Перспективы применения иммуномодулирующих препаратов и модуляторов цереблон Е3-лигазы в лечении множественной миеломы

Abstract

In recent decades, the progress in multiple myeloma (MM) treatment has been linked to a clearer insight into the biology of this disease and practical application of new pharmaceutical classes, such as immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (MABs). Modern IMiDs (lenalidomide and pomalidomide) are thalidomide derivatives which despite the similarity of chemical structure show only a relative cross-resistance. Lenalidomide is a second-generation immunomodulator with high anti-tumor activity and a favorable safety profile. In 2006, the use of lenalidomide combined with dexamethasone (Rd regimen) was approved by FDA (USA) for the treatment of relapsed/refractory MM, and 9 years later, in 2015, for newly diagnosed MM. During 2015–2019, the treatment of relapsed MM applied the newly developed regimens involving Rd combined with bortezomib (VRd), carfilzomib (KRd), ixazomib (IRd), elotuzumab (ERd), and daratumumab (DRd), the so-called triplets. Pomalidomide is a third-generation drug used in lenalidomide-refractory patients. For patients with relapsed/refractory MM who received at least two therapy lines with lenalidomide and bortezomib, regimens with 3 drugs were introduced which include pomalidomide and dexamethasone combined with elotuzumab (EPd), isatuximab (Isa-Pd), and daratumumab (DPd). In 2010, the molecular target of IMiD action was discovered, that is protein cereblon (CRBN), a component of CRBN E3 ligase enzyme complex. The insight into this mechanism provided the basis for developing a new family of thalidomide derivatives which are now called CRBN E3 ligase modulators (CELMoDs). In phase I/II trials, two drugs belonging to this group (iberdomide and mezigdomide) showed promising activity in MM refractory to three classes of antitumor drugs (IMiDs, PIs, and anti-CD38 MABs). The present review is focused on prospective studies of IMiDs and CELMoDs at different stages of MM treatment.