RAS mutation leading to acquired resistance to dabrafenib and trametinib therapy in a multiple myeloma patient harboring BRAF mutation
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-07-01
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| Series: | eJHaem |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jha2.8 |
| _version_ | 1828716012802932736 |
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| author | Baptiste Le Calvez Yannick Le Bris Guillaume Herbreteau Bastien Jamet Céline Bossard Benoit Tessoulin Thomas Gastinne Béatrice Mahé Viviane Dubruille Nicolas Blin Chloé Antier Olivier Theisen Françoise Kraeber‐Bodéré Steven Le Gouill Marie C. Béné Philippe Moreau Cyrille Touzeau |
| author_facet | Baptiste Le Calvez Yannick Le Bris Guillaume Herbreteau Bastien Jamet Céline Bossard Benoit Tessoulin Thomas Gastinne Béatrice Mahé Viviane Dubruille Nicolas Blin Chloé Antier Olivier Theisen Françoise Kraeber‐Bodéré Steven Le Gouill Marie C. Béné Philippe Moreau Cyrille Touzeau |
| author_sort | Baptiste Le Calvez |
| collection | DOAJ |
| description | 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 a NRAS 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. |
| first_indexed | 2024-03-12T14:06:18Z |
| format | Article |
| id | doaj.art-fdba1c8a3d954d1fb8f2ef2387d43f66 |
| institution | Directory Open Access Journal |
| issn | 2688-6146 |
| language | English |
| last_indexed | 2024-03-12T14:06:18Z |
| publishDate | 2020-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | eJHaem |
| spelling | doaj.art-fdba1c8a3d954d1fb8f2ef2387d43f662023-08-21T14:10:49ZengWileyeJHaem2688-61462020-07-011131832210.1002/jha2.8RAS mutation leading to acquired resistance to dabrafenib and trametinib therapy in a multiple myeloma patient harboring BRAF mutationBaptiste Le Calvez0Yannick Le Bris1Guillaume Herbreteau2Bastien Jamet3Céline Bossard4Benoit Tessoulin5Thomas Gastinne6Béatrice Mahé7Viviane Dubruille8Nicolas Blin9Chloé Antier10Olivier Theisen11Françoise Kraeber‐Bodéré12Steven Le Gouill13Marie C. Béné14Philippe Moreau15Cyrille Touzeau16Department of Hematology University Hospital Nantes FranceHematology Biology University Hospital Nantes FranceBiochemistry Laboratory University Hospital Nantes FranceDepartment of Nuclear Medicine University Hospital Nantes FranceService d'Anatomie et Cytologie Pathologiques, INSERM, CRCINA Université de Nantes, CHU Nantes Nantes F44000 FranceDepartment of Hematology University Hospital Nantes FranceDepartment of Hematology University Hospital Nantes FranceDepartment of Hematology University Hospital Nantes FranceDepartment of Hematology University Hospital Nantes FranceDepartment of Hematology University Hospital Nantes FranceDepartment of Hematology University Hospital Nantes FranceHematology Biology University Hospital Nantes FranceDepartment of Nuclear Medicine University Hospital Nantes FranceDepartment of Hematology University Hospital Nantes FranceHematology Biology University Hospital Nantes FranceDepartment of Hematology University Hospital Nantes FranceDepartment of Hematology University Hospital Nantes FranceAbstract 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 a NRAS 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.https://doi.org/10.1002/jha2.8BRAFdabrafenibmultiple myelomaRAStrametinib |
| spellingShingle | Baptiste Le Calvez Yannick Le Bris Guillaume Herbreteau Bastien Jamet Céline Bossard Benoit Tessoulin Thomas Gastinne Béatrice Mahé Viviane Dubruille Nicolas Blin Chloé Antier Olivier Theisen Françoise Kraeber‐Bodéré Steven Le Gouill Marie C. Béné Philippe Moreau Cyrille Touzeau RAS mutation leading to acquired resistance to dabrafenib and trametinib therapy in a multiple myeloma patient harboring BRAF mutation eJHaem BRAF dabrafenib multiple myeloma RAS trametinib |
| title | RAS mutation leading to acquired resistance to dabrafenib and trametinib therapy in a multiple myeloma patient harboring BRAF mutation |
| title_full | RAS mutation leading to acquired resistance to dabrafenib and trametinib therapy in a multiple myeloma patient harboring BRAF mutation |
| title_fullStr | RAS mutation leading to acquired resistance to dabrafenib and trametinib therapy in a multiple myeloma patient harboring BRAF mutation |
| title_full_unstemmed | RAS mutation leading to acquired resistance to dabrafenib and trametinib therapy in a multiple myeloma patient harboring BRAF mutation |
| title_short | RAS mutation leading to acquired resistance to dabrafenib and trametinib therapy in a multiple myeloma patient harboring BRAF mutation |
| title_sort | ras mutation leading to acquired resistance to dabrafenib and trametinib therapy in a multiple myeloma patient harboring braf mutation |
| topic | BRAF dabrafenib multiple myeloma RAS trametinib |
| url | https://doi.org/10.1002/jha2.8 |
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