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

doi:10.3389/fimmu.2023.1286700

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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Abstract

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.

Original language	English
Article number	1286700
Number of pages	18
Journal	Frontiers in Immunology
Volume	14
DOIs	https://doi.org/10.3389/fimmu.2023.1286700
Publication status	Published - 15 Nov 2023

Bibliographical note

Funding Information:
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the German Federal Ministry of Education (“CLIOMMICS” (01ZX1309 and 01ZX1609) as well as “CAMPSIMM” (01ES1103)) and the Deutsche Forschungs- gemeinschaft (SFB/TRR79). Publication costs of this manuscript are kindly covered by the German-Speaking Myeloma Multicenter Group e.V. Acknowledgments

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.

Keywords

immunotherapeutic targets
Multiple Myeloma
RNA-sequencing
proliferation
risk-adapted treatment
Survival
personalized treatment

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Emde-Rajaratnam, M., Beck, S., Benes, V., Salwender, H., Bertsch, U., Scheid, C., Hänel, M., Weisel, K., Hielscher, T., Raab, M. S., Goldschmidt, H., Jauch, A., Maes, K., De Bruyne, E., Menu, E., De Veirman, K., Moreaux, J., Vanderkerken, K., Seckinger, A., & Hose, D. (2023). RNA-sequencing based first choice of treatment and determination of risk in multiple myeloma. Frontiers in Immunology, 14, [1286700]. https://doi.org/10.3389/fimmu.2023.1286700

Emde-Rajaratnam, Martina ; Beck, Susanne ; Benes, Vladimir ; Salwender, Hans ; Bertsch, Uta ; Scheid, Christoph ; Hänel, Mathias ; Weisel, Katja ; Hielscher, Thomas ; Raab, Marc S ; Goldschmidt, Hartmut ; Jauch, Anna ; Maes, Ken ; De Bruyne, Elke ; Menu, Eline ; De Veirman, Kim ; Moreaux, Jérôme ; Vanderkerken, Karin ; Seckinger, Anja ; Hose, Dirk. / RNA-sequencing based first choice of treatment and determination of risk in multiple myeloma. In: Frontiers in Immunology. 2023 ; Vol. 14.

@article{76ccb8ca2df0468c98455dea549b3561,

title = "RNA-sequencing based first choice of treatment and determination of risk in multiple myeloma",

abstract = "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.",

keywords = "immunotherapeutic targets, Multiple Myeloma, RNA-sequencing, proliferation, risk-adapted treatment, Survival, personalized treatment",

author = "Martina Emde-Rajaratnam and Susanne Beck and Vladimir Benes and Hans Salwender and Uta Bertsch and Christoph Scheid and Mathias H{\"a}nel and Katja Weisel and Thomas Hielscher and Raab, {Marc S} and Hartmut Goldschmidt and Anna Jauch and Ken Maes and {De Bruyne}, Elke and Eline Menu and {De Veirman}, Kim and J{\'e}r{\^o}me Moreaux and Karin Vanderkerken and Anja Seckinger and Dirk Hose",

note = "Funding Information: The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the German Federal Ministry of Education (“CLIOMMICS” (01ZX1309 and 01ZX1609) as well as “CAMPSIMM” (01ES1103)) and the Deutsche Forschungs- gemeinschaft (SFB/TRR79). Publication costs of this manuscript are kindly covered by the German-Speaking Myeloma Multicenter Group e.V. Acknowledgments Publisher Copyright: Copyright {\textcopyright} 2023 Emde-Rajaratnam, Beck, Benes, Salwender, Bertsch, Scheid, H{\"a}nel, Weisel, Hielscher, Raab, Goldschmidt, Jauch, Maes, De Bruyne, Menu, De Veirman, Moreaux, Vanderkerken, Seckinger and Hose.",

year = "2023",

month = nov,

day = "15",

doi = "10.3389/fimmu.2023.1286700",

language = "English",

volume = "14",

journal = "Frontiers in Immunology",

issn = "1664-3224",

publisher = "Frontiers Media S.A.",

}

Emde-Rajaratnam, M, Beck, S, Benes, V, Salwender, H, Bertsch, U, Scheid, C, Hänel, M, Weisel, K, Hielscher, T, Raab, MS, Goldschmidt, H, Jauch, A, Maes, K , De Bruyne, E , Menu, E , De Veirman, K, Moreaux, J, Vanderkerken, K , Seckinger, A & Hose, D 2023, 'RNA-sequencing based first choice of treatment and determination of risk in multiple myeloma', Frontiers in Immunology, vol. 14, 1286700. https://doi.org/10.3389/fimmu.2023.1286700

RNA-sequencing based first choice of treatment and determination of risk in multiple myeloma. / Emde-Rajaratnam, Martina; Beck, Susanne; Benes, Vladimir; Salwender, Hans; Bertsch, Uta; Scheid, Christoph; Hänel, Mathias; Weisel, Katja; Hielscher, Thomas; Raab, Marc S; Goldschmidt, Hartmut; Jauch, Anna; Maes, Ken ; De Bruyne, Elke ; Menu, Eline ; De Veirman, Kim; Moreaux, Jérôme; Vanderkerken, Karin ; Seckinger, Anja ; Hose, Dirk.

In: Frontiers in Immunology, Vol. 14, 1286700, 15.11.2023.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - RNA-sequencing based first choice of treatment and determination of risk in multiple myeloma

AU - Emde-Rajaratnam, Martina

AU - Beck, Susanne

AU - Benes, Vladimir

AU - Salwender, Hans

AU - Bertsch, Uta

AU - Scheid, Christoph

AU - Hänel, Mathias

AU - Weisel, Katja

AU - Hielscher, Thomas

AU - Raab, Marc S

AU - Goldschmidt, Hartmut

AU - Jauch, Anna

AU - Maes, Ken

AU - De Bruyne, Elke

AU - Menu, Eline

AU - De Veirman, Kim

AU - Moreaux, Jérôme

AU - Vanderkerken, Karin

AU - Seckinger, Anja

AU - Hose, Dirk

N1 - Funding Information: The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the German Federal Ministry of Education (“CLIOMMICS” (01ZX1309 and 01ZX1609) as well as “CAMPSIMM” (01ES1103)) and the Deutsche Forschungs- gemeinschaft (SFB/TRR79). Publication costs of this manuscript are kindly covered by the German-Speaking Myeloma Multicenter Group e.V. Acknowledgments 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.

PY - 2023/11/15

Y1 - 2023/11/15

N2 - 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.

AB - 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.

KW - immunotherapeutic targets

KW - Multiple Myeloma

KW - RNA-sequencing

KW - proliferation

KW - risk-adapted treatment

KW - Survival

KW - personalized treatment

UR - http://www.scopus.com/inward/record.url?scp=85178077813&partnerID=8YFLogxK

U2 - 10.3389/fimmu.2023.1286700

DO - 10.3389/fimmu.2023.1286700

M3 - Article

C2 - 38035078

VL - 14

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

M1 - 1286700

ER -

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

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