RNA-Seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature

Improving outcomes in multiple myeloma will not only involve development of new therapies, but better use of existing treatments. We performed RNA sequencing (RNA-Seq) on samples from newly diagnosed patients enrolled into the phase II PADIMAC study. Using an empirical Bayes approach and synthetic annealing, we developed and trained a seven-gene signature to predict treatment outcome. We tested the signature on independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass dataset, patients who were treated correctly according to the signature had a better progression-free and overall survival than those who were not. Indeed, the outcome for these correctly treated patients was non-inferior to those treated with combined bortezomib, lenalidomide, and dexamethasone (VRD). PADIMAC: Bortezomib, Adriamycin and Dexamethasone (PAD) therapy for previously untreated patients with multiple myeloma: Impact of minimal residual disease (MRD) in patients with deferred ASCT (autologous stem cell transplant) Overall design: RNA-Seq data from 44 patients enrolled into the PADIMAC study who provided RNA with an RNA Integrity score of 6 or greater. Thirteen out of forty-four patients had at least a very good partial remission sustained for at least a year without progression and were labelled as "bortezomib-good".改善多发性骨髓瘤（multiple myeloma）的临床结局，不仅有赖于新型治疗手段的开发，更需优化现有疗法的临床应用。本研究对纳入II期PADIMAC临床试验的初诊患者样本开展了RNA测序（RNA-Seq）。采用经验贝叶斯（empirical Bayes）方法与合成退火技术，本研究开发并训练了一套七基因特征集以预测治疗结局。随后，本研究在接受硼替佐米（bortezomib）与来那度胺（lenalidomide）为基础疗法的独立验证队列中对该特征集进行了验证。该特征集可有效区分不同患者对不同治疗方案的响应优劣。在CoMMpass数据集（CoMMpass dataset）中，按该特征集精准施治的患者，其无进展生存期与总生存期均优于未按此方案治疗的患者。进一步分析显示，此类精准治疗患者的临床结局不劣于接受硼替佐米、来那度胺与地塞米松联合疗法（VRD）的患者。PADIMAC研究：针对初诊多发性骨髓瘤患者的硼替佐米、多柔比星（Adriamycin）与地塞米松（PAD）疗法，以及延迟自体造血干细胞移植（autologous stem cell transplant, ASCT）患者的微小残留病（minimal residual disease, MRD）影响。研究整体设计：纳入PADIMAC研究的44名患者的RNA测序数据，所有患者的RNA完整性评分均不低于6分。44名患者中，13名实现了至少持续1年的非常好的部分缓解且未发生疾病进展，被标记为"bortezomib-good"。