Inclusion Criteria:

• Absolute neutrophil count (ANC) ≥ 1700/mm^³
• Platelet count ≥ 100,000/mm^³
• Hemoglobin ≥ 8.0 g/dL
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) ≤ 3 x upper limit of normal (ULN)
• Creatinine clearance ≥ 30 mL/min (as determined by Cockroft-Gault equation)
• Diagnosis of multiple myeloma according to International Myeloma Working Group criteria and one of the following:
  • Smoldering multiple myeloma (SMM)
  • Indolent multiple myeloma (IMM)
  • Newly diagnosed multiple myeloma (MM)
  • Note: patients with lytic disease and anemia are eligible
• High risk disease defined by all of the following:
  • ≥ 10% bone marrow plasma cells AND
  • Abnormal serum free light chain (FLC) ratio (< 0.26 or > 1.65) by serum FLC assay AND
  • Monotypic Plasma Cell S-phase ≥0.3%   
• Measurable level of M-protein > 1 g/dL on serum protein electrophoresis or > 200 mg of M-protein on a 24 hour urine protein electrophoresis
• Negative tuberculosis (TB) testing (Quantiferon - TB blood test or skin test) ≤ 7 days prior to registration
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
• Provide signed informed consent
• Negative (serum or urine) pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only; NOTE: a second pregnancy test must be performed within 24 hours prior to the start of lenalidomide; the subject may not receive lenalidomide until the study doctor has verified that the results of these pregnancy tests are negative
• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
• Willing and able to comply with the requirements of the Revlimid Risk Evaluation and Mitigation Strategy (REMS) program
• Females of childbearing potential must be willing to adhere to the scheduled pregnancy testing as required by the Revlimid REMS program

Exclusion Criteria:

• Prior treatment with any other agent that may affect M-protein ≤ 30 days prior to registration
• Acute/chronic infections, open wounds, or any active infection requiring intravenous antibiotic therapy ≤ 12 weeks prior to registration
• Other active malignancy (≤ 3 years) prior to registration; exceptions: basal cell skin cancer or carcinoma-in-situ of the cervix or low-risk prostate cancer after curative therapy
• Any of the following:
  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception
• New York Heart Association (NYHA) class 3 or 4 congestive heart failure (CHF) symptoms
• Other concurrent chemotherapy, radiotherapy, or any ancillary therapy considered investigational; NOTE: bisphosphonates are allowed while on protocol treatment