title: Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study.
abstract: BACKGROUND
  Thalidomide plus dexamethasone (TD) is a standard induction therapy for myeloma. We aimed to assess the efficacy and safety of addition of bortezomib to TD (VTD) versus TD alone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma.
  
  
  METHODS
  Patients (aged 18-65 years) with previously untreated symptomatic myeloma were enrolled from 73 sites in Italy between May, 2006, and April, 2008, and data collection continued until June 30, 2010. Patients were randomly allocated (1:1 ratio) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily for the first 14 days and 200 mg daily thereafter) plus dexamethasone (40 mg daily on 8 of the first 12 days, but not consecutively; total of 320 mg per cycle), either alone or with bortezomib (1·3 mg/m(2) on days 1, 4, 8, and 11). The randomisation sequence was computer generated by the study coordinating team and was stratified by disease stage. After double autologous stem-cell transplantation, patients received two 35-day cycles of their assigned drug regimen, VTD or TD, as consolidation therapy. The primary endpoint was the rate of complete or near complete response to induction therapy. Analysis was by intention to treat. Patients and treating physicians were not masked to treatment allocation. This study is still underway but is not recruiting participants, and is registered with ClinicalTrials.gov, number NCT01134484, and with EudraCT, number 2005-003723-39.
  
  
  RESULTS
  480 patients were enrolled and randomly assigned to receive VTD (n=241 patients) or TD (n=239). Six patients withdrew consent before start of treatment, and 236 on VTD and 238 on TD were included in the intention-to-treat analysis. After induction therapy, complete or near complete response was achieved in 73 patients (31%, 95% CI 25·0-36·8) receiving VTD, and 27 (11%, 7·3-15·4) on TD (p<0·0001). Grade 3 or 4 adverse events were recorded in a significantly higher number of patients on VTD (n=132, 56%) than in those on TD (n=79, 33%; p<0·0001), with a higher occurrence of peripheral neuropathy in patients on VTD (n=23, 10%) than in those on TD (n=5, 2%; p=0·0004). Resolution or improvement of severe peripheral neuropathy was recorded in 18 of 23 patients on VTD, and in three of five patients on TD.
  
  
  CONCLUSIONS
  VTD induction therapy before double autologous stem-cell transplantation significantly improves rate of complete or near complete response, and represents a new standard of care for patients with multiple myeloma who are eligible for transplant.
  
  
  BACKGROUND
  Seràgnoli Institute of Haematology at the University of Bologna, Bologna, Italy.
authors.affiliation: Istituto di Ematologia Seràgnoli, Università degli Studi di Bologna, Bologna, Italy. michele.cavo@unibo.it
authors.forename: Michele
authors.initials: M
authors.lastname: Cavo
authors.forename: Paola
authors.initials: P
authors.lastname: Tacchetti
authors.forename: Francesca
authors.initials: F
authors.lastname: Patriarca
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Petrucci
authors.forename: Lucia
authors.initials: L
authors.lastname: Pantani
authors.forename: Monica
authors.initials: M
authors.lastname: Galli
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Raimondo
authors.forename: Claudia
authors.initials: C
authors.lastname: Crippa
authors.forename: Elena
authors.initials: E
authors.lastname: Zamagni
authors.forename: Antonio
authors.initials: A
authors.lastname: Palumbo
authors.forename: Massimo
authors.initials: M
authors.lastname: Offidani
authors.forename: Paolo
authors.initials: P
authors.lastname: Corradini
authors.forename: Franco
authors.initials: F
authors.lastname: Narni
authors.forename: Antonio
authors.initials: A
authors.lastname: Spadano
authors.forename: Norbert
authors.initials: N
authors.lastname: Pescosta
authors.forename: Giorgio Lambertenghi
authors.initials: GL
authors.lastname: Deliliers
authors.forename: Antonio
authors.initials: A
authors.lastname: Ledda
authors.forename: Claudia
authors.initials: C
authors.lastname: Cellini
authors.forename: Tommaso
authors.initials: T
authors.lastname: Caravita
authors.forename: Patrizia
authors.initials: P
authors.lastname: Tosi
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
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; D017024:Chemotherapy, Adjuvant; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007558:Italy; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis / Q000188:drug therapy* / Q000601:surgery*; D020360:Neoadjuvant Therapy / Q000379:methods*; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D012074:Remission Induction; D012086:Reoperation; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects; D014182:Transplantation, Autologous; D016896:Treatment Outcome
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone