First results of aponermin(Apo) improving teclistamab (tec)/talquetamab (tal) in patients (pts) with Relapsed/Refractory multiple myeloma (RRMM)

Abstract Background: Tec, a BCMA-directed bispecific antibody (Tal, another bispecific antibody targeting GPRC5D), has shown promising efficacy but high infection in pts with RRMM. Combining the validated myeloma target antigens with Apo (the fisrt approved DR4/DR5 agonist) may lead to improved outcomes and much better safety. Here, we report the first results from the phase 1 trial (ChiCTR2500106279) in pts with RRMM. Methods: Enrolled pts had MM per International Myeloma Working Group 2016 criteria; were RR to the last line of therapy (LOT); were exposed to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy; and had measurable disease. The primary endpoint was to evaluate safety and to identify a recommended phase 2 regimen (RP2R) for the combination. Responses were investigator assessed. AEs were graded per CTCAE v5.0. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT criteria. Results: As of August 3, 2025, 6 pts received Apo+ Tec (including 1pts with Tal causing resistant of BCMA) +Thalidomide. Median (range) age was 64 y (53–69); median (range) prior LOT was 7 (4–10); 100% (3/3) had high-risk cytogenetics, 100% (6/6) were triple-class refractory and penta-drug exposed. The majority 50.0% (3/6) had extramedullary disease (EMD). The median follow-up was 2.5 months (range: 1.0–3.5). The most common treatment-emergent adverse event was CRS (83.3%; no grade [gr] 3 or 4). neutropenia (50%; gr 3/4, 33.3%), anemia (50%; gr 3/4, 33.3%), thrombocytopenia (50%; gr 3/4, 33.3%). Dose-limiting toxicities (DLTs) were reported at dose level 1, the pt with renal insufficiency (Foot abscess). No ICANS event was reported. No DLTs were reported at the RP2R. The overall response rate (ORR) of dose level1 was 33.3% (1/3). In Dose level 2, 100% (3/3) of pts reaching ≥VGPR at one month, 66.6% (2/3) achieved ≥CR in 2 cycle treatment.. At the RP2R, ORR was 100% (3/3) among all evaluable pts and 66.7% (2/3) among evaluable pts with EMD. Median duration of response has not been reached. Conclusions: In this first combination study of Apo+BCMA-/GPRC5D-targeted bispecific antibody, at the RP2R has a manageable safety profile consistent with each of the monotherapies. In dose level 2, a 100% ORR was observed in pts with advanced RRMM at the RP2R, and an ORR of 66.7% was achieved in pts with EMD, a high-risk population with unmet need, supporting further evaluation of the combination. Clinical trial information: ChiCTR2500106279. * Dose level 1: APO 10 mg/kg, d1–5 monthly; dose level 2: APO 10 mg/kg, d1–2 weekly.