Abstract 6046: CFT8634, a BRD9 BiDAC™ degrader, is active in a subset of multiple myeloma cell line models and synergistic when combined with pomalidomide or dexamethasone

Abstract Recent literature has shown that loss-of-function of BRD9, a component of the noncanonical SWI/SNF (ncSWI/SNF) complex, mediated by RNA interference or by BRD9 degrader compounds can inhibit multiple myeloma (MM) cell lines and primary MM cell proliferation in vitro, as well as inhibit mouse MM xenograft tumor growth in vivo. Additionally, in vitro synergy was observed when a BRD9 degrader was combined with either dexamethasone or pomalidomide. CFT8634 is a potent and selective oral BiDAC™ degrader of BRD9 that entered a clinical trial for the treatment of SMARCB1-perturbed cancers, including synovial sarcoma and SMARCB1-null tumors. Pharmacokinetic and pharmacodynamic data from this trial demonstrated dose-proportional human plasma exposure and robust BRD9 degradation in patients. Here we show that CFT8634 has anti-proliferative activity in a subset of MM cell lines that translates into tumor growth inhibition in MM xenograft models at clinically relevant CFT8634 exposures. We observe that cell lines less sensitive to pomalidomide tend to be significantly more sensitive to CFT8634 treatment. As pomalidomide is a SoC treatment in MM, we interrogated the ability to combine CFT8634 and pomalidomide. CFT8634 demonstrates synergy with pomalidomide in MM cell lines where CFT8634 is anti-proliferative as a single agent. We further show that clinically relevant exposures of CFT8634 demonstrate synergy with pomalidomide in vivo in the NCI-H929 mouse xenograft model. This model is relatively unresponsive to pomalidomide alone, suggesting that CFT8634 can render otherwise recalcitrant MM tumors sensitive to the effects of pomalidomide in combination. Pharmacokinetic and pharmacodynamic analyses show that in combination, CFT8634 and pomalidomide do not interfere with the ability to degrade each other’s targets (BRD9 and IKZF1/3, respectively) despite both utilizing the E3 ligase cereblon. As the corticosteroid dexamethasone is another SoC treatment given in combination with pomalidomide, we explored the ability to combine dexamethasone with CFT8634. CFT8634 demonstrates synergy with dexamethasone in the RPMI-8226 in vivo xenograft model. This combination leads to tumor regressions at clinically relevant doses and outperforms the current combination of pomalidomide with dexamethasone. In conclusion, we demonstrate in vitro and in vivo activity in an expanded set of MM models using the clinical oral BRD9 degrader CFT8634 as a single agent and show in vivo synergy between CFT8634 and SoC agents pomalidomide and dexamethasone at clinically relevant doses. Citation Format: Laura L. Poling, David Cocozziello, Minsng he, Eunju Hurh, Riadh Lobbardi, Katrina L. Jackson, Stewart L. Fisher, Roy M. Pollock. CFT8634, a BRD9 BiDAC™ degrader, is active in a subset of multiple myeloma cell line models and synergistic when combined with pomalidomide or dexamethasone abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6046.