O6-benzylguanine and BCNU in multiple myeloma: a phase II trial.
OBJECTIVE
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.
Batts
Eric D
ED
Developmental Therapeutics Program, CASE Comprehensive Cancer Center and the Division of Hematology/Oncology, Case Western Reserve University, Cleveland, OH 44106, USA.
Maisel
Christopher
C
Kane
Donna
D
Liu
Lili
L
Fu
Pingfu
P
O'Brien
Timothy
T
Remick
Scot
S
Bahlis
Nizar
N
Gerson
Stanton L
SL
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D002330:Carmustine / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D004247:DNA / Q000097:blood; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D018579:Patient Selection; D012016:Reference Values
C064976:O(6)-benzylguanine; D006147:Guanine; D004247:DNA; D002330:Carmustine