Phenotype-structured model of intra-clonal heterogeneity and drug resistance in multiple myeloma

Abstract

Multiple myeloma (MM) is a genetically complex hematological cancer characterized by the abnormal proliferation of malignant plasma cells in the bone marrow. This disease progresses from a premalignant condition known as monoclonal gammopathy of unknown significance (MGUS) through sequential genetic alterations involving various genes. These genetic changes contribute to the uncontrolled growth of multiple clones of plasma cells. In this study, we present a phenotype-structured model that captures the intra-clonal heterogeneity and drug resistance in multiple myeloma (MM). The model accurately reproduces the branching evolutionary pattern observed in MM progression, aligning with a previously developed multiscale model. Numerical simulations reveal that higher mutation rates enhance tumor phenotype diversity, while access to growth factors accelerates tumor evolution and increases its final size. Interestingly, the model suggests that further increasing growth factor access primarily amplifies tumor size rather than altering clonal dynamics. Additionally, the model emphasizes that higher mutation frequencies and growth factor availability elevate the chances of drug resistance and relapse. It indicates that the timing of the treatment could trajectory of tumor evolution and clonal emergence in the case of branching evolutionary pattern. Given its low computational cost, our model is well-suited for quantitative studies on MM clonal heterogeneity and its interaction with chemotherapeutic treatments.

Keywords: Chemotherapy; Clone emergence; Continuum modeling; IRF4; RAS mutations.