Institut Camille Jordan, UMR 5208 CNRS, University Lyon 1, Villeurbanne, 69622, France.
Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Am J Hematol. 2016 Jun;91(4):371-8. doi: 10.1002/ajh.24291. Epub 2016 Feb 9.
Multiple myeloma (MM) infiltrates bone marrow and causes anemia by disrupting erythropoiesis, but the effects of marrow infiltration on anemia are difficult to quantify. Marrow biopsies of newly diagnosed MM patients were analyzed before and after four 28-day cycles of non-erythrotoxic remission induction chemotherapy. Complete blood cell counts and serum paraprotein concentrations were measured at diagnosis and before each chemotherapy cycle. At diagnosis, marrow area infiltrated by myeloma correlated negatively with hemoglobin, erythrocytes, and marrow erythroid cells. After successful chemotherapy, patients with less than 30% myeloma infiltration at diagnosis had no change in these parameters, whereas patients with more than 30% myeloma infiltration at diagnosis increased all three parameters. Clinical data were used to develop mathematical models of the effects of myeloma infiltration on the marrow niches of terminal erythropoiesis, the erythroblastic islands (EBIs). A hybrid discrete-continuous model of erythropoiesis based on EBI structure/function was extended to sections of marrow containing multiple EBIs. In the model, myeloma cells can kill erythroid cells by physically destroying EBIs and by producing proapoptotic cytokines. Following chemotherapy, changes in serum paraproteins as measures of myeloma cells and changes in erythrocyte numbers as measures of marrow erythroid cells allowed modeling of myeloma cell death and erythroid cell recovery, respectively. Simulations of marrow infiltration by myeloma and treatment with non-erythrotoxic chemotherapy demonstrate that myeloma-mediated destruction and subsequent reestablishment of EBIs and expansion of erythroid cell populations in EBIs following chemotherapy provide explanations for anemia development and its therapy-mediated recovery in MM patients.
多发性骨髓瘤（MM）浸润骨髓并通过破坏红细胞生成导致贫血，但骨髓浸润对贫血的影响难以量化。对新诊断的 MM 患者进行了四个 28 天非致红细胞毒性缓解诱导化疗周期前后的骨髓活检。在诊断时和每个化疗周期前测量全血细胞计数和血清副蛋白浓度。在诊断时，骨髓瘤浸润的骨髓面积与血红蛋白、红细胞和骨髓红系细胞呈负相关。在成功化疗后，诊断时骨髓瘤浸润少于 30%的患者这些参数没有变化，而诊断时骨髓瘤浸润超过 30%的患者则增加了这三个参数。临床数据用于开发骨髓瘤浸润对终末红细胞生成骨髓龛、成红细胞岛（EBIs）的影响的数学模型。基于 EBI 结构/功能的红细胞生成混合离散连续模型扩展到包含多个 EBIs 的骨髓切片。在该模型中，骨髓瘤细胞可以通过物理破坏 EBIs 和产生促凋亡细胞因子来杀死红细胞。化疗后，血清副蛋白的变化作为骨髓瘤细胞的量度，红细胞数量的变化作为骨髓红细胞的量度，分别允许对骨髓瘤细胞死亡和红细胞恢复进行建模。骨髓瘤浸润和非致红细胞毒性化疗的模拟表明，骨髓瘤介导的 EBIs 破坏及其随后的重建以及化疗后 EBIs 中红细胞群体的扩张，为 MM 患者贫血的发生及其治疗介导的恢复提供了解释。
