Combination Chemotherapy With or Without PSC 833 in Treating Patients With Relapsed or Refractory Multiple Myeloma

OBJECTIVES:

• Compare the overall survival and objective response rate of patients with relapsed or refractory multiple myeloma treated with vincristine, doxorubicin, and dexamethasone (VAD) with or without PSC 833.
• Compare event free survival and subjective response in patients treated with these regimens.
• Correlate treatment outcome with p-glycoprotein expression.
• Determine whether prognostic factors previously determined to be useful in untreated patients (i.e., plasma cell labeling index and multidrug resistance determined from bone marrow aspirates, serum beta 2-microglobulin and interleukin-6 receptor levels) correlate with objective and subjective response and event-free and overall survival in patients treated with these regimens.
• Compare the toxicity of VAD with or without PSC 833.

OUTLINE: This is a randomized, multicenter study. Patients are stratified by response to prior treatment, prior doxorubicin and/or vincristine, prior autologous peripheral blood stem cell transplantation, and center.

Patients are randomized to 1 of 2 treatment arms:

• Arm I: The first group receives vincristine, doxorubicin, and dexamethasone (VAD). Patients receive higher dose vincristine IV over 96 hours and higher dose doxorubicin IV over 96 hours on days 1-4 and oral dexamethasone daily on days 1-4 and 15-18.
• Arm II: The second group receives VAD plus oral PSC 833. Patients receive oral PSC 833 every 6 hours beginning on day 1 and continuing for 20 doses. Patients receive lower dose vincristine IV over 96 hours and lower dose doxorubicin IV over 96 hours on days 2-5 and oral dexamethasone daily on days 2-5 and 16-19.

Treatment in both arms repeats every 4 weeks in the absence of disease progression or unacceptable toxicity. After completion of 2 courses, patients are reevaluated, and those with stable or responding disease continue treatment for 2 courses beyond maximum response. Doxorubicin is discontinued in patients who receive a maximum lifetime dose but still have stable or responding disease.

Patients are followed every 2 months for survival.

PROJECTED ACCRUAL: A total of 360 patients will be accrued for this study over approximately 20 months.

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