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Abstract：
Smoldering multiple myeloma (SMM) precedes multiple myeloma (MM). The risk of progression of SMM patients is not uniform, thus different progression-risk models have been developed, although they are mainly based on clinical parameters. Recently, genomic predictors of progression have been defined for untreated SMM. However, the usefulness of such markers in the context of clinical trials evaluating upfront treatment in high-risk SMM (HR SMM) has not been explored yet, precluding the identification of baseline genomic alterations leading to drug resistance. For this reason, we carried out next-generation sequencing and fluorescent in-situ hybridization studies on 57 HR and ultra-high risk (UHR) SMM patients treated in the phase II GEM-CESAR clinical trial (NCT02415413). DIS3, FAM46C, and FGFR3 mutations, as well as t(4;14) and 1q alterations, were enriched in HR SMM. TRAF3 mutations were specifically associated with UHR SMM but identified cases with improved outcomes. Importantly, novel potential predictors of treatment resistance were identified: NRAS mutations and the co-occurrence of t(4;14) plus FGFR3 mutations were associated with an increased risk of biological progression. In conclusion, we have carried out for the first time a molecular characterization of HR SMM patients treated with an intensive regimen, identifying genomic predictors of poor outcomes in this setting.
摘要：
阴燃多发性骨髓瘤（SMM）先于多发性骨髓瘤（MM）。SMM患者的进展风险并不一致，因此，已经开发了不同的进展风险模型，尽管它们主要基于临床参数。最近,已经为未经治疗的SMM定义了进展的基因组预测因子。然而,这些标志物在评估高风险SMM(HRSMM)前期治疗的临床试验中的有用性尚未得到探索，排除了导致耐药性的基线基因组改变的鉴定。出于这个原因,我们对在GEM-CESARII期临床试验(NCT02415413)中接受治疗的57例HR和超高危(UHR)SMM患者进行了下一代测序和荧光原位杂交研究.DIS3,FAM46C,和FGFR3突变，以及t(4;14)和1q变化，丰富了HRSMM。TRAF3突变与UHRSMM特异性相关，但确定了结果改善的病例。重要的是,我们发现了新的治疗耐药的潜在预测因子:NRAS突变和t(4;14)+FGFR3突变的同时出现与生物学进展风险增加相关.总之,我们首次对强化方案治疗的HRSMM患者进行了分子表征，在这种情况下，确定不良结果的基因组预测因子。
