{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:44:01Z","timestamp":1789577041931,"version":"build-2803163510"},"reference-count":48,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:00:00Z","timestamp":1770336000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:00:00Z","timestamp":1770336000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European J of Haematology"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Multiple myeloma (MM) remains an incurable plasma cell malignancy characterized by recurrent relapses and eventual refractoriness to standard agents, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti\u2010CD38 monoclonal antibodies. With frontline therapeutic strategies increasingly employing quadruplet induction regimens and prolonged lenalidomide maintenance, resistance to traditional IMiDs has become more prevalent, creating an urgent need for next\u2010generation cereblon E3 ligase modulators (CELMoDs) capable of overcoming IMiD refractoriness and enhancing the immunologic microenvironment. Iberdomide (CC\u2010220) and mezigdomide (CC\u201092480) are rationally engineered CELMoDs designed to achieve deeper degradation of Ikaros (IKZF1) and Aiolos (IKZF3), restore cereblon\u2010mediated activity, and potentiate immune effector responses. This review explores the core biological features of these agents, detailing their mechanisms of action, preclinical and clinical activity, as well as safety profile. We examine how their pharmacodynamic properties differ from classical IMiDs, their relevance in triple\u2010class and penta\u2010refractory MM, and their integration into emerging combination strategies with monoclonal antibodies and T\u2010cell\u2013redirecting immunotherapies. Special emphasis is placed on ongoing and future trials that may refine their therapeutic positioning, alongside a critical appraisal of the limitations and future directions of this rapidly advancing drug class.<\/jats:p>","DOI":"10.1111\/ejh.70134","type":"journal-article","created":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T03:30:38Z","timestamp":1770435038000},"page":"697-708","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting Ikaros and Aiolos: Next\u2010Generation Cereblon\n                    <scp>E3<\/scp>\n                    Ligase Modulators in\n                    <scp>MM<\/scp>"],"prefix":"10.1111","volume":"116","author":[{"given":"Maria Eugenia","family":"Alvaro","sequence":"first","affiliation":[{"name":"Department of Onco\u2010Hematology AO of Cosenza, Hematology Unit  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrica Antonia","family":"Martino","sequence":"additional","affiliation":[{"name":"Department of Onco\u2010Hematology AO of Cosenza, Hematology Unit  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santino","family":"Caserta","sequence":"additional","affiliation":[{"name":"Department of Onco\u2010Hematology AO of Cosenza, Hematology Unit  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamdouh","family":"Skafi","sequence":"additional","affiliation":[{"name":"Emergency and Internal Medicine Department Saint Joseph Hospital  East Jerusalem Palestine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Bruzzese","sequence":"additional","affiliation":[{"name":"Department of Onco\u2010Hematology AO of Cosenza, Hematology Unit  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Amodio","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine University of Catanzaro  Catanzaro Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenio","family":"Lucia","sequence":"additional","affiliation":[{"name":"Department of Onco\u2010Hematology AO of Cosenza, Hematology Unit  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Olivito","sequence":"additional","affiliation":[{"name":"Department of Onco\u2010Hematology AO of Cosenza, Hematology Unit  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Labanca","sequence":"additional","affiliation":[{"name":"Department of Onco\u2010Hematology AO of Cosenza, Hematology Unit  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6339-632X","authenticated-orcid":false,"given":"Francesco","family":"Mendicino","sequence":"additional","affiliation":[{"name":"Department of Onco\u2010Hematology AO of Cosenza, Hematology Unit  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto","family":"Vigna","sequence":"additional","affiliation":[{"name":"Department of Onco\u2010Hematology AO of Cosenza, Hematology Unit  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fortunato","family":"Morabito","sequence":"additional","affiliation":[{"name":"AIL Sezione di Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5256-0726","authenticated-orcid":false,"given":"Massimo","family":"Gentile","sequence":"additional","affiliation":[{"name":"Department of Onco\u2010Hematology AO of Cosenza, Hematology Unit  Cosenza Italy"},{"name":"Department of Pharmacy Health and Nutritional Science, University of Calabria  Rende 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