Extramedullary myeloma is genomically complex and characterized by near-universal MAPK pathway alterations

作者：Saurabh Zanwar, Joseph P. Novak, Wilson I. Gonsalves, Michael J. A. Howe, Esteban Braggio, S. Vincent Rajkumar, Moritz Binder, Dragan Jevremović, Surendra Dasari, Shaji Kumar · 发表于：Blood Advances · 年份：2025 · DOI：10.1182/bloodadvances.2025016619 · 被引用次数：12 · 研究领域：Multiple Myeloma Research and Treatments、Protein Degradation and Inhibitors、Cancer Mechanisms and Therapy

ABSTRACT: 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 mutationa...