(PA-249) Contribution of ARID1A Mutations in the Development of Extramedullary Plasmacytoma

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Conclusions:   The prognosis of multiple myeloma (MM) has improved dramatically with the advent of novel therapeutic agents, including immunotherapies. Extramedullary disease (EMD) is predominantly observed at the time of relapse and remains a challenge due to its refractoriness to treatment. We recently performed mutational profiling on samples from 24 cases of EMD samples and identified RAS/BRAF mutations in 23 cases (95.8%), suggesting that these mutations are essential in the pathogenesis of EMD development. However, the molecular mechanism underlying the development of EMD remains unclear.

In addition to RAS/BRAF and TP53 mutations, our data demonstrated ARID1A mutations at a relatively high frequency (four of 24 EMD samples). Although the overall prevalence of ARID1A mutations in our cohort was low, 75% (Six out of eight) of patients harboring ARID1A mutations developed EMD. ARID1A mutations have been widely reported across various malignancies and are generally considered loss-of-function mutations. Recent studies have reported that ARID1A plays a critical role in the differentiation of plasma cells from the germinal center stage, and it has emerged as a potential therapeutic target. However, in our in vitro studies using multiple myeloma cell lines, we observed that both low ARID1A-expressing clones and ARID1A knockdown were associated with a less differentiated immature cellular phenotype by qPCR and flowcytometry. These findings suggest that ARID1A mutations may contribute to the development of undifferentiated myeloma clones and the consequent emergence of EMD. Ongoing studies are focused on determining therapeutic targets with the goal of preventing progression to the development and/or the treatment of EMD.