PB2071: SENSITIVITY OF MULTIPLE MYELOMA TO MELFLUFEN ASSOCIATES WITH DECREASED P53 ACTIVITY AND ENRICHMENT OF DNA DAMAGE REPAIR PATHWAY GENES

• DOI: 10.1097/01.hs9.0000975084.93585.40
• Publication Date: 2023-08-09T03:04:29Z
• Authors: Juho Miettinen; Philipp Sergeev; Sadiksha Adhikari; Maiju-Emilia Hupp...; Minna Suvela; Ana Slipicevic; Nina N Nupponen; Klara Acs; Fredrik Lehmann; Caroline Heckman
• Keywords: Melphalan

Topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research Background: The novel peptide-drug conjugate melphalan flufenamide (melflufen) was recently approved by the EMA for treatment of relapsed/refractory multiple myeloma (MM). Considering low overall survival these patients challenges to decide their treatment, information that can support selection predict outcome is urgently needed. Aims: We aimed identify potential indicators melflufen response in MM as well mechanisms underlying sensitivity applying ex vivo multiparametric flow cytometry-based drug resistance testing (DSRT) single cell RNA sequencing (scRNAseq) patient samples. Methods: Bone marrow aspirates were collected mononuclear fractions (BM-MNCs) prepared from 12 newly diagnosed (ND) (RR) after written informed consent following protocols compliance with Declaration Helsinki. For DSRT BM-MNCs seeded onto 96-well plates treated 7 different concentrations or melphalan. After 72 h incubation cells stained CD138 CD38 plasma Annexin V 7AAD distinguish apoptotic dead cells. scRNAseq, sorted based on expression CD138+ mixed CD138- at a 1:1 ratio. Sequencing libraries using 10x Genomics reagents instrument followed Illumina NovaSeq 6000. samples grouped melphalan: high (HS, DSS > 40 16 (melphalan)), intermediate (IS, 31 ≤ 10 (LS, < (melphalan)). Differential gene (DGE) set enrichment analysis (GSEA) between HS LS both drugs performed genes pathways associated response. Results: analyzed DSRT, clinical cytogenetic data groups IS, LS). A significant indicator disease stage all but one RRMM patients. All cytogenetics had gain 1q, while deletion 13q. In addition, 4 8 only 1 t(4;14), 3 2 positive del17p. Mutation TP53 detected suggesting active despite loss p53 activity. this, GSEA DGE results showed decrease downstream pathway targets. contrast, same analyses higher DNA damage repair BRCA1, ATM, CHEK2. healthy revealed differential innate immune system interferon signaling pathways. Summary/Conclusion: demonstrate meflufen highly effective inducing death vivo, particularly Importantly, high-risk features such del17p, 1q mutation. Associated this increase genes. Keywords: Gene expression, Drug sensitivity, Multiple