Should Overall Survival Remain an Endpoint for Multiple Myeloma Trials?

While the traditional gold standard for demonstrating clinical benefit of a therapy has been to show prolongation of overall survival (OS), there are multiple factors which can hinder the use of OS as a primary endpoint in randomized clinical trials (RCTs). Here, we analyze recent myeloma RCTs and evaluate the issues relevant to current and future myeloma RCT design. A review of recent phase III RCTs that led to approval of new agents/combinations reveals that none were designed with OS as the primary endpoint, but instead utilized time to progression (TTP) or progression-free survival (PFS). These studies illuminate the inherent difficulties of designing trials with the primary endpoint of OS/PFS in a disease characterized by increasingly prolonged survival times, availability of effective salvage therapies, and competing events such as co-morbid conditions. Alternative primary endpoints other than OS or PFS need to be developed for future myeloma RCTs. Validated surrogate endpoints with novel clinical trial designs will help improve the feasibility of conducting comparative clinical trials in a timely manner.