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

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Abstract

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.

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Acknowledgments

Supported in part by NIH grant numbers: U01CA62502, M01RR000081, P30CA043703, R01CA086357

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Authors and Affiliations

  1. Developmental Therapeutics Program, CASE Comprehensive Cancer Center and the Division of Hematology/Oncology, Case Western Reserve University and University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH, 44106, USA

    Eric D. Batts, Donna Kane, Lili Liu, Pingfu Fu, Scot Remick & Stanton L. Gerson

  2. Charles A. Sammons Cancer Center, 3535 Worth Street, Dallas, TX, 75246, USA

    Christopher Maisel

  3. Cancer Care Center, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH, 44109, USA

    Timothy O’Brien

  4. Tom Baker Cancer Center, University of Calgary, 1403, 29 Street NW, T2N 2T9, Calgary, AL, Canada

    Nizar Bahlis

Authors
  1. Eric D. Batts
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  2. Christopher Maisel
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  3. Donna Kane
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  4. Lili Liu
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  5. Pingfu Fu
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  6. Timothy O’Brien
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  7. Scot Remick
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  8. Nizar Bahlis
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  9. Stanton L. Gerson
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Corresponding author

Correspondence to Stanton L. Gerson.

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Batts, E.D., Maisel, C., Kane, D. et al. O6-benzylguanine and BCNU in multiple myeloma: a phase II trial. Cancer Chemother Pharmacol 60, 415–421 (2007). https://doi.org/10.1007/s00280-007-0442-7

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  • DOI: https://doi.org/10.1007/s00280-007-0442-7

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