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

Autor:	Emde-Rajaratnam M; Department of Hematology and Immunology, Myeloma Center Brussels & Labor für Myelomforschung, Vrije Universiteit Brussel (VUB), Jette, Belgium., Beck S; Department of Hematology and Immunology, Myeloma Center Brussels & Labor für Myelomforschung, Vrije Universiteit Brussel (VUB), Jette, Belgium.; Universitätsklinikum Heidelberg, Molekularpathologisches Zentrum, Heidelberg, Germany., Benes V; Europäisches Laboratorium für Molekularbiologie, GeneCore, Heidelberg, Germany., Salwender H; Asklepios Tumorzentrum Hamburg, AK Altona and St. Georg, Hamburg, Germany., Bertsch U; Universitätsklinikum Heidelberg, Medizinische Klinik V, Heidelberg, Germany., Scheid C; Department I of Internal Medicine, University of Cologne, Cologne, Germany., Hänel M; Department of Internal Medicine III, Klinikum Chemnitz GmbH, Chemnitz, Germany., Weisel K; Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Hielscher T; Deutsches Krebsforschungszentrum, Abteilung für Biostatistik, Heidelberg, Germany., Raab MS; Universitätsklinikum Heidelberg, Medizinische Klinik V, Heidelberg, Germany., Goldschmidt H; Universitätsklinikum Heidelberg, Medizinische Klinik V, Heidelberg, Germany.; Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany., Jauch A; Universität Heidelberg, Institut für Humangenetik, Heidelberg, Germany., Maes K; Department of Hematology and Immunology, Myeloma Center Brussels & Labor für Myelomforschung, Vrije Universiteit Brussel (VUB), Jette, Belgium., De Bruyne E; Department of Hematology and Immunology, Myeloma Center Brussels & Labor für Myelomforschung, Vrije Universiteit Brussel (VUB), Jette, Belgium., Menu E; Department of Hematology and Immunology, Myeloma Center Brussels & Labor für Myelomforschung, Vrije Universiteit Brussel (VUB), Jette, Belgium., De Veirman K; Department of Hematology and Immunology, Myeloma Center Brussels & Labor für Myelomforschung, Vrije Universiteit Brussel (VUB), Jette, Belgium., Moreaux J; Institute of Human Genetics, UMR 9002 CNRS-UM, Montpellier, France., Vanderkerken K; Department of Hematology and Immunology, Myeloma Center Brussels & Labor für Myelomforschung, Vrije Universiteit Brussel (VUB), Jette, Belgium., Seckinger A; Department of Hematology and Immunology, Myeloma Center Brussels & Labor für Myelomforschung, Vrije Universiteit Brussel (VUB), Jette, Belgium., Hose D; Department of Hematology and Immunology, Myeloma Center Brussels & Labor für Myelomforschung, Vrije Universiteit Brussel (VUB), Jette, Belgium.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2023 Nov 15; Vol. 14, pp. 1286700. Date of Electronic Publication: 2023 Nov 15 (Print Publication: 2023).
DOI:	10.3389/fimmu.2023.1286700
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. (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.)
Databáze:	MEDLINE
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