RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Interferon alfa may interfere with the growth of cancer cells. It is not yet known whether combination chemotherapy plus interferon alfa is more effective than combination chemotherapy alone in treating patients with multiple myeloma.

PURPOSE: Randomized phase III trial to compare the effectiveness of combination chemotherapy with or without interferon alfa in treating patients who have previously untreated stage I, stage II, or stage III multiple myeloma.

OBJECTIVES:

• Compare the response rate, time to response, duration of response, and survival in patients with previously untreated multiple myeloma treated with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP) alone vs VBMCP alternating first with high-dose cyclophosphamide and then with interferon alfa in patients with previously untreated multiple myeloma.
• Compare the toxicity of these regimens in these patients.
• Determine whether ancillary laboratory studies on companion protocol E-3A93 predict response and survival on this protocol.

OUTLINE: This is a randomized study. Patients are stratified according to creatinine (less than 2.0 vs 2.0 mg/dL or greater), performance status (0-1 vs 2-4), plasma cell labeling index (2% or more vs less than 2% vs approved unknown/not interpretable), and beta-2 microglobulin (4 micrograms/dL or greater vs less than 4 micrograms/dL vs approved unknown/not interpretable).

• Induction: Patients receive vincristine IV, carmustine IV, and cyclophosphamide (CTX) IV on day 1; oral melphalan on days 1-4; and oral prednisone on days 1-7 (VBMCP). Treatment continues every 5 weeks for 2 courses.

• Consolidation: Patients are then randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive VBMCP as in induction. Courses repeat every 5 weeks.
  • Arm II: Courses 1-3 each last 5 weeks, while subsequent courses each last 3 weeks. During courses 1 and 3, patients receive oral prednisone and high-dose CTX IV on days 1-4 and filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until blood counts recover. Patients receive VBMCP during course 2 and all subsequent even-numbered courses. Patients receive interferon alfa (IFN-A) SC three times a week for 10 doses during course 5 and all subsequent odd-numbered courses. The last dose for each course of IFN-A is administered concurrently with day 1 of course 6 and subsequent courses of VBMCP. Patients continue to receive alternating courses of VBMCP and IFN-A.

After documentation of plateau, patients receive 2 additional courses of VBMCP (arm I) or 2 additional courses of VBMCP alternating with 2 courses of IFN-A (arm II) in the absence of disease progression. Treatment for arms I and II continues for 1-2 years in the absence of a plateau state plus 2 additional courses of VBMCP (arm I) or 2 courses each of VBMCP and IFN-A (arm II); disease progression; or unacceptable toxicity. Patients undergo observation beginning after completion of the 2 post-plateau courses and continuing in the absence of disease progression. Patients with disease progression after 3 months on observation receive reinduction comprising the consolidation regimen to which they were originally randomized. Reinduction continues in the absence of disease progression.

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

PROJECTED ACCRUAL: A total of 289 patients will be accrued for this study within approximately 8 years.

• Biological: filgrastim
• Biological: recombinant interferon alfa
• Drug: carmustine
• Drug: cyclophosphamide
• Drug: melphalan
• Drug: prednisone
• Drug: vincristine sulfate

DISEASE CHARACTERISTICS:

• Diagnosis of previously untreated, stage I-III multiple myeloma confirmed by:

  • Bone marrow plasmacytosis with at least 10% plasma cells or sheets of plasma cells or biopsy-proven plasmacytoma

  • At least 1 of the following:

    • M-protein in serum or urine
    • Osteolytic lesions on radiograph (generalized osteoporosis qualifies only if bone marrow aspirate contains at least 20% plasma cells)

• Measurable disease

  • Serum M-protein at least 1.0 g/dL by serum protein electrophoresis
  • Urine M-protein (light chain) excretion greater than 200 mg/24 hours by urine protein electrophoresis
  • Biopsy-proven, measurable plasmacytoma(s) of soft tissue
  • Bone marrow plasmacytosis of at least 20%
• No smoldering multiple myeloma
• No nonsecretory myeloma
• No localized plasmacytomas
• No monoclonal gammopathy of undetermined significance
• No primary systemic amyloidosis
• No cord compression or CNS complication unless controlled by appropriate therapy
• Concurrent registration on the ancillary laboratory protocol E-3A93 required except for participants from South African institutions

PATIENT CHARACTERISTICS:

Age:

• 18 and over
• Patients age 70 and over eligible if considered able to tolerate study therapy

Performance status:

• Under age 70: Known EGOG performance status
• Age 70 and over: ECOG 0-2

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count at least 1,000/mm^3
• Platelet count at least 50,000/mm^3
• No thrombophlebitis within the past 6 months

Hepatic:

• Bilirubin no greater than 2.0 mg/dL
• SGOT no greater than 2.5 times upper limit of normal (ULN)
• Alkaline phosphatase no greater than 2.5 times ULN

Renal:

• Creatinine no greater than 5.0 mg/dL
• No renal disease
• No hyperuricemia unless controlled by appropriate therapy

Cardiovascular:

• No myocardial infarction within the past 6 months
• No hypertension requiring treatment other than diuretics and/or beta blockers, angiotensin-converting enzyme inhibitors, or calcium channel blockers
• Blood pressure greater than 140/90 mm Hg must be treated and maintained below 170/100 mm Hg on antihypertensives

• No significant arrhythmia within the past 3 months, i.e.:

  • Sustained atrial or ventricular arrhythmia requiring antiarrhythmic drugs
  • Documented multifocal premature ventricular contractions requiring therapy
  • Ongoing requirement for antiarrhythmia drugs except digoxin to control the ventricular rate of atrial fibrillation that has been chronic for more than 1 year
• Ejection fraction normal by echocardiogram or MUGA scan if history of congestive heart failure or myocardial infarction
• No angina requiring nitrates or beta blockers

Pulmonary:

• No pulmonary emboli within the past 6 months

Other:

• No AIDS
• No concurrent reversible condition (e.g., infection, hyperviscosity syndrome) unless controlled by appropriate therapy
• No other malignancy within the past 5 years except nonmelanomatous skin cancer or carcinoma in situ of the cervix
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Concurrent epoetin alfa allowed for control of anemia

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Concurrent corticosteroids for hypercalcemia allowed

Radiotherapy:

• No prior radiotherapy to more than 15% of bone marrow
• Concurrent radiotherapy allowed if delay of systemic therapy would pose undue risk to patient

Surgery:

• More than 5 years since prior surgery for other cancer

Other:

• See Cardiovascular
• Concurrent bisphosphonates or other agents for hypercalcemia allowed
• No concurrent anticoagulants