@article{WeissbachHerediaGuerreroBarnsteineretal.2020,
  author    = {Weißbach, Susann and Heredia-Guerrero, Sofia Catalina and Barnsteiner, Stefanie and Großhans, Lukas and Bodem, Jochen and Starz, Hanna and Langer, Christian and Appenzeller, Silke and Knop, Stefan and Steinbrunn, Torsten and Rost, Simone and Einsele, Hermann and Bargou, Ralf Christian and Rosenwald, Andreas and St{\"u}hmer, Thorsten and Leich, Ellen},
  title     = {Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines},
  series = {Cancers},
  volume    = {12},
  journal   = {Cancers},
  number    = {2},
  issn      = {2072-6694},
  doi       = {10.3390/cancers12020455},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200617},
  year      = {2020},
  abstract  = {Approximately 20\% of multiple myeloma (MM) cases harbor a point mutation in KRAS. However, there is still no final consent on whether KRAS-mutations are associated with disease outcome. Specifically, no data exist on whether KRAS-mutations have an impact on survival of MM patients at diagnosis in the era of novel agents. Direct blockade of KRAS for therapeutic purposes is mostly impossible, but recently a mutation-specific covalent inhibitor targeting KRAS\(^{p.G12C}\) entered into clinical trials. However, other KRAS hotspot-mutations exist in MM patients, including the less common exon-4 mutations. For the current study, the coding regions of KRAS were deep-sequenced in 80 newly diagnosed MM patients, uniformely treated with three cycles of bortezomib plus dexamethasone and cyclophosphamide (VCD)-induction, followed by high-dose chemotherapy and autologous stem cell transplantation. Moreover, the functional impact of KRAS\(^{p.G12A}\) and the exon-4 mutations p.A146T and p.A146V on different survival pathways was investigated. Specifically, KRAS\(^{WT}\), KRAS\(^{p.G12A}\), KRAS\(^{p.A146T}\), and KRAS\(^{p.A146V}\) were overexpressed in HEK293 cells and the KRAS\(^{WT}\) MM cell lines JJN3 and OPM2 using lentiviral transduction and the Sleeping Beauty vector system. Even though KRAS-mutations were not correlated with survival, all KRAS-mutants were found capable of potentially activating MEK/ERK- and sustaining PI3K/AKT-signaling in MM cells.},
  language  = {en}
}
@article{MitchellLiWeinholdetal.2016,
  author    = {Mitchell, Jonathan S. and Li, Ni and Weinhold, Niels and F{\"o}rsti, Asta and Ali, Mina and van Duin, Mark and Thorleifsson, Gudmar and Johnson, David C. and Chen, Bowang and Halvarsson, Britt-Marie and Gudbjartsson, Daniel F. and Kuiper, Rowan and Stephens, Owen W. and Bertsch, Uta and Broderick, Peter and Campo, Chiara and Einsele, Hermann and Gregory, Walter A. and Gullberg, Urban and Henrion, Marc and Hillengass, Jens and Hoffmann, Per and Jackson, Graham H. and Johnsson, Ellinor and J{\"o}ud, Magnus and Kristinsson, Sigurdur Y. and Lenhoff, Stig and Lenive, Oleg and Mellqvist, Ulf-Henrik and Migliorini, Gabriele and Nahi, Hareth and Nelander, Sven and Nickel, Jolanta and N{\"o}then, Markus M. and Rafnar, Thorunn and Ross, Fiona M. and da Silva Filho, Miguel Inacio and Swaminathan, Bhairavi and Thomsen, Hauke and Turesson, Ingemar and Vangsted, Annette and Vogel, Ulla and Waage, Anders and Walker, Brian A. and Wihlborg, Anna-Karin and Broyl, Annemiek and Davies, Faith E. and Thorsteinsdottir, Unnur and Langer, Christian and Hansson, Markus and Kaiser, Martin and Sonneveld, Pieter and Stefansson, Kari and Morgan, Gareth J. and Goldschmidt, Hartmut and Hemminki, Kari and Nilsson, Bj{\"o}rn and Houlston, Richard S.},
  title     = {Genome-wide association study identifies multiple susceptibility loci for multiple myeloma},
  series = {Nature Communications},
  volume    = {7},
  journal   = {Nature Communications},
  doi       = {10.1038/ncomms12050},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165983},
  pages     = {12050},
  year      = {2016},
  abstract  = {Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10-8), 6q21 (rs9372120, P=9.09 × 10-15), 7q36.1 (rs7781265, P=9.71 × 10-9), 8q24.21 (rs1948915, P=4.20 × 10-11), 9p21.3 (rs2811710, P=1.72 × 10-13), 10p12.1 (rs2790457, P=1.77 × 10-8), 16q23.1 (rs7193541, P=5.00 × 10-12) and 20q13.13 (rs6066835, P=1.36 × 10-13), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.},
  language  = {en}
}
@article{KepplerWeissbachLangeretal.2016,
  author    = {Keppler, Sarah and Weißbach, Susann and Langer, Christian and Knop, Stefan and Pischimarov, Jordan and Kull, Miriam and St{\"u}hmer, Thorsten and Steinbrunn, Torsten and Bargou, Ralf and Einsele, Hermann and Rosenwald, Andreas and Leich, Ellen},
  title     = {Rare SNPs in receptor tyrosine kinases are negative outcome predictors in multiple myeloma},
  series = {Oncotarget},
  volume    = {7},
  journal   = {Oncotarget},
  number    = {25},
  doi       = {10.18632/oncotarget.9607},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177840},
  pages     = {38762-38774},
  year      = {2016},
  abstract  = {Multiple myeloma (MM) is a plasma cell disorder that is characterized by a great genetic heterogeneity. Recent next generation sequencing studies revealed an accumulation of tumor-associated mutations in receptor tyrosine kinases (RTKs) which may also contribute to the activation of survival pathways in MM. To investigate the clinical role of RTK-mutations in MM, we deep-sequenced the coding DNA-sequence of EGFR, EPHA2, ERBB3, IGF1R, NTRK1 and NTRK2 which were previously found to be mutated in MM, in 75 uniformly treated MM patients of the "Deutsche Studiengruppe Multiples Myelom". Subsequently, we correlated the detected mutations with common cytogenetic alterations and clinical parameters. We identified 11 novel non-synonymous SNVs or rare patient-specific SNPs, not listed in the SNP databases 1000 genomes and dbSNP, in 10 primary MM cases. The mutations predominantly affected the tyrosine-kinase and ligand-binding domains and no correlation with cytogenetic parameters was found. Interestingly, however, patients with RTK-mutations, specifically those with rare patient-specific SNPs, showed a significantly lower overall, event-free and progression-free survival. This indicates that RTK SNVs and rare patient-specific RTK SNPs are of prognostic relevance and suggests that MM patients with RTK-mutations could potentially profit from treatment with RTK-inhibitors.},
  language  = {en}
}
@article{BachmannSchrederEngelhardtetal.2021,
  author    = {Bachmann, Friederike and Schreder, Martin and Engelhardt, Monika and Langer, Christian and Wolleschak, Denise and M{\"u}gge, Lars Olof and D{\"u}rk, Heinz and Sch{\"a}fer-Eckart, Kerstin and Blau, Igor Wolfgang and Gramatzki, Martin and Liebisch, Peter and Grube, Matthias and Metzler, Ivana v. and Bassermann, Florian and Metzner, Bernd and R{\"o}llig, Christoph and Hertenstein, Bernd and Khandanpour, Cyrus and Dechow, Tobias and Hebart, Holger and Jung, Wolfram and Theurich, Sebastian and Maschmeyer, Georg and Salwender, Hans and Hess, Georg and Bittrich, Max and Rasche, Leo and Brioli, Annamaria and Eckardt, Kai-Uwe and Straka, Christian and Held, Swantje and Einsele, Hermann and Knop, Stefan},
  title     = {Kinetics of renal function during induction in newly diagnosed multiple myeloma: results of two prospective studies by the German Myeloma Study Group DSMM},
  series = {Cancers},
  volume    = {13},
  journal   = {Cancers},
  number    = {6},
  issn      = {2072-6694},
  doi       = {10.3390/cancers13061322},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234139},
  year      = {2021},
  abstract  = {Background: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD) or btz, lenalidomide (len), and dex (VRd) or len, adriamycin, and dex (RAD). The minimum required estimated glomerular filtration rate (eGFR) was >30 mL/min. We analyzed the percent change of the renal function using the International Myeloma Working Group (IMWG) criteria and Kidney Disease: Improving Global Outcomes (KDIGO)-defined categories. Results: Seven hundred and seventy-two patients were eligible. Three hundred and fifty-six received VCD, 214 VRd, and 202 RAD. VCD patients had the best baseline eGFR. The proportion of pts with eGFR <45 mL/min decreased from 7.3\% at baseline to 1.9\% PInd (p < 0.0001). Thirty-seven point one percent of VCD versus 49\% of VRd patients had a decrease of GFR (p = 0.0872). IMWG-defined "renal complete response (CRrenal)" was achieved in 17/25 (68\%) pts after VCD, 12/19 (63\%) after RAD, and 14/27 (52\%) after VRd (p = 0.4747). Conclusions: Analyzing a large and representative newly diagnosed myeloma (NDMM) group, we found no difference in CRrenal that occurred independently from the myeloma response across the three regimens. A trend towards deterioration of the renal function with VRd versus VCD may be explained by a better pretreatment "renal fitness" in the latter group.},
  language  = {en}
}