Abstract 5439: MDM2 inhibitor alrizomadlin (APG-115) stabilizes p53 and synergizes with proteasome inhibitors in multiple myeloma

Multiple myeloma (MM) accounts for about 2% of all cancers and 18% of all hematologic malignancies in the US. Newly developed treatments (e.g., immunomodulators, proteasome inhibitors, monoclonal antibodies) have significantly improved outcomes, but MM inevitably relapses and is considered incurable. Genomic analysis shows that the TP53 gene encoding tumor suppressor protein p53 is infrequently mutated in patients with MM, of whom about 82% retain wild-type (WT) TP53. Mouse double minute 2 (MDM2) is an E3 ubiquitin ligase that inhibits p53 via proteasome degradation. Proteasome inhibitors might help to stabilize p53 and synergize with MDM2 inhibitors. Therefore, MDM2 inhibitors that activate p53 might constitute an attractive pharmacologic approach to MM. Alrizomadlin (APG-115) is an investigational, new small molecule targeting the p53/MDM2 interaction and is in clinical development for solid and hematologic cancers. This study aimed to evaluate whether alrizomadlin can potentiate the antitumor effects of proteasome inhibitors in MM. In cell-based antiproliferation studies, alrizomadlin demonstrated selective activity against WT TP53 MM cell lines, including MOLP-8, H929, and MM1S, with IC₅₀ values of 0.495 ± 0.132 µM, 0.259 ± 0.251 µM, and 0.325 ± 0.105 µM, respectively. In contrast, alrizomadlin was inactive against TP53-mutant MM cell lines (IC₅₀ >10 µM). In MM cell lines, APG-115 exhibited synergistic activity with anti-MM agents (e.g., carfilzomib, lenalidomide, melphalan, selinexor) and other targeted agents (e.g., panobinostat, bromodomain inhibitor OTX-015, tumor necrosis factor-related apoptotic-inducing ligand). In vivo studies showed that coadministration of alrizomadlin with proteasome inhibitor bortezomib or carfilzomib enhanced tumor regression (vs. single agents) in H929 xenograft models. As to mechanism, alrizomadlin likely disrupts MDM2/p53 interactions and induces accumulation of p53, MDM2, and downstream proteins 4 hours after treatment. The proteasome inhibitors induced dose-related increases in p53 protein expression 24 hours after treatment. The combination of carfilzomib with alrizomadlin further promoted accumulation of p53 and MDM2 and increased phosphorylation of p53. As a transcription factor, p53: (1) activated expression of p21 to cause cell cycle arrest (2) augmented downstream BCL-2-associated X protein (BAX) and p53-upregulated modulator of apoptosis (PUMA), (3) increased cleavage of caspase-3 and poly [ADP-ribose] polymerase 1 (PARP-1; hallmarks of apoptosis), and (4) increased apoptosis and associated antitumor effects. In conclusion, our results demonstrate that the combination of MDM2 inhibitor APG-115 and proteasome inhibitors have synergistic antitumor effects on MM tumors harboring WT TP53. These data lay a foundation for clinical trials of a new and novel therapeutic option for patients with refractory MM.

Citation Format: Guangfeng Wang, Eric Liang, Chunyang Tang, Li Rui, Ping Min, Jing Lv, Yangfeng Ge, Fei Zhang, Lvcheng Wang, Jingjin Shang, Dajun Yang, Yifan Zhai. MDM2 inhibitor alrizomadlin (APG-115) stabilizes p53 and synergizes with proteasome inhibitors in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5439.