Lenalidomide and Dexamethasone With/Without Stem Cell Transplant in Patients With Multiple Myeloma

Inclusion Criteria: * Histologically or cytologically confirmed Multiple Myeloma, Salmon-Durie Stage II or III or International Staging System II or III that has not been previously treated. * Bone marrow plasmacytosis with \> or = 10% plasma cells, or sheets of plasma cells or a biopsy-proven plasmacytoma. * Measurable levels of monoclonal protein (M protein): 1 g/dL Immunoglobulin G (IgG) or .5 g/dL Immunoglobulin A (IgA) on serum protein electrophoresis or \> 200 mg of monoclonal light chain on a 24 hour urine protein electrophoresis. * Age \> or = 18 years. * Life expectancy of greater than 12 months. * Eastern Cooperative Oncology Group (ECOG) performance status \< or = 2 (Karnofsky \> or = 60%). * Adequate organ and marrow function as defined below: * Hgb \> or = 9 g/dL * Absolute Neutrophil Count \> or = 1,500/ ml * Platelets \> or = 50,000/mm3 * Total Bilirubin \< or = 1.5 mg/dL * Aspartate aminotransferase (AST)(SGOT) / alanine aminotransferase (ALT)(SGPT) \< or = 2.5 X upper limit of normal (ULN) * Creatinine \< 2.0 mg/dL * Creatinine Clearance \> or = 50 ml/min * Registered into the mandatory Revlimid REMS® program, and be willing and able to comply with the requirements of the REMS® program. * Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program. * Ability to understand and the willingness to sign a written informed consent document. * Subjects with a history of prior malignancy are eligible provided there is no active malignancy and a low expectation of recurrence within 6 months. * Must be willing and able to take prophylaxis with either aspirin at 81 mg/day or alternative prophylaxis with either low molecular weight heparin or warfarin as recommended. * Eligible for transplant with an age up to and including 75 years. * Subjects in Arm A who are refusing transplant can go onto Arm B and will be evaluated separately. * Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 milli-international units per millilitre (mIU/mL) within 10 - 14 days prior to and again within 24 hours of prescribing lenalidomide and must either commit to continued abstinence or 2 acceptable methods of birth control. FCBP must also agree to ongoing pregnancy testing. Males must agree to use a latex condom. Exclusion Criteria: * Have had chemotherapy or radiotherapy for multiple myeloma within 4 weeks of baseline. * Receiving any other investigational agents or therapy within 28 days of baseline. * Brain metastases. * Subjects who are pregnant or breast feeding. * History of previous deep vein thrombosis or pulmonary embolism must be on anticoagulation therapy with low molecular weight heparin or warfarin at therapeutic dosages (e.g. International Normalized Ratio (INR) 2-3). * If a subject is on full-dose anticoagulants, the following criteria should be met for enrollment: * Must not have active bleeding or pathological conditions that carry high risk of bleeding (e.g. tumor involving major vessels, known varices). * Must not have thrombocytopenia requiring transfusion. * Must have a platelet count \> 50,000. * Must have stable INR between 2-3. * Smoldering myeloma or monoclonal gammopathy of undetermined significance. * Active, uncontrolled infection. * Active, uncontrolled seizure disorder (seizures in the last 6 months). * Concurrent use of other anti-cancer agents or treatments. * Positive for HIV or infectious hepatitis, type B or C. * Hypersensitivity to thalidomide. * Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk.