Rapid Progress in the Use of Immunomodulatory Drugs and Cereblon E3 Ligase Modulators in the Treatment of Multiple Myeloma

Abstract

Over the past two decades, the improvement in our understanding of the biology of MM and the introduction of new drug classes, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PI), and monoclonal antibodies (MoAb), have significantly improved outcomes. The first IMiD introduced to treat MM was thalidomide. The side effects observed during treatment with thalidomide initiated work on the synthesis of IMiD analogs. Subsequently, lenalidomide and pomalidomide were developed, both with different safety profiles, and they have better tolerability than thalidomide. In 2010, the cereblon (CRBN) protein was discovered as a direct target of IMiDs. By binding to CRBN, IMiDs change the substrate specificity of the CRBN E3 ubiquitin ligase complex, which results in the breakdown of internal Ikaros and Aiolos proteins. Most clinical trials conducted, both in newly diagnosed, post-transplant maintenance and relapsed/refractory MM, report a beneficial effect of IMiDs on the extension of progression-free survival and overall survival in patients with MM. Due to side effects, thalidomide is used less frequently. Currently, lenalidomide is used at every phase of MM treatment. Lenalidomide is used in conjunction with other agents such as PIs and MoAb as induction and relapsed therapy. Pomalidomide is currently used to treat relapsed/refractory MM, also with PIs and monoclonal antibodies. Current clinical trials are evaluating the efficacy of IMiD derivatives, the CRBN E3 ligase modulators (CELMoDs). This review focuses on the impact of IMiDs for the treatment of MM.

3,6′- and 1,6′-Dithiopomalidomide Mitigate Ischemic Stroke in Rats and Blunt Inflammation

“…The pro-inflammatory cytokines TNF-α and IL1-β were reduced in plasma from stroke animals, whereas anti-inflammatory IL-10 was elevated for 3,6′-DP. Although both 3,6′-DP and 1,6′-DP bound to human cereblon, 3,6′-DP did not activate processes resulting in the degradation of Ikaros, Aiolos and SAL4 that are central in anticancer and teratogenicity actions of IMiDs [ 16 , 17 ]. Neither 3,6′-DP nor 1,6′-DP had any unfavorable actions in the mammalian chromosome aberration assay and the AMES fluctuation assay, key assessments of potential genotoxicity.…”

“…Like pomalidomide, both agents reduce ischemic stroke infarct volume and associated behavioral impairment. However, although, similar to pomalidomide, 3,6′-DP potently binds to cereblon, and it importantly does not appear to induce the ubiquitination of key downstream neo-substrates (Ikaros, Aiolos and SALL4) associated with the anticancer/teratogenicity of the IMiD drug class [ 16 , 17 , 27 ]. 3,6′-DP and 1,6′-DP lack activity in essential gatekeeper genotoxicity and hERG assays critical to human translation, and, in the light of their clear efficacy signal in the current study, they thus warrant further evaluation and development in preclinical animal models as candidate drugs to mitigate inflammation associated with excessive pro-inflammatory cytokine generation.…”

“…Thalidomide and its second and third generation analogs, lenalidomide and pomalidomide, were later developed as immunomodulatory imide drugs (IMiDs) that display a multitude of biologic effects on cytokine and cell-mediated responses, and are effectively used in the treatment of multiple myeloma [ 16 ]. Pro-angiogenic cytokines and bone marrow vascularization, key elements in multiple myeloma progression, were prospective targets that could be exploited through the anti-angiogenic properties of thalidomide [ 16 ], and more effectively still by pomalidomide with more potent pro-inflammatory cytokine lowering action [ 16 , 17 ]. All three thalidomide analogs [ 18 , 19 ] are structurally similar and share an α-(isoindolinone-2-yl)-glutarimide core structure [ 20 ].…”

CRL4CRBN E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma

“…Before the clarification of the molecular mechanism of action, thalidomide and its analogues were characterized by modulation of T cells, NK and NK-T cells functions by inducing the production of cytokines, including IL-2 (interleukin-2) and interferon-γ [ 16 , 17 , 18 ]. Thus, thalidomide and its analogs are called immunomodulatory drugs in addition to their anti-angiogenic activity, disruption of the myeloma cell-bone marrow stromal interaction, and downregulation of osteoclastogenesis [ 19 , 20 ].…”

Myeloma: A Lot of Progress, Still a Long Way to Go

“…Immunomodulatory drugs (IMiDs) are oral anti-myeloma drugs, pioneered by thalidomide, and have been the mainstay of myeloma therapy since 1999. In a review by Charlinski and co-workers [ 3 ], detailed insight is provided on their mode of action through the modulation of cereblon ubiquitin ligase activity, the main target of all IMiDs. Though highly similar in chemical structure, IMiDs differ in not only their anti-myeloma activity, but their side effect profile, too.…”