title: United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy.
abstract: OBJECTIVE
  On March 25, 2005, bortezomib (Velcade for Injection; Millennium Pharmaceuticals, Inc., Cambridge, MA, and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.) received regular approval from the U.S. Food and Drug Administration (U.S. FDA) for the treatment of multiple myeloma (MM) progressing after at least one prior therapy. This approval was based on bortezomib's efficacy and safety which was shown in a single, large, comparative international open-label phase 3 trial that randomized 669 patients with MM previously treated with at least one systemic regimen to receive single-agent bortezomib or high-dose dexamethasone. The FDA analysis of the trial data and bortezomib's regulatory development are summarized here.
  
  
  RESULTS
  Following a preplanned interim analysis of time to disease progression (the primary end point), an independent data-monitoring committee advised the sponsor to halt the study and offer bortezomib to all dexamethasone-treated study patients. Time to progression was significantly prolonged in the bortezomib treatment arm (median, 6.2 months) compared with the dexamethasone arm (median, 3.5 months; log-rank test, P < 0.0001; hazard ratio, 0.55; 95% confidence interval, 0.44-0.69). Analysis of overall survival done on the interim database (with 20% of events) showed the superiority of bortezomib for patients (log-rank test, P < 0.05; hazard ratio, 0.57; 95% confidence interval, 0.40-0.81). Using criteria from the European Group for Blood and Marrow Transplantation, the response rate (complete plus partial response) with bortezomib was also superior to dexamethasone (38% versus 18%; P < 0.0001). Adverse events on the bortezomib arm were similar to those previously observed in phase 2 studies; some notable adverse events included asthenia, peripheral neuropathy, thrombocytopenia, and neutropenia.
  
  
  CONCLUSIONS
  The U.S. FDA had earlier (May 2003) granted bortezomib accelerated approval for the treatment of patients with MM progressing after two prior therapies. The results of the phase 3 trial and the FDA analysis of the data, along with the sponsor's completion of other postmarketing commitments, confirm bortezomib's benefit and support regular approval.
authors.affiliation: Division of Drug Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993-0004, USA. robert.kane@fda.hhs.gov
authors.forename: Robert C
authors.initials: RC
authors.lastname: Kane
authors.forename: Ann T
authors.initials: AT
authors.lastname: Farrell
authors.forename: Rajeshwari
authors.initials: R
authors.lastname: Sridhara
authors.forename: Richard
authors.initials: R
authors.lastname: Pazdur
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D000069286:Bortezomib; D017326:Clinical Trials, Phase III as Topic; D003907:Dexamethasone / Q000009:adverse effects / Q000627:therapeutic use; D018450:Disease Progression; D017277:Drug Approval; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009101:Multiple Myeloma / Q000188:drug therapy*; D011719:Pyrazines / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D003907:Dexamethasone