02279394
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irb approval date 04/09/2021

Local **Protocol \#:** *14-338* Bristol-Myers Squibb **Protocol** \#: CA 204-119 Celgene **Protocol** \#: RV-CL-MM-PI-004473 TITLE: E- PRISM (Precision Intervention Smoldering Myeloma): A Phase II Trial of Combination of Elotuzumab, Lenalidomide and Dexamethasone in High-Risk Smoldering Multiple Myeloma Coordinating **Center:** Dana-Farber Cancer Institute 450 Brookline Avenue Boston, MA 02115 Phone: 617-632-4198 Fax: 617-582-8608 Principal Investigator **(PI):** Irene M. Ghobrial, MD
Dana-Farber Cancer Institute Irene_Ghobrial@dfci.harvard.edu Statistician: Project **Manager:** Lorenzo Trippa Alexandra Savell Dana-Farber Cancer Institute Dana-Farber Cancer Institute Ltrippa@jimmy.harvard.edu Asavell@partners.org Agent(s): Elotuzumab, Bristol-Myers Squibb Lenalidomide, Celgene Dexamethasone, commercial IND \#: 122322 Amendment 10/ 10.0/ April 9 th, 2021  
  
t(14:16), 17p deletion, or p53 mutation, and 1q amplification
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table of contents

| TABLE OF CONTENTS                                                                                                   |                                                                                                                                                            |                                                                                                                                                |
|---------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------|
| SCHEMA .                                                                                                            |                                                                                                                                                            |                                                                                                                                                |
| SYNOPSIS .                                                                                                          |                                                                                                                                                            |                                                                                                                                                |
| 1.                                                                                                                  | OBJECTIVES ..............................................................................................................................................9 |                                                                                                                                                |
| 1.1                                                                                                                 | Study Design .                                                                                                                                             |                                                                                                                                                |
| Primary Objectives                                                                                                  |                                                                                                                                                            |                                                                                                                                                |
| 1.2                                                                                                                 |                                                                                                                                                            |                                                                                                                                                |
| 1.3                                                                                                                 | Secondary Objectives ...................................................................................................................10                 |                                                                                                                                                |
| 2.                                                                                                                  | BACKGROUND                                                                                                                                                 |                                                                                                                                                |
| 2.1                                                                                                                 | MM                                                                                                                                                         |                                                                                                                                                |
| 2.2                                                                                                                 | MM consistently precedes multiple myeloma ............................................11                                                                   |                                                                                                                                                |
| 2.3                                                                                                                 | Molecular studies in MGUS and SMM.....................................................................................11                                   |                                                                                                                                                |
| 2.4                                                                                                                 | Definition of SMM.................................................................................................................................13       |                                                                                                                                                |
| 2.5                                                                                                                 | Definitions of high-risk SMM.                                                                                                                              |                                                                                                                                                |
| 2.6                                                                                                                 | Treatment of high risk SMM.....................................................................................................14                          |                                                                                                                                                |
| 2.7                                                                                                                 | Elotuzumab                                                                                                                                                 |                                                                                                                                                |
| 2.8                                                                                                                 | Rationale for Elotuzumab in SMM........................................................................................15                                  |                                                                                                                                                |
| 2.9                                                                                                                 | Rationale for dose and schedule of Elotuzumab ...............................................................16                                            |                                                                                                                                                |
| 2.10                                                                                                                | T Trial Rationale                                                                                                                                          |                                                                                                                                                |
| 2.11                                                                                                                | Correlative Studies Background                                                                                                                             |                                                                                                                                                |
| PARTICIPANT SELECTION                                                                                               |                                                                                                                                                            |                                                                                                                                                |
| 3.                                                                                                                  | 3.1                                                                                                                                                        | Eligibility Criteria .......................................................................................................................23 |
| 3.2                                                                                                                 | Exclusion Criteria                                                                                                                                         |                                                                                                                                                |
| Inclusion of Women and Minorities................................................................................26 |                                                                                                                                                            |                                                                                                                                                |
| 3.3                                                                                                                 |                                                                                                                                                            |                                                                                                                                                |
| 4.                                                                                                                  | REGISTRATION PROCEDURES                                                                                                                                    |                                                                                                                                                |
| 4.1                                                                                                                 | General Guidelines for DF/HCC and DF/PCC Institutions                                                                                                      |                                                                                                                                                |
| 4.2                                                                                                                 | Registration Process for DF/HCC and DF/PCC Institutions                                                                                                    |                                                                                                                                                |
| 4.3                                                                                                                 | General Guidelines for Other Investigative Sites ...........................................................27                                             |                                                                                                                                                |
| 4.4                                                                                                                 | Registration Process for Other Investigative Sites ........................................................27                                              |                                                                                                                                                |
| 5.                                                                                                                  | TREATMENT PLAN .                                                                                                                                           |                                                                                                                                                |
| 5.1                                                                                                                 | T Treatment Regimen                                                                                                                                        |                                                                                                                                                |
| 5.2                                                                                                                 | Pre-Treatment Criteria                                                                                                                                     |                                                                                                                                                |
| 5.3                                                                                                                 | Agent Administration ...............................................................................................................31                     |                                                                                                                                                |
| 5.4                                                                                                                 | General Concomitant Medication and Supportive Care Guidelines ......................33                                                                     |                                                                                                                                                |
| 5.5                                                                                                                 | Criteria for Taking a Participant Off Protocol Therapy .............................................34                                                     |                                                                                                                                                |
| 5.6                                                                                                                 | Duration of Follow Up                                                                                                                                      |                                                                                                                                                |
| 5.7                                                                                                                 | Criteria for Taking a Participant Off Study                                                                                                                |                                                                                                                                                |
| DOSING DELA YS/DOSE MODIFICATIONS ......................................................................36          |                                                                                                                                                            |                                                                                                                                                |
| 6.                                                                                                                  | E Elotuzumab                                                                                                                                               |                                                                                                                                                |
| 6.1                                                                                                                 | CONFIDENTIAL                                                                                                                                               |                                                                                                                                                |
| This document is confidential. Do not disclose or use except as authorized.                                         |                                                                                                                                                            |                                                                                                                                                |  
| Version Date: 4.9.2021                                                                                                            |                                                                                                                                                             |
|-----------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 6.2                                                                                                                               | Lenalidomide                                                                                                                                                |
| 6.3                                                                                                                               | DEXAMETHASONE ..................................................................................................................40                          |
| 6.4                                                                                                                               | Guidelines for Elotuzumab Infusion in Subjects with Infusion Reactions.............42                                                                       |
| 7.                                                                                                                                | ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS.................................44                                                                         |
| 7.1                                                                                                                               | Expected Toxicities ................................................................................................................44                      |
| 7.2                                                                                                                               | Adverse Event Characteristics                                                                                                                               |
| 7.3                                                                                                                               | Expedited Adverse Event Reporting .............................................................................46                                           |
| 7.4                                                                                                                               | DF/HCC Expedited Reporting Guidelines ......................................................................46                                              |
| Overdose of Lenalidomide ......................................................................................................49 |                                                                                                                                                             |
| 7.5                                                                                                                               | Expedited Reporting to the Food and Drug Administration (FDA).........................49                                                                    |
| 7.6                                                                                                                               | Expedited Reporting to Bristol-Myers Squibb (BMS)                                                                                                           |
| 7.7                                                                                                                               | Expedited Reporting to Celgene ......................................................................................49                                     |
| 7.8                                                                                                                               | Expedited Reporting to Hospital Risk Management                                                                                                             |
| 7.9                                                                                                                               | Routine Adverse Event Reporting                                                                                                                             |
| 8.                                                                                                                                | PHARMACEUTICAL INFORMATION ..............................................................................................50                                 |
| E Elotuzumab                                                                                                                      |                                                                                                                                                             |
| 8.1                                                                                                                               |                                                                                                                                                             |
| 8.2                                                                                                                               | Lenalidomide                                                                                                                                                |
| 8.3                                                                                                                               | DEXAMETHASONE ...........................................................................................................................................54 |
| 9.                                                                                                                                | BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ................................................56                                                              |
| Bone Marrow Aspirate Samples ..................................................................................................57 |                                                                                                                                                             |
| 9.1                                                                                                                               |                                                                                                                                                             |
| 9.2                                                                                                                               | Peripheral Blood Samples ................................................................................................................58                 |
| 10.                                                                                                                               | STUDY CALENDAR...................................................................................................................................61         |
| 11.                                                                                                                               | MENT OF EFFECT ...............................................................................................................................62            |
| 11.1                                                                                                                              | Development of symptomatic disease .................................................................................62                                      |
| 11.2                                                                                                                              | Antitumor Effect .................................................................................................................................63        |
| 12.                                                                                                                               | DATA REPORTING / REGULATORY REQUIREMENTS ................................................70                                                                 |
| 12.1                                                                                                                              | DATA Reporting ................................................................................................................................70           |
| 12.2                                                                                                                              | DATA SAFETY Monitoring ................................................................................................................70                   |
| 13.                                                                                                                               | STATISTICAL CONSIDERATIONS. ...........................................................................................70                                   |
| 13.1                                                                                                                              | Study Design/Endpoints .........................................................................................................70                          |
| 13.2                                                                                                                              | Sample Size, Accrual Rate and Study Duration ................................................................72                                             |
| 13.3                                                                                                                              | Stratification Factors ....................................................................................................................72               |
| 13.4                                                                                                                              | Interim Monitoring Plan                                                                                                                                     |
| 13.5                                                                                                                              | Stopping Rule for Safety ...............................................................................................................72                  |
| PUBLICATION PLAN                                                                                                                  |                                                                                                                                                             |
| 14.                                                                                                                               | REFERENCES                                                                                                                                                  |
| 15.                                                                                                                               |                                                                                                                                                             |
| APPENDIX A: PERFORMANCE STATUS CRITERIA ..................................................................78                      |                                                                                                                                                             |  
APPENDIX B: PREPARATION AND ADMINISTRATION OF ELOTUZUMAB...................79 APPENDIX C: 14-338 SPECIMEN COLLECTION SCHEDULE ..............................................82 APPENDIX D: 14-338 SPECIMEN REQUISITION....................................................................84 APPENDIX E: DF/HCC MULTI-CENTER DATA AND SAFETY MONITORING PLAN......85  
| 1.   | INTRODUCTION 89 1.1 Purpose 89 1.2 Multi-Center Data and Safety Monitoring Plan Definitions 89                                                                                                                                                                                                                                                                                                                                                 |
|------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 2.   | GENERAL ROLES AND RESPONSIBILITIES 90 2.1 DF/HCC Sponsor 90 2.2 Coordinating Center 91 2.3 Participating Institution 91                                                                                                                                                                                                                                                                                                                        |
| 3.   | DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 92 3.1 Protocol Distribution 92 3.2 Protocol Revisions and Closures 92 3.3 Informed Consent Requirements 93 3.4 IRB Documentation 93 3.5 IRB Re-Approval 93 3.6 Participant Confidentiality and Authorization Statement 94 3.7 DF/HCC Multi-Center Protocol Registration Policy 94 3.8 DF/HCC Protocol Case Number 95 3.9 Safety Assessments and Toxicity Monitoring 96 3.10 Data Management 97 |
| 4.   | REQUISITIONING INVESTIGATIONAL DRUG 97                                                                                                                                                                                                                                                                                                                                                                                                         |
| 5.   | MONITORING: QUALITY CONTROL 98 5.1 Ongoing Monitoring of Protocol Compliance 98 5.2 Monitoring Reports 99 5.3 Accrual Monitoring 99                                                                                                                                                                                                                                                                                                            |
| 6.   | AUDITING: QUALITY ASSURANCE 99 6.1 Audit Plan: DF/HCC Sponsored Trials 99 6.2 Audit Notification 99 6.3 Audit Reports 100 6.4 Participating Institution Performance 100                                                                                                                                                                                                                                                                        |  
| SYNOPSIS                       | Early therapeutic interventions in patients with smoldering MM will  prevent/delay progression to overt MM. Recent studies of a phase III trial of  lenalidomide and dexamethasone vs. placebo showed improved response,  progression free survival and overall survival in patients with high risk SMM compared to placebo control. Therefore, there is a need to examine  novel therapeutic combinations in patients with high risk smoldering MM.  Based on the activity of lenalidomide and dexamethasone in patients with  high risk SMM and based on the safety and activity profile of elotuzumab  and lenalidomide in patients with relapsed MM, we propose to examine the  activity of elotuzumab and lenalidomide in patients with high risk SMM. We  will identify the role of early intervention on prevention of progression in  patients with high-risk SMM who have a 50% rate of progression at 2 years.   |
|--------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Study Rationale                | Elotuzumab is a humanized recombinant monoclonal IgG1 antibody  product directed to human SLAMF7 (CD2-subset-1, also known as  CRACC), a cell surface glycoprotein that is highly expressed in MM cells.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| Products                       | Lenalidomide (REVLIMID®), a thalidomide analogue, is an  immunomodulatory agent with antiangiogenic properties. Dexamethasone is a synthetic adrenocortical steroid. Primary Objectives - To determine the proportion of high risk smoldering multiple  myeloma patients who are progression free at 2 years after receiving  elotuzumab, lenalidomide and dexamethasone combination therapy Secondary Objectives - To assess the response rate of the combination in these patients - To assess time to progression - To assess duration of response - To assess overall survival - To assess safety of the combination - To examine molecular evolution of the tumor cells - To determine the role of immune cells in the progression of  smoldering MM - To determine minimal residual disease (MRD) Response will be assessed using the IMWG criteria for response in Multiple                                         |
| Efficacy                       | Myeloma.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| Endpoints Safety  Endpoints    | AEs will be evaluated during the treatment period using CTCAE v4.03.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| Study  Objectives Study Design | This is a phase II study using the combination of elotuzumab, lenalidomide  and dexamethasone in patients with high-risk smoldering multiple myeloma. Each Cycle = 28 days  Cycle 1 & 2 - Elotuzumab (IV): Days 1, 8, 15 ,22 - Lenalidomide (oral): Day 1-21                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| Dosing Regimen                 | CONFIDENTIAL                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |  
CONFIDENTIAL  
This document is confidential. Do not disclose or use except as authorized.  
6  
| Version Date: 4.9.2021 -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Dexamethasone: (oral and IV): Days 1, 8, 15, 22   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------|
| Cycles 3-8 - Elotuzumab (IV): Days 1 and 15 - Lenalidomide (oral): Day 1-21 - Dexamethasone: (oral and IV): Days 1, 8, 15 Cycles 9-24 (maintenance) - Elotuzumab (IV): Days 1 - Lenalidomide (oral): Day 1-21 - Age  18 years. - Must have smoldering myeloma with high risk markers based on the  Mayo OR the Spanish criteria and including the new criteria for SMM as  described below: o Monoclonal protein in the serum of  3gm/dL and >10% plasma  cells in the bone marrow with a free light chain ratio outside the  range of 0.125 to 8 OR o Ratio or abnormal to normal bone marrow plasma cells greater  than or equal to 95 percent or at least one immunoglobulin level  lower than the normal range - No evidence of CRAB criteria or new criteria of overt MM which  includes the following: o Increased calcium levels (corrected serum calcium >0.25 mmol/L  (>1mg/dL) above the upper limit of normal OR >2.75 mmol/L  (>11mg/dL) o Renal insufficiency (attributable to myeloma); o Anemia (Hgb 2g/dL below the lower limit of normal or <10g/dL); o Bone lesions (lytic lesions or generalized osteoporosis with  compression fractures) o No evidence of the following new criteria for active MM  including the following: Bone marrow plasma cells ≥60%,  Serum involved/uninvolved FLC ratio ≥100, and MRI with more  than one focal lesion (>5mm) - ECOG Performance Status (PS) 0, 1, or 2. (Appendix A) - The following laboratory values obtained  21days prior to registration: o ANC  1000/L o PLT  50,000/L o Total bilirubin ≤ 2.0 mg/dL (If total is elevated check direct and  if normal patient is eligible.) o AST  3 x institutional upper limit of normal (ULN) |                                                   |
| SelectInclusion  Criteria                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                   |  
| o                                         | ALT  3 x institutional upper limit of normal (ULN)                                                                                                                                                                                                                                                                                                                                             |
|-------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| -                                         | Estimated creatinine clearance  60mL/min or a creatinine  2.2 mg/dL                                                                                                                                                                                                                                                                                                                           |
| -                                         | Symptomatic Multiple Myeloma or any evidence of CRAB criteria. Any  prior therapy for active Myeloma should also be excluded. Prior therapy  for smoldering myeloma is not an exclusion criteria. Concurrent therapy  with bisphosphonates are not excluded.                                                                                                                                    |
| -                                         | Other concurrent chemotherapy, immunotherapy, radiotherapy, or any  ancillary therapy considered investigational. Prior therapy with  bisphosphonate is allowed. Prior radiation therapy to a solitary  plasmacytoma is allowed. Prior clinical trials for smoldering MM or  MGUS are allowed as long as the last therapy was at least 2 months prior  and there was no improvement in M spike. |
| Select Exclusion  Criteria Study Duration | 60 months                                                                                                                                                                                                                                                                                                                                                                                       |
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1. objectives

The paradigm of therapy in Smoldering Multiple Myeloma (SMM) is changing as we develop better therapeutic agents that prevent end organ damage and improve survival of patients with multiple myeloma (MM)1-3. Indeed, recent studies of a phase III trial of lenalidomide and dexamethasone versus placebo showed improved response, progression free survival and overall survival in patients with high risk smoldering MM compared to placebo control4. Therefore, there is a need to examine novel therapeutic combinations in patients with high risk smoldering MM. Based on the activity of lenalidomide and dexamethasone in patients with high risk SMM and based on the safety and activity profile of elotuzumab and lenalidomide in patients with relapsed MM5-8, we propose to examine the activity of elotuzumab and lenalidomide in patients with high risk SMM.  
Pretreatment of MM cells with lenalidomide in-vitro enhances elotuzumab-induced antibodydependent cell-mediated cytotoxicity (ADCC) against MM cells and this has also been demonstrated in in *vivo* xenograft MM models6. The mechanism of synergism between these two agents has not been fully explored, however, recent discoveries into the precise mechanism of action of lenalidomide in MM has provided some insight9; lenalidomide-enhanced production of the cytokine interleukin-2 (IL-2), which spurs T cell production and stimulation of NK cells. The importance of the T cell mediated effect of lenalidomide has recently been elegantly demonstrated by two studies9,10, uncovering previously unknown mechanisms of action for this drug in MM. Lenalidomide induced IL-2 production in T cells was found to be due to the depletion of two proteins, IKZF1 and IKZF3. These proteins normally function to bind the IL-2 promoter and repress IL-2 transcription in T cells, treatment with lenalidomide markedly depletes IKZF1 and IKZF3 in T cells inducing IL-2 production and T cell activation. IL-2 is known to exert anti-myeloma activity through activation of NK cells. Treatment with lenalidomide could therefore prime NK-cells for Elotuzumab-mediated ADCC, which may explain the synergistic anti-myeloma effect of these therapies. Additionally, Elotuzumab itself may activate a subset of CD8+ T cells which express EAT-2, and has been shown to bind to CD3+CD8+ T cells in blood and bone marrow from MM patients. Interestingly, both EAT-2 and CS-1 are located on chromosome 1q, this region is amplified in 30-50% of MM patients and is associated with poor prognosis and lack of response to lenalidomide plus dexamethasone. 1q amplification is known to be an early event in myelomagenesis and has been associated with an increased risk of conversion from SMM to overt MM. Our overarching hypothesis is that early therapeutic interventions in patients with smoldering MM will prevent/delay progression to overt MM. We will examine the *in vivo* activity and safety of elotuzumab and lenalidomide in patients with high-risk SMM. We will identify the role of early intervention on prevention of progression in patients with high-risk SMM who have a 50% rate of progression at 2 years. This will be performed in a phase II study to determine progression-free survival (PFS) in this patient population. Secondary endpoints include response rate, safety of this combination in patients with high-risk SMM.
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1.1 study design

This is a phase II study using the combination of elotuzumab, lenalidomide and dexamethasone in patients with high-risk smoldering multiple myeloma.
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1.2 primary objectives

- To determine the proportion of high risk smoldering multiple myeloma patients who are progression free at 2 years after receiving elotuzumab, lenalidomide and dexamethasone combination therapy
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1.3 secondary objectives

- To assess the response rate of the combination in these patients - To assess time to progression
- To assess duration of response
- To assess overall survival - To assess safety of the combination
- To examine molecular evolution of the tumor cells obtained
- To determine the role of immune cells in the progression of smoldering MM
- To determine minimal residual disease (MRD)
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2. background 2.1 multiple myeloma

Multiple myeloma is a plasma cell neoplasm characterized by multifocal proliferation of clonal, long-lived plasma cells associated with an overproduction of monoclonal gammaglobulin 11. In 2010 the International Myeloma Working Group (IMWG) defined monoclonal gammopathy of undetermined significance (MGUS) by the presence of serum M-protein < 3g/dL, clonal plasma cell population in the bone marrow < 10%, and the absence of end-organ damage such as hypercalcemia (serum calcium ≥ 11.5 mg/dL), renal insufficiency (serum creatinine ≥ 2 mg/dL), anemia (hemoglobin value below the lower limit of normal by more than 2 g/dL or hemoglobin value < 10 g/dL) and lytic bone lesions (CRAB features) that can be attributed to the plasma cell proliferative disorder 12. Smoldering multiple myeloma was defined by the presence of serum Mprotein ≥ 3 g/dL and/or clonal bone marrow plasma cells ≥ 10% and the absence of CRAB
features clinically. In a large population based study in Olmsted County, MN, Kyle et al. analyzed serum samples of more than 75% of residents, 50 years or older, within the county 13. They identified MGUS in 694 of 21,463 patients tested (3.2%). While the overall prevalence was noted to be 3.2% (95 % CI, 3.0 to 3.5), there was a significant age dependent increase in both sexes with the prevalence among persons 80 years of age or older 4 times as high as among those 50-59 years of age. Ageadjusted rates were higher in men (4.0 %, 95% C.I., 3.5 to 4.4) than in women (2.7%, 95% C.I.,
2.4 to 3.0). In a subsequent study on a majority of the same patients from Olmsted County, Dispenzieri, et al., used the free light chain assay (FREELITE) and showed that 0.8% of people older than 50 years had light chain-MGUS. The total MGUS prevalence including the light chain-MGUS cases was noted at 4.2% (95% C.I., 3.9 to 4.5%) 14. A limitation of both these studies was that 97.3% of the residents of Olmsted County were white. For SMM patients a M-protein ≥ 3 g/dL, a FLC ratio outside the range of 0.125 to 8, and ≥ 10%
plasma cells in the bone marrow are considered as adverse factors in this model 15,16. The 5-year rate of progression in patients with 1, 2 and 3 risk factors was 25%, 51% and 76% respectively. The time to progression with these risk factors was 10, 5.1 and 1.9 years respectively. Recently Rajkumar et al. have proposed that SMM with >60% plasma cells progress to multiple myeloma within 2 years in 95% cases and should be treated at diagnosis even in the absence of symptoms 17. Table 1: Mayo Clinic model for risk factors and % risk of progression for smoldering MM  
| Model                                                                          | No. of risk factors   | 5-year progression %   | Time to progression  in years   |
|--------------------------------------------------------------------------------|-----------------------|------------------------|---------------------------------|
| Mayo Clinic model                                                              | 1                     | 25                     | 10                              |
| Risk factors: M                                                                                | 2                     | 51                     | 5.1                             |
| protein ≥ 3.0g/dL, ≥10% plasma cells in the BM, FLC ratio outside the range of | 3                     | 76                     | 1.9                             |
| 0.125 to 8                                                                     |                       |                        |                                 |
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2.2 mgus and smm consistently

Since the early description of monoclonal gammopathy of undermined significance it was known that some cases of MGUS progressed to symptomatic myeloma, but it was not clear whether all cases of myeloma are preceded by MGUS. In a study of more than 77,000 individuals, 55 to 74 years of age, from a cancer screening trial, Landgren et al. found 71 patients who developed multiple myeloma18. They performed serum protein electrophoresis, immunofixation and kappalambda free light chain assay on prediagnostic samples in these patients. The study showed that patients who eventually developed multiple myeloma consistently had MGUS in the years preceding development of multiple myeloma. Interestingly, in half the patients, there was a steady increase in the M-protein before the development of symptomatic myeloma, while in the other half the M-protein stayed fairly stable. A second study by Weiss et al. found a monoclonal gammopathy in 27 of 30 patients (90%) in sera 2 or more years before the diagnosis of myeloma 19.
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2.3 molecular studies in mgus

A recent study using SNP-based arrays compared MGUS, SMM and MM samples 20. They found copy number abnormalities in all stages. The incidence of genomic imbalance did increase from a median of 5/case for MGUS to 7.5/case for SMM and 12/case for MM. The study also noted certain genomic changes that were exclusive to MM including 11q and 21q gains and 16q and 22q deletions. Interestingly, the study found these abnormalities in a small subclone in MGUS patients indicating that most if not all of the chromosomal changes may be already present at the MGUS state. These findings also support a possible role of 'clonal tides' in the evolution from precursor state to symptomatic myeloma as explained below. Two major pathways have been proposed as the early oncogenic events in the development of the myeloma cell based on chromosomal abnormalities noted in MGUS, SMM and MM- the non-hyperdiploid and the hyperdiploid pathway. The main cytogenetic changes that have been observed in MGUS and SMM are indicated in the table below.  
| Cytogenetic  abnormality IgH translocations   | See below                      | 40-50%   | 40-50%   | 50-70%   |
|-----------------------------------------------|--------------------------------|----------|----------|----------|
| t(11;14)(q13;q32)                             | CCND1 (cyclin D1)              | 10-25%   | 10-25%   | 15%      |
| t(4;14)(p16;q32)                              | FGFR3 and  MMSET               |          |          |          |
| t(14;16)(q32;q23)                             | C-MAF                          | 2-5%     | 2-5%     | 2-5%     |
| Other IgH  translocationst(6;14)(p21;q32), t(14;20)(q32;q11) etc.                                               | CCND3 (cyclin D3),  MAFB, etc. |          |          |          |
| 13q deletion                                  | Unknown                        | 25-50%   | 35-50%   | 40-50%   |
| Hyperdiploidy                                 | Unknown                        | 40-50%   | 40-50%   | 40-50%   |  
CCND3 (cyclin D3), MAFB, etc.  
6-10% 1-10% 10%  
Other molecular studies in MGUS and SMM included microRNA studies. MicroRNAs are single stranded RNA molecules that regulate gene expression posttranscriptionally and are being implicated in a large number of cancers 21. A study comparing miRNA profiles of normal PC,
MGUS, SMM and MM found overexpression of mir-21, mir-106~25 and mir181a and mir181b in MGUS and MM compared to normal PCs 22. The study also found mir-32 and mir17~92 clusters to be upregulated only in MM and not in any other forms. Mir 17~92 and Mir 106~25 are known to have a role in B cell development as well as B cell lymphomas targeting PTEN,
E2F1, Bcl2 and BIM 21,22. The mir17 cluster has been shown to upregulated by the transcription factor c-Myc, which is considered a late event in myeloma progression 23-25.  
With the advances in deep sequencing techniques, we are now able to study the whole genome of myeloma cells and compare that to the normal human genome. Several studies employing these techniques are beginning to shift our understanding of the pathogenesis of myeloma. These studies have revealed that the previously held dogma that cancer progression occurred through a linear cumulative acquisition of mutational changes may be too simplistic. A new model of clonal heterogeneity is beginning to emerge 26. In fact tumor evolution may indeed proceed like Darwinian evolution with tumor progression involving a branching process with coexistent clonal heterogeneity. In this model various subclones exist in a dynamic equilibrium, competing for limited resources and over time the subclonal populations ebb and flow under environmental evolutionary pressures with alternating dominance of various subclones at different time points2731. Most of these studies were done on patients with symptomatic multiple myeloma and as similar studies involving MGUS and SMM emerge, our understanding of the pathogenesis of myeloma from these precursor states will continue to evolve. It is possible that the progression from myeloma precursor state to symptomatic disease also involves 'clonal tides' with expansion of a subclone leading to progression. Several previous studies have identified clonal heterogeneity in a subset of MGUS patients20,32,33.
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2.4 definition of smm

The diagnosis of smoldering (asymptomatic) multiple myeloma (SMM) is based on the demonstration of M-protein in serum (>3 gm/dL) or urine and/or the presence of 10-60%
clonal bone marrow plasma cells (BMPC). 1-3 The risk of progression of SMM to overt MM is approximately 10 percent per year in the first five years after diagnosis, with decreasing progression rates in later years.
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but with no evidence of

- Increased calcium levels: Corrected serum **calcium** >0.25 mmol/L(>1mg/dL) above the upper limit of normal or >2.75 mmol/L ( >11mg/dL)
- **Renal** insufficiency (attributable to myeloma)
- **Anemia** (Hgb 2g/dL below the lower limit of normal or <10g/dL) - **Bone** lesions (lytic lesions or generalized osteoporosis with compression fractures)
- Other (symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (>2 episodes in 12 months).  
*Participants with CRAB criteria that are attributable to conditions other than the disease under study may be eligible
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new mde criteria that indicates

The following criteria are now incorporated with the CRAB criteria to indicate that patients meet criteria for therapy as symptomatic or overt MM:
- Bone marrow clonal plasma cells >60% on bone marrow examination
- Serum involved/uninvolved FLC ratio ≥100, provided the level of the involved free light chain is at least 100mg/L (a patient's "involved" free light chain- either kappa or lambdais the one that is above the normal reference range; the uninvolved light chain is the one that typically is in, or below the normal range)*
- More than one focal lesion on MRI that is at least 5mm or greater in size
*If serum free light chain ratio is stable ( not increasing) for greater or equal to six months, the patient may be eligible after discussion with the overall PI
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2.5 definitions of high-risk smm

Based on the new defined high risk criteria for smoldering myeloma2,3 as described below:  
| Bone marrow clonal plasma cells ≥10% and any one or more of the following: Serum M protein ≥3.0gm/dL IgA SMM Immunoparesis with reduction of two uninvolved immunoglobulin isotypes Serum involved/uninvolved free light chain ratio ≥8 (but less than 100) Progressive increase in M protein level (Evolving type of SMM)† Bone marrow clonal plasma cells 50-60% Abnormal plasma cell immunophenotype (≥95% of bone marrow plasma cells  are clonal) and reduction of one or more uninvolved immunoglobulin isotypes t (4;14) or del 17p or 1q gain Increased circulating plasma cells MRI with diffuse abnormalities or 1 focal lesion (≥5mm) PET-CT with one focal lesion (≥5mm) with increased uptake without underlying  osteolytic bone destruction Monoclonal light chain excretion of 500mg/24 hours or higher* † Increase in serum monoclonal protein by ≥10% on two successive evaluations within a 6   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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2.6 treatment of high risk

In a randomized open-label phase 3 trial, 119 patients with high-risk smoldering myeloma were randomized to treatment or observation. Patients in the treatment group received an induction regimen (lenalidomide at a dose of 25 mg per day on days 1 to 21, plus dexamethasone at a dose of 20 mg per day on days 1 to 4 and days 12 to 15, at 4-week intervals for nine cycles), followed by a maintenance regimen (lenalidomide at a dose of 10 mg per day on days 1 to 21 of each 28day cycle for 2 years). The primary end point was time to progression to symptomatic disease. Secondary end points were response rate, overall survival, and safety. After a median follow-up of 40 months, the median time to progression was significantly longer in the treatment group than in the observation group (median not reached vs. 21 months; hazard ratio for progression, 0.18; 95% confidence interval [CI], 0.09 to 0.32; P<0.001). The 3-year survival rate was also higher in the treatment group (94% vs. 80%; hazard ratio for death, 0.31; 95% CI, 0.10 to 0.91; P=0.03). A partial response or better was achieved in 79% of patients in the treatment group after the induction phase and in 90% during the maintenance phase. Toxic effects were mainly grade 2 or lower. Early treatment for patients with high-risk smoldering myeloma delays progression to active disease and increases overall survival. (NCT00480363).
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2.7 elotuzumab

Elotuzumab (HuLuc63/BMS-901608) is a humanized monoclonal IgG1 antibody product directed to human SLAMF7 (CD2 subset-1, also known as CRACC ), a cell surface glycoprotein with homology to the CD2 family of cell surface proteins34,35. Originally, SLAMF7 was identified as a natural killer cell (NK) marker and was shown to be expressed in a subset of circulating leukocytes.10 Blood analysis confirmed expression of SLAMF7 on the cell surface of NK, NK-like T-cells (NKT), activated monocytes, CD8 positive T cells and on tissue plasma cells.11 High SLAMF7 expression was seen in plasma cells obtained from normal healthy donors and from patients with MGUS, SMM, and active MM. More than 90% of MM bone marrow samples, irrespective of cytogenetic abnormalities, express SLAMF7.. In addition SLAMF7 expression is maintained in MM subjects after relapse from therapy. A paired analysis of a subset of subjects with MM showed that SLAMF7 gene expression is detectable in subjects both at diagnosis and at relapse.  
In agreement with the gene chip data, flow cytometry analysis demonstrated that CD138+ plasma cells from MM bone marrow stained strongly positive for elotuzumab binding. In addition, immunohistochemistry (IHC) using anti SLAMF7 antibodies showed strong staining of MM cells in 9/9 plasmacytoma tissue samples and in 20/20 myeloma bone marrow cores tested36,37.  
The proposed mechanism of action of elotuzumab involves natural killer (NK) cell mediated antibody dependent cell-mediated cytotoxicity (ADCC). Elotuzumab monotherapy can kill MM cell lines and primary myeloma cells in vitro in the presence of peripheral blood mononuclear cells (PBMCs) or purified NK cells. In addition, elotuzumab exhibits significant in vivo monotherapy anti-tumor activity against human myeloma xenograft models grown in severe combined immunodeficient (SCID) mice36-38. This in vivo anti-tumor activity of elotuzumab appears to be largely dependent on the presence of active NK cells. Experiments using an in vivo mouse xenograft model suggest that maximal antitumor activity is reached at elotuzumab serum levels of 70 to 430 mcg/mL.
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2.8 rationale for elotuzumab in

Although several non-clinical models demonstrated elotuzumab monotherapy activity, no objective responses were observed in subjects in Study HuLuc63-1701 (Study 1701), a Phase 1 elotuzumab monotherapy trial in humans. This is in contrast to the high response rates observed in studies of elotuzumab in combination with lenalidomide/dexamethasone (Study HuLuc-1703 (Study 1703); or bortezomib (Study HuLuc-1702 (Study 1702). The best response in Study 1701 was stable disease (SD) seen in 27% of all subjects. However, elotuzumab may have slowed disease progression in some subjects since SD was also observed in 3 subjects whose best response to prior therapy was progressive disease and some of the subjects had prolonged SD (median time to progression of 4.2 months in subjects with SD at study Day 52) suggesting possible maintenance or disease control. Study 1701 did not completely rule out monotherapy activity for elotuzumab. Subjects in Study 1701 may have had a lower likelihood of responding to elotuzumab monotherapy due to their prior therapies, inadequate elotuzumab dosing, and host immune status. These subjects had advanced, heavily pretreated myeloma, having received a median of 4.5 prior lines of therapy and may have been less likely to respond to any subsequent therapy. In addition, this was a Phase 1 multiple ascending dose escalation study, in which subjects were treated with potentially inadequate doses of elotuzumab. Half of the subjects received doses below the threshold required to consistently saturate bone marrow plasma cell SLAMF7and the percentage of subjects achieving SD was higher (35%) at doses adequate to saturate SLAMF7binding sites (10 and 20 mg/kg). A primary mechanism of action of elotuzumab is NK cell mediated ADCC. In vitro, elotuzumab has no direct anti-tumor effects and requires the presence of active PBMCs or NK cells. In Study 1701, heavily pretreated subjects with advanced myeloma likely had impaired immune systems, which may also have contributed to the lack of objective responses. Host immune status is a function of both the number and intrinsic activity of specific immune cells and advanced cancers and other hematologic diseases have impaired NK cell activity. Reduced NK cell function has been reported in advanced myelodysplastic syndrome. Subjects with active myeloma have lower levels of a protein (DNAM-1) required for NK-mediated ADCC than control subjects or myeloma patients in complete response. In Study 1701, the total lymphocyte and NK cell counts in all study subjects were below the mean for healthy patients. Subjects with earlier stages of myeloma have better NK activity and more cytotoxic NK cells. Therefore, elotuzumab may demonstrate monotherapy activity in untreated subjects in earlier stages of myeloma (e.g., prior to development of symptoms) and who are likely to have a better immune function. SMM is an appropriate patient population to test this hypothesis. Limiting enrollment to high risk SMM narrows the population to subjects in whom the risk of progression to active myeloma is higher (median time to progression of two years) and for whom chemoprevention trials are recommended.
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2.9 rationale for dose and

In this current study, elotuzumab will be administered at 10 mg/kg per cycle. This dose intensity was chosen because it matches the dose intensity in the cohort with the higher response rate in the phase 2 portion of study 1703.
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2.9.1 non-clinical toxicology

The expression of the elotuzumab target, SLAMF7, is restricted to malignant myeloma cells and subsets of normal leukocytes in humans (NK, NK-like T cells [NKT], activated monocytes, a subset of CD8+ T cells, and tissue plasma cells). High SLAMF7 expression was seen in plasma cells obtained from normal healthy donors and from patients with MGUS, SMM, and active MM.11 No significant expression was detected in resting CD4+ T cells, B cells, resting monocytes, neutrophils, and granulocytes. Elotuzumab binding was not observed on epithelia, vessels, or smooth muscle cells of any of the organs examined. Elotuzumab only recognizes human SLAMF7 protein and does not appear to bind SLAMF7 from other species, including chimpanzee, cynomolgus monkey, dog, mini-pig, mouse, rabbit, rat, and rhesus monkey. Due to the lack of species-specific cross-reactivity, there are no relevant animal species in which to conduct toxicological studies. Therefore, the nonclinical studies consisted primarily of in vitro safety assessments and in vivo biological activity assessment to address the selectivity of elotuzumab and potential toxicities. Elotuzumab (100 and 200 mcg/mL) in vitro had no effect on lymphocytes, CD3+, CD4+, CD8+, and B cell counts in blood samples from healthy donors. NK cell counts were decreased on average by 20% at both doses of elotuzumab. The observed decline was variable between donors and ranged between 0% and 45%. Elotuzumab at concentrations up to500 mcg/mL did not adversely affect the ability of bone marrow-derived hematopoietic stem cells to differentiate down the erythroid and myeloid pathways.  
2.9.2 Clinical Experience with Elotuzumab in Multiple Myeloma As of March 2011, the elotuzumab clinical development program has consisted of three studies in active myeloma: Study 1701, a Phase 1 elotuzumab monotherapy study; Study 1702, a Phase 1 study of elotuzumab + bortezomib; and Study 1703, a Phase 1/2 study of elotuzumab + lenalidomide/low-dose dexamethasone.  
2.9.3 HuLuc63-1701, a Phase 1 Elotuzumab Monotherapy Study In this Phase 1 study, escalating doses (0.5 - 20 mg/kg) of elotuzumab monotherapy were administered intravenously (IV) every 2 weeks for a total of 4 doses in subjects with advanced MM. Subjects with stable disease or better had the option to receive additional doses of elotuzumab. As of 03-Jul-2009, the study is complete. A total of 35 subjects were enrolled: 3 in the 0.5 mg/kg cohort, 4 in the 1.0 mg/kg cohort, 6 in the 2.5 mg/kg cohort, 4 in the 5.0 mg/kg cohort, 4 in the 10 mg/kg cohort, and 14 in the 20 mg/kg cohort. One (1) subject in the 10 mg/kg cohort did not receive study drug. The primary objective of this study was to determine the MTD. In the 2.5 mg/kg cohort, 1 out of the first 3 subjects dosed experienced a dose-limiting toxicity of (DLT) Grade 3 increase in blood creatinine levels leading to Grade 4 acute renal failure and that cohort was then expanded to include another 3 subjects. No further DLTs occurred in the 2.5 mg/kg cohort and dosing continued up to the 20 mg/kg cohort. In the 20-mg/kg cohort, 1 out of 14 subjects experienced a DLT of Grade 3 hypersensitivity. Therefore, the MTD was not reached in this study. A total of 31 SAEs were reported in 15 subjects. Six (6) of the SAEs were assessed as related to elotuzumab which included Grade 4 acute renal failure, Grade 2 chills, Grade 2 pyrexia, Grade 3 hypersensitivity, Grade 2 bradycardia, and Grade 2 chest discomfort. The most common treatment emergent AEs (TEAE) overall during the study were chills (13 [38.2%] subjects), fatigue (13 [38.2%] subjects), pyrexia (13 [38.2%] subjects), cough (10 [29.4%] subjects), headache (10 [29.4%] subjects), and anemia (9 [26.5%] subjects). The most common treatment-related AEs were chills (11 [32.4% subjects), pyrexia (6 [17.6%] subjects), and flushing (4 [11.8% subjects). There was no apparent dose response relationship with respect to the incidence of AEs overall or treatment related TEAEs. Most TEAEs and treatment-related TEAEs were Grade 1 or Grade 2. A secondary objective of this study was assessment for preliminary activity. Nine (9) subjects had a best response of stable disease. Although no subject had a confirmed response, this study was 1) conducted in heavily pre-treated subjects with likely compromised immune systems (for example compromised NK cell function), and 2) did not include immune activating myeloma therapies such as lenalidomide or bortezomib.
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2.9.4 huluc63-1702 a phase 1

This is a Phase 1 study of elotuzumab in combination with bortezomib (plus dexamethasone if applicable) in subjects with MM who have had 1 to 3 prior therapies. Escalating doses (2.520mg/kg) of elotuzumab (dosed Days 1, 11) are administered in combination with 1.3 mg/m2 bortezomib (dosed Days 1, 4, 8, 11) in a 21-day cycle. Subjects with disease progression at the end of Cycle 2 or 3 also received an oral dose of 20 mg dexamethasone on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle thereafter. Data are preliminary as of 25-Mar-2011, 8 subjects with relapsed and relapsed and refractory MM have been treated; 3 each at 2.5, 5, and 10 mg/kg and 19 at 20 mg/kg of elotuzumab respectively. Twenty-eight (28) subjects in the intent-to-treat (ITT) population received at least 1 dose of elotuzumab and all 28 subjects (100%) experienced at least 1 AE. No DLT was observed in the study and MTD was not established up to the planned highest dose of 20 mg/kg. There were 23 (82.1%) subjects with an elotuzumab related AE. The most common AEs (in 45% or higher, regardless of causality) include Grade 1 to 3 fatigue, diarrhea, anemia, thrombocytopenia, nausea, hyperglycemia, lymphopenia, leukopenia, neutropenia, constipation, and peripheral neuropathy. Grade 3 or higher AEs occurred in 22 (78.6%) subjects of whom 7 (25%) subjects experienced Grade 3 or higher AEs assessed as related to elotuzumab (lymphopenia, thrombocytopenia, gastroenteritis, chest pain, fatigue, and hypersensitivity). SAEs occurred in 10 (35.7%) subjects. Additionally, 6 (21.4%) subjects, 2 in the 5.0 mg/kg and 4 in the 20.0 mg/kg cohorts, withdrew from treatment due to an AE (neuropathy peripheral (2 subjects), acute myocardial infarction, gastroenteritis, sepsis and pain in extremity). No deaths have been reported due to AEs. Overall there does not appear to be a dose relationship with the incidence of AEs.  
As of 25-Mar-2011, the best clinical response (minimal (minor) response (MR)) and the best response rate (partial response (PR)) by the combined European Group for Blood and Marrow Transplantation and uniform criteria33 in 27 response evaluable subjects compare favorably to the historical, Phase 3 clinical trial of bortezomib monotherapy (APEX) in a similar population.34 The clinical response rate was 63% in Study 1702 compared to 46% in APEX and the objective response rate was 48% in Study 1702 compared to 38% in APEX. Finally, the median time to progression (TTP) was 9.5 months compared to 6.2 months in APEX.  
2.9.5 HuLuc63-1703, a Phase 1/2 Lenalidomide/dexamethasone + Elotuzumab (LdE) Study
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2.9.5.1 phase 1

This is a Phase 1/2 study of elotuzumab with lenalidomide and low dose dexamethasone (Ld) in subjects with MM who have had 1 or more prior therapies. Data are preliminary as of 25-Mar2011. Escalating doses (5-20 mg/kg) of elotuzumab (dosed weekly in the first 2 cycles) are administered with 25 mg lenalidomide (dosed orally Days 1 - 21) and 40 mg dexamethasone (dosed orally on Days 1, 8, 15, and 22) in a 28 day cycle.  
A total of 28 subjects received elotuzumab. One (1) subject was withdrawn from the study prior to receiving study drug due to investigator decision. Subjects had a median of 3 prior MM treatments. Three (3) subjects each received 5 mg/kg and 10 mg/kg and 22 subjects received 20 mg/kg of elotuzumab. No DLT was observed during dose-escalation and an MTD was not established. The interim safety analysis revealed a key safety signal of elotuzumab-associated infusion reactions. These AEs included mostly Grade 1 and 2 nausea, dyspnea, chills, and headache. Two (2) subjects in the 20 mg/kg cohort discontinued due to infusion reactions, one Grade 4 SAE of anaphylaxis
(related to elotuzumab) and one Grade 3 SAE of stridor (related to elotuzumab/dexamethasone).  
Subsequent to these events, a new elotuzumab premedication regimen for the whole program has been instituted to minimize infusion reactions.  
The final data of this trial was published in 2012 36. Three cohorts were enrolled and treated with elotuzumab (5.0, 10, or 20 mg/kg intravenously) on days 1, 8, 15, and 22 of a 28-day cycle in the first two cycles, and days 1 and 15 of each subsequent cycle; lenalidomide 25 mg orally [PO] on days 1 to 21; and dexamethasone 40 mg PO weekly. Dose-limiting toxicities (DLTs) were assessed during cycle 1 of each cohort, and clinical responses were evaluated during each cycle. The first five patients received up to six cycles of therapy; subsequent patients were treated until disease progression. Twenty-nine patients with advanced MM and a median of three prior MM therapies were enrolled; 28 patients were treated, three each in the 5.0-mg/kg and 10-mg/kg cohorts and 22 in the 20-mg/kg cohort. No DLTs were observed up to the maximum proposed dose of 20 mg/kg. The most frequent grade 3 to 4 toxicities were neutropenia (36%) and thrombocytopenia (21%). Two patients experienced a serious infusion reaction (one grade 4 anaphylactic reaction and one grade 3 stridor) during the first treatment cycle. Objective responses were obtained in 82% (23 of 28) of treated patients. After a median of 16.4 months follow-up, the median time to progression was not reached for patients in the 20-mg/kg cohort who were treated until disease progression.
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2.9.5.2 phase 2

Study 1703 is continuing in Phase 2 where subjects who have not been previously exposed to lenalidomide are randomized to 10 vs 20 mg/kg elotuzumab + Ld. Data are preliminary as of 25- Mar-2011. A total of 73 subjects with a median age of 63 years were enrolled in the Phase 2 portion; 36 subjects received 10 mg/kg elotuzumab and 37 received 20 mg/kg. In all subjects, the median number of cycles of therapy to date is 10. At least 1 AE was experienced by 100% of subjects across both dose groups, with largely similar AE rates; there were some exceptions based on preferred terms, but are not considered statistically significant or clinically meaningful. Grade 3/4 AEs, regardless of causality occurred in 68% of subjects, which were also similar between the 2 arms (Table 1.4.2.3-1), and comparable to historical AE data for LD with lymphopenia (16%), neutropenia (14%), thrombocytopenia (15%), and anemia (10%) being most common overall. SAEs were reported in 41% of all subjects of which 6 (8.2%) were assessed as drug related. Related SAEs included 1 subject with Grade 3 febrile neutropenia and Grade 4 neutropenia; 1 subject with Grade 3 visceral leishmaniasis, Grade 4 leukopenia, and Grade 4 thrombocytopenia; 1 subject with Grade 3 bronchitis; 1 subject with Grade 4 increased C - reactive protein and Grade 3 hyperuricemia; 1 subject with Grade 4 H1N1 influenza; and 1 subject with Grade 3 nausea. A total of 25 subjects have discontinued treatment as of the cutoff date: 9 for adverse events, 9 for disease progression, 4 for subject's decision, 2 for investigators decision, and 1 to start a new therapy. As with prior elotuzumab studies, the interim safety analysis revealed a key safety signal of elotuzumab-associated infusion reactions defined for the purposes of these studies to include a pre-specified set of AEs that occurred on the day of, or the day after, elotuzumab infusion. Rates of infusion reactions were similar between arms with 56.2% subjects experiencing at least one infusion associated AE. All subjects have received a premedication regimen instituted at the end of Phase 1. Common infusion-associated AEs in Phase 2 included mostly Grade 1 and 2 nausea (16.4%), dizziness (11%), headache (12.3%), pyrexia (13.7%), and cough (8.2%). There was only Grade 3 infusion associated reaction: rash in a subject at 10 mg/kg. Of the 73 treated subjects in the Phase 2 portion of this study, as of this data cut, all were randomized 12 weeks months prior to the cutoff date and are considered evaluable for response assessment by IMWG criteria. The ORR ( PR) in these 73 subjects was 82.2%. This ORR
compares favorably with other Ld clinical trials in relapsed/refractory myeloma (60% ORR for LD in MM-009/010 and previously untreated myeloma (70% ORR for Ld in E4A03). Although the study is not complete, the interim data analysis demonstrates 91.7% ORR at 10 mg/kg arm and 73.0% ORR at 20 mg/kg arm. This ORR is based on a median of 10 cycles. Responses were rapid, with a median time to response of approximately 1 month in evaluable subjects.
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2.9.5.3 infusion reactions

Treatment with therapeutic monoclonal antibodies is associated with infusion reactions with variable time of onset and varying levels of incidence and severity. As of March 2011 the key safety signal with elotuzumab is infusion reactions. As stated above, the definition of an infusion reaction for this analysis includes relevant signs and symptoms reported the day of or the day after elotuzumab infusion. The most frequent elotuzumab infusion reaction AEs regardless of causality across all Phase 1 studies included nausea, vomiting, chills, fever, flushing, dyspnea, cough, headache, dizziness, and rash. The majority of infusion reaction AEs were Grade 1 or 2 and resolved with little or no treatment. There was no apparent dose relationship for infusion reaction. To minimize infusion reactions, all ongoing elotuzumab studies were amended in 2010, after the Grade 3 infusion AEs in the Phase 1 program (1701, 1702, and 1703Ph1), to ensure that all subjects receive premedication with IV corticosteroids, oral or IV diphenhydramine and oral acetaminophen prior to each elotuzumab infusion. As of 25-Mar-2011 all subjects treated in the Phase 2 expansion of Study 1703 have received this amended premedication regimen. Of the 73 treated subjects, 56% of subjects experienced at least 1 Grade 1/2 infusion associated AE either the day of or the day after elotuzumab infusion. In contrast, 89% of subjects in the Phase 1 of Study 1703 (prior to new pre-medication regimen) experienced at least 1 infusion associated AE regardless of causality. Most infusion reactions occurred during the first cycle of therapy. In summary, elotuzumab infusions have been associated with predominantly Grade 1 or 2 infusion reactions. All infusion reactions were managed by infusion rate changes and/or medications and almost all resolved the same day or within 24 hours. In most cases, subjects have been able to continue on study. Only 1 subject premedicated with diphenhydramine, acetaminophen, and IV corticosteroids prior to all doses of elotuzumab developed a Grade 3 infusion reaction related to elotuzumab and discontinued.
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2.9.5.4 clinical pharmacokinetics

Blood samples were collected for estimation of serum elotuzumab concentrations following single and multiple dose administration in Studies 1701, 1702, and 1703. Preliminary pharmacokinetic (PK) analysis results limited to Cmin and Cmax have been reported for all 3 of these studies.  
Following single dose administration (Study 1701) of escalating doses of elotuzumab alone, Cmax increased with increasing dose over the dose range of 0.5 to 20 mg/kg. Following multiple dose administration of escalating doses of elotuzumab on Days 1 and 11 of a 21-day cycle in combination with bortezomib (Study 1702), the observed steady-state Cmin values consistently remained above 70 µg/mL, the minimum maximally efficacious trough concentration, following administration of the 10 mg/kg dose (296 to 698 µg/mL) and the 20 mg/kg dose (572 to 1092 µg/mL). Following administration of elotuzumab every 7 days for the first 2 cycles, and every 14 days for all subsequent cycles in combination with lenalidomide and dexamethasone (Study 1703), the steady state Cmin concentrations associated with the 10 mg/kg dose ranged from 163 to 301 µg/mL, which was above the minimum maximally efficacious trough concentration.
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2.9.5.5 overall risk/benefit assessment

Elotuzumab is a humanized monoclonal IgG1 antibody directed to human SLAMF7, a cell surface glycoprotein. SLAMF7 is expressed on plasma cells and a subset of circulating leukocytes. Since elotuzumab does not recognize non-human SLAMF7, minimal animal toxicology has been performed. Non-clinical activity as monotherapy as well as in combination led to human trials. Although as monotherapy in heavily pretreated subject the best responses were SD, elotuzumab showed high response rates in combination with bortezomib or lenalidomide. Elotuzumab as monotherapy or with bortezomib or lenalidomide is well tolerated. As of March 2011 the key elotuzumab related serious AEs have been infusion-related AEs.
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2.10 trial rationale

Pretreatment of MM cells with lenalidomide in-vitro enhances elotuzumab induced ADCC
against MM cells, and this has also been demonstrated in in vivo xenograft MM models,37. The mechanism of synergism between these two agents has not been fully explored, however, recent discoveries into the precise mechanism of action of lenalidomide in MM has provided some insight; lenalidomide enhanced production of the cytokine interleukin-2 (IL-2), which spurs T cell production and stimulation of NK cells. The importance of the T cell mediated effect of lenalidomide has recently been elegantly demonstrated by two studies10,39, uncovering previously unknown mechanisms of action for this drug in MM. Lenalidomide induced IL-2 production in T cells was found to be due to the depletion of two proteins, IKZF1 and IKZF3. These proteins normally function to bind the IL-2 promotor and repress IL-2 transcription in T cells, treatment with lenalidomide markedly depletes IKZF1 and IKZF3 in T cells inducing IL-2 production and T cell activation. IL-2 is known to exert anti-myeloma activity through activation of NK cells. Treatment with lenalidomide could therefore prime NK-cells for Elotuzumab-mediated ADCC, which may explain the synergistic anti-myeloma effect of these therapies. The evidence for elotuzumab activation of immune system is based on SLAMF7 on NK cells (where EAT-2 is expressed). Interestingly, both EAT-2 and SLAMF7 are located on chromosome 1q, this region is amplified in 30-50% of MM patients and is associated with poor prognosis and lack of response to lenalidomide plus dexamethasone. 1q amplification is known to be an early event in myelomagenesis and has been associated with an increased risk of conversion from SMM to overt MM. We will be using lenalidomide for only two years and not for longer time periods. In addition, patients who develop symptomatic disease will receive induction therapy with standard therapeutic options for multiple myeloma including combinations such as those of proteasome inhibitors, immunomodulators and steroids or cyclophosphamide, proteasome inhibitors and dexamethasone. If we observe any problems with stem cell collection, we will follow the current standard guidelines of using cyclophosphamide or plerixafor mobilization. Based on data using combination therapies for induction, there has been no major concerns regarding stem cell collections after treatment with those agents.
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2.11 correlative studies background 2.11.1

The "clonal evolution" model of cancer emerged amid ongoing advances in technology, especially in recent years, during which next generation sequencing has provided ever higher resolution pictures of the genetic changes in cancer cells and heterogeneity in tumors where tumor progression proceeds in a branching rather than in a linear manner, leading to substantial clonal diversity and coexistence of wide genetic heterogeneity40,41. The genomic complexity in MM was recently corroborated by massive parallel-sequencing studies displaying the lack of a universal driving mutation26. Recent studies have shown intraclonal heterogeneity that occurs at different stages of progression in MM27,28. Most recently, exome sequencing confirmed that the heterogeneity observed in the transformation from MGUS/SMM to MM is likely to be an essential feature of clonal evolution and disease progression42,43. Point mutations such as N-RAS,
K-RAS, MYC up-regulation44, and gain or loss of chromosome 1q or 1p seem to correlate with disease progression from MGUS and SMM25. A progressive increase in the incidence of copy number abnormalities from MGUS to SMM and to MM has been recently observed45.
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2.11.2 immune cells and mm

An important step in the progression of tumors is evasion and suppression of the host immune system46,47. Several numerical and functional T cell abnormalities have been reported in MM48.  
Studies have shown an increase of functional T-regs in MM patients and MM mouse models, which may lead to suppression of immune effector cells49,50. It was also reported that T-regs increase during progression in MM, and increased number of T-regs are associated with survival.  
Since, there are some conflicting data8 and lack of good murine myeloma models for analyzing immune cells, the significance of T-regs and other immune cells in MM pathogenesis is not fully understood. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous, immature myeloid cell population with the ability to suppress immune responses. Recent studies have shown that MDSCs induce MM growth while suppressing T-cell-mediated immune responses. SLAMF7 is highly expressed on NK cells. Accumulating evidence indicates that EAT-2 mediates its activating effect on NK cells via tyrosine 127 which is believed to undergo phosphorylation on engagement of SLAMF7. Elotuzumab may interfere with the ability of myeloid derived suppressor cells (MDSC's) to suppress anti-myeloma immune responses by T cells or other immune cells, In mice it has been demonstrated that engagement of SLAMF7 on T helper cells inhibited antigen induced T cell proliferation and cytokine production51, indicating that SLAMF7 may be inhibitory in T-cells however this would depend on the presence or absence of EAT2. Therefore the characterization of SLAMF7, EAT2 and elotuzumab treatment on T cell subsets remains an unanswered question in MM and may help to unravel the mechanism of synergy between elotuzumab and lenalidomide. Based on these studies and based on the SLAMF7 role in these cells, we will focus our studies of immune regulation on 3 types of cells: NK cells, T-regs and MDSCS.
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3. participant selection 3.1 eligibility

3.1.1 Age  18 years.  
3.1.2 Must meet criteria of high risk smoldering MM as described with one of the below criteria:
- Bone marrow clonal plasma cells ≥10% and any one or more of the following:
o Serum M protein ≥3.0 gm/dL o IgA SMM o Immunoparesis with reduction of two uninvolved immunoglobulin isotypes o Serum involved/uninvolved free light chain ratio ≥8 (but less than 100)
- Free Light Chain Smoldering Myeloma patients as defined in section 2.4 are not excluded o Progressive increase in M protein level (Evolving type of SMM)† o Bone marrow clonal plasma cells 50-60%
o Abnormal plasma cell immunophenotype (≥95% of bone marrow plasma cells are clonal) and reduction of one or more uninvolved immunoglobulin isotypes
* All patients should have four or six color flow cytometry performed on the baseline bone marrow sample, as feasible. Patients evaluated for eligibility by Spanish Criteria must have their result confirmed by four color flow *cytometry.* If four or six color flow cytometry is not available at the site, the baseline bone marrow must be sent to Dana-Farber Cancer Institute to confirm eligibility prior to enrollment.  
o t (4;14) or del 17p or 1q gain o Increased circulating plasma cells o MRI with diffuse abnormalities or 1 focal lesion (≥5mm) o PET-CT with one focal lesion (≥5mm) with increased uptake without underlying osteolytic bone destruction
† Increase in serum monoclonal protein by ≥10% on two successive evaluations within a 6 month period 3.1.3 No evidence of CRAB criteria* or new criteria of active MM which including the following:
- Increased calcium levels: Corrected serum calcium >0.25 mmol/L
(>1mg/dL) above the upper limit of normal or >2.75 mmol/L (>11mg/dL);
- Renal insufficiency (attributable to myeloma);
- Anemia (Hgb 2g/dL below the lower limit of normal or <10g/dL);
- Bone lesions (lytic lesions or generalized osteoporosis with compression fractures)
- No evidence of the following new criteria for active MM including the following: Bone marrow plasma cells >60%, Serum involved/uninvolved FLC ratio ≥100, and MRI with more than one focal lesion
* Participants with CRAB criteria that are attributable to conditions other than the disease under study may be eligible
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3.1.4 ecog performance status (ps)

3.1.5 The following laboratory values obtained  21 days prior to registration:
- ANC  1000/L
- PLT  50,000/L
- Total bilirubin ≤ 2.0 mg/dL (If total is elevated check direct and if normal patient is eligible.)
- AST  3 x institutional upper limit of normal (ULN) - ALT  3 x institutional upper limit of normal (ULN)
- Estimated creatinine clearance  60mL/min or a creatinine  2.2 mg/dL
3.1.6 Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.  
3.1.7 Females of childbearing potential* must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days as required by Revlimid REMS®) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide.  
* A female of childbearing potential is a sexually mature female *who:*
- has not undergone a hysterectomy (the surgical removal of the *uterus)* or bilateral oophorectomy (the surgical removal of both ovaries) or
- *has not been naturally postmenopausal (amenorrhea following cancer* therapy does not rule out childbearing potential) for at least 24 *consecutive* months (i.e., has had menses at any time during the preceding 24 consecutive months)
3.1.8 All study participants must be registered into the mandatory Revlimid REMS®
program, and be willing and able to comply with the requirements of the REMS® program.  
3.1.9 Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program.  
3.1.10 Men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy.  
3.1.11 Ability to understand and the willingness to sign a written informed consent.
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3.2 exclusion criteria

3.2.1 Symptomatic Multiple Myeloma or any evidence of CRAB criteria including the new criteria for overt myeloma. Any prior therapy for active Myeloma should also be excluded. Prior therapy for smoldering myeloma is not an exclusion criterion. Bisphosphonates are not excluded 3.2.2 Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational. Prior therapy with bisphosphonate is allowed. Prior radiation therapy to a solitary plasmacytoma is allowed. Prior clinical trials or therapy for smoldering MM or MGUS are allowed but should be discussed with the Principal Investigator.  
3.2.3 Serious medical or psychiatric illness likely to interfere with participation in this clinical study.  
3.2.4 Diagnosed or treated for another malignancy within 2 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
3.2.5 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.  
3.2.6 Pregnant or nursing women will be excluded from the study because lenalidomide is an agent with the potential for teratogenic or abortifacient effects.  
3.2.7 History of allergic reactions attributed to compounds of similar chemical or biologic composition to elotuzumab or lenalidomide.  
3.2.8 Known seropositive for or active viral infection with human immunodeficiency virus
(HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible. Patients who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.
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3.3 inclusion of women and

3.3.1 Both men and women of all races and ethnic groups are eligible for this trial.
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4. registration procedures 4.1 general

Institutions will register eligible participants in the Clinical Trials Management System (CTMS)
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not registered to the protocol before protocol therapy begins will be considered ineligible and registration will be denied. An investigator will confirm eligibility criteria and a member of the study team will complete the protocol-specific eligibility checklist. Following registration, participants may begin protocol therapy. Issues that would cause treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant does not receive protocol therapy following registration, the participant's registration on the study must be canceled. Registration cancellations must be made in OnCore as soon as possible
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4.2 registration process for df/hcc

DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol Registration (SOP \#: REGIST-101) must be followed.
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4.3 general guidelines for other

Eligible participants will be entered on study centrally at DFCI by the Study Coordinator. All sites should call the Research Project Manager, at the lead site. Following registration, participants should begin protocol therapy as soon as possible. Issues that would cause treatment delays should be discussed with the Overall PI. If a participant does not receive protocol therapy following registration, the participant's registration on the study must be canceled. The lead study team should be notified of cancellations as soon as possible.
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4.4 registration process for other

To register a participant, the following documents should be completed by the research nurse or data manager and e-mailed to the Research Project Manager:
- Copy of labs and clinical information that satisfy inclusion criteria
- Signed participant consent form
- HIPAA authorization form
- Registration Form
- Completed eligibility checklist The research nurse or data manager at the participating site will then call or e-mail the Research Project Manager to verify eligibility. To complete the registration process, the Research Project Manager will follow DF/HCC Standard Operating Procedure for Human Subject Research titled Subject Protocol Registration (SOP\# REGIST-101) and register the participant on the protocol. The lead site will then fax or email the participant study number to confirm registration. Treatment may not begin without confirmation from the Coordinating Center that **the** participant has been registered. NOTE: Registration and randomization can only be conducted during the business **hours** of 8:00 AM and 5:00 PM Eastern Time Monday through Friday. Same day treatment registrations will only be accepted with prior notice and discussion with the DF/HCC.
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5. treatment plan 5.1 treatment

All patients will be treated with elotuzumab, lenalidomide and dexamethasone. Patients will also by stratified by age>65 years or older and high risk cytogenetics based on t(4:14), t(14:16), 17p deletion or p53 mutation, +1q amplification. A treatment cycle is defined as 28 consecutive days. Elotuzumab will be administered Cycles 1 and 2 on days 1, 8, 15, 22 and cycles 3-8 on days 1 and 15. Lenalidomide will be administered days 1-21 every 28 days. Dexamethasone will be administered on days 1, 8, 15 and 22 on cycles 1-2 then on days 1, 8 and 15 on cycles 3-8. Patients on maintenance treatment will be administered elotuzumab on day 1, and lenalidomide on days 1-21. For treatment cycles 1 and 2, a +/- 3 day window is allowed. For treatment cycle 3-24, a +/-7 day window is allowed. Treatment will be administered on an outpatient basis. Reported adverse events and potential risks are described in Section 7. Appropriate dose modifications are described in Section 6. No investigational or commercial agents or therapies other than those described below may be administered with the intent to treat the participant's malignancy.  
The participant will be requested to maintain a medication diary of each dose of lenalidomide and dexamethasone. The medication diary should be returned to clinic staff at the end of each cycle.  
| Agent                                                                     | Premedication and  Precautions   | Schedule          | Dose     | Route   | Cycle Length   |
|---------------------------------------------------------------------------|----------------------------------|-------------------|----------|---------|----------------|
| Intravenous-See  appendix B for  more details                             |                                  |                   |          |         |                |
| Days 1-21                                                                 | 28 days (4 weeks)                |                   |          |         |                |
| Lenalidomide                                                              | None                             | of each           | 25 mg    | Oral    |                |
| cycle                                                                     |                                  |                   |          |         |                |
| Elotuzumab                                                                | Premedications are               | Days 1, 8, 15, 22 | 10 mg/kg |         |                |
| described below Take with food;  recommended to be  taken in the  morning | 8 mg                             | IV                |          |         |                |
| Days 1, 8, 15, 22                                                         |                                  |                   |          |         |                |
| Dexamethasone                                                             | 32 mg                            | Oral              |          |         |                |  
Elotuzumab Premedications are  
described below  
Days 1 and  
15 *10 mg/kg*  
| Agent         | Premedication and                                              |
|---------------|----------------------------------------------------------------|
| Elotuzumab    | Premedications are  described below                            |
| Lenalidomide  | None Take with food;  recommended to be  taken in the  morning |
| Dexamethasone |                                                                |  
Agent Premedication *and*  
Precautions Schedule Dose Route Cycle *Length*  
| Precautions                                   | Schedule   | Dose   | Route   | Cycle Length   |
|-----------------------------------------------|------------|--------|---------|----------------|
| Intravenous- See appendix B for  more details |            |        |         |                |
| Days 1 and 15                                 | 10 mg/kg   |        |         |                |
| Days 1-21  of each                            | 25 mg      | Oral   | 28 days |                |
| cycle                                         | (4 weeks)  |        |         |                |
| 8 mg                                          | IV         |        |         |                |
| Days 1, 15                                    | 32 mg      | Oral   |         |                |
| Day 8                                         | 40mg       | Oral   |         |                |  
28 days (4 weeks)  
Lenalidomide *None*  
Days *1-21* of each cycle  
25 mg *Oral*  
Elotuzumab **and Lenalidomide Maintenance Therapy (Cycles 9-24)**  
| Agent                                                                                  | Premedication and  Precautions      | Schedule        | Dose              | Route   | Cycle Length   |
|----------------------------------------------------------------------------------------|-------------------------------------|-----------------|-------------------|---------|----------------|
| Days 1 of                                                                              | 20 mg/kg                            | Intravenous-See |                   |         |                |
| each cycle                                                                             | appendix B for  more details        |                 |                   |         |                |
| Elotuzumab                                                                             | Premedications are  described below | Days 1-21       | 28 days (4 weeks) |         |                |
| Lenalidomide                                                                           | None                                | of each  cycle  | 15 mg             | Oral    |                |
| 8 mg                                                                                   | IV                                  |                 |                   |         |                |
| Take with food;  recommended to be  taken in the  morning                              | Day 1 of  each cycle                |                 |                   |         |                |
| Dexamethasone*                                                                         | 28 mg                               | Oral            |                   |         |                |
| * After discussion with the overall PI, high-dose dexamethasone may be re-added during |                                     |                 |                   |         |                |  
* After discussion with the overall PI, high-dose dexamethasone may be re-added during maintenance due to biochemical progression (progressive increase in SPEP [25% and an absolute increase of 0.5g/d] or UPEP [25% and an absolute increase of 200mg/24hours] on 2 successive evaluations as determined by the IMWG response criteria or documented progression by the FreeLiteTM progressive disease criteria in the absence of serum or urine involvement).  
Dexamethasone should be given as follows after overall PI approval:  
Day Dose **Route**  
| 1 8   | 40 mg   | Oral   |
|-------|---------|--------|
| 15    | 40 mg   | Oral   |
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5.2 pre-treatment criteria

There are no pretreatment criteria for elotuzumab dosing. Refer to section 6.2 for Lenalidomide pretreatment criteria and 6.3 for Dexamethasone pre treatment criteria.  
5.2.1 Premedication Regimen in Subjects without a Prior Infusion Reaction  
- Premedication is required prior to all Elotuzumab infusions. Refer to table 3 for the guidelines for premedication.
5.2.2 Premedication Regimen in Subjects With a Prior Infusion Reaction To be re-treated with elotuzumab, subjects with a prior infusion reaction must receive H1, H2 blockers and acetaminophen at maximum doses specified (e.g., 50 mg diphenhydramine, 50 mg ranitidine [or equivalent], and 1000 mg acetaminophen) 90-45 minutes before initiating the elotuzumab. Doses of intravenous dexamethasone above 10 mg require a decrease in the oral dexamethasone. Recommended dexamethasone dosing is summarized below and in Table 3. For subjects with prior Grade 2 infusion reaction, administer 10 mg IV dexamethasone (instead of 8 mg IV) as the premedication steroid 90-45 minutes before elotuzumab. Subjects should take 30 mg oral dexamethasone 24-3 hours before elotuzumab administration. For subjects with Grade 3 or recurrent Grade 2 elotuzumab infusion reactions, consultation with the Principal Investigator is recommended. Administer 18 mg IV dexamethasone as the premedication steroid at least 45 minutes before elotuzumab. These patients should receive 8mg of oral dexamethasone 24-12 hours the day prior to elotuzumab administration. Then, administer 14 mg oral dexamethasone at most 3 hours prior to elotuzumab administration. If a subject with a prior Grade 2 (recurrent) or 3 infusion reaction also requires dose reduction of oral dexamethasone, the dexamethasone dose on the days of elotuzumab infusion should be no less than 18 mg IV (on the day of elotuzumab infusion at least 45 minutes before elotuzumab). Subjects with a Grade 4 infusion reaction are not eligible to receive additional elotuzumab. These subjects may continue to receive lenalidomide and dexamethasone. Subjects who experience an infusion reaction of any grade should be administered the recommended premedication for that reaction severity for the duration of the trial. Subjects with prior infusion reactions may receive more aggressive pre-medications after discussion with the Overall Principal Investigator Table 3: Recommended Corticosteroid **Premedication**  
| None or                                                   | 24-3 hours prior to                                                                                                           | 32 mg PO Dexamethasone                                                                                                      |
|-----------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------|
| Grade 1                                                   | Elotuzumab Infusion                                                                                                           |                                                                                                                             |
| Prior                                                     | 90-45 min prior to                                                                                                            | 8mg IV Dexamethasone                                                                                                        |
| Infusion                                                  | Elotuzumab Infusion                                                                                                           | Diphenhydramine 25-50 mg IV or PO or equivalent                                                                             |
| Reaction                                                  | H1 blocker Ranitidine 50mg IV or equivalent H2 blocker Acetaminophen 650-1000mg PO                                            |                                                                                                                             |
| Prior                                                     | 24-3 hours prior to                                                                                                           | 30mg PO Dexamethasone                                                                                                       |
| Grade 2                                                   | Elotuzumab Infusion                                                                                                           |                                                                                                                             |
| Infusion                                                  | 90-45 min prior to                                                                                                            | 10mg IV Dexamethasone                                                                                                       |
| Reaction                                                  | Elotuzumab                                                                                                                    | Diphenhydramine 50 mg IV or PO or equivalent H1 blocker Ranitidine 50mg IV or equivalent H2 blocker Acetaminophen 1000mg PO |
| Prior  Grade 3  Infusion  Reaction or  recurrent  Grade 2 | 24-12 hours prior to                                                                                                          | 8mg PO Dexamethasone                                                                                                        |
| Elotuzumab Infusion No more than 3 hours prior            | 14mg PO Dexamethasone                                                                                                         |                                                                                                                             |
| to Elotuzumab Infusion 90-45min prior to                  | 18mg IV Dexamethasone                                                                                                         |                                                                                                                             |
| Elotuzumab                                                | Diphenhydramine 50 mg IV or PO or equivalent H1  blocker Ranitidine 50mg IV or equivalent H2 blocker  Acetaminophen 1000mg PO |                                                                                                                             |
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5.3 agent administration

The order in which elotuzumab and lenalidomide are administered does not matter.
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5.3.1 elotuzumab

Elotuzumab will be administered intravenously at a dose of 10 mg/kg on Days 1, 8, 15 and 22 for the first 2 cycles (a cycle =28 days). During cycles 3 through 8, elotuzumab will be given on days 1 and 15. Elotuzumab will be administered intravenously at a dose of 20 mg/kg only on Day 1 for cycles 9-24. The patient should be observed for 60 minutes after the infusion is complete for cycle 1 and should be observed for 30 minutes after the infusion for subsequent cycles. All patients should have their vital signs checked before and after elotuzumab infusion or per institutional standard. If an infusion reaction occurs, reference section 6.4.2 for guidelines on additional vital monitoring. Cycle 1 and Cycle 2 treatment may be administered +/- 3 days. For subsequent cycles +/- 7 days is allowed.  
5.3.1.1 Guidelines for Elotuzumab infusion in subjects with infusion reactions Please refer to section 6.4 of the protocol.  
5.3.1.2 Dose Delay or Interruption Please refer to section 6.4.3 of the protocol.  
5.3.2 Lenalidomide Lenalidomide will be given as a single daily oral dose of 25 mg per day on days 1-21 followed by a 7-day rest period for cycles 1-8 and 15 mg per day on days 1-21 for cycles 9-24. Cycle 1 and Cycle 2 treatment may be administered +/- 3 days. For subsequent cycles +/- 7 days is allowed. Dose modification guidelines are described in Section 6.2 (Dose Modifications/Delays).  
Lenalidomide capsules should be swallowed whole, and should not be broken, chewed or opened. Administration of lenalidomide should be at approximately the same time each day. Drug may be taken with or without food. If a dose is missed and less than 12 hours has elapsed since the missed dose, the patient can take the dose for that day. If more than 12 hours has elapsed since missing a dose at the normal time, the patient should not take the dose, but take the next dose at the normal time on the following day. If a dose is missed, it should be taken as soon as possible on the same day. If a dose is vomited, the dose should not be made up and the participant should continue with the regular schedule of the drug at the next dose. A drug diary will be provided to participants to record oral administration of doses. Participants who take more than the prescribed dose of lenalidomide should be instructed to seek emergency medical care if needed and contact study staff immediately. Participants experiencing adverse events may need study treatment modifications (see Section 6.2). Lenalidomide related resources will be provided to all patients prior to receiving lenalidomide therapy as part of the Revlimid REMS program. For more information regarding program registration and drug ordering, refer to section 8.2.  
5.3.2.1 Dose Delay or Interruption Dose modification and delay guidelines are described in Section 6.2 (Dose Modifications/Delays)
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5.3.3 dexamethasone

Dexamethasone will be obtained by commercial supply in this study. This may lead to added costs for the participant or the participant's insurance company. It will be given as an oral dose. Dexamethasone should be taken at approximately the same time each day. Doses of oral dexamethasone should be taken with food and administered per the recommended guidelines in Table 3. It is recommended that dexamethasone be taken in the morning to reduce insomnia. A drug diary will be provided to participants to record oral administration of doses. Please refer to Section 5.1 for instructions on dexamethasone dosing.  
5.3.3.1 Dose Delay or Interruption Dose modification and delay guidelines are described in Section 6.3 (Dose Modifications/Delays).
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5.4 general concomitant medication and

5.4.1 Medications permitted at Investigator's Discretion  
- Steroids, diphenhydramine, or hydroxyzine, acetaminophen/ paracetamol, H2 inhibitors (e.g., cimetidine), leukotriene inhibitors (montelukast sodium) for the management of elotuzumab infusion reactions. Additional supportive measures should be provided as indicated including oxygen inhalation, epinephrine, and bronchodilators.  
- At the discretion of the treating investigator, patients will receive Pneumocystis jiroveci pneumonia (PJP) prophylaxis during treatment (Bactrim or acceptable alternative). This may be discontinued at the start of maintenance therapy, or at the investigator's discretion.  
- Stem cell mobilization will be allowed at the time of best response or at the end of 8 cycles for patients who are eligible for stem cell transplant. Stem cell collection may be done sooner after discussion with overall PI. Standard mobilization treatment (with GCSF or with cyclophosphamide or plerixafor, etc) will be used based on Institutional guidelines. Patients may delay treatment for up to 3 weeks after stem cell collection is complete.  
- Use of white cell growth factors [G-CSF (Filgrastim or acceptable equivalent)]
is allowed for management of treatment induced neutropenia at physician discretion. Daily use of Filgrastim is not allowed, and participants may receive a maximum of 3 doses per week. Filgrastim should be given according to the ASCO guidelines. Pegfilgrastim is not to be used in replace of filgrastim.  
- Patients will receive bisphosphonates per recommendations of myeloma therapy. A note should be placed about patients who are not receiving bisphosphonates for clinical reasons such as osteonecrosis of the jaw.  
- Nausea/Vomiting: If nausea and/or vomiting is noted at any point in time, premedication with prochlorperazine or other antiemetics may be used before future doses. If nausea persists in spite of the use of standard antiemetics additional symptom management should be as per standard antiemetic guidelines.  
- Thromboprophylaxis is required for all participants. Participants may receive
daily aspirin administration (81 or 325 mg), daily enoxaparin (40 mgs), or low molecular weight heparin (type Innohep® 4500 UI anti-Xa as needed) or equivalent to decrease the risk of thromboembolic complications. Aspirin prophylaxis will be the preferred first choice unless contraindicated. It is recommended that if the platelet count falls below 50,000/mm3, thromboprophylaxis be held to minimize the risk of bleeding and then resumed when platelet counts are equal to or above this level.
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o for patients at high

In the absence of treatment delays due to adverse event(s), treatment may continue for *24 cycles* or until one of the following criteria applies:  
- Disease progression o Participants who have developed symptoms similar to CRAB criteria or MDE (see section 2.4), but are not attributable to active, symptomatic myeloma may remain on study after discussion with the Overall PI.
- Intercurrent illness that prevents further administration of treatment
- Unacceptable adverse event(s)  
- Participant demonstrates an inability or unwillingness to comply with the oral medication regimen and/or documentation requirements
- Participant decides to withdraw from the protocol therapy
- General or specific changes in the participant's condition render the participant unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply. The reason for removal from protocol therapy, and the date the participant was removed, must be documented in the case report form (CRF). Alternative care options will be discussed with the participant. A QACT Treatment Ended/Off Study Form will be filled out when a participant is removed from protocol therapy. This form can be found on the QACT website or obtained from the QACT registration staff. External sites should submit the form to the Research Project Manager. In the event of unusual or life-threatening complications, treating investigators must immediately notify the Overall PI, Irene Ghobrial at telephone \# 617-632-4198.
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5.6 duration of follow up

Participants will be followed for up to *3 years* after removal from protocol therapy or until progression to active symptomatic MM, whichever occurs first. Assessments will be performed every 3 to 6 months ( +/- 28 days ) for up to 3 years. Patients who have undergone stem cell mobilization will also be followed for 3 years after removal from protocol therapy or until progression to active symptomatic myeloma, whichever occurs first. Participants removed from protocol therapy for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event. Participants unable to participate in follow up every 3 months may follow up every 6 months at PI discretion in accordance with standard of care follow-up frequency and COVID precautions.  
Physical exams and correlative blood draws that are not done due to virtual visits will not be considered violations. Local myeloma labs must be provided to the participating site for data entry purposes. Bone marrow biopsy and scans are strongly recommended yearly after EOT, but not require however, scans and bone marrow biopsy and research samples are required at time of suspected disease progression The following is required during the Active Follow Up period (for up to 3 years):
1. Physical exams are voluntary during this period a. Virtual visits/telehealth visits are acceptable 2. SPEP and Immunofixation 3. Serum Free Light Chains (SFLC) 4. UPEP and Immunofixation only for those where disease is tracked by the urine 5. Serum Immunoglobulin test 6. PET/CT assessments are strongly recommended yearly and is required at the time of suspected progression a. The same assessment modality should be used consistently across the duration of the trial 7. Bone marrow biopsies are and strongly recommended yearly after EOT and is required at the time of suspected progression 8. Research bone marrow samples will be collected at the time of any bone marrow biopsy/aspirate procedure 9. Research blood will be collected whenever an in person visit to the site occurs. Research blood samples that are not collected at time points in the collection calendar due to COVID precautions or q6 month follow up will not be considered violations unless it is missed at the time of suspected progression.  
10. Response 11. CRAB/MDE Assessment 12. Bone marrow biopsy/aspirate results and cytogenetics/FISH if ordered 13. Scan results and modality Participants who come off active follow up when they pursue other SMM or MM directed therapy will be followed for survival indefinitely which will capture survival stats, and subsequent therapy information.
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5.7 criteria for taking a

Participants will be removed from study when any of the following criteria apply:  
- Lost to follow-up - Completion of 3 years of follow up
- Withdrawal of consent for data submission
- Death
The reason for taking a participant off study, and the date the participant was removed, must be documented in the case report form (CRF).
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6. dosing delays/dose modifications 6.1

No dose reductions for elotuzumab are allowed. If Elotuzumab is held on Day 1 of a new cycle, treatment with Lenalidomide/Dexamethasone will also be delayed. If Elotuzumab is held during any cycle on days 8, 15, or 22, the treating investigator will decide if Lenalidomide will be held using recommended guidance for retreatment below. Dexamethasone should always be given with Elotuzumab. The dose of dexamethasone may be modified per guidance below. Treatment may be delayed for a maximum of 21 days. If a patient must discontinue treatment with lenalidomide, they may continue to receive elotuzumab on study after discussion with the overall principal investigator.  
If a patient must discontinue elotuzumab for unacceptable toxicity, they may continue to receive lenalidomide and dexamethasone on study after discussion and approval of the overall principal investigator.
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6.2 lenalidomide

Patients may hold treatment of lenalidomide for up to 21 if the toxicity is considered either possibly, probably or definitely related to the drug. Patients may hold lenalidomide for greater than 21 days only after discussion and subsequent approval of the overall principal investigator. Hematologic **Toxicities:** For adverse hematologic events that are considered possibly, probably or definitely related to Lenalidomide, the following criteria for retreatment and dose modification should be followed. Treatment may be held for a maximum of 21 days. Refer to Table 4 for dose reduction levels for Lenalidomide. Non Hematologic Toxicity: For adverse non hematologic events that are considered to be possibly, probably or definitely related to Lenalidomide, the following criteria for retreatment and dose modification should be followed. The treating investigator should determine the clinical significance of laboratory values or radiographic findings and attribution to study medications before a treatment decision is made. Treatment may be held for a maximum of 21 days. Refer to Table 4 for dose reduction levels for Lenalidomide. Dose delays and modifications will be made as indicated in the following table(s). The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A copy of the CTCAE version 4.0 can be downloaded from the CTEP website http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
| CTCAE 4.0 Category                                           | CTCAE Grade                                                                                                                                                                                                                                                               | Lenalidomide Dose Modification                                                                                                                                                |
|--------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 1  or  Grade 2                                         | Continue to treat- Do NOT OMIT and DO NOT REDUCE  therapy Hold dose Administer Filgrastim Resume at same dose when ANC is ≥ 1000 if neutropenia is  the only hematologic toxicity If other hematologic toxicity ≥Grade 2 is present, reduce  dose one level when ANC≥1000 |                                                                                                                                                                               |
| Absolute Neutrophil Count  (ANC)1                            | Grade 3                                                                                                                                                                                                                                                                   | Hold dose Administer Filgrastim Resume therapy at one dose level lower when ANC is ≥ 1000                                                                                     |
| Grade 4                                                      |                                                                                                                                                                                                                                                                           |                                                                                                                                                                               |
| Neutropenia with Fever                                       | Grade 3  or  Grade 4                                                                                                                                                                                                                                                      | Hold dose Administer Filgrastim Reduce dose one level when ANC≥1000                                                                                                           |
| ANC <1000 and temperature ≥38.5o C or 101ºF                  | Grade 1  or  Grade 2                                                                                                                                                                                                                                                      | Continue to treat- Do NOT OMIT and DO NOT REDUCE  therapy Provide platelet transfusion support  Redraw platelets                                                              |
| Thrombocytopenia                                             | If redrawn platelet value ≥ 50,000 -> Do NOT OMIT and  DO NOT REDUCE therapy                                                                                                                                                                                              |                                                                                                                                                                               |
| Aspirin prophylaxis should be  held if platelets are ≤50,000 | Grade 3  or  Grade 4                                                                                                                                                                                                                                                      | If redrawn platelet value <50,000 continue to transfuse at  the discretion of the investigator and hold therapy until  platelets are ≥ 50,000 on Day 1 or ≥ 30,000 intracycle |
| CONFIDENTIAL                                                 |                                                                                                                                                                                                                                                                           |                                                                                                                                                                               |
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hematologic toxicities

| Resume therapy at one dose level lower when the patient's  platelets are ≥ 50,000 on Day 1 or ≥ 30,000 intracycle   |                                                                                                                |
|---------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------|
| Grade 1 Grade 2 Grade 3                                                                                             | Continue to treat- Do NOT OMIT and DO NOT REDUCE  therapy Transfuse at the discretion of treating investigator |
| Anemia                                                                                                              | Hold treatment                                                                                                 |
| Grade 4                                                                                                             | Transfuse Resume treatment when hemoglobin ≥ 8.0 g/dL  DO NOT REDUCE therapy                                   |
| 1 ANC can be calculated two ways: From the percentage of neutrophils: White Blood Count (WBC) x total               |                                                                                                                |  
neutrophils (polys% + bands%) x 10. From the absolute number of cells: (Absolute polys + Absolute bands) x 10.
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non hematologic toxicities

| CTCAE 4.0                                    | CTCAE Grade                                                                                                                                                                                                                                                                        | Lenalidomide Dose Modification                                                                                                                                                                                                                                                                           |
|----------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Category                                     | Day 1 of Cycle: Delay cycle until infection/viral  illness has resolved. Resume treatment at the same  dose level. Do not dose reduce.                                                                                                                                             |                                                                                                                                                                                                                                                                                                          |
| Infection or Viral  Ilness with ANC1 ≥1000   | Intracycle: Hold lenalidomide for a maximum of 21  days to allow for recovery. Resume treatment at same  dose level.                                                                                                                                                               |                                                                                                                                                                                                                                                                                                          |
| N/A                                          |                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                          |
| Including herpes  zoster reactivation        | If patient has delay of greater than 21 days, the patient  must come off-study Day 1 of Cycle: Delay cycle until infection/viral  illness has resolved. Administer filgrastim or  equivalent as indicated. Reduce one dose level when infection/virus has  resolved, and ANC ≥1000 |                                                                                                                                                                                                                                                                                                          |
| Infection or Viral  Illness with ANC1 < 1000 | N/A                                                                                                                                                                                                                                                                                | Intracycle: Hold lenalidomide for a maximum of 21  days. Reduce one dose level when infection/virus has  resolved and ANC ≥ 500 If patient has a delay of less than or equal to 21 days,  dose reduce to next dose level. If patient has delay of  greater than 21 days, the patient must come off-study |
| Allergic reaction or                         | Continue to treat- Do NOT OMIT and DO NOT                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                          |
| hypersensitivity to                          | Grade 1                                                                                                                                                                                                                                                                            | REDUCE therapy                                                                                                                                                                                                                                                                                           |
| CONFIDENTIAL                                 |                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                          |  
| Lenalidomide                                                                                                              | Grade 2                                                                                                                                                                                                          | Continue to treat- Do NOT OMIT and DO NOT  REDUCE therapy   |
|---------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------|
| Including Rash  related to  Lenalidomide                                                                                  | Hold lenalidomide  Follow at least weekly.                                                                                                                                                                       |                                                             |
| Grade 3  or  Grade 4                                                                                                      | If toxicity resolves to ≤ grade 2, restart at next lower  dose level                                                                                                                                             |                                                             |
| Grade 1                                                                                                                   | Continue to treat- Do NOT OMIT and DO NOT  REDUCE therapy                                                                                                                                                        |                                                             |
| Renal/Metabolic                                                                                                           | Hold Lenalidomide until < grade 2 and resume  treatment at the same dose level                                                                                                                                   |                                                             |
| Grade 2                                                                                                                   | If toxicity recurs, dose reduce one dose level at the  treating investigator's discretion                                                                                                                        |                                                             |
| For all grades,  provide hydration and  other supportive care  as needed at the  discretion of the  treating investigator | Hold Lenalidomide until < grade 2 and resume  treatment with one dose level reduction                                                                                                                            |                                                             |
| Grade 3  or  Grade 4                                                                                                      | If the toxicity remains ≥ grade 3, omit dose and restart  at subsequent scheduled visit with one dose level  reduction If treatment-related toxicity occurs on day one of the  cycle, the cycle will be delayed. |                                                             |
| Grade 1                                                                                                                   | Continue to treat- Do NOT OMIT and DO NOT  REDUCE therapy Treat at the discretion of the investigator  Provide aggressive supportive care                                                                        |                                                             |
| Grade 2                                                                                                                   |                                                                                                                                                                                                                  |                                                             |
| Diarrhea,  Constipation,  Nausea, or Vomiting                                                                             | DO NOT REDUCE therapy Hold Lenalidomide until toxicity resolves to < grade 2                                                                                                                                     |                                                             |
| Grade 3                                                                                                                   | If the patient has received maximum supportive care,  resume therapy with one dose level reduction Hold Lenalidomide until toxicity resolves to < grade 2                                                        |                                                             |
| Grade 4                                                                                                                   | Resume therapy with one dose level reduction                                                                                                                                                                     |                                                             |
| CONFIDENTIAL                                                                                                              |                                                                                                                                                                                                                  |                                                             |  
| Grade 1                                                                                               | Continue to treat- Do NOT OMIT and DO NOT  REDUCE therapy Continue to treat- Do NOT OMIT and DO NOT  REDUCE therapy unless considered to be a clinically  significant finding                                                                                                               |
|-------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 2                                                                                               | Provide supportive care as needed Hold Lenalidomide until toxicity resolves to < grade 2                                                                                                                                                                                                    |
| Grade 3                                                                                               |                                                                                                                                                                                                                                                                                             |
| All other related  toxicities not listed  previously in this  table                                   | Resume therapy with one dose level reduction at the  discretion of the treating investigator Hold Lenalidomide until toxicity resolves to < grade 2  Resume therapy with one dose level reduction If treatment-related toxicity occurs on day one of the  cycle, the cycle will be delayed. |
| Grade 4                                                                                               | If patient has a delay of less than or equal to 21 days,  dose reduce to next dose level. If patient has delay of  greater than 21 days, the patient must come off-study                                                                                                                    |
| 1 ANC can be calculated two ways: From the percentage of neutrophils: White Blood Count (WBC) x total |                                                                                                                                                                                                                                                                                             |  
neutrophils (polys% + bands%) x 10. From the absolute number of cells: (Absolute polys + Absolute bands) x 10
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table 4 lenalidomide dose reduction

Dose Level **Lenalidomide Dose** Starting Dose Level 25 mg First Dose Reduction 20 mg Second Dose Reduction 15 mg Third Dose Reduction 10 mg Fourth Dose Reduction 5 mg
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6.3 dexamethasone dexamethasone dose modifications

Premedication with dexamethasone is required prior to all elotuzumab infusions. If there are clinically significant, intolerable ≥Grade 3 adverse events attributed to dexamethasone (given as a premedication) treatment may be delayed until recovery to ≤ Grade 2 at the discretion of treating investigator. For adverse events that are considered to be possibly, probably or definitely related to dexamethasone, the following criteria for retreatment and dose modification should be followed. The treating investigator should determine the clinical significance and attribution of the toxicity to dexamethasone. If toxicity is unlikely or not related to dexamethasone, do not omit or reduce therapy. Patients may continue on study if oral dexamethasone has been permanently discontinued Patients who have not experienced an infusion reaction related to elotuzmab and have experienced an adverse event attributable to dexamethasone may have their premedication of dexamethasone decreased after completion of cycle 1 at the discretion of the treating investigator and after discussion with the overall PI.  
| CTCAE 4.0 Category                                                                | CTCAE Grade                                                                                                                     | Dexamethasone Dose Modification                                                 |
|-----------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------|
| Grade 1                                                                           | Continue to treat- Do NOT OMIT and DO NOT  REDUCE therapy Hold dexamethasone until < Grade 2 and resume at                      |                                                                                 |
| Hyperglycemia                                                                     | Grade 2                                                                                                                         | same dose level at the discretion of the treating  investigator                 |
| Treat with oral  medication or  insulin at  discretion of  treating  investigator | Hold dexamethasone until < Grade 2                                                                                              |                                                                                 |
| Grade 3                                                                           | Resume therapy with one dose level reduction at the  discretion of the treating investigator Hold dexamethasone until < Grade 2 |                                                                                 |
| Grade 4                                                                           | Resume therapy with one dose level reduction                                                                                    |                                                                                 |
| Symptomatic  pancreatitis                                                         | Any Grade                                                                                                                       | Discontinue dexamethasone permanently                                           |
| Grade 1 or 2                                                                      | Continue to treat- Do NOT OMIT and DO NOT  REDUCE therapy                                                                       |                                                                                 |
| OTHER                                                                             | Grade 3                                                                                                                         | Hold dexamethasone until ≤ Grade 2 Resume therapy with one dose level reduction |
| Grade 4                                                                           | Hold dexamethasone ≤ Grade 2 Resume therapy with one dose level reduction                                                       |                                                                                 |
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table 5 dexamethasone dose reduction

| Infusion Reaction                                                  |                      |                          |    |    |
|--------------------------------------------------------------------|----------------------|--------------------------|----|----|
| Dose Levels                                                        | Week with Elotuzumab | Week Without Elotuzumab* |    |    |
| PO                                                                 | IV                   | PO                       | IV |    |
| Starting Dose Level                                                | 32                   | 8                        | 40 | 0  |
| First Dose Reduction                                               | 28                   | 8                        | 20 | 0  |
| Second Dose Reduction                                              | 28                   | 8                        | 10 | 0  |
| * During Maintenance, patients only receive dexamethasone on Day 1 |                      |                          |    |    |  
| Infusion Reaction                                                  |                      |                          |    |    |
|--------------------------------------------------------------------|----------------------|--------------------------|----|----|
| Dose Levels                                                        | Week with Elotuzumab | Week Without Elotuzumab* |    |    |
| PO                                                                 | IV                   | PO                       | IV |    |
| Starting Dose Level                                                | 30                   | 10                       | 40 | 0  |
| First Dose Reduction                                               | 28                   | 10                       | 20 | 0  |
| Second Dose Reduction                                              | 28                   | 10                       | 10 | 0  |
| * During Maintenance, patients only receive dexamethasone on Day 1 |                      |                          |    |    |  
| Dose Levels                                                        | Week with Elotuzumab   | Week Without Elotuzumab*   |    |    |
|--------------------------------------------------------------------|------------------------|----------------------------|----|----|
| PO                                                                 | IV                     | PO                         | IV |    |
| Starting Dose Level                                                | 22                     | 18                         | 40 | 0  |
| First Dose Reduction                                               | 16                     | 18                         | 20 | 0  |
| Second Dose Reduction                                              | 16                     | 18                         | 10 | 0  |
| * During Maintenance, patients only receive dexamethasone on Day 1 |                        |                            |    |    |  
** If patient is intolerant of dexamethasone, after discussion with overall PI, oral dexamethasone may be omitted at any dose level.
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6.4 guidelines for elotuzumab infusion

Grade 1 elotuzumab infusion-related reactions by definition do not require intervention; however, increased monitoring is recommended.
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6.4.2 grade 2 infusion reaction

Infusion reactions during the elotuzumab infusion: For a Grade  2 elotuzumab infusion- related reaction, the infusion must be interrupted. The subject should be treated as clinically indicated with one or more of the following medications or interventions: antiemetics, antihistamines, analgesics, corticosteroids, leukotriene inhibitors, oxygen inhalation, epinephrine, bronchodilators, or other supportive measures as indicated. Subjects with a Grade 3 infusion reaction may be discontinued from study drug at the discretion of the investigator, but must be discontinued if the Grade 3 infusion reaction recurs. Subjects with any Grade 4 infusion reaction are not eligible to receive additional elotuzumab. If a patient's elotuzumab regimen is discontinued before the completion of cycle 2, he or she must come off protocol therapy. If elotuzumab is discontinued after completion of cycle 2, he or she can remain on protocol therapy.  
Once the elotuzumab infusion-related reaction has resolved to  Grade 1, the infusion can be restarted at 0.5 mL/minute. If symptoms do not recur after 30 minutes, the infusion rate may be increased in a stepwise fashion (0.5 mL/minute every 30 minutes) to a maximum of 2 mL/minute or the rate at which the infusion reaction occurred, whichever is lower. Subjects who experience an infusion reaction require vital signs to be monitored approximately every 30 minutes for up to 2 hours after the end of the elotuzumab infusion. If the elotuzumab infusion reaction recurs, the infusion must be stopped and not restarted on that day. Appropriate therapy should be administered to address the subject's signs and symptoms. The infusion can be reattempted at the next protocol defined infusion time point at the investigator's discretion with additional premedication as described previously.  
Infusion reactions after the completion of elotuzumab infusion: Should a Grade 2 infusion reaction occur following completion of an elotuzumab infusion, the subject should be treated as clinically indicated with 1 or more of the following medications or interventions: diphenhydramine, acetaminophen, hydrocortisone, H2 inhibitor, leukotriene inhibitor, oxygen inhalation, epinephrine, bronchodilators, or other supportive measures as indicated.  
Elotuzumab infusions on subsequent weeks after a prior Grade 2 infusion reaction: Subjects with prior Grade 2 or higher infusion reactions should have future infusions started at 0.5 mL/min and then escalated in a stepwise fashion (0.5 mL/minute every 30 minutes). If no Grade 2 infusion reaction recurs, the escalation regimen may be resumed and the next infusion may be initiated as planned per the regimen. If a patient experiences an infusion reaction of less than or equal to Grade 2, and the infusion reaction does not recur, the patient can resume elotuzumab administration at the rate at which the reaction occurred at the start of the next cycle at the investigator's discretion
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6.4.3 dose delay or interruption

If a patient's elotuzumab administration is delayed on day 1 of a cycle, both lenalidomide and dexamethasone will also be delayed until the elotuzumab is resumed, which would then become
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the new day 1 of

If a patient's elotuzumab is held in the middle of a cycle, lenalidomide dosing will continue as scheduled. If the patient's elotuzumab is delayed during the cycle and is resumed within the designated window, (+/-3 days Cycles 1 and 2; +/-7 days Cycles 3 and beyond) the patient may receive that scheduled dose. If the elotuzumab is not resumed within the given window (+/-3 days Cycles 1 and 2; +/-7 days Cycles 3 and beyond), the patient is to omit that dose, and resume dosing at the next dosing time point. Dexamethasone should be held and resumed when Elotuzumab is held and subsequently resumed. Patients may delay treatment for up to 3 weeks for elective surgeries and other non toxicity related events.  
| To be resumed  within window?                                                                  | Lenalidomide                     | Dexamethasone                                          | Elotuzumab   |
|------------------------------------------------------------------------------------------------|----------------------------------|--------------------------------------------------------|--------------|
| Elotuzumab                                                                                     | To be delayed                    |                                                        |              |
| delayed on Day                                                                                 | N/A                              | until Elotuzumab                                       |              |
| 1 of Cycle                                                                                     | is resumed                       | To be delayed                                          |              |
| until Elotuzumab  is resumed                                                                   | Resume                           |                                                        |              |
| dosing= new  Day 1 of Cycle Resume dose  any day within  window; dose  time point not  skipped |                                  |                                                        |              |
| Elotuzumab  held on Day  8,15, or 22 of  Cycle Elotuzumab  held on Day  8,15,or 22 of  Cycle   | To be delayed                    |                                                        |              |
| until Elotuzumab  is resumed                                                                   |                                  |                                                        |              |
| Yes                                                                                            | Dosing to continue  as scheduled | Resume dosing  at next dosing  time point  (skip dose) |              |
| To be delayed                                                                                  |                                  |                                                        |              |
| until Elotuzumab  is resumed                                                                   |                                  |                                                        |              |
| No                                                                                             | Dosing to continue  as scheduled |                                                        |              |
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table 6 dose delay instructions

Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list of reported and/or potential AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine whether the event requires expedited reporting in addition to routine reporting.
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7.1 expected toxicities

7.1.1 Adverse Events List(s)
7.1.1.1 Adverse Event List of Elotuzumab Treatment with therapeutic monoclonal antibodies is associated with infusion reactions with variable time of onset and varying levels of incidence and severity. The key safety signal with elotuzumab is infusion reactions. As stated above, the definition of an infusion reaction for this analysis includes relevant signs and symptoms reported the day of or the day after elotuzumab infusion. The most frequent elotuzumab infusion reaction AEs regardless of causality across all Phase 1 studies included nausea, vomiting, chills, fever, flushing, dyspnea, cough, headache, dizziness, and rash. The majority of infusion reaction AEs were Grade 1 or 2 and resolved with little or no treatment. There was no apparent dose relationship for infusion reaction.
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7.1.1.2 adverse event list for

Events that have occurred in >10% of individuals treated with lenalidomide include neutropenia, anemia, thrombocytopenia, fatigue, rash, diarrhea, constipation, nausea, loss of appetite, itching, dry skin, muscle cramps, lack or loss of strength, dizziness, insomnia, swelling of the extremities, headache, back and joint pain, fever, cough, upper respiratory infection, and dyspnea.  
Events that have occurred in >1% of individuals treated with lenalidomide include risk of DVT, PE, and blood clots that could lead to stroke, heart attack, or organ failure, febrile neutropenia, atrial fibrillation, pneumonia or lung infections, sepsis, dehydration and renal failure. Events that have occurred in <1% of individuals treated with lenalidomide include rare treatment-emergent adverse events of angioedema, serious skin reactions including StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) or an allergic skin reaction similar to that seen with thalidomide, tumor lysis syndrome (TLS), tumor flare reaction (TFR), and rhabdomyolysis. In addition, lenalidomide has been shown to increase the level of digoxin in the blood in some patients. Patients will be instructed to inform their doctor if taking digoxin. There may be an increased risk of second cancers in patients who are on lenalidomide maintenance therapy after a bone marrow transplant.
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7.1.1.3 adverse events list of

Events that have occurred in 10-15% of individuals treated with dexamethasone include increased appetite, weight gain, sleep disturbance, hypertension, fluid retention, ankle swelling, bruising, infection, mood changes, slow wound healing, depression, and hyperglycemia, which may lead to fatigue, weight loss, excessive thirst and frequent urination. Events that have occurred in 1-9% of individuals treated with dexamethasone include loss of appetite, muscle twitching, increased thirst, frequent urination, increased perspiration, diarrhea, nausea, headache, bone thinning, spinal fracture or fracture of bones, tachycardia, fungal infections. Events that have occurred in <1% of individuals treated with dexamethasone include blurred vision, personality changes, stomach ulcers with bleeding that may cause hematemesis, blood in the stool and abdominal pain. Other, less frequent, events may include bowel perforation, irritation and bleeding of the esophagus, heart failure, allergic reaction that may lead to facial redness, shortness of breath, abdominal cramps and hypotension, convulsions, brain swelling, dizziness, cataracts, glaucoma and increased blood pressure in the eye, development of diabetes, pancreatic inflammation, abdominal swelling, hypokalemia, DVT or PE, malaise, swelling and/or redness of skin, allergic skin reactions, itching, hirsutism, muscle weakness or loss of muscle mass, rupture of tendons, menstrual cycle disturbances, facial puffiness, leading to the appearance of a "moon face" hormonal disturbances, and hiccups.
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7.2 adverse event characteristics

- **CTCAE term (AE description) and grade:** The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
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- for expedited reporting purposes

o AEs for the agent(s) that are listed above should be reported only if the adverse event varies in nature, intensity or frequency from the expected toxicity information which is provided.  
o Other AEs for the protocol that do not require expedited reporting are outlined in the next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-Specific Expedited Adverse Event Reporting Exclusions.
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- attribution of the ae

o Definite - The AE is clearly *related* to the study treatment.  
o Probable - The AE is likely *related* to the study treatment.  
o Possible - The AE may be *related* to the study treatment. o Unlikely - The AE is doubtfully *related* to the study treatment. o Unrelated - The AE is clearly NOT *related* to the study treatment.
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7.3 expedited adverse event reporting

Investigators **must** report to the Overall PI any serious adverse event (SAE) that occurs after the initial dose of study treatment, during treatment, or within 30 days of the last dose of treatment on the local institutional SAE form. For multi-institution studies where a DF/HCC investigator is serving as the Overall Principal Investigator, each participating institution **must** abide by the reporting requirements set by the DF/HCC. This applies to any medical event equivalent to an unexpected grade 2 or 3 with a possible, probable or definite attribution, all grade 4 toxicities, and grade 5 (death) regardless of study phase or attribution.
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7.4 df/hcc expedited reporting guidelines

Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the DFCI Office for Human Research Studies (OHRS) per the DFCI IRB reporting policy. Other investigative sites will report SAEs to their respective IRB according to the local IRB's policies and procedures in reporting adverse events. A copy of the submitted institutional SAE  
| DF/HCC Reportable AEs                                                                                           | Gr. 5 AE     |              |            |                  |           |
|-----------------------------------------------------------------------------------------------------------------|--------------|--------------|------------|------------------|-----------|
| Expected or  Unexpected                                                                                         |              |              |            |                  |           |
| Unrelated  Unlikely                                                                                             | Not required | Not required | 5 calendar | 5 calendar  days | 24 hours* |
| days#                                                                                                           |              |              |            |                  |           |
| Possible                                                                                                        | Not required | 5 calendar   | 5 calendar | 5 calendar       |           |
| Probable                                                                                                        | days         | 24 hours*    |            |                  |           |
| days                                                                                                            | days#        |              |            |                  |           |
| Definite                                                                                                        | Gr. 2 & 3    |              |            |                  |           |
| Attribution                                                                                                     | AE           |              |            |                  |           |
| Expected                                                                                                        | Gr. 2 & 3 AE | Gr. 4 AE     | Gr. 4 AE   |                  |           |
| Unexpected                                                                                                      | Expected     | Unexpected   |            |                  |           |
| # If listed in protocol as expected and not requiring expedited reporting, event does not need to  be reported. |              |              |            |                  |           |  
form should be forwarded to the Overall PI within the timeframes detailed in the table below.  
\# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. * For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last intervention, the AE should be reported within 1 business day of learning of the event.  
The Overall PI will submit SAE reports from outside institutions to the DFCI OHRS according to DFCI IRB policies and procedures in reporting adverse events. If, following initiation of the investigational product, it is subsequently discovered that a study subject is pregnant or may have been pregnant at the time of investigational product exposure, including during at least 6 half lives after product administration, the investigational product will be permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for subject safety). Protocol-required procedures for study discontinuation and follow-up must be performed on the subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy follow-up procedures should be considered if indicated. The investigator must immediately notify the BMS, Celgene (or designee) Medical Monitor of this event and complete and forward an SAE Form to BMS and Celgene (or designee) within 24 hours and in accordance with SAE reporting procedures described in this section.
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pregnancy

Any pregnancy that occurs in a female partner of a male study participant should be reported to the Overall PI. Information on this pregnancy will be collected on the BMS Pregnancy Surveillance Form. Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome and, where applicable, offspring information must be reported on the Pregnancy Surveillance Form. Please contact the Research Project Manager if you do not have this form in your regulatory files. Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or disease state) of a female subject occurring while the subject is on lenalidomide, or within 28 days of the subject's last dose of lenalidomide, are considered immediately reportable events. Lenalidomide is to be discontinued immediately. The pregnancy, suspected pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety immediately by facsimile or email using the Pregnancy Initial Report Form. The female subject should be referred to an obstetrician-gynecologist, preferably one experienced in reproductive toxicity for further evaluation and counseling. The Investigator will follow the female subject until completion of the pregnancy, and must notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or abnormal outcome) using the Pregnancy Follow-up Report Form. If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the Investigator should report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious criteria, it must be reported as an SAE to Celgene Drug Safety immediately by facsimile, or other appropriate method, within 24 hours of the Investigator's knowledge of the event using the SAE
Report Form. All neonatal deaths that occur within 28 days of birth should be reported, without regard to causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is related to the in utero exposure to the IP should also be reported to Celgene Drug Safety immediately by facsimile, or other appropriate method, within 24 hours of the Investigator's knowledge of the event using the SAE Report Form.
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male subjects

If a female partner of a male subject taking investigational product becomes pregnant, the male subject taking lenalidomide should notify the Investigator, and the pregnant female partner should be advised to call their healthcare provider immediately.
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celgene drug safety contact information

Celgene Corporation Global Drug Safety and Risk Management Connell Corporate Park 300 Connell Dr. Suite 6000 Berkeley Heights, NJ 07922 Fax: (908) 673-9115 E-mail: drugsafety@celgene.com
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overdose

Include any product-specific definition of overdose in addition to the following mandatory statement as the last sentence. An overdose is defined as the accidental or intentional administration of any dose of a product that is considered both excessive and medically important. All occurrences of overdose must be reported as SAEs.
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overdose of lenalidomide

Overdose, as defined for this protocol, refers to Revlimid dosing only. On a per dose basis, an overdose is defined as the following amount over the protocol-specified dose of Revlimid assigned to a given patient, regardless of any associated adverse events or sequelae.  
- PO any amount over the protocol-specified dose On a schedule or frequency basis, an overdose is defined as anything more frequent than the protocol required schedule or frequency.  
Complete data about drug administration, including any overdose, regardless of whether the overdose was accidental or intentional, should be reported in the case report form.  
7.4.1 Protocol-Specific Expedited Adverse Event Reporting Exclusions There are no protocol specific exclusions.
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7.5 expedited reporting to the

The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event that meets the FDA's criteria for expedited reporting following the reporting requirements and timelines set by the FDA.
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7.6 expedited reporting to bristol-myers

The Overall PI, as study sponsor, will be responsible for all communications with the BMS. With the exception of any serious adverse event that meets the FDA's criteria for expedited reporting following the reporting requirements and timelines set by the FDA. All SAEs and SUSARs should simultaneously be faxed or e-mailed to BMS by each participating site at: Global Pharmacovigilance & Epidemiology Bristol-Myers Squibb Company Fax Number: 609-818-3804 Email: Worldwide.safety@bms.com The written report must be completed and supplied to BMS by facsimile or e-mail within 3 business days.. The report should also include the BMS trial number, which is CA204-119.
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7.7 expedited reporting to celgene

Serious adverse events (SAE) are defined above. The investigator must inform Celgene in writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 hours of being aware of the event. The written report must be completed and supplied to Celgene by facsimile within 24 hours. The initial report must be as complete as possible, including an assessment of the causal relationship between the event and the investigational product(s). Information not available at the time of the initial report (e.g., an end date for the adverse event or laboratory values received after the report) must be documented on a follow-up report. A
final report to document resolution of the SAE is required. The Celgene tracking number (RVCL-MM-PI-004473) and the institutional protocol number should be included on SAE reports (or on the fax cover letter) sent to Celgene. A copy of the fax transmission confirmation of the SAE report to Celgene should be attached to the SAE and retained with the patient records.
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7.8 expedited reporting to hospital

Participating investigators will report to their local Risk Management office any participant safety reports or sentinel events that require reporting according to institutional policy.
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7.9 routine adverse event reporting

All Adverse Events **must** be reported in routine study data submissions to the Overall PI on the toxicity case report forms. **AEs reported through expedited processes (e.g., reported to the** IRB, FDA, etc.) must also be reported in routine study data submissions.
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8. pharmaceutical information

A list of the adverse events and potential risks associated with the Elotuzumab and lenalidomide administered in this study can be found in Section 7.
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8.1 elotuzumab 8.1.1 description

Elotuzumab (BMS- 901608; formerly known as HuLuc63) is a humanized recombinant monoclonal IgG1 antibody product directed to human SLAMF7 (CD2-subset-1, also known as CRACC), a cell surface glycoprotein that is highly expressed in MM cells.
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8.1.2 form

Elotuzumab for injection has been developed to be used as an intravenous (IV) infusion for the clinical studies. Drug product is a non-pyrogenic lyophilized powder which is white to off-white contained in 20-cc Type I glass vials, closed with 20-mm stoppers and sealed with aluminum seals. Each vial of drug product contains the labeled amount of BMS-901608 drug substance, sucrose, sodium citrate dihydrate, citric acid, and polysorbate 80. A 10% overfill is included in each vial to account for vial, needle, syringe (VNS) holdup. The drug product will be reconstituted prior to administration.
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table 7

Product Potency Primary Secondary Appearance Storage  
| Description and                                | Packaging                     |                               |                         |
|------------------------------------------------|-------------------------------|-------------------------------|-------------------------|
| Dosage Form                                    | (Volume)/  Label Type         | Packaging  (Qty) /Label  Type | Conditions  (per label) |
| Sterile, white  to off-white,  preservativefree,  lyophilized cake                                                |                               |                               |                         |
| Elotuzumab  Powder for  Solution for  Infusion | 10 vials per  kit/open  Label | Store at 2°C - 8°C            |                         |
| 400mg/vial                                     | 20 ml vial/  open Label       |                               |                         |  
8.1.3 Storage and Stability The product storage manager should ensure that the study drug is stored in accordance with the environmental conditions (temperature, light, and humidity) as determined by the sponsor. If concerns regarding the quality or appearance of the study drug arise, do not dispense the study drug and contact the sponsor immediately. The lyophilized elotuzumab drug product should be stored at 2° to 8° C. Prior to administration the drug product must be reconstituted with Sterile Water for Injection, USP, and then further diluted in 0.9% sodium chloride normal saline, USP, as per the instructions in Appendix B. After the dose is diluted in normal saline, it must be administered within 8 hours if stored at room temperature. If a delay is anticipated, the prepared dose may be refrigerated at 2° to 8° C for up to 24 hours. If stored under refrigerated conditions, the prepared study drug solution should be equilibrated to room temperature (process takes 2 - 2.5 hours) and the container must be gently inverted to mix well before administration. Do not use the accelerated warming method. If administration is delayed beyond the specified time, the prepared dose solution must be discarded, and the reason documented by the pharmacist in study drug accountability records. The dose of elotuzumab to be administered to a subject will be calculated by multiplying the subject's weight (kg) by 10 mg/kg. The subject's predose weight on Day 1 of each cycle or predose weight at each visit, whichever is institutional policy, will be used to calculate the dose for each cycle. Each dose should be infused as per instructions in Appendix B.
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8.1.4 handling

The lyophilized elotuzumab drug product should be stored at 2° to 8°C. Prior to administration the drug product must be reconstituted with Sterile Water for Injection, USP, and then further diluted in 0.9% sodium chloride normal saline, USP, as per the instructions in Appendix B. Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the environment, should undertake the preparation, handling, and safe disposal of the chemotherapeutic agent in a self-contained and protective environment.
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8.1.5 availability

Bristol-Myers Squibb will supply elotuzumab. Elotuzumab is an investigational agent and will be supplied free-of- charge. Drug will be shipped to the pharmacy at the study site.
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8.1.6 preparation

The product storage manager should ensure that the study drug is stored in accordance with the environmental conditions (temperature, light, and humidity) as determined by the sponsor. If concerns regarding the quality or appearance of the study drug arise, do not dispense the study drug and contact the sponsor immediately. After the dose is diluted in normal saline, it must be administered within 8 hours if stored at room temperature. If a delay is anticipated, the prepared dose may be refrigerated at 2° to 8°C for up to 24 hours. If stored under refrigerated conditions, the prepared study drug solution should be equilibrated to room temperature (process takes 2 - 2.5 hours) and the container must be gently inverted to mix well before administration. Do not use the accelerated warming method. If administration is delayed beyond the specified time, the prepared dose solution must be discarded, and the reason documented by the pharmacist in study drug accountability records.
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8.1.7 administration

Elotuzumab will be given cycle 1 & 2 at 10 mg/kg IV once a week (days, 1, 8, 15, and 22). Elotuzumab will be given cycle 3 to 8 at 10mg/kg IV days 1 and 15 every cycle. Maintenance elotuzumab will be given at 20 mg/kg IV day 1 every cycle up to cycle 24 (total of 2 years).
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8.1.8 ordering

The investigator or designee will order drug from Bristol-Myers Squibb, according to the ordering instructions provided by company. A study specific order form will be provided by the lead site.
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8.1.9 accountability

The investigator, or designee, is responsible for taking an inventory of each shipment of elotuzumab received, and comparing it with the accompanying accountability form. The Investigator, or designee, will verify the accuracy of the information on the form, sign and date it, retain a copy in the study fill. Accurate records will be kept in the source documentation of all drug administration (including dispensing and dosing).
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8.1.10 destruction and return

If study drugs (those supplied by the sponsor or sourced by the investigator) are to be destroyed on site, it is the investigator's responsibility to ensure that arrangements have been made for the disposal, procedures for proper disposal have been established according to applicable regulations, guidelines and institutional procedures, and appropriate records of the disposal have been documented.
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8.2 lenalidomide 8.2.1 description

Lenalidomide (REVLIMID®), a thalidomide analogue, is an immunomodulatory agent with antiangiogenic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H- isoindol-2yl) piperidine-2,6-dione and it has the following chemical structure:
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione. The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3.
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8.2.2 form

Lenalidomide is off-white to pale-yellow solid powder. It is soluble in organic solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of zero. Lenalidomide is available for this study as 5 and 25 mg capsules for oral administration. Each capsule contains lenalidomide as the active ingredient and the following inactive ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.
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8.2.3 storage and stability

At the study site, all investigational study drugs will be stored in a locked, safe area to prevent unauthorized access. Lenalidomide should be stored at room temperature away from direct sunlight and protected from excessive heat and cold.
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8.2.4 handling

Females of childbearing potential should not handle or administer lenalidomide unless they are wearing gloves. Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the environment, should undertake the preparation, handling, and safe disposal of the chemotherapeutic agent in a self-contained and protective environment.
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8.2.5 availability

Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no charge through Celgene's Revlimid Risk Evaluation and Mitigation Strategy™ (REMS) (formerly known as RevAssist® Program, Research). Each patient's individual drug supply will be delivered to the site by the drug courier Biologics and be distributed to the patient through the research side of the pharmacy of that site.
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8.2.6 preparation

Lenalidomide is an oral drug, and does not require specific preparation details.
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8.2.7 administration

Lenalidomide will be given daily at 25 mg days 1-21 on a 28 day cycle, cycles 1-8. Maintenance therapy can be given until cycle 24 (total of 2 years). During maintenance, lenalidomide will be given 15 mg daily days 1-21 every cycle. At all times when dispensing lenalidomide protocol therapy, study site personnel will review the instructions, printed on the packaging, with participants.