<i>BRAF</i> and <i>DIS3</i> Mutations Associate with Adverse Outcome in a Long-term Follow-up of Patients with Multiple Myeloma.

Abstract

Copy-number changes and translocations have been studied extensively in many datasets with long-term follow-up. The impact of mutations remains debated given the short time to follow-up of most datasets. We performed targeted panel sequencing covering 125 myeloma-specific genes and the loci involved in translocations in 223 newly diagnosed myeloma samples recruited into one of the total therapy trials. As expected, the most commonly mutated genes were <i>NRAS, KRAS</i>, and <i>BRAF</i>, making up 44% of patients. Double-Hit and <i>BRAF</i> and <i>DIS3</i> mutations had an impact on outcome alongside classical risk factors in the context of an intensive treatment approach. We were able to identify both V600E and non-V600E <i>BRAF</i> mutations, 58% of which were predicted to be hypoactive or kinase dead. Interestingly, 44% of the hypoactive/kinase dead <i>BRAF</i>-mutated patients showed co-occurring alterations in <i>KRAS, NRAS</i>, or activating <i>BRAF</i> mutations, suggesting that they play a role in the oncogenesis of multiple myeloma by facilitating MAPK activation and may lead to chemoresistance. Overall, these data highlight the importance of mutational screening to better understand newly diagnosed multiple myeloma and may lead to patient-specific mutation-driven treatment approaches.