Supplementary Table S1. Summary statistics of the estimated slopes and turning points for the model fitting of the six cohorts from the three trials. Supplementary Table S2. Information on the number of data points in the pre-treatment phase, phase during administration of therapy, and posttreatment phase. Supplementary Table S3. Summary statistics of slopes and turning points for the treatment response data of the VISTA, MMY-2001, and APEX trials. Supplementary Table S4. Dependence of MM stage, prior administration of steroids, and the best-fitting model. Supplementary Table S5. Counts of death for single-phasic and 2-phasic patients as well as different sub-cohorts based on modeling parameters in the VISTA MP and VISTA VMP cohort during treatment. Supplementary Table S6. Summary statistics of the day differences between scheduled and actual visit dates for during-treatment response data for the VISTA MP and VISTA VMP cohort. Supplementary Table S7. Parameter values used for the hybrid mathematical model for all three cohorts.
ARTICLE 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.
