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

Abstract

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 followup 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.Conclusion: Overall, these data highlight the importance of mutational screening to better understand newly diagnosed multiple myeloma and may lead to patient-specific mutationdriven treatment approaches.

The molecular make up of smoldering myeloma highlights the evolutionary pathways leading to multiple myeloma

“…Genetic abnormalities that are more frequent in MM have been suggested to be drivers of progression. Thus, in order to determine the spectrum of genomic differences characterizing SMM, we performed targeted sequencing to interrogate known drivers and immunoglobulin (Ig) translocations in a set of 82 previously untreated SMM patients and compared the results to a published data set of 223 MM patients analyzed using the same sequencing approach (Table 1 18 ).…”

“…We next investigated the frequency of important mutations in SMM and MM using the same targeted sequencing panel. We applied analysis of a catalog of key MM mutations 18 to cases with MGUS, SMM, EM, and MM. There was a significant difference in the overall number of mutations identified at various disease stages (Supplemental Fig.…”

Monitoring treatment response and disease progression in myeloma with circulating cell‐free DNA

“…50 ng of DNA from plasma cells and control DNA was enzymatically fragmented and a library was prepared using the HyperPlus Kit (KAPA Biosystems). The panel for targeted sequencing consisted of 123 genes to capture mutations and probes to capture translocations involving immunoglobulin regions and MYC (SeqCap EZ target enrichment; Nimblegen) 16 . Libraries were sequenced on a NextSeq500 (Illumina) with 75 bp paired‐end reads.…”

“…For cfDNA libraries from the chemotherapy timeline (n = 8) and SMM patients (n = 25), we included dual‐index unique molecular identifiers (UMI, Integrated DNA Technologies, Inc) during the adapter ligation step before amplification 17 . Libraries were hybridized to the 123 gene targeted panel and the translocation panel (SeqCap EZ target enrichment; Nimblegen) 16 and sequenced on NextSeq500 (Illumina) with 75 bp paired‐end reads. Median coverage for translocations and mutations was 365x and 668x, respectively.…”

RAS mutation leading to acquired resistance to dabrafenib and trametinib therapy in a multiple myeloma patient harboring BRAF mutation

“…revealed the presence of BRAF mutations in 11-15% of patients[2][3][4][5].The clinical experience of BRAF-targeted therapy in myeloma patients harboring B-RAF mutation is still limited[6][7][8][9][10]. Here, we report the case of a patient with triple-class refractory myeloma harboringBRAF mutation that achieved clinical response to dual BRAF and MEK F I G U R E 1 Patient disease with extramedullary involvement.…”