Jennifer G Le-Rademacher, Ryan A Peterson, Terry M Therneau, Ben L Sanford, Richard M Stone, Sumithra J Mandrekar

Background/aims The goal of this article is to illustrate the utility of multi-state models in cancer clinical trials. Our specific aims are to describe multi-state models and how they differ from standard survival methods, to illustrate how multi-state models can facilitate deeper understanding of the treatment effect on multiple paths along the disease process that patients could experience in cancer clinical trials, to explain the differences between multi-state models and time-dependent Cox models, and to briefly describe available software to conduct such analyses. Methods Data from 717 newly diagnosed acute myeloid leukemia patients who enrolled in the CALGB 10603 trial were used as an illustrative example. The current probability-in-state was estimated using the Aalen-Johansen estimator. The restricted mean time in state was calculated as the area under the probability-in-state curves. Cox-type regression was used to evaluate the effect of midostaurin on the various clinical paths. Simulation was conducted using a newly constructed shiny application. All analyses were performed using the R software. Results Multi-state model analyses of CALGB 10603 suggested that the overall improvement in survival with midostaurin seen in the primary analysis possibly resulted from a higher complete remission rate in combination with a lower risk of relapse and of death after complete remission in patients treated with midostaurin. Simulation results, in a three-state illness-death without recovery model, demonstrate that multi-state models and time-dependent Cox models evaluate treatment effects from different frameworks. Conclusion Multi-state models allow detailed evaluation of treatment effects in complex clinical trial settings where patients can experience multiple paths between study enrollment and the final outcome. Multi-state models can be used as a complementary tool to standard survival analyses to provide deeper insights to the effects of treatment in trial settings with complex disease process.