Originally published as JCO Early Release 10.1200/JCO.2005.03.2383 on January 17 2006

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Phase I/II Trial Assessing Bortezomib and Melphalan Combination Therapy for the Treatment of Patients With Relapsed or Refractory Multiple Myeloma

From Oncotherapeutics Inc; Institute for Myeloma & Bone Cancer Research, West Hollywood; Pacific Shores Medical Group, Glendale; Cedars-Sinai Medical Center, Los Angeles, CA, Millennium Pharmaceuticals Inc; and Infinity Pharmaceuticals, Cambridge, MA

Address reprint requests to James R. Berenson, MD, Institute for Myeloma & Bone Cancer Research, 9201 West Sunset Blvd, Suite 300, West Hollywood, CA 90069; e-mail: jberenson{at}myelomasource.org

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/m² 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/m² and melphalan 0.10 mg/kg as the maximum-tolerated dose (MTD). Responses (minimal [MR], 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.

Supported in part by Millennium Pharmaceuticals Inc, and Johnson & Johnson Pharmaceutical Research & Development LLC.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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