European Myeloma Network Consensus Statement on Functional High‐Risk Multiple Myeloma

Multiple myeloma (MM) is an incurable blood cancer characterized by clonal bone marrow plasmacytosis, hypercalcemia, renal failure, anemia, and osteolytic bone disease. Approximately 20% of NDMM patients, not predicted to have high-risk disease at diagnosis, progress early, despite optimal induction +/- ASCT and lenalidomide maintenance, and are subsequently categorized as functional high-risk (FHR) disease. Standardized risk-stratification models incorporate biomarkers of tumor burden, existence of high-risk cytogenetics, with the presence/absence of plasma cell leukemia/extramedullary disease to attribute high-risk at diagnosis; however, depth/duration of response to novel agent-based induction (NA-IND) as dynamic markers of disease risk have not been defined. However, irrespective of diagnostic risk-stratification, response to NA-IND may be the single most effective method of identifying patients whose FHR biology portends an unacceptably short overall survival (OS). In this EMN consensus statement, we define FHR-MM as disease progression within 18 months of commencement of first-line therapy in the absence of high-risk cytogenetics, discuss the underlying disease biology, and strategies to improve outcomes for these patients.