A PHASE III STUDY OF PSC-833 IN COMBINATION WITH VINCRISTINE, DOXORUBICIN AND DEXAMETHASONE (PSC-833/VAD) VERSUS VAD ALONE IN PATIENTS WITH RELAPSING OR REFRACTORY MULTIPLE MYELOMA

Inclusion Criteria

DISEASE CHARACTERISTICS:

- Multiple myeloma of any stage confirmed by:

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

- Myeloma (M) protein in serum and/or urine

- Measurable disease by at least one of the following:

- Serum M-component at least 1.0 g/dL by electrophoresis

- Baseline measurement by nephelometry also, if used to follow response

- Urine M-protein excretion greater than 200 mg/24 hours by electrophoresis

- The following are not considered measurable but are followed for response:

- Lytic bone lesions

- Bone marrow plasmacytosis

- Anemia

- Serum beta 2-microglobulin

- Objective evidence of progression by at least one of the following:

- Increased serum M-protein (by electrophoresis unless M-spike less than 1.5 g/dL)

- At least 50% above lowest remission level or by at least 2 g/dL

- To more than 1.0 g/dL if sole protein indication of relapse

- Nephelometry may be used instead of electrophoresis

- Increased urine M-protein

- To 50% above lowest level OR by 2 g/24 hours

- To greater than 200 mg/24 hours

- Definite new lytic bone lesions or at least a 50% increase in size of existing
lesions (discussion with ECOG Study Chairman required if sole indication of
progression)

- Increase in serum or urine M-protein by 25% to under 50% (as above) plus one of
the following:

- Serum calcium greater than 12 mg/dL without other cause

- Hemoglobin decreased by more than 2.0 g/dL not attributed to chemotherapy,
interferon therapy, or a myelodysplastic syndrome

- Less than 11 g/dL in men

- Less than 10 g/dL in women

- At least a 50% increase in bone marrow plasmacytosis

- Failure of prior cytotoxic therapy defined by one of the following:

- Never responded

- Relapsed within 2 months of last treatment

- Relapsed 2-12 months after last treatment following initial response

- Adequate prior chemotherapy required, e.g.:

- At least 2 courses of combination chemotherapy (e.g., VBMCP, VBAP, MP)

- Prior vincristine, doxorubicin, and dexamethasone (VAD) allowed

- No demonstrated resistance to VAD

- At least 3 months since prior VAD

- Cumulative doxorubicin dose no more than 250 mg/m2

- Prior autologous peripheral blood stem cell transplant allowed if performed
prior to development of drug resistance

- No prior allogeneic transplant

- No smoldering myeloma, localized plasmacytoma, or monoclonal gammopathy of
undetermined significance (MGUS)

PATIENT CHARACTERISTICS:

Age:

- 18 and over

Performance status:

- ECOG 0-3

Life expectancy:

- At least 2 months

Hematopoietic:

- Absolute neutrophil count at least 1,000/mm^3

- Platelet count at least 50,000/mm^3

Hepatic:

- Bilirubin less than 1.5 times upper limit of normal (ULN)

- AST less than 1.5 times ULN

- No chronic or active hepatitis or cirrhosis

Renal:

- Creatinine less than 3.0 mg/dL

Cardiovascular:

- Ejection fraction at least 50%

- No history of congestive heart failure

- No overt angina despite medication

- No myocardial infarction within 2 months

- No poorly controlled hypertension (i.e., pressure 200/110 or higher despite
medication)

- No arrhythmia requiring therapy (i.e., sustained atrial or ventricular arrhythmia or
multifocal premature ventricular contraction)

- Digoxin to control ventricular rate of atrial fibrillation that has been chronic
for more than 1 month allowed

Neurologic:

- No peripheral neuropathy with weakness

- No cerebellar disease with ataxia

Gastrointestinal:

- Adequate gastrointestinal function to allow absorption of PSC 833

- No active peptic ulcer

Other:

- No hypersensitivity to PSC 833 or cyclosporine

- No active infection

- HIV negative

- No uncontrolled diabetes mellitus

- No second malignancy within the past 5 years except curatively treated
nonmelanomatous skin cancer, carcinoma in situ of the cervix, or other localized
cancer treated with surgery alone

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No other serious medical problem unless sufficiently stabilized

PRIOR CONCURRENT THERAPY:

Biologic therapy:

- Prior biologic therapy (e.g., interferon) allowed

Chemotherapy:

- See Disease Characteristics

- At least 3 weeks since other prior chemotherapy (including plicamycin)

Endocrine therapy:

- At least 2 weeks since high dose steroids (at least 100 mg/m2/day of prednisone or at
least 40 mg/day of dexamethasone (including steroids for hypercalcemia)

Radiotherapy:

- At least 2 weeks since prior radiotherapy except limited radiotherapy to a single
bone lesion

Surgery:

- At least 4 weeks since prior major surgery

Other:

- No concurrent anticoagulants

- No concurrent drugs known to modulate cyclosporine blood concentrations