High-risk multiple myeloma: Redefining genetic, clinical, and functional high-risk disease in the era of molecular medicine and immunotherapy

Multiple myeloma (MM) exhibits significant heterogeneity in its presentation, genetics, and treatment response. Despite therapeutic advances, some patients continue to relapse early (ER, <18-months) and rapidly cycle through therapies. Myriad prognostic factors have been identified and incorporated into risk stratification models; however, these produce discordant, often three-tiered outputs that fail to identify many patients destined for ER. Treatment strategies are increasingly focused on disease biology and trials enriched for high-risk (HR)MM, but consensus on the minimum required testing and a succinct, specific, and clinically meaningful definition for HRMM remains elusive. We review the risk-factors, definitions, and future directions for HRMM.