Lefevre James G, Lawson Brodie A J, Burrage Pamela M, Donovan Diane M, Burrage Kevin
School of Mathematics and Physics, The University of Queensland, Brisbane, Queensland, Australia.
ARC Centre of Excellence, Plant Success in Nature and Agriculture, St. Lucia, Queensland, Australia.
PLoS Comput Biol. 2025 Aug 11;21(8):e1012225. doi: 10.1371/journal.pcbi.1012225. eCollection 2025 Aug.
Multiple myeloma (MM) is a plasma cell cancer that occurs in the bone marrow. A leading treatment for MM is the monoclonal antibody Daratumumab, targeting the CD38 receptor, which is highly overexpressed in myeloma cells. In this work we model drug resistance via loss of CD38 expression, which is a proposed mechanism of resistance to Daratumumab treatment. We develop an ODE model that includes drug resistance via two mechanisms: a direct effect in which CD38 expression is lost without cell death in response to Daratumumab, and an indirect effect in which CD38 expression switches on and off in the cancer cells; myeloma cells that do not express CD38 have lower fitness but are shielded from the drug action. The model also incorporates competition with healthy cells, death of healthy cells due to off-target drug effects, and a Michaelis-Menten type immune response. Using optimal control theory, we study the effect of the drug resistance mechanisms and the off-target drug effect on the optimal treatment regime. We identify a general increase in the duration and costs of optimal treatment, as a result of these added mechanisms. Several distinct optimal treatment regimes are identified within the parameter space.
多发性骨髓瘤（MM）是一种发生于骨髓的浆细胞癌。MM的一种主要治疗方法是单克隆抗体达雷妥尤单抗，它靶向CD38受体，该受体在骨髓瘤细胞中高度过表达。在这项研究中，我们通过CD38表达缺失来模拟耐药性，这是一种对达雷妥尤单抗治疗耐药的推测机制。我们开发了一个常微分方程模型，该模型通过两种机制体现耐药性：一种直接效应是，在达雷妥尤单抗作用下，CD38表达缺失但细胞不死；另一种间接效应是，癌细胞中CD38表达开启和关闭；不表达CD38的骨髓瘤细胞适应性较低，但能免受药物作用。该模型还纳入了与健康细胞的竞争、脱靶药物效应导致的健康细胞死亡以及米氏型免疫反应。利用最优控制理论，我们研究了耐药机制和脱靶药物效应对最优治疗方案的影响。由于这些附加机制，我们发现最优治疗的持续时间和成本普遍增加。在参数空间内确定了几种不同的最优治疗方案。
