PURPOSE Copy-number changes and translocations have been studied extensively in many datasets with long-term follow-up. The impact of mutations remains debated given the short time to follow-up of most datasets. EXPERIMENTAL DESIGN We performed targeted panel sequencing covering 125 myeloma-specific genes and the loci involved in translocations in 223 newly diagnosed myeloma samples recruited into one of the total therapy trials. RESULTS As expected, the most commonly mutated genes were NRAS, KRAS, and BRAF, making up 44% of patients. Double-Hit and BRAF and DIS3 mutations had an impact on outcome alongside classical risk factors in the context of an intensive treatment approach. We were able to identify both V600E and non-V600E BRAF mutations, 58% of which were predicted to be hypoactive or kinase dead. Interestingly, 44% of the hypoactive/kinase dead BRAF-mutated patients showed co-occurring alterations in KRAS, NRAS, or activating BRAF mutations, suggesting that they play a role in the oncogenesis of multiple myeloma by facilitating MAPK activation and may lead to chemoresistance. CONCLUSIONS Overall, these data highlight the importance of mutational screening to better understand newly diagnosed multiple myeloma and may lead to patient-specific mutation-driven treatment approaches.

中文翻译：

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在多发性骨髓瘤患者的长期随访中，BRAF和DIS3突变与不良结果相关。

目的拷贝数变化和易位已在许多数据集中进行了长期跟踪研究。鉴于大多数数据集的随访时间较短，因此突变的影响仍存在争议。实验设计我们进行了针对性的小组测序，涉及125个骨髓瘤特异性基因，以及参与一项总疗法试验的223个新诊断的骨髓瘤样品中涉及易位的基因座。结果正如预期的那样，最常见的突变基因是NRAS，KRAS和BRAF，占患者的44％。在强化治疗方法的背景下，Double-Hit和BRAF和DIS3突变与经典危险因素一起对结果产生影响。我们能够鉴定出V600E和非V600E的BRAF突变，其中58％的突变被预测为活性不足或激酶死亡。有趣的是 缺乏活力/激酶的死BRAF突变患者中有44％的人同时出现KRAS，NRAS或激活的BRAF突变，表明他们通过促进MAPK激活在多发性骨髓瘤的发生中发挥作用，并可能导致化学耐药性。结论总体而言，这些数据突出了突变筛查对更好地了解新诊断的多发性骨髓瘤的重要性，并可能导致患者特异性的突变驱动治疗方法。