title: Completion of premaintenance phases in total therapies 2 and 3 improves clinical outcomes in multiple myeloma: an important variable to be considered in clinical trial designs.
abstract: BACKGROUND
  Total Therapy (TT) programs are complex and their execution over the course of several years is fraught with patient attrition due to failure and toxicity of therapy and patient/physician acceptance.
  
  
  METHODS
  The impact of completion versus noncompletion of intended treatment steps was examined in protocols TT2 (n=668) and TT3 (n=303) on overall survival (OS) and event-free survival (EFS).
  
  
  RESULTS
  By using appropriate landmarks of 36 months with TT2 and 18 months with TT3, representing the maxima to completion of premaintenance phases, postconsolidation OS was superior for 211 patients completing versus 311 patients not completing premaintenance steps on TT2 (P=.001), which also pertained to the 161 patients completing versus 47 not completing intended treatment steps on TT3 (P=.01). On multivariate analysis that included all patients, completion of therapy independently favored longer OS and EFS in the context of both standard prognostic factors and gene expression profiling-defined risk; in addition, TT3 prolonged EFS over results obtained with TT2.
  
  
  CONCLUSIONS
  1) Completion of intended therapy was a significant independent variable conferring superior OS and EFS in TT programs; and 2) after adjusting for completion of therapy, EFS was still superior with TT3 versus TT2, supporting the beneficial role of bortezomib included in TT3. Collectively, these data point to the importance of designing clinical trials that balance the treatment requirements for disease control with host acceptance and tolerance.
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. barlogiebart@uams.edu
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
authors.forename: Jeff
authors.initials: J
authors.lastname: Haessler
authors.forename: Mauricio
authors.initials: M
authors.lastname: Pineda-Roman
authors.forename: Elias
authors.initials: E
authors.lastname: Anaissie
authors.forename: Frits
authors.initials: F
authors.lastname: van Rhee
authors.forename: Elias
authors.initials: E
authors.lastname: Kiwan
authors.forename: Douglas
authors.initials: D
authors.lastname: Steward
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gurley
authors.forename: Bonnie
authors.initials: B
authors.lastname: Jenkins
authors.forename: John
authors.initials: J
authors.lastname: Crowley
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D012074:Remission Induction; D012107:Research Design; D015996:Survival Rate