Inclusion Criteria

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