Introduction Heavily pre-treated multiple myeloma (MM) patients have very poor outcomes and limited survival. Mezigdomide, a novel oral cereblon E3 ligase modulator (CELMoD), has demonstrated promising efficacy and safety in combination with dexamethasone (Mez-D) for relapsed/refractory MM (RRMM), as documented in the phase I–II trial (NCT03374085). Due to its recent approval, especially in Europe, real-world evidence remains limited. In this retrospective, observational, multicenter, real-world Italian case series, we collected clinical data on RRMM patients treated with Mez-D outside clinical trials, to assess efficacy and safety of this novel combination.

Methods A total of 10 RRMM patients treated with Mez-D through expanded access programs (EAP) outside clinical trials were enrolled from August 2024 to July 2025 across seven Italian Hematology Units. High-risk genetic abnormalities and prior treatment exposure/refractoriness were defined according to the International Myeloma Working Group (IMWG) criteria.

Results The median age was 71 years (range 61–85), and 30% were males. Half of the patients had an ECOG performance status of 0–1, while the remaining ≥2. The M-protein subtype was IgG in 40% of cases, IgA in 30%, light chain only in 20%, and biclonal IgG-IgA in 10% of subjects. Kappa light chain was more frequent (60%) compared to lambda (40%).

High genetic risk was observed in 40% of patients, and 30% met the definition of high-risk based on updated criteria presented at the 2025 EMMA meeting. Extramedullary disease was reported in 20%. Based on the Revised International Staging System (R-ISS), 40% were stage II, 20% stage III, and 40% had unavailable data. No patients had severe renal impairment (GFR <40 ml/min) at baseline.

Patients had received a median of 6 prior therapy lines (range 3–12) before initiating Mez-D, and all of them were previously treated with anti-CD38 monoclonal antibodies with 80% of refractoriness, as well as with immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). Half of the cohort was refractory to two IMiDs, the rest to three. Among PI-treated patients, 90% were refractory, and 10% were previously exposed.

Prior BCMA-directed therapy included belantamab-mafodotin in monotherapy (40%), belantamab mafodotin and teclistamab (10%), or triple exposure to CAR-T cells, belantamab-mafodotin, and teclistamab (10%). Selinexor was used in 30% of cases. Half of the patients (50%) had undergone autologous stem cell transplantation (30% single, 20% tandem).

All patients were triple-class exposed and 70% were triple-class refractory. Penta-drug exposure and refractoriness occurred in 80% and 40% of cases, respectively.

Patients received a median of 6 cycles of Mez-D (range 1–11), with a median time from diagnosis to mezigdomide of 95 months (range 20–192). The overall response rate (ORR) was 80%, including 1 complete response, 2 very good partial responses, and 5 partial responses with a median time to best response of 2 months (range 1–6). Dose adjustments were required in 40% of patients and consisted of both mezigdomide and dexamethasone reductions.

Treatment discontinuation occurred in 60%, due to toxicity (30%) or disease progression (30%). At data cutoff (median follow-up 7 months), 3 patients had progressed. Median progression-free survival (PFS) and overall survival (OS) were not reached. Estimated 6-month PFS and OS rates were 58% and 69%, respectively.

Hematologic toxicities were frequent: grade III–IV neutropenia (60%) and thrombocytopenia (40%). Infectious events included pneumonia (50%), febrile neutropenia (10%), invasive aspergillosis (10%), and CMV reactivation (20%). No cases of peripheral neuropathy were reported, while diarrhea occurred in 20% of patients.

Conclusions Mez-D demonstrated significant anti-myeloma activity in a real-world cohort of heavily pre-treated patients, including those with high genetic risk. However, the high rate of infectious complications underlines the need for appropriate management to prevent early treatment discontinuation. These findings support the potential role of Mez-D combination in routine clinical practice, though larger prospective trials are warranted to confirm its long-term efficacy and safety, particularly in frail MM populations such as the elderly or those with renal impairment.

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2025
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