RATIONALE: PS-341 may stop the growth of cancer cells by blocking the enzymes necessary for cancer cell growth. It is not yet known if PS-341 is effective in treating patients who have multiple myeloma.

PURPOSE: Randomized phase III trial to study the effectiveness of PS-341 in treating patients who have refractory or progressive multiple myeloma.

OBJECTIVES:

• Determine the time to progressive disease in patients with refractory or progressive multiple myeloma treated with PS-341.
• Determine the safety and tolerability of this drug in these patients.
• Determine survival of patients treated with this drug.
• Determine the rate and duration of response (complete and partial) in patients treated with this drug.
• Assess the relationship between selected genetic disease markers and response in patients treated with this drug.

OUTLINE: This is an open-label, multicenter study.

• Induction therapy: Patients receive PS-341 IV on days 1, 4, 8, and 11. Treatment repeats every 3 weeks for up to 8 courses.
• Maintenance therapy: Patients receive PS-341 IV on days 1, 8, 15, and 22. Treatment repeats every 5 weeks for up to 3 courses.

Patients who experience progressive disease (PD) after at least 2 courses or no change after at least 4 courses may also receive oral dexamethasone on the day of and the day after PS-341 administration. Patients who experience PD after at least 2 courses of this combined therapy go off study.

Patients are followed at 30 days, every 6 weeks until disease progression, and then every 3 months thereafter.

PROJECTED ACCRUAL: A total of 400 patients will be accrued for this study within 1 year.

• Drug: bortezomib
• Drug: dexamethasone

DISEASE CHARACTERISTICS:

• Diagnosis of multiple myeloma (MM) and meeting 1 of the following criteria:

  • Progressive disease during or after treatment with high-dose dexamethasone on MPI Study M34101-039 (FHCRC-1746.00), with no other antineoplastic treatment for MM initiated
  • Relapsed or progressive disease after receiving at least 4 prior treatment regimens for MM (non-MPI patients)

PATIENT CHARACTERISTICS:

Age

• Adult

Performance status

• Karnofsky 60-100% (non-MPI patients)

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count at least 500/mm^3 (no growth factor support)
• Platelet count at least 20,000/mm^3 (transfusions allowed)
• Hemoglobin at least 7.0 g/dL (transfusions allowed)

Hepatic

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• AST and ALT no greater than 2.5 times ULN
• Hepatitis B surface antigen negative
• No known active hepatitis C infection

Renal

• Calcium less than 14 mg/dL
• Creatinine clearance at least 20 mL/min

Cardiovascular

• Non-MPI patients:

  • No myocardial infarction within the past 6 months
  • No New York Heart Association class III or IV heart failure
  • No uncontrolled angina
  • No severe uncontrolled ventricular arrhythmias
  • No acute ischemia or active conduction system abnormalities by EKG
  • No cardiac amyloidosis
  • No poorly controlled hypertension

Other

• All patients:

  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • HIV negative

• Non-MPI patients:

  • No other serious medical or psychiatric illness that would preclude study
  • No prior allergic reaction attributable to compounds containing boron or mannitol
  • No peripheral neuropathy grade 2 or greater
  • No diabetes mellitus
  • No active systemic infection requiring treatment

• MPI patients:

  • Recovered from dexamethasone-related toxicity
  • No other new or worsening existing illness that would preclude study

PRIOR CONCURRENT THERAPY:

Biologic therapy

• At least 4 weeks since prior immunotherapy or antibody therapy (non-MPI patients)
• No concurrent thalidomide

Chemotherapy

• At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas) (non-MPI patients)

Endocrine therapy

• See Disease Characteristics
• At least 3 weeks since prior corticosteroids (greater than 10 mg/day of prednisone or equivalent) (non-MPI patients)
• No other concurrent corticosteroids (e.g., greater than 10 mg/day of prednisone or equivalent)

Radiotherapy

• Concurrent local short-duration radiotherapy allowed

Surgery

• At least 4 weeks since prior major surgery (except kyphoplasty) (non-MPI patients)
• Concurrent kyphoplasty allowed
• Concurrent emergency orthopedic procedures allowed

Other

• No other concurrent antineoplastic treatment for MM
• No other concurrent investigational agents, including commercial agents approved for other indications but investigational for MM
• No concurrent clarithromycin
• Concurrent bisphosphonates allowed