The outcomes for the majority of patients with myeloma have improved over recent decades, driven by treatment advances. However, there is a subset of patients considered to have high-risk disease who have not benefited. Understanding how high-risk disease evolves from more therapeutically tractable stages is crucial if we are to improve outcomes. This can be accomplished by identifying the genetic mechanisms and mutations driving the transition of a normal plasma cell to one with the features of the following disease stages: monoclonal gammopathy of undetermined significance, smouldering myeloma, myeloma and plasma cell leukaemia. Although myeloma initiating events are clonal, subsequent driver lesions often occur in a subclone of cells, facilitating progression by Darwinian selection processes. Understanding the co-evolution of the clones within their microenvironment will be crucial for therapeutically manipulating the process. The end stage of progression is the generation of a state associated with treatment resistance, increased proliferation, evasion of apoptosis and an ability to grow independently of the bone marrow microenvironment. In this Review, we discuss these end-stage high-risk disease states and how new information is improving our understanding of their evolutionary trajectories, how they may be diagnosed and the biological behaviour that must be addressed if they are to be treated effectively.

在最近几十年中，在治疗进展的推动下，大多数骨髓瘤患者的结局已有所改善。但是，有一部分患者被认为患有高危疾病，但并未从中受益。如果我们要改善结局，那么了解高危疾病如何从更具治疗性的易感性阶段演变至关重要。这可以通过确定驱动正常浆细胞向一种具有以下疾病阶段特征的遗传基因的遗传机制和突变来实现：具有不确定性的单克隆丙种球蛋白病，闷热的骨髓瘤，骨髓瘤和浆细胞白血病。尽管骨髓瘤的起始事件是克隆性的，但随后的驱动程序损伤通常发生在细胞的亚克隆中，从而促进了达尔文选择过程的进展。了解克隆在其微环境中的共同进化对于治疗性地控制该过程至关重要。进展的最终阶段是与治疗抗性，增加的增殖，逃避细胞凋亡以及独立于骨髓微环境生长的能力有关的状态的产生。在本综述中，我们讨论了这些终末期高危疾病状态，以及新信息如何改善我们对其进化轨迹的理解，如何诊断它们以及如何对其进行有效治疗必须采取的生物学行为。规避凋亡和独立​​于骨髓微环境生长的能力。在本综述中，我们讨论了这些终末期高危疾病状态，以及新信息如何改善我们对其进化轨迹的了解，如何诊断它们以及如何对其进行有效治疗必须采取的生物学行为。规避凋亡和独立​​于骨髓微环境生长的能力。在本综述中，我们讨论了这些终末期高危疾病状态，以及新信息如何改善我们对其进化轨迹的了解，如何诊断它们以及如何对其进行有效治疗必须采取的生物学行为。