E- PRISM: Precision Intervention Smoldering Myeloma: Phase II Trial of Combination of Elotuzumab, Lenalidomide and Dexamethasone in High-Risk Smoldering Multiple Myeloma

• Age ≥ 18 years

• Must have smoldering myeloma with high risk markers based on the Mayo OR the Spanish criteria as described below

• >10% plasma cells in the bone marrow and any one or more of the following:

• Serum M protein of 3 g/dL or greater

• 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

• PET-CT with focal lesion with increased uptake without underlying osteolytic bone destruction † Increase in serum monoclonal protein by ≥25% on two successive evaluations within a 6 month period

• No evidence of CRAB (see below for details) criteria or new criteria of active multiple myeloma which including the following:

• Increased calcium levels (corrected serum calcium >0.25 mmol/dL above the upper limit of normal or >.275 mmol/dL)

• Renal insufficiency (attributable to myeloma)

• Anemia (Hb 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

• ECOG Performance Status (PS) 0, 1, or 2 (Appendix A)

• The following laboratory values obtained ≤ 14 days prior to registration:

• ANC ≥1000/µL

• PLT ≥ 50,000/µL

• 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

• 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

• Females of childbearing potential* must have a negative serum or urine pregnancy test

• 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

• Ability to understand and the willingness to sign a written informed consent.