COMy 2025 | Investigating the genomic characteristics and complexity of extramedullary myeloma

In our study, we sequenced 18 extramedullary tumors and 20 bone marrow aspirates collected from patients that had extramedullary disease at the time point of development of extramedullary disease. Six of these had bad bone marrow samples. What we noted right off the bat was extramedullary disease is highly enriched in MAP kinase pathway alterations– 94% of extramedullary samples had one or more MAP kinase pathway alterations, including the common driver mutations in RAS-RAF genes. Compared to that bone marrow aspirates, about 60% of those samples harboring a MAP kinase pathway alteration, and this difference was statistically significant. 

What we also observed was these mutations in the NRAS, KRAS, and BRAF genes are frequently clonal in extramedullary disease compared to bone marrow aspirates. Another important finding from our paper was looking at the genomic complexity in terms of copy number alterations. And EMDs seem to be enriched in 1q gains and amplifications, and the frequency and amplitude was higher than what was noted in the bone marrow samples. 

An interesting thing that we noted was there were frequent biallelic alterations in the tumor suppressor gene MAX, which acts as a binding partner for MEK and regulates the role of MEK. These were observed in 22% of the EMD samples – this is a much higher frequency than what has been previously published in myeloma literature. Also, biallelic alterations in CDKN2C, an important tumor suppressor gene located on the 1p chromosome, was noted in 17% of the EMD samples. Overall, we noted that extramedullary samples have a much higher tumor mutational burden as well compared to bone marrow aspirates. In general, it shows that these tumors are genomically complex and quite heterogeneous.

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