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Simple Summary: Patients diagnosed with multiple myeloma today can expect to live for substantially longer than in the past thanks to the range of highly active treatment options now available. Over the course of their disease, patients may receive several different treatment combinations to keep their disease under control. Thus, there is an ongoing need for additional new drugs and regimens to be developed, and, in particular, ones that are convenient, accessible, and active against disease that has returned following multiple different therapies. Among today's standards of care are the immunomodulatory drugs lenalidomide and pomalidomide, which are commonly used in quadruplet and triplet regimens in newly diagnosed patients and those with relapsed disease. However, resistance to these drugs can arise over the course of treatment; therefore, novel, more potent agents are being developed to restore and increase activity against relapsed multiple myeloma, one of which is the investigational agent mezigdomide. Mezigomide is an oral cereblon E3 ligase modulator (CELMoD) that is under clinical investigation in patients with relapsed/refractory (RR) multiple myeloma (MM). Like other CELMoD compounds, mezigdomide acts by altering the conformation of cereblon within the cullin 4A ring ligase–cereblon (CRL4CRBN) E3 ubiquitin ligase complex, thereby recruiting novel protein substrates for selective proteasomal degradation. These include two critical lymphoid transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3), also known as Ikaros and Aiolos, which have important roles in the development and differentiation of hematopoietic cells, in MM pathobiology, and in suppressing the expression of interferon-stimulating genes and T-cell stimulation. Among the CELMoDs, mezigdomide has the greatest cereblon-binding potency, plus the greatest potency for the degradation of Ikaros and Aiolos and subsequent downstream antimyeloma effects. Preclinical studies of mezigdomide have demonstrated its anti-proliferative and apoptotic effects in MM, along with its immune-stimulatory effects and its synergistic activity with other antimyeloma agents, including in lenalidomide-/pomalidomide-resistant MM cell lines and mouse xenograft models. Early-phase clinical trial data indicate notable activity in heavily pretreated patients with RRMM, including those with triple-class-refractory disease, together with a tolerable and manageable safety profile. This review summarizes current preclinical and clinical findings with mezigdomide and its potential future roles in the treatment of MM. [ABSTRACT FROM AUTHOR]