Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard and high risk myeloma

Patients with multiple myeloma (MM) carrying high-risk cytogenetic abnormalities (CA) have inferior outcome despite achieving similar complete response (CR) rates when compared to cases with standard-risk CA. This questions the legitimacy of CR as treatment endpoint for high-risk MM, and represents a biological conundrum regarding the nature of tumor reservoirs persisting after therapy in patients with standard- and high-risk CA. Here, we used next-generation flow (NGF) to evaluate measurable residual disease (MRD) in MM patients with standard- (N=300) vs high-risk CA (N=90) enrolled in the PETHEMA/GEM2012MENOS65 trial (NCT01916252), and to identify mechanisms determining MRD resistance in both patient subgroups (N=40). The 36-month progression-free and overall survival rates were higher than 90% in patients with undetectable MRD, with no significant differences (P=0.202) between cases having standard- vs high-risk CA. Persistent MRD resulted in median progression-free survival of approximately three and two years in patients with standard- and high-risk CA, respectively (P