BRAF and DIS3 Mutations Associate with Adverse Outcome in a Long-term Follow-up of Patients with Multiple Myeloma

Clin Cancer Res. 2020 May 15;26(10):2422-2432. doi: 10.1158/1078-0432.CCR-19-1507. Epub 2020 Jan 27.


Purpose: 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.

Experimental design: 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.

Results: As expected, the most commonly mutated genes were NRAS, KRAS, and BRAF, making up 44% of patients. Double-Hit and BRAF and DIS3 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 BRAF mutations, 58% of which were predicted to be hypoactive or kinase dead. Interestingly, 44% of the hypoactive/kinase dead BRAF-mutated patients showed co-occurring alterations in KRAS, NRAS, or activating BRAF mutations, suggesting that they play a role in the oncogenesis of multiple myeloma by facilitating MAPK activation and may lead to chemoresistance.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor / genetics*
  • DNA Mutational Analysis
  • Exosome Multienzyme Ribonuclease Complex / genetics*
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Middle Aged
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / mortality
  • Multiple Myeloma / pathology
  • Mutation*
  • Prognosis
  • Proto-Oncogene Proteins B-raf / genetics*
  • Survival Rate


  • Biomarkers, Tumor
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Exosome Multienzyme Ribonuclease Complex
  • DIS3 protein, human