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A phase I/II study of arsenic trioxide, bortezomib, and ascorbic acid in relapsed or refractory multiple myeloma.

7611 Background: The combination of arsenic trioxide (ATO) and bortezomib (B) has shown synergistic anti-tumor activity against human multiple myeloma (MM) cells in preclinical studies, suggesting that this combination may effectively treat patients with MM. In addition, ascorbic acid (AA) can sensitize MM cells to the cytotoxic effects of ATO.


METHODS
Patients with relapsed or refractory MM were enrolled in this phase I/II dose-escalation trial in 6 cohorts. Patients were given ATO (0.125 or 0.250 mg/kg), B (0.7, 1.0, or 1.3 mg/m2), and a fixed dose of AA (1000 mg) IV on days 1, 4, 8, and 11 of a 21-day cycle for a maximum of 8 cycles. The planned sample size was a maximum of 27 evaluable patients. The primary endpoint was safety and tolerability of the ATO/B/AA regimen in patients with relapsed or refractory MM.


RESULTS
At the time of this interim analysis, 22 patients (median age, 63 years) have been enrolled, and accrual has been completed on all cohorts. This group had failed a median of 4 (range, 3-9) prior therapies. One occurrence of grade 4 thrombocytopenia was observed. One occurrence of asymptomatic arrhythmia led to patient withdrawal. All other adverse events were grade 1 or 2. For the 21 patients evaluable for efficacy, objective responses were observed in 10 patients (43%), including 2 complete (CR), 2 partial (PR), and 5 minor (MR) responses. Only 1 (1 MR) of 6 patients receiving the lowest dose of B (0.7 mg/m2) showed a response, whereas 8 (2 CR, 2 PR, and 4 MR) of 15 patients receiving the higher doses (1.0 or 1.3 mg/m2) responded.


CONCLUSIONS
The ATO/B/AA regimen was well tolerated by the majority of patients, and produced objective responses in 43% of the patients in this heavily pretreated group. The results of this phase I/II study warrant further clinical evaluation of the ATO/B/AA combination regimen for the treatment of patients with relapsed or refractory MM. [Table: see text].