• Toxicity [ Designated as safety issue: Yes ]
• Response rate [ Designated as safety issue: No ]

• Toxicity
• Response rate

RATIONALE: Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Lenalidomide and thalidomide may also stop the growth of multiple myeloma by blocking blood flow to the cancer. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving lenalidomide, thalidomide, and dexamethasone together may kill more cancer cells.

PURPOSE: This randomized phase III trial is studying lenalidomide and low-dose dexamethasone to see how well it works compared to lenalidomide and standard-dose dexamethasone, given with or without thalidomide, in treating patients with multiple myeloma.

OBJECTIVES:

Primary

• Compare the response rate in patients with newly diagnosed multiple myeloma treated with lenalidomide and standard-dose vs low-dose dexamethasone.
• Compare the toxicity of these regimens in these patients.

Secondary

• Determine the response rate in patients who do not achieve an objective response at any point during the first 4 courses of lenalidomide and dexamethasone and are subsequently treated with salvage therapy comprising thalidomide and dexamethasone.
• Determine the efficacy of aspirin (325 mg/day) versus warfarin (dose adjusted to maintain a target INR of 2-3) in preventing deep vain thrombosis in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral lenalidomide once daily on days 1-21, oral acetylsalicyclic acid (or other deep vein thrombosis prophylaxis at the discretion of the principal investigator) once daily on days 1-28, and standard-dose oral dexamethasone once daily on days 1-4, 9-12, and 17-20.
• Arm II: Patients receive oral lenalidomide and acetylsalicyclic acid as in arm I and low-dose oral dexamethasone once daily on days 1, 8, 15, and 22.

In both arms, courses repeat every 28 days in the absence of unacceptable toxicity or disease progression. Patients not responding at any point during the first 4 courses of lenalidomide and dexamethasone are assigned to 1 of 2 salvage therapy arms. Patients who progress during treatment on arms I or II have the option to register on salvage therapy arms III or IV respectively.

• Arm III (patients with no response after treatment on arm I): Patients receive oral thalidomide once daily on days 1-28 and standard-dose oral dexamethasone once daily on days 1-4, 9-12, and 17-20.
• Arm IV (patients with no response after treatment on arm II): Patients receive oral thalidomide as in arm III and low-dose oral dexamethasone once daily on days 1, 8, 15, and 22.

In both salvage therapy arms, courses repeat every 28 days in the absence of unacceptable toxicity or disease progression. After completion of 4 courses of therapy, patients may undergo stem cell harvest (using growth factors only) for cryopreservation.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually for 2 years.

PROJECTED ACCRUAL: A total of 412 patients (206 per treatment arm) will be accrued for this study within 24 months.

• Drug: acetylsalicylic acid
• Drug: dexamethasone
• Drug: lenalidomide
• Drug: thalidomide

DISEASE CHARACTERISTICS:

• Diagnosis of multiple myeloma within the past 90 days, confirmed by the following criteria:

  • Bone marrow plasmacytosis with ≥ 10% plasma cells or sheets of plasma cells OR biopsy-proven plasmacytoma within the past 4 weeks
  • Measurable monoclonal protein ≥ 1.0 g/dL by serum protein electrophoresis OR monoclonal light chain ≥ 200 mg by 24-hour urine protein electrophoresis within the past 4 weeks
• Symptomatic disease
• Prior plasmacytoma treated with curative-intent radiotherapy allowed provided disease progressed to active multiple myeloma
• No smoldering myeloma
• No monoclonal gammopathy of undetermined significance

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Hemoglobin > 7 g/dL
• Platelet count > 75,000/mm^3
• Absolute neutrophil count > 1,000/mm^3

Hepatic

• Bilirubin ≤ 1.5 mg/dL
• ALT and AST ≤ 2.5 times upper limit of normal (ULN)

Renal

• Creatinine < 2.5 mg/dL

Cardiovascular

• No uncontrolled hypertension
• No uncontrolled cardiac arrhythmia
• No symptomatic congestive heart failure
• No unstable angina
• No prior or concurrent deep vein thrombosis

Pulmonary

• No prior or concurrent pulmonary embolism

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective double-method contraception (1 highly effective and one additional method) for 4 weeks prior, during, and for 4 weeks after completion of study treatment

• No other active malignancy

  • Prior malignancy with a low expectation of recurrence within the next 6 months allowed
• No prior Stevens Johnson syndrome

• No active uncontrolled seizure disorder

  • No seizures within the past 6 months
• No active uncontrolled infection
• No uncontrolled psychiatric illness or social situation that would preclude study compliance
• No peripheral neuropathy ≥ grade 2 due to other medical conditions
• No other uncontrolled illness
• Patients must be willing and able to take antithrombosis prophylaxis
• Patients must

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent sargramostim (GM-CSF)

Chemotherapy

• Not specified

Endocrine therapy

• No prior glucocorticosteroid therapy for multiple myeloma

• The following treatments for non-malignant disorders are allowed:

  • Prior systemic glucocorticosteroids
  • Prior or concurrent topical or localized glucocorticosteroids
  • Concurrent systemic glucocorticosteroids at a dose of ≤ 10 mg of prednisone per day (or equivalent)

Radiotherapy

• See Disease Characteristics
• At least 4 weeks since prior palliative and/or localized radiotherapy

Surgery

• Not specified

Other

• No prior systemic therapy for multiple myeloma except bisphosphonates