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RASmutation leading to acquired resistance to dabrafenib and trametinib therapy in a multiplemyeloma patient harboring BRAF mutation

Baptiste Le Calvez 1 Yannick Le Bris 2 Guillaume Herbreteau 3 Bastien Jamet 4, 5 Céline Bossard 6 Benoit Tessoulin 7, 1 Thomas Gastinne 1 Béatrice Mahé 1 Viviane Dubruille 1 Nicolas Blin 1 Chloé Antier 1 Olivier Theisen 2 Françoise Kraeber-Bodéré 8, 5 Steven Le Gouill 7, 1 Marie C. Béné 2 Philippe Moreau 9, 1 Cyrille Touzeau 7, 1
1 Service d'Hématologie [Nantes]
2 Laboratoire d'Hématologie Biologique [Hôpital Hôtel-Dieu, Nantes]
3 Département de Biochimie [CHU Nantes]
4 Service de Médecine Nucléaire [Nantes]
5 ILIAD - Imaging and Longitudinal Investigations to Ameliorate Decision-making [Nantes]
6 Département de Pathologie [CHU Nantes]
7 CRCINA-ÉQUIPE 10 - Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma
CRCINA - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers
8 CRCINA-ÉQUIPE 13 - Nuclear Oncology
CRCINA - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers
9 CRCINA-ÉQUIPE 11 - Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression
CRCINA - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers
Abstract : Multiple myeloma (MM) is still considered incurable and new therapeutic approaches are therefore needed. Deep-sequencing analysis revealed the presence of BRAF mutations in up to 15% of patients. The clinical experience of BRAF-targeted therapy in myeloma patients harboring BRAF mutation is still limited. We here report the case of a patient with penta-refractory (bortezomib, lenalidomide, carfilzomib, pomalidomide, and daratumumab) MM with extramedullary BRAF-mutated disease that achieved clinical response to dual BRAF and MEK inhibition. At the time of disease progression, gene sequencing analysis of the tumor at the time of progression demonstrated a clonal evolution with emergence of aNRAS mutation and persistence of BRAF and TP53 mutations. Backtracking of the NRAS mutation was performed by digital polymerase chain reaction on the baseline biopsy and identified the pre-existence of the NRAS at a subclonal level. This observation is the first report of acquired NRAS mutation leading to resistance to dual BRAF/MEK inhibitors in MM. These data suggest that a systematic search for RAS mutations using highly sensitive techniques should be performed before considering targeted therapy in relapsed myeloma with BRAF mutation.
Keywords : BRAF dabrafenib multiple myeloma RAS trametinib
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https://www.hal.inserm.fr/inserm-02874002
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Submitted on : Thursday, June 18, 2020 - 4:56:30 PM
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Baptiste Le Calvez, Yannick Le Bris, Guillaume Herbreteau, Bastien Jamet, Céline Bossard, et al.. RASmutation leading to acquired resistance to dabrafenib and trametinib therapy in a multiplemyeloma patient harboring BRAF mutation. European Journal of Haematology, Wiley, 2020, Online ahead of print. ⟨10.1002/jha2.8⟩. ⟨inserm-02874002⟩

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