Reiterative survival analyses of total therapy 2 for multiple myeloma elucidate follow-up time dependency of prognostic variables and treatment arms

Purpose: 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. Patients and 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. Conclusion: 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.