Abstract Background: Multiple myeloma (MM) is still an incurable neoplasm, and treatment options for heavily pretreated relapsed and refractory multiple myeloma (RRMM) are still limited. Aponermin is a recombinant circularly permuted human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which can activate death receptor 4 (DR4)/death receptor 5 (DR5) on the surface of tumor cells, triggering intracellular caspase reactions and exerting anti-tumor effects. Aponermin received its first approval in China for the treatment of patients with relapsed or refractory multiple myeloma who have received at least two prior therapies (Dhillon S, Drugs, 2024; Xia Z,Leng Y, Fang B, BMC Cancer, 2023). It could synergize with proteasome inhibitors and corticosteroids to enhance antimyeloma activity (Leng Y, Hematol Oncol, 2022). Here we report the efficacy and safety of aponermin-carfilzomib-dexamethasone (Apo-KD) based regimens for RRMM. Methods: This is a prospective, multi-center study (ChiCTR2500100365) involving patients with RRMM who had received at least two prior lines of therapy. Apo-KD was adminstered in 28-day treatment cycles as follows: aponermin (10mg/kg on days 1–5 per cycle, or alternatively on days 1–3 and 15–17 per cycle), carfilzomib (20 mg/m² on days 1 and 2 of Cycle 1; 27 mg/m² on days 1 and 2 of Cycle 2 and subsequent cycles), and dexamethasone (20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 per cycle). Other medications, such as immunomodulatory drugs or chemotherapy agents, were allowed based on the patient's disease status and tolerance (Jun Ma, Leukemia & Lymphoma, 2024). The primary endpoint was the overall response rate (ORR) according to IMWG criteria. Secondary endpoints included the response rate of at least very good partial response (VGPR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Results: As of July 10, 2025, 40 patients were recruited to the study, with a median age of 62 years (range, 38–78) and a median of 4 prior lines of therapy (range, 2–13). Baseline characteristics included 40% of patients classified as ISS Stage III, and 37.5% with high-risk cytogenetics. Extramedullary disease (EMD) was documented in 28 patients (70%), and 40.0% had previously undergone autologous stem cell transplantation (ASCT) as first-line therapy. In terms of prior treatments, 80% had been exposed to immunomodulatory drugs, proteasome inhibitors (PIs), and anti-CD38 antibodies (triple-class exposure TCE), while 15/40 (37.5%) had been treated with BCMA-CD3 antibodies or CAR-T therapy. Treatment regimens included Apo-KD in 10 patients (25%), Apo-KD combined with immunomodulatory drugs (IMiDs) in 12 patients (30%), and Apo-KD combined with chemotherapy in 18 patients (45%). The median number of treatment cycles was 3 (range, 2–8). The ORR was 70% (95% CI: 53.3%-82.9%), with a VGPR rate of 32.5% (95% CI: 19.1%-40.2%). Among patients with EMD, the ORR was 71.3%, and the VGPR rate was 32.1%. In the subgroup of 32 TCE patients, the ORR was 65.6%, with 31.3% achieving VGPR. Fifteen patients who had undergone prior CAR-T or BCMA-CD3 antibody treatment showed an ORR of 80.0% (20.0% complete response CR, 20.0% VGPR, and 40.0% partial response PR). The efficacy of the Apo-KD-based regimens was similar in patients with extramedullary disease, TCE, or those previously treated with CAR-T/ bispecific antibody. The median follow-up period was 4 months (range: 2-12). Nine patients experienced disease progression. The estimated median PFS was 11.4 months (95% CI: 4.8–17.2). Three patients died due to disease progression, and the median OS was not reached. The most common treatment-emergent adverse events (TEAEs) were bone marrow suppression (62.5%), infections (40%), elevated transaminases (25%), fatigue (12.5%), hyperuricemia (10%), and hypokalemia (10%). Notably, grade III or higher TEAEs were reported in 42.5% for cytopenia and 12.5% for infections. Conclusion: The aponermin-carfilzomib-dexamethasone (Apo-KD)-based regimens demonstrated promising activity in heavily pretreated patients with RRMM, especially those with EMD, TCE, or T-cell-redirecting therapies. The adverse events were manageable.
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