title: Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma.
abstract: OBJECTIVE
  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/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 > or = 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.
  
  
  CONCLUSIONS
  Bortezomib plus melphalan given on a 28-day schedule showed encouraging activity with manageable toxicity and represents a promising treatment for myeloma patients.
authors.affiliation: Oncotherapeutics Inc, West Hollywood, CA, USA. jberenson@myelomasource.org
authors.forename: James R
authors.initials: JR
authors.lastname: Berenson
authors.forename: Hank H
authors.initials: HH
authors.lastname: Yang
authors.forename: Karen
authors.initials: K
authors.lastname: Sadler
authors.forename: Supol G
authors.initials: SG
authors.lastname: Jarutirasarn
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vescio
authors.forename: Russell
authors.initials: R
authors.lastname: Mapes
authors.forename: Matthew
authors.initials: M
authors.lastname: Purner
authors.forename: Shi-pyng
authors.initials: SP
authors.lastname: Lee
authors.forename: Joanna
authors.initials: J
authors.lastname: Wilson
authors.forename: Blake
authors.initials: B
authors.lastname: Morrison
authors.forename: Julian
authors.initials: J
authors.lastname: Adams
authors.forename: David
authors.initials: D
authors.lastname: Schenkein
authors.forename: Regina
authors.initials: R
authors.lastname: Swift
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005260:Female; 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; D009503:Neutropenia / Q000139:chemically induced; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D012720:Severity of Illness Index; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D008558:Melphalan