Phase I/II trial assessing bortezomlb and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma

被引:168
作者
Berenson, JR
Yang, HH
Sadler, K
Jarutirasarn, SG
Vescio, RA
Mapes, R
Purner, M
Lee, SP
Wilson, J
Morrison, B
Adams, J
Schenkein, D
Swift, R
机构
[1] Inst Myeloma & Bone Canc Res, W Hollywood, CA 90069 USA
[2] Oncotherapeut Inc, W Hollywood, CA USA
[3] Pacific Shores Med Grp, Glendale, CA USA
[4] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA
[5] Millennium Pharmaceut Inc, Cambridge, MA USA
[6] Infin Pharmaceut, Cambridge, MA USA
关键词
D O I
10.1200/JCO.2005.03.2383
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose Bortezomib has shown synergy with melphalan in preclinical models. We assessed the safety, tolerability, and response rate in a dose-escalation study of this combination for relapsed or refractory multiple myeloma patients. Methods Bortezomib was administered from 0.7 to 1.0 mg/m(2) on days 1, 4, 8, and 11 of a 28-day cycle for up to eight cycles. Oral melphalan was administered in escalating doses from 0.025 to 0.25 mg/kg on days 1 to 4. Results Thirty-five patients with relapsed or refractory myeloma were enrolled, 34 of whom were assessable for response. Dose-limiting toxicity of grade 4 neutropenia in two of six patients in the highest dose cohort led to the assignment of bortezomib 1.0 mg/m(2) and melphalan 0.10 mg/kg as the maximum-tolerated dose (MTD). Responses (minimal [MB], partial [PR], or complete [CR]) occurred in 23 of 34 patients (68%), including two CRs (6%), three immunofixation-positive CRs (9%), 11 PRs (32%), and seven MRs (21%). Responses were observed in five of six assessable patients (83%) at the MTD. Median progression-free survival for all patients was 8 months (range, 2 to 18 months). Grade >= 3 toxicities were related mostly to myelosuppression. Among the 15 patients with grade 1/2 neuropathy at baseline, it resolved during treatment in one, worsened in four, and remained stable in 10 patients. Eight other patients developed grade 1/2 neuropathy during the study. Conclusion Bortezomib plus melphalan given on a 28-day schedule showed encouraging activity with manageable toxicity and represents a promising treatment for myeloma patients.
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页码:937 / 944
页数:8
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