P-374: Stratifying Multiple Myeloma Patients for Personalized Therapy Based on TP53 Mutation, Deletion, and Drug Response Profiles

Dimitrios Tsallos, Nemo Ikonen, Juho Miettinen, MM Majumder, Samuli Eldfors, Alun Owen Parsons, Minna Suvela, Paul Dowling, Despina Bazou, Peter O´Gorman, Juha Lievonen, Raija Silvennoinen, Pekka Anttila, Caroline Heckman

Tutkimustuotos: KonferenssimateriaalitKonferenssiabstraktivertaisarvioitu


Introduction: Multiple myeloma (MM) is a clinically diverse disease with a heterogeneous genomic architecture. Recent improvements in MM treatment outcomes are due to better diagnosis and new therapies. Grasping MM biology and genetics can enhance patient care and expedite drug approval for investigational treatments. Patients are currently stratified into risk groups based on clinical prognosis and cytogenetic markers. Despite advances in therapy, most MM patients will still relapse or become refractory to treatment. There are patient groups that could benefit from alternative therapeutic options. We aimed to identify these groups by analyzing MM patients' clinical and molecular profiles via exome and RNA sequencing and ex vivo drug sensitivity testing.

Methods: We collected bone marrow aspirates from 173 MM patients. CD138+ cells from these samples were selected, and somatic alterations identified via exome sequencing of DNA and matched skin biopsies. We performed RNA sequencing on CD138+ cells (n = 145) for differential gene expression study and screened them against 142 compounds in a 10,000-fold concentration range. In parallel, we performed proteomics analysis on 39 of these samples using mass spectrometry, providing protein expression data for up to 2753 proteins.

Results: Our analysis revealed distinct transcriptional and phenotypic consequences of TP53 mutation and del(17p). Mutation to TP53 was associated with upregulation of genes related to the cell cycle, including G2M checkpoint and E2F targets, and the downregulationg of genes controlled by NF-kB in response to TNF. Conversely, samples with del(17p) were characterized by an upregulation of TNF signaling via NF-kB and other immune response pathways. Interestingly, samples with both TP53 mutation and del(17p) exhibited an even more pronounced downregulation of NF-kB compared to solely TP53-mutated samples, while maintaining reduced expression of response to interferon alpha and gamma. These distinct molecular profiles translated into unique drug sensitivity patterns. CD138+ cells with mutation in TP53 showed increased sensitivity to mTOR/PI3K, IGF1R inhibitors and JAK inhibitors ex vivo, an effect that was observable irrespective of the co-occurrence of del(17p). Preliminary proteomic analyses of cell signaling pathways is ongoing.

Conclusions: Our findings suggest that MM patients with TP53 mutation may benefit from targeted therapies involving mTOR/PI3K, IGF1R and JAK inhibitors, regardless of whether del(17p) is present or not. Improved understanding of those mechanisms would allow for a more nuanced patient stratification that factors in TP53 mutation status and del17p, offering promise for more personalized therapeutic strategies for MM patients. Further research is warranted to explore potential therapeutic options tailored to the unique genetic and response profiles of patients with TP53 mutation and del17p.
DOI - pysyväislinkit
TilaJulkaistu - 2023
OKM-julkaisutyyppiEi sovellu
Tapahtuma20th International Myeloma Society Annual Meeting - Athens, Kreikka
Kesto: 27 syysk. 202330 syysk. 2023


Konferenssi20th International Myeloma Society Annual Meeting

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