This randomized phase III trial studies lenalidomide, dexamethasone, and bortezomib to see how well it works compared to dexamethasone and lenalidomide alone in treating patients with previously untreated multiple myeloma. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the cancer. It is not yet known whether lenalidomide and dexamethasone is more effective with or without bortezomib in treating multiple myeloma.

PRIMARY OBJECTIVES:

I. To compare progression-free survival (PFS) in patients with newly diagnosed myeloma treated with lenalidomide plus low dose dexamethasone versus bortezomib plus lenalidomide and low dose dexamethasone.

SECONDARY OBJECTIVES:

I. Assess response using the new international response criteria. II. To bank specimens for future translational medicine research. III. Follow patients to assess overall survival and other long-term outcomes stratified by intent to transplant at progression.

TERTIARY OBJECTIVES:

I. To evaluate custom and genome-wide single nucleotide polymorphisms in correlation with biology, prognosis and outcome for both treatment regimens combined; to verify the findings recently obtained with the custom Bank on a Cure program (BOAC) single nucleotide polymorphism (SNP) chip on Total Therapy 2 (TT2) data with respect to bone disease in the cooperative group setting.

II. To use baseline gene expression profiling as a tool to evaluate the biology, prognostic and risk factors, and response to therapy for both treatment regimens combined. To validate John Shaughnessy's 70 gene risk model developed for Total Therapy 2 (TT2) in the cooperative group setting.

OUTLINE:

INDUCTION THERAPY: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive dexamethasone orally (PO) once daily (QD) on days 1, 8, 15, and 22 and lenalidomide PO QD on days 1-21. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive dexamethasone PO QD on days 1, 2, 4, 5, 8, 9, 11, and 12; lenalidomide PO QD on days 1-14; and bortezomib intravenously (IV) over 3-5 seconds on days 1, 4, 8, and 11. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity.

In both arms, patients who intend to undergo transplantation at relapse undergo peripheral blood stem cell collection, preferably after course 2.

MAINTENANCE THERAPY: After the completion of at least 4 courses (Arm I) or at least 6 courses (Arm II) of induction therapy, patients receive maintenance therapy comprising dexamethasone PO QD on days 1, 8, 15, and 22 and lenalidomide PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for up to 6 years.

Inclusion Criteria:

• Patients must have newly diagnosed multiple myeloma with measurable disease; patients with non-secretory multiple myeloma (MM) based upon standard M-component criteria (i.e., measurable serum/urine M-component) are not eligible for this study; exception: patients with non-secretory MM will be eligible only if the baseline serum Freelite is elevated (Note that serum Freelite must be drawn; serum light chains are not acceptable); all tests for establishing baseline disease status must be completed within 28 days prior to registration and documented on the baseline and follow-up tumor assessment form for multiple myeloma
• Patients must have received no prior chemotherapy for this disease; patients must have received no prior radiotherapy to a large area of the pelvis (more than half of the pelvis); prior steroid treatment is allowed provided treatment was not more than 2 weeks in duration; patients must not have received any prior treatment with bortezomib or lenalidomide
• Patients must have a Zubrod performance status (PS) of 0 - 3; NOTE: patients with PS 3 are eligible only if it is documented by the treating physician that the patient's multiple myeloma is the central cause of his/her disability; patients who have a PS of 3 due to other concurrent medical conditions are not eligible for this trial
• Platelet count >= 80 x 10^3/mcL; must be obtained within 28 days prior to registration; exception: patients with biopsy-proven heavy-marrow involvement, as defined by having at least 30% marrow cellularity, with > 50% of the cells being malignant plasma cells (documented marrow results required); in this case, although there are no required lower limits of normal for the blood counts, the treating physician must use his/her medical judgment as to the appropriateness of this study therapy for these patients
• Absolute neutrophil count (ANC) >= 1 x 10^3/mcL; must be obtained within 28 days prior to registration; exception: patients with biopsy-proven heavy-marrow involvement, as defined by having at least 30% marrow cellularity, with > 50% of the cells being malignant plasma cells (documented marrow results required); in this case, although there are no required lower limits of normal for the blood counts, the treating physician must use his/her medical judgment as to the appropriateness of this study therapy for these patients
• Hemoglobin (including patients who have been either transfused or treated with erythropoietin [EPO]) >= 9 g/dL; must be obtained within 28 days prior to registration; exception: patients with biopsy-proven heavy-marrow involvement, as defined by having at least 30% marrow cellularity, with > 50% of the cells being malignant plasma cells (documented marrow results required); in this case, although there are no required lower limits of normal for the blood counts, the treating physician must use his/her medical judgment as to the appropriateness of this study therapy for these patients
• Patients must be offered participation in the Myeloma Specimen Repository for banking and future research; with the patient's consent, bone marrow aspirates and serum specimens will be submitted to the Myeloma Specimen Repository for additional testing and banking (including SNP testing); patient consent must be obtained before specimens may be submitted
• Patients must have baseline skeletal survey to include lateral skull, anterior-posterior (AP) pelvis and posterior-anterior (PA) chest within 28 days prior to registration
• Institutions must submit a local cytogenetics report and fluorescence in situ hybridization (FISH) analysis report obtained prior to enrollment to S0777; for FISH analysis two probes will be utilized: LSI 13 (RBI) 13q14 SpectrumOrange Probe for detection of chromosome 13 deletion and LSI p53 (17p13.1) SpectrumOrange probe for detection of tumor protein (p)53 locus on chromosome 17; if these exact probes are not available locally, it is acceptable to submit results using local protocol; this must be noted on the prestudy form; NOTE: it is not required that the results of the FISH analysis be known prior to registration, only that pre-registration specimens be drawn and sent for analysis prior to registration, and the FISH analysis report be submitted
• Patients with pathologic fractures, pneumonia at diagnosis or symptomatic hyperviscosity must have these conditions attended to prior to registration (i.e., intramedullary rod, I.V. antibiotics, plasmapheresis)
• Patients must have a calculated or measured creatinine clearance > 30 cc/min; measured creatinine clearance or serum creatinine used in calculation must be obtained within 28 days prior to registration
• Patients must not have uncontrolled, active infection requiring intravenous antibiotics, New York Heart Association (NYHA) class III or class IV heart failure, myocardial infarction within the last 6 months, history of treatment for clinically significant ventricular cardiac arrhythmias, poorly controlled hypertension, or poorly controlled diabetes mellitus; patients must have undergone an electrocardiogram (EKG) within 28 days prior to registration
• Patients must not have any psychiatric illness that could potentially interfere with the completion of treatment according to this protocol
• Patients must not be hepatitis B, hepatitis C or human immunodeficiency virus (HIV) positive; patients must have a negative hepatitis B and HIV test performed within 28 days prior to registration; exception: treatment-sensitive HIV infection patients will be eligible provided that immunological and virologic indices are indicative of favorable long-term survival prospects on the basis of HIV infection, but whose life expectancy is limited predominantly by multiple myeloma rather than HIV infection in the judgment of the treating physician
• Patients must not have a history of cerebral vascular accident with persistent neurologic deficits
• Patients must be able to take aspirin 325 mg daily (or enoxaparin 40 mg subcutaneously [SQ] daily if patient is unable to take aspirin) as prophylactic anticoagulation; exception: patients receiving anticoagulation therapy such as Coumadin or heparin will NOT receive aspirin, and therefore need not be able to take it
• 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 and again within 24 hours prior to starting cycle 1 of lenalidomide; further, they 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; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP, even if they have had a successful vasectomy; a FCBP is a sexually mature woman who: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months); all patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure
• No prior malignancy is allowed except for adequately treated basal cell (or squamous cell) skin cancer, in situ cervical cancer or other cancer for which the patient has been disease-free for five years
• Patients must be offered participation in gene expression profiling (GEP) molecular studies for the evaluation of genetic polymorphisms
• All patients must be informed of the investigational nature of this study and must sign and give written consent in accordance with institutional federal guidelines
• At the time of patient registration, the treating institution's name and identification (ID) number must be provided to the statistical center in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered into the data base