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@ARTICLE{EmdeRajaratnam:285713,
      author       = {M. Emde-Rajaratnam and S. Beck and V. Benes and H.
                      Salwender and U. Bertsch and C. Scheid and M. Hänel and K.
                      Weisel and T. Hielscher$^*$ and M. S. Raab and H.
                      Goldschmidt and A. Jauch and K. Maes and E. De Bruyne and E.
                      Menu and K. De Veirman and J. Moreaux and K. Vanderkerken
                      and A. Seckinger and D. Hose},
      title        = {{RNA}-sequencing based first choice of treatment and
                      determination of risk in multiple myeloma.},
      journal      = {Frontiers in immunology},
      volume       = {14},
      issn         = {1664-3224},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {DKFZ-2023-02521},
      pages        = {1286700},
      year         = {2023},
      abstract     = {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.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).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.RNA-sequencing based assessment
                      of risk and targets for first choice treatment is possible
                      in clinical routine.},
      keywords     = {RNA-sequencing (Other) / immunotherapeutic targets (Other)
                      / multiple myeloma (Other) / personalized treatment (Other)
                      / proliferation (Other) / risk-adapted treatment (Other) /
                      survival (Other)},
      cin          = {C060},
      ddc          = {610},
      cid          = {I:(DE-He78)C060-20160331},
      pnm          = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
      pid          = {G:(DE-HGF)POF4-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38035078},
      pmc          = {pmc:PMC10684778},
      doi          = {10.3389/fimmu.2023.1286700},
      url          = {https://inrepo02.dkfz.de/record/285713},
}