Supplementary Figure S1. Demonstration of exponential curves and corresponding linear curves after log-transforming the original data. Supplementary Figure S2. Baseline values for the analysis of disease dynamics during treatment. Supplementary Figure S3. Histograms of the days from treatment cessation until rebound for patients in the VISTA and APEX trials when defining rebound as any value {greater than or equal to} 20% pre-treatment baseline. Supplementary Figure S4. Histograms of the days from treatment cessation until rebound for patients in the VISTA and APEX trials when defining rebound as any value {greater than or equal to} pre-treatment baseline. Supplementary Figure S5. Histograms of the days from treatment cessation until rebound for patients in the VISTA MP and VISTA VMP cohorts when defining rebound as any value {greater than or equal to} 120% pre-treatment baseline. Supplementary Figure S6. Histogram of the deviation between scheduled visit and real visit dates during the trial. Supplementary Figure S7. The predictions of the differentiation hierarchy model of MM. Supplementary Figure S8. Nine representative examples of predictions of the clonal evolution model of MM. Supplementary Figure S9. Early M-protein rebound for the refractory patients in the VISTA and APEX trials.
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.
