Safety and efficacy of aponermin-based chemotherapy as bridging therapy before CAR-T cell treatment in relapsed/refractory multiple myeloma

Abstract Introduction Chimeric antigen receptor (CAR) T-cell therapy represents a breakthrough in the treatment of relapsed or refractory (R/R) multiple myeloma (MM), however, severe cytokine release syndrome and neurotoxicity may compromise outcomes. A well-tolerated bridging therapy that controls disease without additional toxicities could improve the safety and efficacy of subsequent CAR-T infusion. Aponermin, a novel circularly permuted TRAIL ligand, induces selective apoptosis in malignant plasma cells through death receptors DR4 and DR5 (Dhillon S, Drugs, 2024; Xia Z, Leng Y, Fang B, BMC Cancer, 2023). The safety and efficacy of aponermin-based regimens as bridging therapy before CAR-T treatment remain to be explored. Methods We performed a retrospective, three-centre cohort study of consecutive RRMM patients who received aponermin-based chemotherapy after leukapheresis and before lymphodepletion (fludarabine 30 mg/m²/day and cyclophosphamide 300 mg/m²/day × 3 days) followed by a single BCMA CAR-T infusion. Safety and efficacy were assessed from the start of bridging therapy until 30 days after CAR-T administration. Results Twenty-eight patients with R/R MM were enrolled. All had received a median of four prior lines of therapy (range 3–7). Among them, 27 patients presented with extramedullary disease. All patients were refractory to proteasome inhibitors, immunomodulatory drugs, and CD38 monoclonal antibodies. Of the 28 patients, 23 received one cycle of bridging therapy, 3 received two cycles, and 1 patient received three cycles. After aponermin-based bridging therapy, the overall response rate (ORR) was 41.7% (7/28), including a complete response (CR) in 7.1% (2/28) patients and a partial response (PR) in 17.9% (5/28) patients. Stable disease (SD) was observed in 17 (60.7%) patients, and 2 (7.1%) patients experienced disease progression after bridging therapy. The safety profile of bridging therapy was favorable, with only one case of hypersensitivity reaction and two cases of elevated transaminases. Notably, six patients with stable disease after bridging therapy experienced significant platelet elevation after bridging therapy, potentially reducing bleeding risk during subsequent CAR-T cell treatment. Among 23 evaluable patients after CAR-T cell treatment, the ORR was 95.7 % (sCR 4.3 %, CR 17.4 %, PR 52.2 %). The median progression-free survival (PFS) was 6.43 months. Conclusion: Aponermin-based bridging therapy is well tolerated, does not exacerbate organ dysfunction or marrow suppression, and provides significant disease control or platelet recovery. These findings support prospective evaluation of aponermin-based regimens as an effective bridge to BCMA CAR-T therapy in R/R MM.