Trial of Combination of Elotuzumab Lenalidomide and Dexamethasone in High-Risk Smoldering Multiple Myeloma

This research study is a Phase II clinical trial, which tests the effectiveness of the
investigational drugs elotuzumab, lenalidomide and dexamethasone in smoldering multiple
myeloma. Recent research studies have shown that early treatment of smoldering multiple
myeloma may delay or prevent the progression to active multiple myeloma. The purpose of this
research study is to learn whether the combination of elotuzumab, lenalidomide and
dexamethasone works in treating smoldering multiple myeloma.

Inclusion Criteria:

- 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.

- Exclusion Criteria:

- 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 criteria.
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

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study

- 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

- Uncontrolled intercurrent illness

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to elotuzumab or lenalidomide

- Known seropositive for or active viral infection with human immunodeficiency virus,
hepatitis B virus or hepatitis C virus. Patients who are seropositive because of
hepatitis B virus vaccine are eligible