A phase I/II study of arsenic trioxide/bortezomib/ascorbic acid combination therapy for the treatment of relapsed or refractory multiple myeloma.
OBJECTIVE
This multicenter, open-label, phase I/II dose escalation study assessed the safety/tolerability and initial efficacy of arsenic trioxide/bortezomib/ascorbic acid (ABC) combination therapy in patients with relapsed/refractory multiple myeloma.


METHODS
Enrolled in six cohorts, patients were given arsenic trioxide (0.125 or 0.250 mg/kg), bortezomib (0.7, 1.0, or 1.3 mg/m(2)), and a fixed dose of ascorbic acid (1 g) i.v. on days 1, 4, 8, and 11 of a 21-day cycle for a maximum of eight cycles. The primary end point was safety/tolerability of the ABC regimen.


RESULTS
Twenty-two patients (median age, 63 years) were enrolled, having failed a median of 4 (range, 3-9) prior therapies. One occurrence of grade 4 thrombocytopenia was observed. One patient had asymptomatic arrhythmia and withdrew from the study. Objective responses were observed in 6 (27%) patients, including two partial responses and four minor responses. Median progression-free survival was 5 months (95% confidence interval, 2-9 months), and median overall survival had not been reached. The 12-month progression-free survival and overall survival rates were 34% and 74%, respectively. One (minor response) of six patients receiving the lowest dose of bortezomib (0.7 mg/m(2)) and 5 (2 partial responses and 3 minor responses) of 16 patients receiving the higher doses (1.0 or 1.3 mg/m(2)) responded.


CONCLUSIONS
The ABC regimen was well tolerated by most patients, and it produced preliminary signs of efficacy with an objective response rate of 27% in this heavily pretreated study population. These findings warrant further clinical evaluation of the ABC combination for treatment of relapsed/refractory multiple myeloma.
Berenson
James R
JR
Institute for Myeloma and Bone Cancer Research and Oncotherapeutics Inc, West Hollywood, CA 90069, USA. jberenson@imbcr.org
Matous
Jeffrey
J
Swift
Regina A
RA
Mapes
Russell
R
Morrison
Blake
B
Yeh
Howard S
HS
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000009:adverse effects; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000009:adverse effects; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000401:mortality; D010087:Oxides / Q000008:administration & dosage / Q000009:adverse effects; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D012008:Recurrence; D016019:Survival Analysis; D017211:Treatment Failure; D016896:Treatment Outcome
D001152:Arsenicals; D001897:Boronic Acids; D010087:Oxides; D011719:Pyrazines; D000069286:Bortezomib; D001205:Ascorbic Acid; D000077237:Arsenic Trioxide