A B S T R A C TThe revised International Staging System (R-ISS) combines ISS with genetic markers and lactate dehydrogenase and can prognosticate newly diagnosed multiple myeloma (MM). Early relapse (<24 months) after upfront autologous hematopoietic cell transplantation (AHCT) strongly predicts inferior overall survival (OS). We examined the ability of R-ISS in predicting early relapse and its independent prognostic effect on postrelapse survival after an journal homepage: www.bbmt.org early relapse. Using the Center for International Blood and Marrow Transplant Research database we identified MM patients receiving first AHCT within 18 months after diagnosis with available R-ISS stage at diagnosis (n = 628). Relative risks of relapse/progression, progression-free survival (PFS), and OS were calculated with the R-ISS group as a predictor in multivariate analysis. Among early relapsers, postrelapse survival was tested to identify factors affecting postrelapse OS. The cumulative incidence of early relapse was 23%, 39%, and 50% for R-ISS I, R-ISS II, and R-ISS III, respectively (P < .001). Shorter PFS and OS were seen with higher stage R-ISS. R-ISS was independently predictive for inferior postrelapse OS among early relapsers, as was the presence of 3 comorbidities and the use of 2 induction chemotherapy lines. R-ISS stage at diagnosis predicts early post-AHCT relapse and independently affects postrelapse survival among early relapsers.