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.
冒烟型多发性骨髓瘤（SMM）是多发性骨髓瘤（MM）的前期阶段。SMM患者的进展风险并不一致，因此已开发出不同的进展风险模型，尽管这些模型主要基于临床参数。最近，针对未经治疗的SMM，已确定了一些基因组进展预测因子。然而，在评估高危SMM（HR SMM）前期治疗的临床试验背景下，这些标志物的应用价值尚未得到探索，导致无法识别导致耐药性的基线基因组改变。为此，我们对参与II期GEM-CESAR临床试验（NCT02415413）的57例高危和超高危（UHR）SMM患者进行了下一代测序和荧光原位杂交研究。研究发现，高危SMM患者中DIS3、FAM46C和FGFR3突变，以及t(4;14)和1q改变较为常见。TRAF3突变与超高危SMM特异性相关，但部分携带该突变的病例预后较好。重要的是，研究还发现了新的潜在治疗耐药预测因子：NRAS突变以及t(4;14)合并FGFR3突变与生物学进展风险增加相关。总之，本研究首次对接受强化方案治疗的高危SMM患者进行了分子特征分析，确定了在此类患者中预后不良的基因组预测因子。
肿瘤(癌症)患者之家