Expression of Bcl-2 in multiple myeloma is associated with resistance to chemotherapeutic drugs. Conversely, suppression of Bcl-2 enhanced the chemosensitivity of myeloma cells in vitro. G3139 is an antisense oligodeoxynucleotide targeted to the first six codons of the Bcl-2 mRNA open reading frame. In this study, G3139 was delivered as a continuous intravenous infusion for 7 days at a fixed dose of 7 mg/kg/day in combination with VAD (vincristine, adriamycin, and dexamethasone) chemotherapy. In total, 10 heavily pretreated patients with refractory myeloma participated in this trial, including eight patients with VAD refractory disease. The combination of G3139 and VAD was feasible and well tolerated. Seven patients (70%) responded including four patients (40%) with a partial response and three patients (30%) with a minor response. Median progression-free survival was 6 months (range, 2-7+ months) and median overall survival has not been reached. G3139 downregulated Bcl-2 protein levels in peripheral blood circulating myeloma cells, B cells, T cells, and monocytes. These results indicate that G3139 may overcome classical resistance and restore sensitivity of myeloma tumor cells to VAD chemotherapy.