Effect of MAPK activation via mutations in NRAS, KRAS and BRAF on clinical outcome in newly diagnosed multiple myeloma
Open accessAbstract
Until now, next generation sequencing (NGS) data has not been incorporated into any prognostic stratification of multiple myeloma (MM) and no therapeutic considerations are based upon it. In this work, we correlated NGS data with (1) therapy response and survival parameters in newly diagnosed multiple myeloma, treated by VRd * and (2) MM disease stage: newly diagnosed multiple myeloma (ndMM) versus relapsed and/or refractory (relapsed/refractory multiple myeloma). We analyzed 126 patients, with ndMM and relapsed refractory multiple myeloma (rrMM), treated at the University Hospital of Bern (Inselspital). Next generation sequencing was performed on bone marrow, as part of routine diagnostics. The NGS panel comprised eight genes CCND1, DIS3, EGR1, FAM4 6C (TENT5C), FGFR3, PRDM1, TP53, TRAF3 and seven hotspots in BRAF, IDH1, IDH2, IRF4, KRAS, NRAS. The primary endpoint was complete remission (CR) after VRd in ndMM, in correlation with mutational profile. Mutational load was generally higher in rrMM, with more frequently mutated TP53: 11/87 (13%) in ndMM versus 9/11 (81%) in rrMM (OR 0.0857, p = 0.0007). In ndMM, treated by VRd, mutations in MAPK‐pathway members (NRAS, KRAS or BRAF) were associated with reduced probability of CR (21/38, 55%), as compared with wild type NRAS, KRAS or BRAF (34/40, 85%; OR 0.2225, p = 0.006). NRAS c.181C > A (p.Q61K) as a single mutation event showed a trend to reduced probability of achieving CR (OR 0.0912, p = 0.0247). Activation of MAPK pathway via mutated NRAS, KRAS and BRAF genes seems to have a negative impact on outcome in ndMM patients receiving VRd therapy. VRd* ‐ bortezomib (Velcade®), lenalidomide (Revlimid®) and dexamethasone.
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Activation of RAS/MAPK in MM is often driven by mutations and increased levels of cytokines in the tumor microenvironment, such as IL-6, IGF, and VEGF.
“The activation of this pathway in MM is often driven by mutations and increased levels of cytokines present in the tumor microenvironment, such as IL-6, insulin-like growth factor (IGF), and vascular endothelial growth factor (VEGF) [84–86].”
From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [86]
The RAS/MAPK pathway plays a crucial role in MM by influencing cell proliferation, survival, and differentiation.
“The RAS/MAPK pathway plays a crucial role in MM by influencing cell proliferation, survival, and differentiation.”
From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [86]
Cites
Heterogeneity of genomic evolution and mutational profiles in multiple myeloma
Bolli, N., Avet-Loiseau, H., Wedge, D. C., Van Loo, P., Alexandrov, L. B., Martincorena, I., Dawson, K. J., Iorio, F., Nik-Zainal, S., Bignell, G. R., et al. (2014) · Nature Communications · doi:10.1038/ncomms3997 · Cited by 875 · see citing works
Liu, P., Leong, T., Quam, L., Billadeau, D., Kay, N., Greipp, P., Kyle, R., Oken, M., & Van Ness, B. (1996) · Blood · doi:10.1182/blood.v88.7.2699.bloodjournal8872699 · Cited by 215 · see citing works
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Multiple myeloma: signaling pathways and targeted therapy
Lu, Q., Yang, D., Li, H., Niu, T., & Tong, A. (2024) · Molecular biomedicine · doi:10.1186/s43556-024-00188-w · Cited by 90 · see citing works
- Authors
- Perroud, C., Thurian, D., Andres, M., Künzi, A., Wiedemann, G., Zeerleder, S., Bacher, U., Pabst, T., Banz, Y., Porret, N., & Rebmann, E.
- Affiliations
- University Hospital of Bern (CH)
- University of Bern (CH)
- Corresponding author
- Rebmann, Ekaterina
- ORCID
- Venue
- Hematological Oncology
- Publisher
- Wiley
- Published
- 2023-07-15
- Volume
- 41
- Issue
- 5
- Pages
- 912-921
- ISSN
- 0278-0232 (ISSN-L)
- 1099-1069
- OpenAlex
- W4384401236
- Cited by
- 24
- References
- 2
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 8
- FWCI
- 4.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Hematological Oncology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- BORIS (University Library Bern) (submittedVersion, cc-by-nc-nd)
- Open Access CRIS of the University of Bern
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- multiple myeloma, MAPK signaling, NRAS mutation, KRAS mutation, BRAF mutation, prognostic factors, complete remission, relapsed/refractory multiple myeloma, TP53 mutation, mutational load, lenalidomide, bortezomib, dexamethasone
- MeSH terms
- Bortezomib, Lenalidomide, Humans, Membrane Proteins, Multiple Myeloma, Mutation, Proto-Oncogene Proteins p21(ras), GTP Phosphohydrolases, Proto-Oncogene Proteins B-raf
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