RNA-sequencing based first choice of treatment and determination of risk in multiple myeloma

Martina Emde-Rajaratnam, Susanne Beck, Vladimir Benes, Hans Salwender, Uta Bertsch, Christoph Scheid, Mathias Hänel, Katja Weisel, Thomas Hielscher, Marc S Raab, Hartmut Goldschmidt, Anna Jauch, Ken Maes, Elke De Bruyne, Eline Menu, Kim De Veirman, Jérôme Moreaux, Karin Vanderkerken, Anja Seckinger, Dirk Hose

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BACKGROUND: Immunotherapeutic targets in multiple myeloma (MM) have variable expression height and are partly expressed in subfractions of patients only. With increasing numbers of available compounds, strategies for appropriate choice of targets (combinations) are warranted. Simultaneously, risk assessment is advisable as patient's life expectancy varies between months and decades.

METHODS: We first assess feasibility of RNA-sequencing in a multicenter trial (GMMG-MM5, n=604 patients). Next, we use a clinical routine cohort of untreated symptomatic myeloma patients undergoing autologous stem cell transplantation (n=535, median follow-up (FU) 64 months) to perform RNA-sequencing, gene expression profiling (GEP), and iFISH by ten-probe panel on CD138-purified malignant plasma cells. We subsequently compare target expression to plasma cell precursors, MGUS (n=59), asymptomatic (n=142) and relapsed (n=69) myeloma patients, myeloma cell lines (n=26), and between longitudinal samples (MM vs. relapsed MM). Data are validated using the independent MMRF CoMMpass-cohort (n=767, FU 31 months).

RESULTS: RNA-sequencing is feasible in 90.8% of patients (GMMG-MM5). Actionable immune-oncological targets (n=19) can be divided in those expressed in all normal and >99% of MM-patients (CD38, SLAMF7, BCMA, GPRC5D, FCRH5, TACI, CD74, CD44, CD37, CD79B), those with expression loss in subfractions of MM-patients (BAFF-R [81.3%], CD19 [57.9%], CD20 [82.8%], CD22 [28.4%]), aberrantly expressed in MM (NY-ESO1/2 [12%], MUC1 [12.7%], CD30 [4.9%], mutated BRAF V600E/K [2.1%]), and resistance-conveying target-mutations e.g., against part but not all BCMA-directed treatments. Risk is assessable regarding proliferation, translated GEP- (UAMS70-, SKY92-, RS-score) and de novo (LfM-HRS) defined risk scores. LfM-HRS delineates three groups of 40%, 38%, and 22% of patients with 5-year and 12-year survival rates of 84% (49%), 67% (18%), and 32% (0%). R-ISS and RNA-sequencing identify partially overlapping patient populations, with R-ISS missing, e.g., 30% (22/72) of highly proliferative myeloma.

CONCLUSION: RNA-sequencing based assessment of risk and targets for first choice treatment is possible in clinical routine.

Originele taal-2English
Aantal pagina's18
TijdschriftFrontiers in Immunology
StatusPublished - 15 nov 2023

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Publisher Copyright:
Copyright © 2023 Emde-Rajaratnam, Beck, Benes, Salwender, Bertsch, Scheid, Hänel, Weisel, Hielscher, Raab, Goldschmidt, Jauch, Maes, De Bruyne, Menu, De Veirman, Moreaux, Vanderkerken, Seckinger and Hose.


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