title: Proliferation is a central independent prognostic factor and target for personalized and risk-adapted treatment in multiple myeloma.
abstract: BACKGROUND
  Proliferation of malignant plasma cells is a strong adverse prognostic factor in multiple myeloma and simultaneously targetable by available (e.g. tubulin polymerase inhibitors) and upcoming (e.g. aurora kinase inhibitors) compounds.
  
  
  METHODS
  We assessed proliferation using gene expression-based indices in 757 samples including independent cohorts of 298 and 345 samples of CD138-purified myeloma cells from previously untreated patients undergoing high-dose chemotherapy, together with clinical prognostic factors, chromosomal aberrations, and gene expression-based high-risk scores.
  
  
  RESULTS
  In the two cohorts, 43.3% and 39.4% of the myeloma cell samples showed a proliferation index above the median plus three standard deviations of normal bone marrow plasma cells. Malignant plasma cells of patients in advanced stages or those harboring disease progression-associated gain of 1q21 or deletion of 13q14.3 showed significantly higher proliferation indices; patients with gain of chromosome 9, 15 or 19 (hyperdiploid samples) had significantly lower proliferation indices. Proliferation correlated with the presence of chromosomal aberrations in metaphase cytogenetics. It was significantly predictive for event-free and overall survival in both cohorts, allowed highly predictive risk stratification (e.g. event-free survival 12.7 versus 26.2 versus 40.6 months, P < 0.001) of patients, and was largely independent of clinical prognostic factors, e.g. serum β₂-microglobulin, International Staging System stage, associated high-risk chromosomal aberrations, e.g. translocation t(4;14), and gene expression-based high-risk scores.
  
  
  CONCLUSIONS
  Proliferation assessed by gene expression profiling, being independent of serum-β₂-microglobulin, International Staging System stage, t(4;14), and gene expression-based risk scores, is a central prognostic factor in multiple myeloma. Surrogating a biological targetable variable, gene expression-based assessment of proliferation allows selection of patients for risk-adapted anti-proliferative treatment on the background of conventional and gene expression-based risk factors.
authors.affiliation: Medizinische Klinik V, Universitätsklinikum Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany. dirk.hose@med.uni-heidelberg.de
authors.forename: Dirk
authors.initials: D
authors.lastname: Hose
authors.forename: Thierry
authors.initials: T
authors.lastname: Rème
authors.forename: Thomas
authors.initials: T
authors.lastname: Hielscher
authors.forename: Jérôme
authors.initials: J
authors.lastname: Moreaux
authors.forename: Tobias
authors.initials: T
authors.lastname: Messner
authors.forename: Anja
authors.initials: A
authors.lastname: Seckinger
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhou
authors.forename: Jens
authors.initials: J
authors.lastname: Hillengass
authors.forename: Uta
authors.initials: U
authors.lastname: Bertsch
authors.forename: Kai
authors.initials: K
authors.lastname: Neben
authors.forename: Thomas
authors.initials: T
authors.lastname: Möhler
authors.forename: Jean François
authors.initials: JF
authors.lastname: Rossi
authors.forename: Anna
authors.initials: A
authors.lastname: Jauch
authors.forename: Bernard
authors.initials: B
authors.lastname: Klein
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D002869:Chromosome Aberrations; D015331:Cohort Studies; D020869:Gene Expression Profiling; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D020411:Oligonucleotide Array Sequence Analysis; D010950:Plasma Cells / Q000473:pathology*; D057285:Precision Medicine; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger