https://orcid.org/0000-0001-5074-8453
Key Points
Extramedullary disease in MM is characterized by a near universal presence of MAPK pathway alterations.
Extramedullary MM is genomically complex with a higher tumor mutational burden, enriched in 1q gain/amplification and MAX alterations.
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 (WES) on EMD tumor tissue from 18 unique patients and bone marrow aspirates (BMA) from 20 patients at the time of EMD development. Notably, paired EMD and BMA samples were collected from six 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=0.02, q<0.1). Additionally, mutations in established driver genes (NRAS, KRAS, 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, FAT1) and the SWI/SNF complex and epigenetic regulators (ARID1A, KMT2C, KMT2D, EP300), although these were predominantly subclonal. Furthermore, we frequently detected biallelic alterations in the tumor suppressor genes MAX (22%) and CDKN2C (17%). Genomic complexity was significantly higher in EMD samples compared to BMA, as evidenced by increased tumor mutational burden and the enrichment of 1q gain/amplifications. These findings highlight the distinct molecular profile of EMD compared to BMA and highlighted the genomically complex and heterogeneous nature of extramedullary tumors.
