Combination Chemotherapy in Treating Patients With Multiple Myeloma

OBJECTIVES:

• Compare the overall survival of patients with previously untreated stage I-III multiple myelome treated with melphalan combined with dexamethasone or prednisone as induction therapy.
• Compare the overall survival of patients with stable or responding disease after induction treated with dexamethasone vs observation alone as maintenance therapy.
• Compare the time to progression, response rate, and quality of life of patients treated with these regimens.
• Compare the toxic effects of these regimens in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified by center, stage (I or II vs III), creatinine (less than 2.0 mg/dL vs 2.0 mg/dL or greater), and intention to use prophylactic bisphosphonate (yes vs no).

• Induction: Patients are randomized to 1 of 4 treatment arms.

• Arms I and II: Patients receive induction comprising oral prednisone followed by oral melphalan on days 1-4.
• Arms III and IV: Patients receive induction comprising oral melphalan and oral dexamethasone (DM) on days 1-4 of all courses and DM on days 15-18 of courses 1-3.

Induction for arms I-IV continues every 4 weeks for 12 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease after induction proceed to maintenance therapy.

• Maintenance:

• Arms I and III: Patients undergo observation.
• Arms II and IV: Patients receive oral DM on days 1-4. Maintenance therapy continues every 4 weeks for arms II and IV and every 3 months for arms I and III in the absence of disease progression or unacceptable toxicity. Patients on arms I-IV who develop disease progression proceed to reinduction.
• Reinduction: Patients restart induction on the arm to which they were originally randomized. Reinduction continues every 4 weeks in the absence of stable response lasting 16 weeks, disease progression, or unacceptable toxicity. Patients who achieve a stable response lasting 16 weeks restart maintenance therapy. Patients who experience further disease progression during reinduction are taken off study.

Quality of life is assessed at baseline, on day 1 of courses 1-3 and then every 3 courses during induction, and then every 3 months during maintenance therapy.

Patients are followed every 6 months.

PROJECTED ACCRUAL: A maximum of 600 patients will be accrued for this study within 6 years.

DISEASE CHARACTERISTICS:

• Histologically proven previously untreated stage I-III multiple myeloma

• Patients with stage I disease must be symptomatic
• Must meet at least 1 of the following conditions:

• Plasma cells in osteolytic lesion or soft tissue tumor biopsy
• At least 10% plasmacytosis in bone marrow aspirate and/or biopsy
• Less than 10% plasma cells in bone marrow but at least 1 bony lesion
• Detectable serum M-component of IgG, IgA, IgD, or IgE

• If only light chain disease (urine M-protein) present, urinary excretion of light chain (Bence Jones) protein must be at least 1.0 g/24 hours

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-4

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Not specified

Renal:

• Not specified

Other:

• No other concurrent serious illness
• Concurrent diabetes allowed, at the discretion of the treating physician, if changes in insulin requirements can be managed
• No other prior or concurrent malignancy except curatively treated nonmelanomatous skin cancer or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No concurrent immunizations
• No concurrent filgrastim (G-CSF) or other growth factors as prophylaxis
• Concurrent epoetin alfa for anemia allowed

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Prior dexamethasone or prednisone with radiotherapy for spinal cord compression allowed if cumulative dexamethasone dose no greater than 120 mg and cumulative prednisone dose no greater than 792 mg
• Prior or concurrent corticosteroids for hypercalcemia allowed

Radiotherapy:

• See Endocrine therapy
• Prior focal radiotherapy allowed
• Concurrent focal radiotherapy during induction allowed
• Concurrent radiotherapy for palliation (e.g., painful osteolytic lesions or spinal cord compression) allowed

Surgery:

• At least 2 years since prior surgery for radiologic or endoscopic diagnosis of gastric or duodenal ulcer

Other:

• At least 2 years since prior medication for radiologic or endoscopic diagnosis of gastric or duodenal ulcer
• Prior or concurrent bisphosphonates for hypercalcemia allowed