A PHASE I/II MULTICENTER, SAFETY AND EFFICACY STUDY OF COMBINATION TREATMENT WITH MELPHALAN, ARSENIC AND VITAMIN C (ASCORBIC ACID) (MAC) IN PATIENTS WITH RELAPSED OR REFRACTORY MULTIPLE MYELOMA
[Pretty encouraging results. 10 responses out of 10 for these patients].
Author: J.R. Berenson, Institute for Myeloma & Bone Cancer Res, Los Angeles, United States of America
Co-author(s):
Topic: 27A. Myeloma and other monoclonal gammopathies Keywords (obligatory): arsenic trioxide, combination treatment, drug resistance, multiple myeloma
Multiple myeloma (MM) patients relapse after an initial response to chemotherapy. Thus, there is a need to examine new treatments to overcome chemoresistance in MM patients. ATO disrupts key signal transduction mechanisms thereby leading to MM cell growth inhibition and apoptosis. Recent studies in our laboratory also show marked anti-MM effects in vivo when ATO is used alone in SCID-hu murine models of MM. ATO inhibits NF-kB activation through inhibition of IkB kinase. Activation of this transcription factor has been shown to be associated with the development of chemoresistance in MM cells. The state of the intracellular glutathione redox system also affects the efficacy of ATO so that decreasing glutathione leads to increased ATO-induced apoptosis. Addition of ascorbic acid, an oxidizing agent that decreases intracellular glutathione levels, to ATO has been shown to increase apoptosis in MM cells. Recent in vitro studies in our laboratory show that ATO can sensitize chemoresistant MM cells to melphalan-induced cytotoxic effects. In vitro experiments also show the most profound anti-MM effects when ATO, ascorbic acid and melphalan are used in combination compared with the effects observed when the drugs are used alone or combinations of any two of these agents.
Based on these pre-clinical studies, the MAC regimen was initially examined in 10 pts with refractory MM. All patients had failed multiple prior therapeutic regimens. Five of the 10 patients had renal failure at the onset of therapy. ATO was administered 0.25 mg/kg twice weekly followed immediately by ascorbic acid 1g IV and oral melphalan (0.05-0.1 mg/kg qd) for 4 days every 4 to 6 weeks.
All pts responded to the combination, administered for 14 to 70+ weeks, with significant reductions in M-protein levels (37-85%) and reversal of renal failure in all five patients with elevated serum creatinine at baseline. The regimen was well tolerated.
Based on encouraging results from this pilot study, a larger, multicenter trial was recently started.
100 MM patients who showed relapse after responding to first-line chemotherapy and/or having proved to be refractory to chemotherapy will be enrolled. Pts will receive a loading dose of ATO at 0.25 mg/kg IV followed by ascorbic acid 1 g IV days 1-4 of week 1 of each six-week cycle. ATO/ascorbic acid will be given twice-weekly for the next 4 weeks of each cycle. Low-dose melphalan (0.10 mg/kg) will be administered orally for the first 4 days of each cycle. Pts will receive a maximum of 6 cycles followed by weekly maintenance treatment with weekly ATO followed by Vitamin C. The primary objectives of this study are to determine response rate and safety and tolerability of MAC therapy.
Currently, 20 patients have been enrolled in this study. Preliminary evidence of antitumor activity has been reported in this heavily pre-treated population. The overall efficacy and safety data to date will be presented at the meeting.
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