Abstract Introduction Despite therapeutic advances in multiple myeloma (MM) treatment, managing heavily pretreated relapsed/refractory MM (RRMM) remains clinically challenging. Aponermin (Apo), a recombinant circularly permuted human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), is the first-in-class death receptor 4/5 agonist recently approved for RRMM. The combination of Apo with the standard carfilzomib-pomalidomide-dexamethasone (KPd) regimen was based on preclinical evidence demonstrating that proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) can enhance TRAIL-induced apoptosis. This prospective, open-label, multicenter study evaluated the efficacy and safety of Apo-KPd in this difficult-to-treat population. Methods Eligible patients were 18-75 years of age, met the diagnostic criteria for RRMM defined by International Myeloma Working Group (IMWG). Patients had previously received at least 3 different prior lines of therapy or were triple-class exposed to a PI, an IMiD and an anti-CD38 antibody. Measurable disease and adequate organ function were required. Patients received 28-day cycles of intravenous Apo (10mg/kg on days 1-5), carfilzomib (20mg/m² on days 1-2 of cycle 1, then 27mg/m² on days 1-2, 8-9, and 15-16), oral pomalidomide (4mg daily on days 1-21), and dexamethasone (20mg on days 1-2, 8-9, and 15-16) until disease progression or unacceptable toxicity. The primary endpoint was the overall response rate (ORR) assessed by IMWG criteria. Results As of July 2025, 21 patients with RRMM were enrolled. Median age was 57 years (range 46-67) and 12 (57.1%) patients were male. The median time from diagnosis was 3.3 years (range 0.3-8.4). The patients treated in the trial received a median of 4 (range 1-7) prior lines of therapy. Patients in Durie-Salmon stage I/II/III/NA were 9.5%, 4.8%, 76.2% and 9.5%, respectively. High-risk cytogenetic abnormalities were present in 66.7% (14/21) of patients, while 76.2% (16/21) had extramedullary plasmacytoma (EMP) at screening. Most patients (85.7%, 18/21) were triple-class exposed and 61.9% (13/21) had previously received carfilzomib or pomalidomide. Seven (33.3%) patients had undergone autologous stem cell transplantation (ASCT). Seven (33.3%) patients were refractory to prior CAR-T therapy, with 5 patients having at least 2 CAR-T treatments including BCMA-CAR-T and GPRC5D-CAR-T. After a median of 2 treatment cycles, the ORR was 66.7% (14/21; 95% CI 43.0%-85.4%), with 28.6% (6/21) achieving a very good partial response (VGPR) or better. Subgroup analysis demonstrated consistent efficacy across poor-prognostic subgroups, with comparable outcomes observed between patients with 3 versus ≤ 3 prior lines of therapy (ORR 72.7% vs. 60.0%), those with versus without prior exposure to carfilzomib/pomalidomide (ORR 61.5% vs. 75.0%), those with versus without prior ASCT (ORR 71.4% vs. 64.3%), and patients with versus without EMP (ORR 68.8% vs. 60.0%). High-risk cytogenetic patients exhibited a moderately lower, though still clinically meaningful response rate compared to standard-risk patients (ORR 57.1% vs. 80.0%). Notably, among the 7 CAR-T-pretreated patients (all with EMP and heavily pretreated median 5 prior lines), an encouraging ORR of 57.1% was achieved (1 PR and 3 VGPR), which was comparable to that achieved in CAR-T-naïve patients (71.4%). All treatment-emergent adverse events (TEAEs) were manageable, most commonly abnormal liver function (23.8%), increased lactate dehydrogenase (23.8%), respiratory infection (19.0%), and tumor lysis syndrome (14.3%). Grade 3-4 AEs occurred in 23.8% (5/21) of patients, including tumor lysis syndrome (14.3%), neutropenia (4.8%), thrombocytopenia (4.8%) and pneumonia (4.8%). Conclusion The Apo-KPd regimen demonstrated favorable activity in heavily pretreated RRMM, including patients with poor prognostic and high-risk features. Notably, even in CAR-T-pretreated patients, who had exhausted multiple prior lines of therapy and were refractory to most available anti-myeloma agents, encouraging responses were observed. These findings highlight the potential benefits of Apo's novel mechanism of action and its synergistic effects when combined with KPd. The combination showed a manageable safety profile consistent with the known toxicities of the individual agents. These promising results warrant further investigation of this novel combination regimen in larger clinical trials.
He et al. (Mon,) studied this question.