多发性骨髓瘤（MM）是一种遗传复杂的血液癌症，其特征是骨髓中恶性浆细胞的异常增殖。这种疾病是从一种被称为意义不明的单克隆丙种球蛋白病 (MGUS) 的癌前病症，通过涉及各种基因的连续遗传改变而发展而来。这些基因变化导致浆细胞多个克隆的不受控制的生长。在这项研究中，我们提出了一个表型结构模型，该模型捕捉多发性骨髓瘤（MM）的克隆内异质性和耐药性。该模型准确地再现了 MM 进展中观察到的分支进化模式，与之前开发的多尺度模型保持一致。数值模拟表明，较高的突变率会增强肿瘤表型多样性，而获得生长因子会加速肿瘤的进化并增加其最终大小。有趣的是，该模型表明，进一步增加生长因子的获取主要会放大肿瘤大小，而不是改变克隆动态。此外，该模型强调较高的突变频率和生长因子可用性会增加耐药性和复发的机会。这表明在分支进化模式的情况下，治疗时机可以影响肿瘤进化和克隆出现的轨迹。鉴于计算成本较低，我们的模型非常适合对 MM 克隆异质性及其与化疗治疗的相互作用进行定量研究。版权所有 © 2023。由 Elsevier Ltd 出版。

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.Copyright © 2023. Published by Elsevier Ltd.