title: A phase I/II trial combining high-dose melphalan and autologous transplant with bortezomib for multiple myeloma: a dose- and schedule-finding study.
abstract: OBJECTIVE
  We did a randomized phase I/II trial designed to evaluate the safety and efficacy of combining the proteasome inhibitor bortezomib with high-dose melphalan as the conditioning for high-dose therapy and autologous transplant for myeloma.
  
  
  METHODS
  Enrolled patients were limited to those who did not achieve a very good partial remission (VGPR) following one or more induction regimens, and were randomized to receive a single escalating dose of bortezomib (1.0, 1.3, or 1.6 mg/m(2)) either 24 hours before or 24 hours after high-dose melphalan. Dose escalation was based on the escalation with overdose control (EWOC), a Bayesian statistical model. Bone marrow aspirates were collected before initiation of therapy and at the time of transplant to evaluate which sequence resulted in maximal plasma cell apoptosis, and response to transplant was assessed by the International Myeloma Working Group criteria.
  
  
  RESULTS
  Among 39 randomized patients, 20 received bortezomib after melphalan and 19 received bortezomib before melphalan. Toxicities and posttransplant hematopoietic recovery rates were similar between arms. The overall response rate for all patients was 87%, with 51% achieving a VGPR or better. Pharmacodynamic studies showed greater plasma cell apoptosis among patients who received bortezomib following melphalan.
  
  
  CONCLUSIONS
  The use of bortezomib in conjunction with high-dose melphalan is safe, with data suggesting improved efficacy. A single dose of bortezomib administered after high-dose melphalan is the recommended dose and schedule for future clinical investigation.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA. sloni01@emory.edu
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kaufman
authors.forename: Mourad
authors.initials: M
authors.lastname: Tighiouart
authors.forename: Ajay
authors.initials: A
authors.lastname: Nooka
authors.forename: Amelia A
authors.initials: AA
authors.lastname: Langston
authors.forename: Leonard T
authors.initials: LT
authors.lastname: Heffner
authors.forename: Claire
authors.initials: C
authors.lastname: Torre
authors.forename: Stephanie
authors.initials: S
authors.lastname: McMillan
authors.forename: Heather
authors.initials: H
authors.lastname: Renfroe
authors.forename: R Donald
authors.initials: RD
authors.lastname: Harvey
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Lechowicz
authors.forename: H Jean
authors.initials: HJ
authors.lastname: Khoury
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Flowers
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Waller
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000601:surgery / Q000628:therapy*; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D008558:Melphalan