arsenic trioxide plus vitamin c in treating patients with recurrent or refractory multiple myeloma

Conditions: Multiple Myeloma and Plasma Cell Neoplasm

Summary: 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.

Eligibility criteria:
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

Keywords: refractory multiple myeloma stage ii multiple myeloma stage iii multiple myeloma