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Clin Cancer Res. 2016 Aug 15;22(16):4206-4214. doi: 10.1158/1078-0432.CCR-15-2793. Epub 2016 Mar 22.

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

Author information

1
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.
2
Takeda Pharmaceuticals, Inc., Cambridge, MA.
3
Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA 02115, USA.
4
Dana-Farber Cancer Institute, Boston, USA.
5
Oncology R&D, Janssen Research & Development LLC, Raritan, USA.
6
Hospital Universitario Salamanca, CIC, IBMCC (USAL-CSIC), Salamanca, Spain.
7
Division of Oncology, School of Medicine, Washington University in St. Louis.
#
Contributed equally

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

PMID:
27006493
PMCID:
PMC4987182
DOI:
10.1158/1078-0432.CCR-15-2793
[Indexed for MEDLINE]
Free PMC Article

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