title: Reiterative survival analyses of total therapy 2 for multiple myeloma elucidate follow-up time dependency of prognostic variables and treatment arms.
abstract: OBJECTIVE
  In Total Therapy 2, after randomly assigning 323 patients with myeloma to thalidomide and 345 to a control arm, no difference was observed in overall survival, with a median follow-up of 42 months, although at 72 months, survival was superior on the thalidomide arm in the one third exhibiting cytogenetic abnormalities (CA). After further follow-up of 87 months, we examined, in reiterative analyses, the effect of increasing time intervals on clinical outcomes relevant to baseline prognostic variables and treatment randomization.
  
  
  METHODS
  We investigated clinical trial end points as a function of increasing time intervals from protocol enrollment to determine consistencies of results by treatment and prognostic variables.
  
  
  RESULTS
  The complete congruence of serial survival plots for both study arms combined attested to stable patient characteristics over the time of accrual and the quality of follow-up management. Presence of CA was associated with consistently inferior survival curves from year 3 onward. Although 80% of patients randomly assigned to thalidomide discontinued study drug after 2 years because of toxicity, its clinical benefit did not reach statistical significance until year 10. The relative ranking order in multivariate models of prognostic factors remained stable over time. Decline in initially high hazard ratio values of gene array-defined high risk is consistent with an initial crisis phase that is time limited.
  
  
  CONCLUSIONS
  Reporting potentially time-sensitive features as a part of clinical trial results will enable the critical reader to judge the robustness of prognostic factors and the time sensitivity of outcome predictors, with important implications for future trial designs.
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. barlogiebart@uams.edu
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
authors.forename: Elias
authors.initials: E
authors.lastname: Anaissie
authors.forename: Frits
authors.initials: F
authors.lastname: van Rhee
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
authors.forename: Jackie
authors.initials: J
authors.lastname: Szymonifka
authors.forename: Antje
authors.initials: A
authors.lastname: Hoering
authors.forename: Nathan
authors.initials: N
authors.lastname: Petty
authors.forename: John
authors.initials: J
authors.lastname: Crowley
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D005500:Follow-Up Studies; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality; D012074:Remission Induction; D015996:Survival Rate; D013792:Thalidomide / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D013792:Thalidomide