RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage cancer cells. Combining chemotherapy and radiation therapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy and radiation therapy and kill more cancer cells. It is not yet known which treatment regimen is more effective for multiple myeloma.

PURPOSE: Randomized phase III trial to compare the effectiveness of melphalan, total-body irradiation, and peripheral stem cell transplantation with that of combination chemotherapy in treating patients who have previously untreated multiple myeloma.

OBJECTIVES:

• Compare tumor cytoreduction achieved with VBMCP (vincristine/carmustine/melphalan/cyclophosphamide/prednisone) vs myeloablative melphalan (L-PAM) and total-body irradiation (TBI) with peripheral blood stem cell (PBSC) rescue in symptomatic myeloma patients with stable or responding disease after induction therapy with VAD (vincristine/doxorubicin/dexamethasone) followed by high dose cyclophosphamide plus filgrastim (G-CSF).
• Compare the efficacy of interferon alfa vs no maintenance therapy in those patients achieving at least 75% cytoreduction to either VBMCP or myeloablative therapy with PBSC rescue.
• Assess allogeneic bone marrow transplantation following the same myeloablative regimen of L-PAM/TBI in patients up to age 55 with an HLA-compatible, MLC-nonreactive donor. (As of 8/1/97, permanent partial closure)
• Determine whether myeloablative therapy with PBSC rescue can extend the duration of survival by 33% compared to results from standard dose VBMCP.
• Evaluate the toxic effects and possible long term side effects, including development of myelodysplastic disease and/or acute myeloblastic leukemia, associated with these treatments.

OUTLINE: This is a randomized study. Patients are registered at 5 different points, with stratification occurring at some of these registrations.

• Registration I: Induction I
• Registration II: Induction II. Patients are stratified according to stage of disease (I/II vs IIIA vs IIIB), beta-2 microglobulin at diagnosis (less than 6 micrograms/mL vs at least 6 micrograms/mL), and response to Induction I (75-100% regression vs 50-74% regression vs less than 50% regression vs not applicable).
• Registration III: Patients are randomized to allogeneic bone marrow transplant (BMT) (this arm closed as of 8/1/97) or autologous BMT. Patients are stratified according to treatment received (high dose cyclophosphamide (CTX) and peripheral blood stem cells (PBSC) prior to autologous BMT vs prior to chemotherapy) and beta-2 microglobulin at this registration (less than 2 micrograms/mL vs no greater than 3 micrograms/mL vs unknown).
• Registration IV: Patients are randomized to maintenance therapy or no further therapy. Those patients who are randomized to maintenance therapy are stratified according to treatment (autologous BMT vs chemotherapy vs chemotherapy followed by autologous BMT) and response to treatment (75-99% regression vs complete response).
• Registration V: Patients receive autologous BMT as in registration III. Patients are stratified according to prior best response (50% or better vs less than 50% vs not applicable), duration of chemotherapy (at least 6 months vs less than 6 months), and progression after therapy (chemotherapy vs interferon alfa vs observation).
• Induction I: Patients receive vincristine IV and doxorubicin IV by continuous infusion on days 1-4 and dexamethasone IV or orally on days 1-4, 9-12, and 17-20. Treatment repeats every 5 weeks for up to 4 courses. Patients with progressive disease after 2 courses proceed to PBSC stimulation/harvest.

Allogeneic BMT arm is permanently closed as of 8/1/97.

• Autologous BMT: Therapy begins 4-8 weeks following high dose cyclophosphamide. Patients receive melphalan IV over 1 hour on day -5 and total body irradiation twice a day on days -4 to -1. PBSC are reinfused on day 0. G-CSF SQ is administered beginning on day 1 until blood counts recover.
• Chemotherapy: Patients receive vincristine IV, carmustine IV, and cyclophosphamide IV on day 1, oral melphalan on days 1-4, and oral prednisone on days 1-7. Treatment repeats every 5 weeks for at least 12 months.

Patients who have at least a 75% response to autologous BMT or chemotherapy are randomized to maintenance vs no further therapy. Patients who progress on chemotherapy proceed to autologous BMT (registration V).

• Maintenance therapy: Therapy begins between 5 and 12 weeks after PBSC rescue. Patients receive interferon alfa SQ three times a week. Treatment continues for 4 years in the absence of disease progression or unacceptable toxicity.

Patients who progress on chemotherapy undergo an autologous BMT within 8 weeks after the last course of chemotherapy.

Patients who are randomized to receive no further therapy are observed for 1 year.

PROJECTED ACCRUAL: A total of 500 patients will be randomized over about 4 years to autologous transplantation vs chemotherapy as follows: about 250 patients/year will be accrued for induction of whom 200 will achieve at least stable disease, 125 will be randomized, and 15 will have a suitable donor for allogeneic transplant (as of 8/1/97, allogeneic arm of study is closed). Approximately 300 patients are expected to be randomized to maintenance vs no further therapy.

• Biological: recombinant interferon alfa
• Drug: carmustine
• Drug: cyclophosphamide
• Drug: dexamethasone
• Drug: doxorubicin hydrochloride
• Drug: melphalan
• Drug: prednisone
• Drug: vincristine sulfate
• Procedure: allogeneic bone marrow transplantation
• Procedure: autologous bone marrow transplantation
• Procedure: peripheral blood stem cell transplantation
• Radiation: radiation therapy

• Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, Hurd DD, McCoy J, Moore DF Jr, Dakhil SR, Lanier KS, Chapman RA, Cromer JN, Salmon SE, Durie B, Crowley JC. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol. 2006 Feb 20;24(6):929-36. Epub 2006 Jan 23. Erratum in: J Clin Oncol. 2006 Jun 10;24(17):2687. Moore, Dennis F Jr [added].
• Rimsza LM, Campbell K, Dalton WS, Salmon S, Willcox G, Grogan TM. The major vault protein (MVP), a new multidrug resistance associated protein, is frequently expressed in multiple myeloma. Leuk Lymphoma. 1999 Jul;34(3-4):315-24.

DISEASE CHARACTERISTICS:

• Newly diagnosed, active multiple myeloma of any stage requiring treatment

  • Smoldering myeloma (Durie-Salmon stage I) must have a 25% or greater increase in M component levels and/or Bence-Jones protein excretion or development of symptoms

• Quantifiable M component of IgG, IgA, IgD, IgE, and/or urinary kappa or lambda light chain (Bence-Jones protein) excretion required

  • Plasmacytosis of at least 30% allowed for non-secretory disease or secretory disease without quantifiable protein
  • IgM peaks excluded

• Evaluation of siblings as potential allogeneic bone marrow transplant donors required for patients 55 years of age and younger (As of 8/1/97, permanently closed)

  • HLA followed by DR and MLC testing required

• Renal failure, even on dialysis, eligible provided:

  • Cause is attributed to myeloma (Bence-Jones protein or hypercalcemia)
  • Duration does not exceed 2 months

• If medically appropriate, the following conditions should be treated prior to registration:

  • Pathologic fractures
  • Pneumonia at diagnosis
  • Hyperviscosity with shortness of breath

PATIENT CHARACTERISTICS:

Age:

• 70 and under

Performance status:

• SWOG 0-2 (SWOG 3 or 4 based solely on bone pain allowed)

Hematopoietic:

• Not specified

Hepatic:

• Not specified

Renal:

• See Disease Characteristics

Cardiovascular:

• Normal ejection fraction by ECHO or MUGA
• No myocardial infarction within 6 months
• No unstable angina
• No difficult to control congestive heart failure
• No uncontrolled hypertension
• No difficult to control arrhythmias
• No history of chronic cerebral vascular accident

Pulmonary:

• No history of chronic obstructive or restrictive pulmonary disease
• Pulmonary function studies and DLCO at least 50% of predicted except for demonstrated myeloma involvement on bronchoscopy and/or open lung biopsy

Other:

• No uncontrolled diabetes
• No significant comorbid medical condition
• No uncontrolled, life-threatening infection
• No prior malignancy within 5 years except adequately treated nonmelanoma skin cancer or carcinoma in situ of the cervix
• No prior malignancy treated with cytotoxic drugs used on this protocol
• Not pregnant or nursing
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy except local radiotherapy provided the following cumulative dose limits for prior dose plus potential TBI dose on protocol are not exceeded:

  • Less than 5,000 cGy to bone
  • Less than 4,000 cGy to mediastinum, heart, small bowel, brain, and spinal cord
  • Less than 2,000 cGy to the liver
  • Less than 1,500 cGy to the kidney and lungs

Surgery:

• Not specified

• National Cancer Institute (NCI)
• Cancer and Leukemia Group B
• Eastern Cooperative Oncology Group