Arsenic Trioxide Plus Vitamin C in Treating Patients With Recurrent or Refractory Multiple Myeloma
Arsenic Trioxide Plus Vitamin C in Treating Patients With Recurrent or Refractory Multiple Myeloma
RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing
 so they stop growing or die. Vitamin C may increase the effectiveness of arsenic trioxide by
 making cancer cells more sensitive to the drug.

 PURPOSE: Phase I/II trial to determine the effectiveness of arsenic trioxide plus vitamin C
 in treating patients who have recurrent or refractory multiple myeloma.
OBJECTIVES:

 -  Determine the maximum tolerated dose of arsenic trioxide when administered with ascorbic
 acid in patients with recurrent or refractory multiple myeloma.

 -  Determine the therapeutic efficacy of this treatment combination in these patients.

 -  Determine the expression of MDR and Bcl-xL genes and the intracellular levels of GSH in
 these patients before and after this treatment regimen and assess whether these measures
 have prognostic value.

 OUTLINE: This is a multicenter, dose-escalation study of arsenic trioxide.

 -  Phase I: Patients receive arsenic trioxide IV over 1-4 hours and ascorbic acid IV over
 5-10 minutes on days 1-5 weekly for 5 weeks. Treatment continues every 7 weeks for up to
 6 courses in the absence of disease progression or unacceptable toxicity.

 Cohorts of 3-6 patients receive escalating doses of arsenic trioxide until the maximum
 tolerated dose (MTD) is reached. The MTD is defined as the dose preceding that at which 2 of
 3 or 2 of 6 patients experience dose-limiting toxicity.

 -  Phase II: Patients receive the MTD of arsenic trioxide with ascorbic acid as outlined
 above.

 Patients are followed monthly for up to 5 years.

 PROJECTED ACCRUAL: A total of 31-43 patients (6-18 for phase I and 16-25 for phase II) will
 be accrued for this study within 2.5 years.
DISEASE CHARACTERISTICS:

 -  Histologically confirmed multiple myeloma

 -  M-protein by serum protein electrophoresis or urine protein electrophoresis

 -  Quantitative determination of immunoglobulin

 -  Bone marrow biopsy and aspirate with a plasma cell count greater than 10%

 -  Refractory or chemoresistant disease defined as failure to respond (less than 50%
 reduction in M protein level) or progression within 2 months after receiving at
 least 2 chemotherapy regimens including:

 -  Alkylating based regimen (melphalan) in combination with steroids
 (prednisone) or other chemotherapy regimens (e.g., vincristine, bleomycin,
 melphalan, cyclophosphamide, and prednisone or vincristine, carmustine,
 doxorubicin, and prednisone)

 -  Vincristine, doxorubicin, and dexamethasone (VAD) regimen

 -  Pulse therapy with high dose steroids alone

 -  High dose alkylating agent and autologous stem cell transplantation

 -  Allogeneic bone marrow transplantation

 -  Plateau phase defined as M protein in the serum or urine for more than 6 weeks
 despite response to prior therapy

 -  Must have received at least 2 of the chemotherapy regimens listed above or
 equivalent regimens

 -  Recurrent disease defined as progression more than 2 months after initial therapy
 and failure to respond (less than 50% reduction or progression in M protein
 levels) to 1 chemotherapy regimen listed above or other salvage regimens (e.g.,
 high-dose cyclophosphamide or topotecan)

 -  Must have received VAD or other equivalent chemotherapy regimen

 -  Should be considered for autologous or allogenic transplantation

 -  Prior local radiotherapy allowed

 PATIENT CHARACTERISTICS:

 Age:

 -  Over 18

 Performance status:

 -  Karnofsky 60-100%

 Life expectancy:

 -  Not specified

 Hematopoietic:

 -  WBC at least 2,000/mm^3*

 -  Platelet count at least 50,000/mm^3* NOTE: *Unless attributable to bone marrow
 infiltration by multiple myeloma

 Hepatic:

 -  Bilirubin less than 3 mg/dL

 -  Transaminases less than 2.5 times upper limit of normal (ULN)

 Renal:

 -  Creatinine less than 1.5 times ULN OR

 -  Creatinine clearance at least 60 mL/min

 Cardiovascular:

 -  No cardiac arrhythmias including recurrent supraventricular arrhythmia, any type of
 sustained ventricular arrhythmia, or conduction block (atrioventricular block grade II
 or III, left bundle branch block)

 -  Ejection fraction at least 30%

 -  No uncontrolled ischemic heart disease

 Other:

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective barrier contraception during and for 4 months
 after study

 -  HIV negative

 -  No grade 3 or higher neurological disorder, including seizure disorders

 -  No underlying medical condition that would preclude study

 -  No other active malignancy except adequately treated basal or squamous cell carcinoma
 of the skin or carcinoma in situ of the cervix

 PRIOR CONCURRENT THERAPY:

 Biologic therapy:

 -  See Disease Characteristics

 Chemotherapy:

 -  See Disease Characteristics

 -  At least 2 weeks since prior chemotherapy

 Endocrine therapy:

 -  See Disease Characteristics

 -  Concurrent steroid treatment allowed except for primary treatment of myeloma

 Radiotherapy:

 -  See Disease Characteristics

 -  Concurrent local radiotherapy for pain or symptom control allowed provided the pain or
 symptom is not related to disease progression

 Surgery:

 -  Not specified

 Other:

 -  No other concurrent ascorbic acid supplements

 -  No other concurrent investigational drug or therapy

 -  Concurrent bisphosphonates allowed