Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma

Patients with multiple myeloma (MM) invariably relapse with chemotherapy-resistant disease, underscoring the need for new agents that bypass these resistance mechanisms. We have reported that ascorbic acid (AA) enhances the activity of arsenic trioxide (As₂0₃) against drug-resistant MM in vitro by depleting intracellular glutathione (GSH). These data led us to open a National Cancer Institute/Cancer Therapy Evaluation Program-sponsored Phase I/II trial of AS₂0₃ + AA for relapsed/refractory MM. We now present the completed Phase I component of this trial. The primary objective of the trial's Phase I component was to assess whether the addition of AA affected the well-described toxicity profile of As₂0₃ alone. Correlative studies were undertaken of As₂0₃ and AA pharmacokinetics, the ability of AA to deplete intracellular GSH in vivo, and the development of arsenic resistance. Six patients with stage IIIA relapsed/refractory myeloma were studied. We found that 0.25 mg/kg/day As₂O₃ + 1000 mg/day AA could be given for 25 days (over a 35-day period) without dose-limiting toxicity. One episode of grade 3 hematological toxicity (leukopenia) and no grade 3 nonhematological toxicities (in particular, cardiac) were observed. The coadministration of AA did not alter the pharmacokinetics of As₂0₃, and elevated AA levels were associated with decreased intracellular GSH. Serial in vitro studies demonstrated continued sensitivity of patient myeloma cells to As₂0₃ + AA. Two patients (both with thalidomide-refractory disease) had partial responses; four patients had stable disease. In conclusion, we have found that As₂0₃ + AA has acceptable toxicity and that there is promising evidence of activity in refractory/relapsed myeloma.