PURPOSE: Early intervention for High-Risk Smoldering Multiple Myeloma (HR-SMM) achieves deep and prolonged responses. It is unclear if beneficial outcomes are due to treatment of less complex, susceptible disease or inaccuracy in clinical definition of cases entered. EXPERIMENTAL DESIGN: Here, we interrogated whole genome and whole exome sequencing for 54 patients across two HR-SMM interventional studies (NCT01572480, NCT02279394). RESULTS: We reveal that the genomic landscape of treated HR-SMM is generally simple as compared to Newly Diagnosed (ND)MM counterparts with less inactivation of tumor suppressor genes, RAS pathway mutations, MYC disruption, and APOBEC contribution. The absence of these events parallels that of indolent precursor conditions, possibly explaining overall excellent outcomes. However, some patients harboring genomic complexity fail to sustain response and experience resistant, progressive disease. Overall, clinical risk scores do not effectively discriminate between genomically indolent and aggressive disease. CONCLUSIONS: Genomic profiling can contextualize the advantage of early intervention in SMM and guide personalization of therapy.

中文翻译：

---

基因组分析以了解闷烧型多发性骨髓瘤干预结果

目的：对高风险冒烟型多发性骨髓瘤 (HR-SMM) 进行早期干预可实现深度和持久的缓解。目前尚不清楚有益的结果是否是由于治疗不太复杂、易受影响的疾病或输入病例的临床定义不准确所致。实验设计：在这里，我们对两项 HR-SMM 介入研究（NCT01572480、NCT02279394）中的 54 名患者进行了全基因组和全外显子组测序。结果：我们发现，与新诊断 (ND)MM 对应物相比，经过治疗的 HR-SMM 的基因组图谱通常比较简单，肿瘤抑制基因失活、RAS 通路突变、MYC 破坏和 APOBEC 贡献较少。这些事件的缺乏与惰性先兆条件相似，这可能解释了整体良好的结果。然而，一些基因组复杂的患者无法维持反应并出现耐药性、进展性疾病。总体而言，临床风险评分不能有效地区分基因组惰性疾病和侵袭性疾病。结论：基因组分析可以体现 SMM 早期干预的优势并指导个性化治疗。