Inclusion Criteria:
1. Age 18 years or older with a confirmed diagnosis of multiple myeloma (MM) and documentation of one to three prior therapies.
2. Confirmed evidence of disease progression from immediately prior MM therapy or refractory to the immediately prior treatment.
3. Measurable monoclonal (M-) protein component in serum (≥ 0.5 g/dL) and/or urine (if present), (≥ 0.2 g excreted in a 24 hour collection sample). Subjects with free light chain only disease are excluded.
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2.
5. Creatinine clearance ≥ 50 mL/min measured by Cockcroft-Gault method.
6. Hematologic parameters defined by:
* Absolute neutrophil count \>1000 cells/mm\^3 without growth factors for 7 days.
* Platelets ≥ 75,000 cells/mm\^3 (75 × 10\^9/L), without platelet transfusion, within 72 hours of screening evaluation.
* Hemoglobin ≥ 8 g/dL without red blood cell transfusion within 72 hours of screening.
7. Alanine aminotransferase (ALT) AND aspartate aminotransferase (AST) \< 3 × upper limit of normal.
8. Total bilirubin \< 2 × upper limit of normal, direct bilirubin \< 2.0 mg/dL.
9. Negative urine pregnancy test in women of childbearing potential at screening and prior to prescribing lenalidomide. Females of childbearing potential (FCBP) must either commit to continued abstinence from heterosexual intercourse or begin acceptable methods of birth control for 28 days prior to prescribing lenalidomide. Men must agree to use a latex condom during sexual contact with FCBP even if they have had a successful vasectomy, and must agree not to donate semen during study drug therapy and for a period of time after therapy.
10. Able to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject's privacy regulations).
11. Able to take aspirin daily as prophylactic anticoagulation therapy (subjects intolerant to aspirin may use warfarin or low-molecular-weight heparin).
Exclusion Criteria:
1. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in-situ cervical cancer, or other cancer from which the subject has been disease-free for at least 2 years.
2. Active or prior plasma cell leukemia (defined as either 20% of peripheral WBC comprised of plasma/CD138+ cells or an absolute count of 2 x 10\^9/L).
3. Uncontrolled medical problems such as diabetes mellitus, coronary artery disease, hypertension, unstable angina, arrhythmias, pulmonary disease, and symptomatic heart failure.
4. Solitary bone or solitary extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia.
5. Treatment with any investigational drug within 2 weeks or 3 half lives (whichever is longer) of the first dose of elotuzumab.
6. Use of corticosteroids, thalidomide, bortezomib, or cytotoxic chemotherapy within 2 weeks of the first dose of elotuzumab except for steroids with little or no systemic absorption (ie, topical or inhaled steroids).
7. Prior lenalidomide therapy.
8. Prior peripheral stem-cell transplant within 12 weeks of the first dose of elotuzumab.
9. Treatment with nitrosoureas, such as carmustine (BiCNU), nitrogen mustard agents, or melphalan, within 6 weeks of first dose of elotuzumab.
10. Neuropathy ≥ Grade 3 or painful neuropathy ≥ Grade 2 (National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] v3.0).
11. Known active infections requiring IV antibiotic, antiviral, or antifungal therapy.
12. Hypersensitivity to recombinant proteins or excipients in elotuzumab, lenalidomide, or dexamethasone.
13. Female subjects who are pregnant or breastfeeding.
14. Subjects with serum calcium (corrected for albumin) ≥ 12 mg/dL.
