De-escalation trials in multiple myeloma: past, present and future.

De-escalation of therapy constitutes a new phase in the development of therapeutic approaches for patients with multiple myeloma (MM) and is aimed at maintaining durable disease control while reducing the toxicity and burden associated with prolonged treatment. Given that increasingly effective agents, including immunotherapies, are now used earlier in the course of MM, we must assess not only how much therapy is needed to enable a clinical response but also how much is required to sustain it. In this Review, we synthesize emerging evidence supporting multiple de-escalation strategies, including dose and schedule modification, withdrawal of individual agents from multidrug regimens, fixed-duration approaches with treatment-free intervals, minimal residual disease-adapted strategies, omission of autologous stem cell transplantation and single infusion of chimeric antigen receptor T cells. We highlight how contemporary trials are beginning to define the patient populations and treatment components most amenable to de-escalation while exposing ongoing uncertainties and challenges, including those relating to monitoring strategies, re-treatment criteria and feasibility. Finally, we discuss methodological and implementation challenges including end point selection, clinical trial design, integration of correlative translational research, funding models and the involvement of key stakeholders required to translate de-escalation approaches from concept to a clinical trial and, eventually, routine clinical practice.