7th Users' Conference of IT4Innovations

Extramedullary multiple myeloma: insights into pathogenesis and tumor microenvironment using whole exome, RNA and single-cell sequencing

30 Oct 2023, 12:00

20m

atrium (IT4Innovations)

User's talk Users' talks Users' Talks I

Speaker

David Žihala (Department of Hematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic; Department of Hematooncology , University Hospital Ostrava, Ostrava, Czech Republic)

Description

Our study represents the most comprehensive next-generation sequencing analysis of extramedullary multiple myeloma (EMM) tumor cells to date, uncovering key molecular features and describing the tumor microenvironment. We found the co-occurrence of 1q21 gain/amplification and MAPK pathway mutations in 79% of EMM samples, suggesting these are crucial mutational events in EMM development. Additionally, we demonstrated that patients with mutated KRAS and 1q gain/amp at the time of diagnosis display significantly higher risk of EMM development (HR=2.1, p=0.008) using large coMMpass dataset (N=1039). Next, we observed a downregulation of vital molecules for EMM cell homing – CXCR4, enhanced cell proliferation and predominant production of light chains compared to heavy chains. We revealed decreased expression of therapeutic targets such as CD38, SLAMF7, GPCR5D and FCRH5 as well as reduced expression of HLA-B/C molecules, potentially explaining lower efficacy of immunotherapy in EMM. On the other hand, we identified significantly up-regulated EZH2 and CD70 as potential future therapeutic options. For the first time we report on EMM's tumor microenvironment, revealing CD8+ T cells and NK cells as predominant immune effector cells using single cell sequencing. Finally, this is the first longitudinal study in EMM ever performed catching the molecular changes since the time of diagnosis.