Abstract 4432: mRNA-based restoration of pomalidomide sensitivity in multiple myeloma

Abstract Multiple myeloma (MM) remains an incurable hematologic malignancy, and immunomodulatory imide drugs (IMiDs) have been used as an effective treatment option. A significant challenge with IMiDs such as pomalidomide, as with other treatment options, is the development of drug resistance. This has become a substantial impediment to extending patients' lives. Currently, no effective strategy exists for overcoming IMiD resistance in MM patients. Exploring alternative approaches that could improve the efficacy of pomalidomide might help myeloma patients live longer. Genetic alterations in cereblon (CRBN) contribute to more than one-third of clinical cases of pomalidomide resistance. This study aims to restore sensitivity to pomalidomide-resistant cells through mRNA-based wildtype CRBN restoration. First, we repeatedly exposed multiple myeloma cell lines (MM1.S) to pomalidomide at increasing doses, starting from 2 nM to 10 μM. Following six months of pomalidomide exposure, we generated MM1.S cells that are resistant to pomalidomide and confirmed the absence of CRBN with RNA sequencing and western blotting. Through in vitro transcription, we synthesized CRBN mRNA and electroporated it to the resistant cells. We found restoration of wildtype cereblon and subsequent pomalidomide sensitivity compared to cells without CRBN mRNA treatment. As electroporation is impractical beyond laboratory studies, we are designing a polymer-lipid hybrid nanoparticle to efficiently deliver the mRNA to the cells. Additionally, to ensure targeted delivery of the nanoparticle-coated CRBN mRNA to plasma cells, we applied phage display peptide library screens and identified a cyclic peptide with a high affinity for B-cell maturation antigen (BCMA), a protein known to be almost exclusively expressed by plasma and myeloma cells. This peptide is being validated for BCMA binding, and will be conjugated with the nanoparticle-coated CRBN mRNA for targeted delivery to the malignant plasma cells. Findings from this work will advance mRNA-based therapeutics for overcoming drug resistance caused by genetic alterations in target proteins. Citation Format: Joseph U. Ogbede, Michael S. Rogers, Robert J. D'Amato, Bruce R. Zetter. mRNA-based restoration of pomalidomide sensitivity in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4432.