title: Safety and efficacy of bortezomib and melphalan combination in patients with relapsed or refractory multiple myeloma: updated results of a phase 1/2 study after longer follow-up.
abstract: Bortezomib synergizes with melphalan in preclinical and early clinical studies. Updated data from our phase 1/2 study assessing the safety and efficacy of bortezomib plus melphalan in relapsed/refractory multiple myeloma (MM) are presented. Bortezomib (0.7, 1.0, or 1.3 mg/m(2)) on days 1, 4, 8, and 11 and oral melphalan (0.025-0.25 mg/kg) on days 1-4 of a 28-day cycle were administered. Hematologic toxicities defined the maximum tolerated dose as bortezomib 1.0 mg/m(2) and melphalan 0.10 mg/kg. Because dose-limiting toxicities were attributed to the more myelosuppressive melphalan, cohorts 9 and 10 with higher bortezomib (1.3 mg/m(2)) and lower melphalan (0.025 and 0.10 mg/kg) doses were added. Responses occurred in 32/46 (70%) evaluable patients: two complete (4%), five near-complete (11%), 16 partial (35%), and nine minimal (20%). Complete and near-complete responses were observed only with higher bortezomib doses. Response rates were similar in patients with prior melphalan or bortezomib. Median progression-free survival was 9 months (range, 1-24), and overall survival was 32 months (range, 1-54). The most common grade 3/4 hematologic adverse events (AEs) were neutropenia (31%/0%), thrombocytopenia (25%/2%), and anemia (13%/0%). Grade 4 tumor lysis syndrome was reported in one patient. Fewer grade 3/4 hematologic AEs were reported in cohorts 9 and 10 than in cohorts receiving lower bortezomib and higher melphalan doses. In conclusion, bortezomib plus melphalan is a steroid- and immunomodulatory drug-free regimen that may provide a treatment alternative for elderly patients and patients with significant comorbidity.
authors.affiliation: Institute for Myeloma and Bone Cancer Research, West Hollywood, CA 90069, USA. jberenson@imbcr.org
authors.forename: James R
authors.initials: JR
authors.lastname: Berenson
authors.forename: Hank H
authors.initials: HH
authors.lastname: Yang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vescio
authors.forename: Youram
authors.initials: Y
authors.lastname: Nassir
authors.forename: Russell
authors.initials: R
authors.lastname: Mapes
authors.forename: Shi-Pyng
authors.initials: SP
authors.lastname: Lee
authors.forename: Joanna
authors.initials: J
authors.lastname: Wilson
authors.forename: Ori
authors.initials: O
authors.lastname: Yellin
authors.forename: Blake
authors.initials: B
authors.lastname: Morrison
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Hilger
authors.forename: Regina
authors.initials: R
authors.lastname: Swift
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D008558:Melphalan