Efficacy and safety of aponermin combined with immunomodulators in relapsed/refractory multiple myeloma

Abstract Background Patients with relapsed/refractory multiple myeloma (RRMM) are prone to drug resistance after multiple lines of treatment, resulting in poor prognosis. Aponermin, the world's first DR4/DR5 agonist, induces P53-independent apoptosis by activating death receptors and is approved for RRMM (Dhillon S, Drugs, 2024; Xia Z, Leng Y, Fang B, BMC Cancer, 2023). This study aimed to evaluate the efficacy and safety of aponermin combined with immunomodulators (IMiDs) in RRMM. Methods A retrospective analysis was conducted on a real-world cohort study involving 38 RRMM patients from eight centers in China between September 2024 and July 2025. Treatment regimens included aponermin plus carfilzomib, thalidomide, and dexamethasone (Apo-KTd); aponermin plus carfilzomib, pomalidomide, and dexamethasone (Apo-KPd); aponermin plus pomalidomide and dexamethasone (Apo-Pd); aponermin plus thalidomide and dexamethasone (Apo-Td), and other combination therapies based on aponermin. The dosage of aponermin was uniformly set at 10 mg/kg, administered via intravenous infusion on days 1–5, combined with other drugs at standard doses. Results The cohort consisted of male/female: 21/17; median age was 63 years (range: 30–83 years); median prior lines of therapy were 4 lines (34.2% received ≥5 lines). TP53 deletion/mutation was present in 13.2%, while extramedullary disease occurred in 63.2%. After a median of 3 (range: 2-8) cycles of treatment, the overall response rate (ORR) was 55.3%. Subgroup analysis revealed that patients aged <63 years had significantly better outcomes compared to those aged ≥63 years (ORR: 72.2% vs. 40.0%, P<0.05). No statistically significant differences were observed between patients with or without extramedullary disease regarding ORR rates (62.5% vs. 42.8%, P>0.05), prior CAR-T therapy status regarding ORR rates (71.4% vs. 51.6%, P>0.05); TP53 abnormalities regarding ORR rates (60.0% vs. 60.1%); or presence/absence of 1q21 amplification regarding ORR rates (70.0% vs. 60.1%, P>0.05). There was no statistically significant difference between patients with ≥3 and <3 cycles (ORR 56.5% vs. 53.3%, P>0.05). The median PFS was significantly longer in those receiving ≥3 cycles than those receiving <3 cycles (4.5 months vs. 2 months, P<0.05). In terms of safety, 53.8% of patients had hematological toxicity (≥3 grade 28.2%), 23.1% had abnormal liver function (≥3 grade 7.7%), and the incidence of tumor lysis syndrome was 5.1%. All adverse events were manageable, and no treatment-related death occurred. Conclusion Aponermin combined with immunomodulators demonstrates good tolerability and definite efficacy for RRMM, especially for long-term treatment. Patients with high-risk cytogenetics, extramedullary lesions, and those who have failed multiple lines of treatment can still benefit.