title: Myeloma Cell Dynamics in Response to Treatment Supports a Model of Hierarchical Differentiation and Clonal Evolution.
abstract: OBJECTIVE
  Since the pioneering work of Salmon and Durie, quantitative measures of tumor burden in multiple myeloma have been used to make clinical predictions and model tumor growth. However, such quantitative analyses have not yet been performed on large datasets from trials using modern chemotherapy regimens.
  
  
  METHODS
  We analyzed a large set of tumor response data from three randomized controlled trials of bortezomib-based chemotherapy regimens (total sample size n = 1,469 patients) to establish and validate a novel mathematical model of multiple myeloma cell dynamics.
  
  
  RESULTS
  Treatment dynamics in newly diagnosed patients were most consistent with a model postulating two tumor cell subpopulations, "progenitor cells" and "differentiated cells." Differential treatment responses were observed with significant tumoricidal effects on differentiated cells and less clear effects on progenitor cells. We validated this model using a second trial of newly diagnosed patients and a third trial of refractory patients. When applying our model to data of relapsed patients, we found that a hybrid model incorporating both a differentiation hierarchy and clonal evolution best explains the response patterns.
  
  
  CONCLUSIONS
  The clinical data, together with mathematical modeling, suggest that bortezomib-based therapy exerts a selection pressure on myeloma cells that can shape the disease phenotype, thereby generating further inter-patient variability. This model may be a useful tool for improving our understanding of disease biology and the response to chemotherapy regimens. Clin Cancer Res; 22(16); 4206-14. ©2016 AACR.
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Tang
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Takeda Pharmaceuticals, Inc., Cambridge, MA.
authors.forename: Helgi
authors.initials: H
authors.lastname: van de Velde
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.|Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA 02115, USA.
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Tross
authors.affiliation: Dana-Farber Cancer Institute, Boston, USA.
authors.forename: Constantine
authors.initials: C
authors.lastname: Mitsiades
authors.affiliation: Oncology R&D, Janssen Research & Development LLC, Raritan, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Viselli
authors.affiliation: Takeda Pharmaceuticals, Inc., Cambridge, MA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Neuwirth
authors.affiliation: Takeda Pharmaceuticals, Inc., Cambridge, MA.
authors.forename: Dixie-Lee
authors.initials: DL
authors.lastname: Esseltine
authors.affiliation: Dana-Farber Cancer Institute, Boston, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Anderson
authors.affiliation: Dana-Farber Cancer Institute, Boston, USA.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
authors.affiliation: Hospital Universitario Salamanca, CIC, IBMCC (USAL-CSIC), Salamanca, Spain.
authors.forename: Jesús F
authors.initials: JF
authors.lastname: San Miguel
authors.affiliation: Dana-Farber Cancer Institute, Boston, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.affiliation: Division of Oncology, School of Medicine, Washington University in St. Louis.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Tomasson
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Franziska
authors.initials: F
authors.lastname: Michor
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D002986:Clinical Trials as Topic; D060965:Clonal Evolution / Q000235:genetics; D006801:Humans; D015233:Models, Statistical; D008962:Models, Theoretical; D009101:Multiple Myeloma / Q000209:etiology* / Q000473:pathology* / Q000628:therapy; D015203:Reproducibility of Results