title: Early tumor-cell gene expression changes may predict the response to first-line bortezomib-based therapy in patients with newly diagnosed multiple myeloma.
abstract: OBJECTIVE
  Maximizing the response rate to first-line therapy in patients with multiple myeloma (MM) is important because it leads to improved outcome. Gene-expression studies have identified prognostic gene sets in patients receiving bortezomib-based therapy. Comparison of the lists of genes derived from two gene-expression-based models (GEP70, GEP80) showed that they overlap in three genes, namely PSMD4, BIRC5, and KIAA1754. An unanswered question is whether early gene-expression changes can be used as predictors of the response to first-line bortezomib. In this study we aimed to examine the predictive value of gene expression changes for the depth of response after bortezomib-based therapy in newly diagnosed MM.
  
  
  METHODS
  We prospectively assessed the relation between early PSMD4, BIRC5, and KIAA1754 gene expression changes (before therapy and one week later) and the response rate after bortezomib-based therapy in 25 patients with newly diagnosed MM. Gene expression was studied by RT-PCR on CD138-selected plasma cells, and changes were recorded as upregulation, downregulation, or unchanged.
  
  
  RESULTS
  Whereas baseline prognostic factors including genetic lesions and stage were not predictive of the response rate, we found that early BIRC5 and KIAA1754 gene-expression changes were significantly associated with the depth of response to bortezomib (p=0.001 and p<0.001, respectively). PSMD4 was not predictive of the depth of response. KIAA1754 upregulation was linked to complete remission (CR) or very good partial remission (VGPR). BIRC5 upregulation was linked to stable disease (SD) or progressive disease (PD). We also observed that BIRC5 upregulation was associated with worse progression-free survival (PFS).
  
  
  CONCLUSIONS
  Our results suggest that BIRC5 and KIAA1754 gene-expression changes may predict the response to bortezomib-based therapy. These data may have relevance for the stratification and early adaptation of first-line treatment in patients with newly diagnosed MM.
authors.affiliation: Haemato-Oncology Unit, The Royal Marsden Hospital, The Royal Marsden NHS Foundation Trust, Surrey, London, UK.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Liapis
authors.forename: Efstathios
authors.initials: E
authors.lastname: Kastritis
authors.forename: Tina
authors.initials: T
authors.lastname: Bagratouni
authors.forename: Spyridoula
authors.initials: S
authors.lastname: Vassiliou
authors.forename: Alexandros
authors.initials: A
authors.lastname: Papachristidis
authors.forename: Evangelia
authors.initials: E
authors.lastname: Charitaki
authors.forename: Nektarios
authors.initials: N
authors.lastname: Alevizopoulos
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Harhalakis
authors.forename: Evangelos
authors.initials: E
authors.lastname: Terpos
authors.forename: Sosanna
authors.initials: S
authors.lastname: Delimpasi
authors.forename: Meletios A
authors.initials: MA
authors.lastname: Dimopoulos
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000069286:Bortezomib / Q000627:therapeutic use*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D011446:Prospective Studies; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; C516570:ITPRIP protein, human; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; D000077022:Survivin; D000069286:Bortezomib