Investigation of a gene signature to predict response to immunomodulatory derivatives for patients with multiple myeloma: an exploratory, retrospective study using microarray datasets from prospective clinical trials
Investigation of a gene signature to predict response to immunomodulatory derivatives for patients with multiple myeloma: an exploratory, retrospective study using microarray datasets from prospective clinical trials
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DOI：
10.1016/s2352-3026(17)30143-6
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发表时间：
2017-09-01
影响因子：
24.7
通讯作者：
Usmani, Saad Z.
中科院分区：
文献类型：
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作者：
Bhutani, Manisha;Zhang, Qing;Usmani, Saad Z.
背景免疫调节衍生物(IMids)和蛋白酶体抑制剂是多发性骨髓瘤治疗方案的关键组成部分。尽管如此，结果在接受治疗的个人中有所不同。药物特异性基因表达谱(GEP)签名有助于预测有利和不利的结果，可以为患者提供针对其个别疾病的最有效的治疗方法。我们的目标是开发和验证一个基因表达特征，以表明哪些患者将从基于IMID的治疗中受益最多。方法在这项探索性的回顾研究中，我们选择了一组在临床试验中接受含IMID方案治疗的初诊或复发或难治性多发性骨髓瘤患者。如果队列有来自患者骨髓浆细胞的公开GEP数据，并有长期随访和临床病理数据，则符合条件。在模型的发展阶段，我们利用药物基因组GEP数据鉴定了176个在IMiD暴露前后差异表达的IMiD反应基因，这些患者在接受沙利度胺(n=42)、来那度胺(n=18)或泊马度胺(n=18)试验剂量暴露前和48小时后采集了骨髓样本。在全面治疗(TT)2试验(即训练队列)中，在接受沙利度胺诱导和维持治疗的患者中，其中14个基因的p值低于0.05。我们将这14个基因组合在一起，创造了一个连续的IMIDD-14评分和一个最佳的分界值。IMIDD-14得分高于临界值的亚组被认为是IMIDD抵抗组。我们从四项IMID联合方案研究中获得了验证队列：TT3a试验(沙利度胺诱导和维持)，TT3b试验(沙利度胺诱导和来那度胺维持)，TT6试验(沙利度胺诱导和来那度胺维持)，HOVON65/GMMG-HD4试验的长春新碱、阿霉素和地塞米松(VAD)组(维持沙利度胺)。主要终点是显示IMID-14基因标记对无进展生存的预后价值。在训练队列中发现，83名IMID-14高分患者的无进展生存显著短于92名IMID-14低分患者；3年无进展生存率在IMID-14高分组为52%(95%CI 42-)，而在IMID-14低分组为85%(78-92)，风险比(HR)为2.51(95%可信区间1.72-3.66；p
Background Immunomodulatory derivatives (IMiDs), along with proteasome inhibitors, are key components of treatment regimens for multiple myeloma. Nonetheless, outcomes vary among treated individuals. Drug-specific gene-expression profile (GEP) signatures that aid the prediction of favourable and unfavourable outcomes can provide patients with the most effective therapy for their individual disease. We aimed to develop and validate a gene expression signature to suggest which patients would benefit most from IMiD-based therapies.Methods For this exploratory retrospective study, we selected a cohort of patients with newly diagnosed or relapsed or refractory multiple myeloma who were treated in clinical trials with IMiD-containing regimens. Cohorts were eligible if they had publicly available GEP data from patients' bone marrow plasma cells, with long-term follow-up and clinicopathological data. In the development stage of the model, we identified 176 IMiD response genes that were differentially expressed before and after IMiD exposure using pharmacogenomic GEP data from patients who had bone marrow samples taken before and 48 h after a test dose exposure with thalidomide (n=42), lenalidomide (n=18), or pomalidomide (n=18). 14 of these genes had p values less than 0.05 for associations with progression-free survival in patients who received thalidomide in induction and maintenance therapy in the Total Therapy (TT) 2 trial (ie, the training cohort). We combined the 14 genes to create a continuous IMiD-14 score and an optimal cutoff. The subgroup with an IMiD-14 score higher than the cutoff was deemed to be IMiD-resistant. We obtained validation cohorts from four studies of IMiD combination regimens: the TT3a trial (thalidomide in induction and maintenance), the TT3b trial (thalidomide in induction and lenalidomide in maintenance), the TT6 trial (thalidomide in induction and lenalidomide in maintenance), and the vincristine, doxorubicin, and dexamethasone (VAD) group of the HOVON65/GMMG-HD4 trial (thalidomide in maintenance). The primary endpoint was to show the prognostic value of the IMiD-14 gene signature for progression-free survival.Findings In the training cohort, progression-free survival was significantly shorter in the 83 patients with IMiD-14 high scores than in the 92 patients with IMiD-14 low scores; 3 year progression-free survival was 52% (95% CI 42-64) for the IMiD-14 high group versus 85% (78-92) for the IMiD-14 low group, with a hazard ratio (HR) of 2.51 (95% CI 1.72-3.66; p