Hematology Department, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca, Salamanca, Spain.
Cancer Research Center, Institute of Cancer Molecular and Cellular Biology, University of Salamanca-National Research Council (USAL-CSIC), Salamanca, Spain.
Blood Adv. 2020 Dec 8;4(23):6023-6033. doi: 10.1182/bloodadvances.2020002711.
The search for biomarkers based on the mechanism of drug action has not been thoroughly addressed in the therapeutic approaches to multiple myeloma (MM), mainly because of the difficulty in analyzing proteins obtained from purified plasma cells. Here, we investigated the prognostic impact of the expression of 12 proteins involved in the mechanism of action of bortezomib, lenalidomide, and dexamethasone (VRD), quantified by capillary nanoimmunoassay, in CD138-purified samples from 174 patients with newly diagnosed MM treated according to the PETHEMA/GEM2012 study. A high level of expression of 3 out of 5 proteasome components tested (PSMD1, PSMD4, and PSMD10) negatively influenced survival. The 5 analyzed proteins involved in lenalidomide's mode of action were associated with time to progression (TTP); low levels of cereblon and IRF4 protein and high levels of Ikaros, AGO2, and Aiolos were significantly associated with shorter TTP. Although the glucocorticoid receptor (GCR) level by itself had no significant impact on MM prognosis, a high XPO1 (exportin 1)/GCR ratio was associated with shorter TTP and progression-free survival (PFS). The multivariate Cox model identified high levels of PSMD10 (hazard ratio [HR] TTP, 3.49; P = .036; HR PFS, 5.33; P = .004) and Ikaros (HR TTP, 3.01, P = .014; HR PFS, 2.57; P = .028), and low levels of IRF4 protein expression (HR TTP, 0.33; P = .004; HR PFS, 0.35; P = .004) along with high-risk cytogenetics (HR TTP, 3.13; P < .001; HR PFS, 2.69; P = .002), as independently associated with shorter TTP and PFS. These results highlight the value of assessing proteins related to the mechanism of action of drugs used in MM for predicting treatment outcome.
基于药物作用机制寻找生物标志物在多发性骨髓瘤（MM）的治疗方法中尚未得到彻底解决，主要是因为难以分析从纯化浆细胞中获得的蛋白质。在这里，我们通过毛细管纳米免疫分析研究了 174 例根据 PETHEMA/GEM2012 研究接受治疗的新诊断 MM 患者的 CD138 纯化样本中，12 种与硼替佐米、来那度胺和地塞米松（VRD）作用机制相关的蛋白的表达水平对预后的影响。在测试的 5 种蛋白酶体成分中有 3 种（PSMD1、PSMD4 和 PSMD10）的高表达水平会对生存产生负面影响。参与来那度胺作用模式的 5 种分析蛋白与进展时间（TTP）相关；低水平的 cereblon 和 IRF4 蛋白以及高水平的 Ikaros、AGO2 和 Aiolos 与较短的 TTP 显著相关。尽管糖皮质激素受体（GCR）水平本身对 MM 预后没有显著影响，但高 XPO1（exportin 1）/GCR 比值与较短的 TTP 和无进展生存期（PFS）相关。多变量 Cox 模型确定高水平的 PSMD10（TTP 的危险比 [HR]，3.49；P =.036；PFS 的 HR，5.33；P =.004）和 Ikaros（TTP 的 HR，3.01，P =.014；PFS 的 HR，2.57；P =.028）以及低水平的 IRF4 蛋白表达（TTP 的 HR，0.33；P =.004；PFS 的 HR，0.35；P =.004）以及高危细胞遗传学（TTP 的 HR，3.13；P <.001；PFS 的 HR，2.69；P =.002）与较短的 TTP 和 PFS 独立相关。这些结果突出了评估与 MM 中使用的药物作用机制相关的蛋白以预测治疗结果的价值。
