Multiple myeloma (MM) is an acquired malignant plasma cell disorder that develops late in life. Although progression free and overall survival has improved across all age, race, and ethnic groups, a subset of patients have suboptimal outcomes and are labeled as having high risk disease. A uniform approach to risk in NDMM remains elusive despite several validated risk stratification systems in clinical use. While we attempt to capture risk at diagnosis, the reality is that many important prognostic characteristics remain ill-defined as some patients relapse early who were defined as low risk based on their genomic profile at diagnosis. It is critical to establish a definition of high risk disease in order to move towards risk-adapted treatment approaches. Defining risk at diagnosis is important to both effectively design future clinical trials and guide which clinical data is needed in routine practice. The goal of this review paper is to summarize and compare the various established risk stratification systems, go beyond the R-ISS and international myeloma working group risk stratifications to evaluate specific molecular and cytogenetic abnormalities and how they impact prognosis independently. In addition, we explore the wealth of new genomic information from recent whole genome/exome sequencing as well as gene expression data and review known clinical factors affecting outcome such as disease burden and early relapse as well as patient related factors such as race. Finally, we provide an outlook on developing a new high risk model system and how we might make sense of co-occurrences, oncogenic dependencies, and mutually exclusive mutations.
多发性骨髓瘤是一种获得性恶性浆细胞疾病，发病于生命晚期。尽管各年龄、种族和民族群体的无进展生存期和总生存期均有所改善，但仍有部分患者治疗效果欠佳，被归类为高危疾病。目前临床上虽有多个经过验证的风险分层系统，但针对新诊断多发性骨髓瘤仍缺乏统一的风险评估方法。虽然我们试图在诊断时评估风险，但现实是许多重要预后特征仍不明确——部分根据诊断时基因组谱定义为低危的患者仍会早期复发。确立高危疾病的定义对于推进风险适应性治疗方案至关重要。明确诊断时的风险分级对有效设计未来临床试验、指导临床实践所需数据收集具有重要意义。本综述旨在总结比较现有风险分层系统，超越R-ISS和国际骨髓瘤工作组的分层标准，评估特定分子与细胞遗传学异常及其对预后的独立影响。同时，我们探讨了近期全基因组/外显子组测序产生的大量新基因组信息及基因表达数据，并回顾了影响预后的已知临床因素（如疾病负荷与早期复发）和患者相关因素（如种族）。最后，我们对开发新型高危模型系统提出展望，探讨如何解析基因共现现象、致癌依赖性及互斥性突变。
High-risk disease in newly diagnosed multiple myeloma: beyond the R-ISS and IMWG definitions
肿瘤(癌症)患者之家