Real-world safety and efficacy of aponermin and daratumumab-based regimens in patients with multiple myeloma

Abstract Background: Treatment of relapsed/refractory multiple myeloma (RRMM) and frail newly diagnosed multiple myeloma (NDMM) patients remains challenging with substantial unmet needs. Aponermin is a novel recombinant circular TRAIL that selectively induces apoptosis in tumor cells by binding to death receptors DR4 and DR5, while sparing normal cells (Dhillon S, Drugs, 2024). Clinical studies have shown promising activity of aponermin against MM, including those resistant to conventional therapies, with minimal off-target toxicity (Xia Z, Leng Y, Fang B, BMC Cancer, 2023). It demonstrates synergistic effects with daratumumab through complementary mechanisms of action - enhancing immune-mediated tumor cell killing and directly activating the extrinsic apoptotic pathway (Jun Ma, Leukemia 14) in 21.43%, 17p deletion in 21.43% and t(14;16) in 7.14%. Double-hit myeloma was present in 35.71% of cases. Patients were heavily pretreated with a median of 2 prior lines of therapy (range 0-6), with 42.86% previously exposed to the triple-class combination of proteasome inhibitors, immunomodulatory drugs, and CD38 monoclonal antibodies. Treatment regimens consisted of aponermin combined with daratumumab and various backbone therapies: dexamethasone (35.71%), selinexor-dexamethasone (28.57%), bortezomib-dexamethasone (14.29%), lenalidomide-dexamethasone (7.14%), cyclophosphamide-dexamethasone (7.14%), and carfilzomib-dexamethasone (7.14%). Patients received a median of 3 treatment cycles (range 2-5). Efficacy analysis demonstrated an overall response rate of 78.57%, with complete response in 14.29%, very good partial response in 21.43%, and partial response in 42.86% of patients. Stable disease and progressive disease were observed in 7.14% and 14.29% of patients, respectively. The median duration of response was 3.7 months (range 1.16-6.0 months). The safety profile was favorable, with manageable hematologic toxicities including anemia and thrombocytopenia (each 14.29%). Non-hematologic adverse events were mild, consisting of palpitations (14.29%), constipation (14.29%), and dizziness (7.14%). No hepatotoxicity was observed throughout the treatment period. Discussion: Real-world data demonstrate that aponermin and daratumumab-based regimens exhibit promising efficacy and favorable safety profiles in MM patients, particularly in heavily pretreated RRMM patients, offering a potential new treatment option for this challenging population.