title: Phase I trial of vorinostat combined with bortezomib for the treatment of relapsing and/or refractory multiple myeloma.
abstract: Preclinical studies have shown that targeted combination therapy consisting of vorinostat and bortezomib has antitumor activity in multiple myeloma (MM). We examined this drug combination in advanced relapsing and/or refractory MM patients (n = 34). Although the maximum tolerated dose was not reached, the study found this combination regimen generally well tolerated and clinically active in relapsed and/or refractory MM patients.
  
  
  BACKGROUND
  Development of targeted therapies for MM has improved response rates and increased patient survival, but ultimately the disease becomes refractory and progresses. Vorinostat combined with bortezomib has demonstrated synergistic antiproliferative and proapoptotic activity in preclinical models of MM. The objectives of this study were to determine the maximum tolerated dose for vorinostat with bortezomib in patients with advanced MM and to evaluate the clinical benefit of this new drug combination.
  
  
  METHODS
  Patients ≥ 18 years old with relapsed and/or refractory MM were enrolled into escalating dose cohorts of vorinostat and bortezomib combination therapy. Thirty-four patients were enrolled and were evaluable for safety and efficacy analyses.
  
  
  RESULTS
  All patients reported adverse events, 89% of which were mild to moderate in severity. Thirteen patients experienced 29 serious adverse events, 12 (41%) of which were considered drug-related. The maximum tolerated dose was not reached. Partial responses were observed in 9 (27%) patients. Minimal responses were observed in 2 additional patients (6%), and another 20 patients (59%) experienced disease stabilization.
  
  
  CONCLUSIONS
  Vorinostat with bortezomib is generally well-tolerated and has clinical activity in patients with relapsed and/or refractory MM. Response rates were similar in patients previously exposed to bortezomib and patients who were naive to bortezomib therapy.
authors.affiliation: University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Weber
authors.forename: Thorsten
authors.initials: T
authors.lastname: Graef
authors.forename: Mohamad
authors.initials: M
authors.lastname: Hussein
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Sobecks
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Schiller
authors.forename: Lisa
authors.initials: L
authors.lastname: Lupinacci
authors.forename: James S
authors.initials: JS
authors.lastname: Hardwick
authors.forename: Sundar
authors.initials: S
authors.lastname: Jagannath
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D015331:Cohort Studies; D004357:Drug Synergism; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D055502:Secondary Prevention; D000077337:Vorinostat
chemical_list: D001897:Boronic Acids; D006877:Hydroxamic Acids; D011719:Pyrazines; D000077337:Vorinostat; D000069286:Bortezomib