Zanwar Saurabh, Novak Joseph, Gonsalves Wilson, Howe Michael, Braggio Esteban, Rajkumar S Vincent, Binder Moritz, Jevremovic Dragan, Dasari Surendra, Kumar Shaji
Division of Hematology, Mayo Clinic, Rochester, MN.
Hematology Data Science, Mayo Clinic, Rochester, MN.
Blood Adv. 2025 Aug 12;9(15):3979-3987. doi: 10.1182/bloodadvances.2025016619.
Extramedullary disease (EMD) is associated with an inferior prognosis and lower response rates to conventional multiple myeloma (MM)-directed therapies compared to MM without EMD. A deeper understanding of the molecular landscape and underlying drivers of EMD is essential to identify potential targets for novel therapeutic strategies. To address this, we performed whole-exome sequencing on EMD tumor tissue from 18 unique patients and bone marrow aspirates (BMAs) from 20 patients at the time of EMD development. Notably, paired EMD and BMA samples were collected from 6 patients at the point of EMD diagnosis, allowing for direct comparison of molecular profiles. Our analysis revealed a near-universal presence of mutations within the MAPK pathway in EMD samples (94%), compared to BMAs (60%; odds ratio, 10.7; P = .02; q < 0.1). Additionally, mutations in established driver genes (NRAS, KRAS, and BRAF) were common and frequently clonal, suggesting their central role in EMD pathogenesis. We also identified alterations in genes associated with cell adhesion and migration (ROBO1, ROBO2, and FAT1) and the SWI/SNF complex and epigenetic regulators (ARID1A, KMT2C, KMT2D, and EP300), although these were predominantly subclonal. Furthermore, we frequently detected biallelic alterations in the tumor suppressor genes MAX (22%), a binding partner for MYC, and CDKN2C (17%). Genomic complexity was significantly higher in EMD samples than BMAs, as evidenced by increased tumor mutational burden and the enrichment of 1q gain/amplifications. These findings underscore the distinct molecular profile of EMD compared to BMA and highlight the genomically complex and heterogeneous nature of extramedullary disease in MM.
与无髓外疾病（EMD）的多发性骨髓瘤（MM）相比，髓外疾病（EMD）的预后较差，对传统MM靶向治疗的反应率较低。深入了解EMD的分子格局和潜在驱动因素对于确定新型治疗策略的潜在靶点至关重要。为了解决这个问题，我们对18例独特患者的EMD肿瘤组织以及20例患者在EMD发生时的骨髓穿刺液（BMA）进行了全外显子测序。值得注意的是，在6例患者的EMD诊断时收集了配对的EMD和BMA样本，从而能够直接比较分子谱。我们的分析显示，与BMA（60%；优势比，10.7；P = 0.02；q < 0.1）相比，EMD样本中MAPK通路内的突变几乎普遍存在（94%）。此外，已确定的驱动基因（NRAS、KRAS和BRAF）中的突变很常见且经常是克隆性的，表明它们在EMD发病机制中起核心作用。我们还发现了与细胞黏附和迁移相关的基因（ROBO1、ROBO2和FAT1）以及SWI/SNF复合物和表观遗传调节因子（ARID1A、KMT2C、KMT2D和EP300）的改变，尽管这些主要是亚克隆性的。此外，我们经常在肿瘤抑制基因MAX（22%）和CDKN2C（17%）中检测到双等位基因改变，MAX是MYC的结合伴侣。如肿瘤突变负担增加和1q增益/扩增的富集所证明，EMD样本中的基因组复杂性显著高于BMA。这些发现强调了EMD与BMA相比独特的分子谱，并突出了MM中髓外疾病的基因组复杂和异质性本质。
