NOVEL MECHANISMS OF ACTION FOR IMMUNOMODULATORY DRUGS (IMIDS) AGAINST MULTIPLE MYELOMA: FROM A TRAGEDY TO A THERAPY

Thalidomide, a sedative to ease morning sickness in pregnant women, was banned more than a half century ago due to causing a severe birth defect known as phocomelia. However, the late discovery of its immunomodulatory properties have led to a new era in the treatment of Multiple Myeloma (MM), a fatal disease that back then had no effective therapy available. The recent development and FDA-accelerated approval of the second- and third-generation thalidomide analogs lenalidomide and pomalidomide to treat MM have led to a paradigm shift in standard of care of MM patients by introducing this novel class of anti-MM therapeutics, termed Immunomodulatory Drugs (IMiDs). Although IMiDs have tremendously improved survival of MM patients, their Mechanism Of Action (MOA) remains largely unknown until cereblon, a component of the E3 ubiquitin ligase complex CRL4CRBN, was discovered as a primary target of IMiDs for both thalidomide teratogenicity and IMiD anti-MM activity. Furthermore, studies have also identified IKZF1 and IKZF3 as the downstream substrates and effectors of cereblon to mediate dual actions of IMiDs, targeting both the MM bone marrow microenvironment and MM cells themselves. These cutting-edge findings have not only tackled the long-lasting conundrum for MOAs of IMiDs but more importantly could lead to more precise use of these agents in the treatment of MM. This article summarizes the new insights into the MOAs of IMiDs as an anti-MM therapy, with a perspective on the existing issues and future directions in this field.