Background: The therapeutic challenge in relapsed/refractory multiple myeloma (RRMM) stems from high genomic instability, clonal heterogeneity, and microenvironment-mediated immune evasion, limiting the efficacy of proteasome inhibitors (PIs) and immunomodulatory drugs. Our preclinical studies demonstrated that the histone deacetylase inhibitor (HDACi) chidamide enhances chromatin accessibility by reversing epigenetic remodeling, potentially overcoming PIs resistance. Thus, we aimed to evaluate the efficacy and safety of chidamide combined with the ICD regimen (ixazomib, cyclophosphamide, dexamethasone) in RRMM patients exposed to bortezomib. Methods: This single-center, non-randomized, open-label prospective study (Chinese Clinical Trial Registry: ChiCTR2200066532; Ethics Approval: 2022YF055-01) enrolled RRMM patients previously treated with bortezomib. Patients received chidamide (20 mg, d1, 4, 8, 11) combined with ixazomib (4 mg, d1, 8, 15), cyclophosphamide (400 mg/m², d1, 8, 15), and dexamethasone (20 mg, d1, 2, 8, 9, 15, 16) in 21-day cycles until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.Results: As of July 30, 2025,11 RRMM patients were enrolled. Median age was 62 years (range: 53–72), with 64% male. Baseline characteristics: IgG type (81.8%), light-chain type (12.2%); ISS stage II–III (81.8%), R-ISS stage II–III (81.8%); 36.4% high-risk by mSMART 3.0; ECOG score 2 (36.4%). All patients had received a median of 2 prior lines (range: 1–6), with 100% exposed to bortezomib and 90.9% to lenalidomide, 18.2% to ixazomib, 18.2% to carfilzomib, and 18.2% to daratumumab. 36.4% had undergone prior autologous stem cell transplantation.Among 9 evaluable patients, the best ORR was 66.6% (CR 44.4%, VGPR 22.2%), with MR 11.1% and PD 22.2%. With a median follow-up of 2.8 months (range: 0.1–19.2), 2 patients experienced progression, and 3 died. Median PFS was 12.24 months (95% CI: 0–38.50). Median OS was not reached, with an estimated 12-month OS rate of 51.4%.Safety profile included hematologic toxicity (36.4%, grade ≥3: 27.3%), pneumonia (18.2%, grade ≥3: 18.2%), and hepatic injury (18.2%, grade ≥3: 9.1%). Most adverse events were manageable. Conclusions: Preliminary results demonstrate promising clinical efficacy and manageable safety of chidamide combined with ICD in RRMM patients double-exposed to bortezomib and lenalidomide. Further validation with larger cohorts and longer follow-up is warranted.

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2025
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