Previously, we and others have shown that bortezomib overcomes chemotherapy resistance in multiple myeloma cells. We recently published a Phase I trial that established the maximum tolerated dose (1.0 mg/m2 of bortezomib on days 1, 4, 8, and 11 with melphalan 0.1. mg/kg PO daily on days 1–4 of a 28-day cycle) for this combination and suggested its clinical activity in relapsed or refractory MM. The anti-MM activity of melphalan is dependent upon reactive oxygen species (ROS) and free glutathione (GSH) reduces intracellular ROS. Ascorbic acid (AA) reduces free GSH levels; and thus, should enhance the anti-MM activity of melphalan as our laboratory has recently demonstrated both in vitro and in vivo (Campbell et al. Brit J Haematol 2007). Therefore, we conducted a single-arm multi-center phase II study that evaluated the combination of bortezomib, ascorbic acid and melphalan (BAM) regimen in newly diagnosed pts with symptomatic myeloma. Treatment consisted of a 28-day cycle of bortezomib administered at a dose of 1.0 mg/m2 on days 1, 4, 8, and 11, and on days 1, 2, 3, and 4 oral AA at a dose of 1 g and oral melphalan 0.1 mg/kg were given. Based on preclinical studies suggesting potential inhibitory effects of AA on bortezomib’s anti-MM activity, bortezomib was administered in the morning and AA with melphalan in the evening. Pts were treated to maximum response plus two additional cycles or completed eight cycles of therapy without disease progression. These pts were eligible to be subsequently treated with bortezomib at a dose of 1.3 mg/m2 every other week until progressive disease occurred. Thirty-five pts, at a median age of 70 years (range, 50–90 years); have been enrolled in this study. To date, 27 pts are evaluable with a median survival of 12 months (range, 2 to 19+ months). Responses occurred in 17 of 27 pts (63%), including four complete responses (15%), two very good responses (7%), four partial responses (15%), and seven minimal responses (26%). Eight pts (30%) had stable disease. Thus, disease control was achieved in 25 (93%) pts. Six of the 27 pts have shown progressive disease after 2–13 months of treatment. Eleven pts experienced ≥ grade III adverse events with only one patient demonstrating a grade IV toxicity (shortness of breath). Six of these adverse events were judged not to be related to the study medications including the only grade IV event. The most common grade III adverse events included reversible neutropenia (4 events), neuropathy (2 events) and reversible thrombocytopenia (2 events). Only 11 pts had some form of increased neuropathy from baseline (Grade I (n=7), Grade II (n=2), and Grade III (n=2) with one of those pts starting with a Grade I). The peripheral neuropathy was reversible. BAM represents a steroid and IMID-free regimen with a high response rate (63%) as frontline therapy for MM pts. Importantly, this regimen was well tolerated with few significant adverse events. Treatment-related neuropathy was reported but reversible in all but one case. Thus, BAM has proven to be a promising new regimen for the first-line treatment of pts with MM.