O6-benzylguanine and BCNU in multiple myeloma: a phase II trial
Eric D Batts1, Christopher Maisel, Donna Kane
1Developmental Therapeutics Program, CASE Comprehensive Cancer Center and the Division of Hematology/Oncology, Case Western Reserve University, Cleveland, OH 44106, USA.
Purpose:
Carmustine (BCNU) is known to have modest activity in multiple myeloma; however, resistance to BCNU manifests by the activity of O6-methylguanine methyltransferase (MGMT). The objective of this study was to determine the safety and efficacy of depletion of MGMT activity in plasma cells using O6-benzylguanine (O6-BG) with BCNU in patients with multiple myeloma.
Methods:
Patients with previously treated or untreated multiple myeloma were eligible. Cycles of O6-BG at a dose of 120 mg/m2 and BCNU at a dose of 40 mg/m2 were repeated every 6 weeks.
Results:
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%).
Conclusions:
Chemotherapy utilizing the MGMT inhibitor O6-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.
Insights
This study investigated O6-benzylguanine (O6-BG) with carmustine (BCNU) to overcome resistance in multiple myeloma. The combination inhibited MGMT activity and showed modest responses, but caused significant hematologic toxicity.
Area of Science:
- Oncology
- Pharmacology
- Hematology
Background:
- Carmustine (BCNU) demonstrates limited efficacy in multiple myeloma due to resistance mediated by O6-methylguanine methyltransferase (MGMT).
- Targeting MGMT is a potential strategy to enhance BCNU activity in multiple myeloma treatment.
Purpose of the Study:
- To evaluate the safety and efficacy of depleting MGMT activity in plasma cells using O6-benzylguanine (O6-BG) in combination with BCNU for multiple myeloma patients.
- To assess the impact of O6-BG on MGMT activity within malignant plasma cells.
Main Methods:
- A phase study involving patients with previously treated or untreated multiple myeloma.
- Administration of O6-BG (120 mg/m2) and BCNU (40 mg/m2) every 6 weeks.
- Monitoring of MGMT activity in bone marrow CD38+ cells and assessment of treatment response and adverse events.
Main Results:
- Seventeen patients were enrolled; 7% achieved complete response and 20% partial response, with 60% having stable disease.
- Significant depletion (94%) of MGMT activity was observed in bone marrow CD38+ cells.
- Common grade 3/4 adverse events included neutropenia (71%), lymphocytopenia (53%), and thrombocytopenia (53%).
Conclusions:
- The combination of O6-benzylguanine and BCNU effectively inhibits MGMT activity in multiple myeloma plasma cells.
- This regimen produced meaningful responses in a subset of patients but was associated with dose-limiting hematologic toxicity.
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