Minimal Residual Disease Status as a Surrogate Endpoint for Progression-free Survival in Newly Diagnosed Multiple Myeloma Studies: A Meta-analysis

A surrogate endpoint that can support accelerated approval of a drug in newly diagnosed multiple myeloma is dearly needed. Here, we performed a meta-analysis of 6 randomized trials to evaluate the potential of minimal residual disease (MRD) status in predicting clinical benefit. A strong correlation between the relative changes of experimental to control treatments in MRD-negative rates and progression-free survival supported MRD status as a surrogate endpoint. Background: Therapeutic advances have greatly extended survival times in patients with multiple myeloma, necessitating increasingly lengthy trials when using survival outcomes as primary endpoints. A surrogate endpoint that can more rapidly predict survival could accelerate drug development. We conducted a meta-analysis to evaluate minimal residual disease (MRD) status as a valid progression-free survival (PFS) surrogate in patients with newly diagnosed multiple myeloma (NDMM). Materials and Methods: We searched abstracts in PubMed, The American Society of Hematology, and the European Hematology Association for myeloma, minimal residual disease, and clinical trial. Because of the need to evaluate the treatment effect on MRD response, only randomized studies for subjects with NDMM were included. Details on the MRD-tested populations were required. The meta-analysis was performed by principles outlined at the 2013 United States Food and Drug Administration workshop on MRD in acute myeloid leukemia.(42) For samples that were not measured for MRD and within the subset specified for MRD assessment, their MRD status was imputed from the samples that had known MRD status. Patients that were excluded from planned MRD assessment were considered MRD-positive. Results: Six randomized studies, representing 3283 patients and 2208 MRD samples, met analysis inclusion criteria. MRD negativity rates ranged from 0.06 to 0.70. The treatment effect on the odds ratio for MRD-negative response strongly correlated with the hazard ratio for PFS with a coefficient of determination for the weighted regression line of 0.97. Our meta-analysis suggested that MRD status met both the Prentice criteria for PFS surrogacy. Conclusions: These results support the claim that MRD status can be used as a surrogate for PFS in NDMM. (C) 2019 Published by Elsevier Inc.