DISEASE CHARACTERISTICS:

• Patients must have newly diagnosed active multiple myeloma (MM)
  • Patients with non-secretory MM or known amyloidosis are not eligible
• For the Phase II portion only, patients must have high-risk MM based on one or more of the following criteria at the time of initial diagnosis (prior to any chemotherapy):
  • Poor-risk genomic signature according to the University of Arkansas 70-gene model (available clinically as MyPRS score, Signal Genetics, Inc.)
  • Translocation (14;16), and/or translocation (14;20), and/or deletion (17p) by florescence in-situ hybridization (FISH) or cytogenetics
  • Primary plasma cell leukemia (defined by either ≥ 2,000 plasma cells/mL of peripheral blood, or 20% on a manual differential count
  • Serum lactate dehydrogenase (LDH) ≥ 2 times institutional upper limit of normal (IULN)
• Patients must have measurable disease within 28 days prior to registration (or prior to initiation of first induction course for patients with prior therapy)
• Patients on the Phase I portion may not have received ANY prior chemotherapy
• Patients on the Phase II portion may have received one prior cycle of any noninvestigational chemotherapy
• Patients must not have active involvement of the central nervous system (CNS) with MM (by clinical evaluation)
  • Patients with documentation of or clinical signs or symptoms consistent with CNS involvement by MM must have a lumbar puncture that is negative for CNS involvement
  • Patients with no previous history of documented CNS involvement and with no clinical signs or symptoms consistent with CNS involvement are not required to have completed a lumbar puncture prior to registration

PATIENT CHARACTERISTICS:

• Zubrod performance status ≤ 2
• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm³ without growth factor support
• Platelet count ≥ 70,000 cells/mm³ for patients who have bone marrow plasmacytosis < 50% OR ≥ 50,000 cells/mm³ for patients who have bone marrow plasmacytosis of ≥ 50%
• Total bilirubin ≤ 1.5 times institutional upper limit of normal (IULN)
• Serum glutamic oxalo-acetic transaminase (SGOT)/aspartate aminotransferase (AST) and serum glutamic pyruvate transaminase (SGPT)/alanine aminotransferase (ALT) ≤ 2.5 times IULN
• Creatinine clearance (CrCL) ≥ 30 mL/min
• Patients who are known to be human immunodeficiency virus (HIV)-positive are eligible providing they meet all of the following additional criteria within 28 days prior to registration:
  • CD4 cells ≥ 500/mm³
  • Viral load of < 50 copies HIV mRNA/mm³ if on antiretroviral therapy (ART) or < 25,000 copies HIV mRNA if not on ART
  • No zidovudine or stavudine as part of ART
• Patients must have baseline skeletal survey to document lytic lesions, osteopenia, or compression fracture
• Patients with known hepatitis B or hepatitis C infection may be eligible providing they have viral load < 800,000 IU/L within 28 days prior to registration
• Patients must not have POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• Patients must not have clinically significant illness including any of the following:
  • Uncontrolled, active infection requiring intravenous antibiotics
  • New York Heart Association (NYHA) Class III or Class IV heart failure
  • Unstable angina pectoris
  • Myocardial infarction within the past 6 months
  • ≥ Grade 3 cardiac arrhythmias per Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
    • Patients must have undergone an electrocardiogram (EKG) within 28 days prior to registration
  • Uncontrolled blood pressure (BP) or hypertension
    • Defined as systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg within 14 days prior to registration
      • An exception can be made by a healthcare provider for a patient with a single BP elevation who, upon rechecking, has a normal BP
    • Patients are permitted to be receiving multiple antihypertensive medications (unless otherwise indicated in the study)
  • Uncontrolled diabetes mellitus (defined as a glycosylated hemoglobin A1C (Hg A1C) > 7% within 14 days prior to registration)
    • The same criterion will be used in patients with confirmed diagnosis of diabetes mellitus who have been on a stable dietary or therapeutic regimen for this condition in the last three months
• Patients must not have any psychiatric illness that could potentially interfere with the completion of treatment according to this protocol
• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to registration
• FCBP must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control: one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before starting lenalidomide and continuing for at least 4 months after completion of study therapy
  • Men must agree to use a latex condom during sexual contact with a FCBP, even if they have had a successful vasectomy
• Not pregnant or breastfeeding
• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Prior chemotherapy must have been completed within 56 days prior to registration and all toxicities must have resolved to ≤ Grade 1
• Patients may have received prior radiotherapy for symptomatic localized bone lesions or impending spinal cord compression only
• Radiotherapy must be completed at least 14 days prior to registration and all toxicities must have resolved to ≤ Grade 1