Logo image
Back
Myeloma Cell Dynamics in Response to Treatment Supports a Model of Hierarchical Differentiation and Clonal Evolution
Journal article   Open access   Peer reviewed

Myeloma Cell Dynamics in Response to Treatment Supports a Model of Hierarchical Differentiation and Clonal Evolution

Min Tang, Rui Zhao, Helgi van de Velde, Jennifer G Tross, Constantine Mitsiades, Suzanne Viselli, Rachel Neuwirth, Dixie-Lee Esseltine, Kenneth Anderson, Irene M Ghobrial, …
Clinical cancer research, Vol.22(16), pp.4206-4214
08/15/2016
DOI: 10.1158/1078-0432.CCR-15-2793
PMCID: PMC4987182
PMID: 27006493
url
https://doi.org/10.1158/1078-0432.CCR-15-2793View
Published (Version of record) Open Access

Abstract

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. 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. 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. 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.
 Cell Differentiation - genetics Clinical Trials as Topic Clonal Evolution - genetics Humans Models, Statistical Models, Theoretical Multiple Myeloma - etiology Multiple Myeloma - pathology Multiple Myeloma - therapy Reproducibility of Results

Details

Metrics

22 Record Views
22 Times Cited - Web of Science
Logo image