CEPHEUS Design and the Role of MRD in Multiple Myeloma

Dr. Saad Usmani reviews the design of the phase 3 CEPHEUS study in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma, highlighting the importance of patient fitness and age in defining the study population. He describes the randomized comparison of daratumumab plus bortezomib, lenalidomide, and dexamethasone followed by daratumumab plus lenalidomide versus bortezomib, lenalidomide, and dexamethasone followed by lenalidomide. The discussion emphasizes that CEPHEUS incorporated MRD negativity as its primary endpoint while also being powered to evaluate progression-free survival. Dr. Usmani and Dr. Shaji Kumar then discuss why MRD negativity has become increasingly important in frontline multiple myeloma clinical trials as conventional PFS endpoints require longer follow-up with increasingly effective therapies. Dr. Kumar reviews evidence supporting MRD negativity as a prognostic marker and potential surrogate endpoint for progression-free and overall survival, including large meta-analytic efforts and prospective validation initiatives. He also discusses the regulatory significance of these findings and the use of MRD negativity to support accelerated approval in multiple myeloma.