IMiD resistance in multiple myeloma: current understanding of the underpinning biology and clinical impact

Abstract

Immunomodulatory agents (IMiDs) are a cornerstone of treatment for patients with multiple myeloma. IMiDs are used in therapeutic combinations at all stages of disease and are approved as a single-agent maintenance treatment after autologous stem cell transplantation. However, patients become resistant to ongoing therapy over time and inevitably relapse. It is only in the last decade that the mechanism of IMiD action has been elucidated; through binding to the cereblon component of the CRL4CRBN E3 ubiquitin ligase, a set of neosubstrates is designated for degradation by the proteasome. In myeloma cells, this includes the zinc-finger B-cell transcription factors Ikaros and Aiolos, which, in turn, lead to decreased levels of IRF4 and c-MYC and cell death. As our knowledge of IMiD mechanism of action has advanced, the ability to study resistance mechanisms has also developed. This review explores the existing work on IMiD resistance and proposes areas of future research that may advance our understanding and management of this common clinical condition.