Immunomodulatory drugs in the treatment of multiple myeloma.

Abstract

The prognosis of multiple myeloma was quite poor in the last century, but it has significantly improved with the incorporation of novel agents, immunomodulatory drugs (IMiDs) and proteasome inhibitors. Thalidomide was first developed as a sedative in 1950s, but it was withdrawn from the market because of teratogenicity. In 1990s, however, thalidomide received attention due to the discovery of its anticancer potential derived from antiangiogenic and immunomodulatory activities, and its therapeutic effect on myeloma. In 2006, the U.S. Food and Drug Administration approved the use of thalidomide under strict control for the treatment of multiple myeloma. After that, two new IMiDs, lenalidomide and pomalidomide, were developed for the sake of more antitumor activity and less adverse events than thalidomide. The molecular mechanism of action of IMiDs remained unclear for a long time until 2010 when the protein cereblon (CRBN) was identified as a primary direct target. IMiDs binds to CRBN and alters the substrate specificity of the CRBN E3 ubiquitin ligase complex, resulting in breakdown of intrinsic downstream proteins such as IKZF1 (Ikaros) and IKZF3 (Aiolos). There are many clinical trials of multiple myeloma using IMiDs under various conditions, and most of them show the efficacy of IMiDs. Nowadays lenalidomide plays a central role in both newly diagnosed and relapsed/refractory settings, mainly in combination with other novel agents such as proteasome inhibitors and monoclonal antibodies. This review presents an overview of recent advances in immunomodulatory drugs in the treatment of multiple myeloma.