Combination Chemotherapy With or Without PSC 833 in Treating Patients With Relapsed or Refractory Multiple Myeloma
Combination Chemotherapy With or Without PSC 833 in Treating Patients With Relapsed or Refractory Multiple Myeloma
RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so
 they stop growing or die. Some tumors become resistant to chemotherapy drugs. Combining PSC
 833 with chemotherapy may reduce resistance to the drug, and allow more tumor cells to be
 killed. It is not yet known whether combination chemotherapy plus PSC 833 is more effective
 than combination chemotherapy alone in treating patients with relapsed or refractory multiple
 myeloma.

 PURPOSE: Randomized phase III trial to compare the effectiveness of 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