Requirements for operational cure in multiple myeloma

Multiple myeloma is usually considered an incurable disease. However, with the therapeutic improvement observed in the past few years, achievement of an operational cure is increasingly becoming a realistic goal. The advent of novel agents, with or without high-dose chemotherapy or autologous transplantation, revealed a correlation between depth of response to treatment and outcome. Of note, minimal residual disease (MRD) negativity has been shown to be associated with improved progression-free survival (PFS), and MRD status is becoming a well-established and strong prognostic factor. Here, we discuss the impact of MRD negativity on PFS and long-term disease control, as a surrogate for potential cure in a significant proportion of patients. MRD value and impact should be examined by focusing on different parameters: (1) sensitivity or lower limit of detection level (method used), (2) timing of assessment and sustainability, (3) type and duration of treatment, (4) initial prognostic factors (most importantly cytogenetics), and (5) patient age. Currently, the highest probability of operational cure is in younger patients receiving the most active drugs, in combination with autologous transplantation followed by maintenance therapy. Older patients are also likely to achieve operational cure, especially if they are treated upfront with anti-CD38 antibody-based therapy but also with novel immunotherapies in future protocols. Incorporation of MRD as a surrogate end point in clinical trials would enable shorter trials, leading to more personalized management and achievement of long-term cure.