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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 …