直到现在,下一代测序(NGS)数据尚未纳入多发性骨髓瘤(MM)的任何预后分层中,也没有基于该数据的治疗考虑.在这项工作中,我们将NGS数据与(1)新诊断的多发性骨髓瘤的治疗反应和生存参数相关联,通过VRd*治疗和(2)MM疾病阶段:新诊断的多发性骨髓瘤(ndMM)与复发和/或难治性(复发/难治性多发性骨髓瘤)。我们分析了126名患者,伴有ndMM和复发性难治性多发性骨髓瘤(rrMM),在伯尔尼大学医院(Inselspital)接受治疗。对骨髓进行下一代测序,作为常规诊断的一部分。NGS面板包含八个基因CCND1,DIS3,EGR1,FAM46C(TENT5C),FGFR3,PRDM1,TP53,TRAF3和BRAF中的七个热点,IDH1,IDH2,IRF4,KRAS,NRAS.主要终点是ndMMVRd后完全缓解(CR),与突变谱相关。rrMM中的突变负荷普遍较高,更频繁地突变TP53:ndMM中的11/87(13%)与rrMM中的9/11(81%)(OR0.0857,p=0.0007)。在ndMM中,经VRd处理,MAPK通路成员中的突变(NRAS,KRAS或BRAF)与CR概率降低相关(21/38,55%),与野生型NRAS相比,KRAS或BRAF(34/40,85%;OR0.2225,p=0.006)。NRASc.181C>A(p。Q61K)作为单个突变事件显示出达到CR的概率降低的趋势(OR0.0912,p=0.0247)。通过突变的NRAS激活MAPK通路,KRAS和BRAF基因似乎对接受VRd治疗的ndMM患者的预后有负面影响。VRd*-硼替佐米(Velcade®),来那度胺(Revlimid®)和地塞米松。
Until now, next generation sequencing (NGS) data has not been incorporated into any prognostic stratification of multiple myeloma (MM) and no therapeutic considerations are based upon it. In this work, we correlated NGS data with (1) therapy response and survival parameters in newly diagnosed multiple myeloma, treated by VRd * and (2) MM disease stage: newly diagnosed multiple myeloma (ndMM) versus relapsed and/or refractory (relapsed/refractory multiple myeloma). We analyzed 126 patients, with ndMM and relapsed refractory multiple myeloma (rrMM), treated at the University Hospital of Bern (Inselspital). Next generation sequencing was performed on bone marrow, as part of routine diagnostics. The NGS panel comprised eight genes CCND1, DIS3, EGR1, FAM46C (TENT5C), FGFR3, PRDM1, TP53, TRAF3 and seven hotspots in BRAF, IDH1, IDH2, IRF4, KRAS, NRAS. The primary endpoint was complete remission (CR) after VRd in ndMM, in correlation with mutational profile. Mutational load was generally higher in rrMM, with more frequently mutated TP53: 11/87 (13%) in ndMM versus 9/11 (81%) in rrMM (OR 0.0857, p = 0.0007). In ndMM, treated by VRd, mutations in MAPK-pathway members (NRAS, KRAS or BRAF) were associated with reduced probability of CR (21/38, 55%), as compared with wild type NRAS, KRAS or BRAF (34/40, 85%; OR 0.2225, p = 0.006). NRAS c.181C > A (p.Q61K) as a single mutation event showed a trend to reduced probability of achieving CR (OR 0.0912, p = 0.0247). Activation of MAPK pathway via mutated NRAS, KRAS and BRAF genes seems to have a negative impact on outcome in ndMM patients receiving VRd therapy. VRd* - bortezomib (Velcade®), lenalidomide (Revlimid®) and dexamethasone.