O6-benzylguanine and BCNU in multiple myeloma:: a phase II trial

Purpose Carmustine (BCNU) is known to have modest activity in multiple myeloma; however, resistance to BCNU manifests by the activity of O-6-methylguanine methyltransferase (MGMT). The objective of this study was to determine the safety and efficacy of depletion of MGMT activity in plasma cells using O-6-benzylguanine (O-6-BG) with BCNU in patients with multiple myeloma. Patients with previously treated or untreated multiple myeloma were eligible. Cycles of O-6-BG at a dose of 120 mg/m(2) and BCNU at a dose of 40 mg/m(2) were repeated every 6 weeks. Methods Seventeen patients were enrolled on the study, with a median follow-up of 24.5 (range 5-69) months. One complete response (7%) and 3 partial responses (20%) were observed. Nine patients (60%) had stable disease. Bone marrow studies demonstrated 94% depletion of MGMT activity in CD38+ marrow cells. The most frequent grade 3 and 4 adverse events were neutropenia (71%), lymphocytopenia (53%), and thrombocytopenia (53%). Results Chemotherapy utilizing the MGMT inhibitor O-6-benzylguanine and BCNU results in inhibition of MGMT activity in malignant plasma cells and produces meaningful responses in a modest proportion of patients with multiple myeloma. Hematologic toxicity with this regimen is significant and dose-limiting.