Plasma cell myeloma with RAS/BRAF mutations is frequently associated with a complex karyotype, advanced stage disease, and poorer prognosis.
Humans
Proto-Oncogene Proteins B-raf
/ genetics
Multiple Myeloma
/ genetics
Calcium
/ metabolism
Hematopoietic Stem Cell Transplantation
Proto-Oncogene Proteins p21(ras)
/ genetics
Prognosis
Transplantation, Autologous
Mutation
Lactate Dehydrogenases
/ genetics
Karyotype
Colorectal Neoplasms
/ pathology
BRAF
KRAS
NRAS
Plasma cell myeloma
poor prognosis
Journal
Cancer medicine
ISSN: 2045-7634
Titre abrégé: Cancer Med
Pays: United States
ID NLM: 101595310
Informations de publication
Date de publication:
07 2023
07 2023
Historique:
revised:
09
04
2023
received:
03
09
2022
accepted:
04
05
2023
medline:
21
7
2023
pubmed:
22
5
2023
entrez:
22
5
2023
Statut:
ppublish
Résumé
Mutations in the RAS-MAPK pathway, such as KRAS, NRAS, and BRAF, are known as high-risk factors associated with poor prognosis in patients with various cancers, but studies in myeloma have yielded mixed results. We describe the clinicopathologic, cytogenetic, molecular features, and outcomes of 68 patients with RAS/BRAF-mutated myeloma, and compare with 79 patients without any mutations. We show that KRAS, NRAS, and BRAF were mutated in 16%, 11%, and 5% of cases, respectively. RAS/BRAF-mutated patients had lower hemoglobin and platelet counts, higher levels of serum lactate dehydrogenase and calcium, higher percentage of bone marrow plasma cells, and more advanced R-ISS stage. RAS/BRAF mutations were associated with complex karyotype and gain/amplification of CKS1B. The median overall survival and progression-free survival were significantly shorter for RAS/BRAF-mutated patients (69.0 vs. 220.7 months, p = 0.0023 and 46.0 vs. 60.6 months, p = 0.0311, respectively). Univariate analysis revealed that KRAS mutation, NRAS mutation, lower hemoglobin, elevated lactate dehydrogenase, higher R-ISS stage, complex karyotype, gain/amplification of CKS1B, monosomy 13/RB1 deletion and lack of autologous stem cell transplantation were associated with poorer prognosis. Multivariate analysis showed that KRAS mutation, lower hemoglobin level, higher level of serum calcium, higher ISS stage, and lack of autologous stem cell transplantation predict inferior outcome. RAS/BRAF mutations occur in 30%-40% of myeloma cases and are associated with higher tumor burden, higher R-ISS stage, complex karyotype, and shorter overall survival and progression-free survival. These findings support testing for RAS/BRAF mutations in myeloma patients and underscore the potential therapeutic benefits of RAS/BRAF inhibitors.
Sections du résumé
BACKGROUND
Mutations in the RAS-MAPK pathway, such as KRAS, NRAS, and BRAF, are known as high-risk factors associated with poor prognosis in patients with various cancers, but studies in myeloma have yielded mixed results.
METHODS
We describe the clinicopathologic, cytogenetic, molecular features, and outcomes of 68 patients with RAS/BRAF-mutated myeloma, and compare with 79 patients without any mutations.
RESULTS
We show that KRAS, NRAS, and BRAF were mutated in 16%, 11%, and 5% of cases, respectively. RAS/BRAF-mutated patients had lower hemoglobin and platelet counts, higher levels of serum lactate dehydrogenase and calcium, higher percentage of bone marrow plasma cells, and more advanced R-ISS stage. RAS/BRAF mutations were associated with complex karyotype and gain/amplification of CKS1B. The median overall survival and progression-free survival were significantly shorter for RAS/BRAF-mutated patients (69.0 vs. 220.7 months, p = 0.0023 and 46.0 vs. 60.6 months, p = 0.0311, respectively). Univariate analysis revealed that KRAS mutation, NRAS mutation, lower hemoglobin, elevated lactate dehydrogenase, higher R-ISS stage, complex karyotype, gain/amplification of CKS1B, monosomy 13/RB1 deletion and lack of autologous stem cell transplantation were associated with poorer prognosis. Multivariate analysis showed that KRAS mutation, lower hemoglobin level, higher level of serum calcium, higher ISS stage, and lack of autologous stem cell transplantation predict inferior outcome.
CONCLUSIONS
RAS/BRAF mutations occur in 30%-40% of myeloma cases and are associated with higher tumor burden, higher R-ISS stage, complex karyotype, and shorter overall survival and progression-free survival. These findings support testing for RAS/BRAF mutations in myeloma patients and underscore the potential therapeutic benefits of RAS/BRAF inhibitors.
Identifiants
pubmed: 37212518
doi: 10.1002/cam4.6103
pmc: PMC10358222
doi:
Substances chimiques
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Calcium
SY7Q814VUP
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Lactate Dehydrogenases
EC 1.1.-
BRAF protein, human
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
14293-14304Informations de copyright
© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
Références
Semin Oncol Nurs. 2017 Aug;33(3):237-253
pubmed: 28729121
JCO Precis Oncol. 2019 Jun 27;3:
pubmed: 32914022
J Clin Oncol. 2011 May 10;29(14):1893-7
pubmed: 21482986
Cancer Discov. 2013 Aug;3(8):862-9
pubmed: 23612012
Int J Oncol. 2003 Mar;22(3):469-80
pubmed: 12579299
Thyroid. 2013 Oct;23(10):1277-83
pubmed: 23489023
Blood. 2014 Nov 13;124(20):3043-51
pubmed: 25293776
Leukemia. 2008 Dec;22(12):2280-4
pubmed: 18528420
Int J Clin Oncol. 2015 Jun;20(3):413-22
pubmed: 25953678
Blood. 2005 Jan 1;105(1):317-23
pubmed: 15339850
Blood. 2014 Jan 30;123(5):632-9
pubmed: 24335104
Nat Commun. 2021 Jan 12;12(1):293
pubmed: 33436579
Clin Cancer Res. 2015 Apr 15;21(8):1802-9
pubmed: 25878361
Blood. 1996 Oct 1;88(7):2699-706
pubmed: 8839865
BMJ Case Rep. 2022 Apr 8;15(4):
pubmed: 35396243
Leuk Lymphoma. 2016;57(1):8-9
pubmed: 26430811
Clin Lymphoma Myeloma Leuk. 2021 Oct;21(10):659-666
pubmed: 34275772
Clin Lymphoma Myeloma Leuk. 2018 Jul;18(7):e315-e325
pubmed: 29807803
Oncogenesis. 2017 May 15;6(5):e337
pubmed: 28504689
J Clin Invest. 2020 Apr 1;130(4):1565-1575
pubmed: 32149732
Vopr Onkol. 2016;62(4):429-38
pubmed: 30475526
JAMA Oncol. 2018 Mar 01;4(3):384-388
pubmed: 29188284
J Mol Diagn. 2019 Jan;21(1):89-98
pubmed: 30577887
Nature. 2011 Mar 24;471(7339):467-72
pubmed: 21430775
Cancer Lett. 2018 Feb 1;414:214-221
pubmed: 29174802
J Clin Oncol. 2015 Nov 20;33(33):3911-20
pubmed: 26282654
Br J Haematol. 2015 Jun;169(6):905-8
pubmed: 25580780
Leuk Lymphoma. 2016;57(1):226-9
pubmed: 25947035
Ann Oncol. 2017 Oct 01;28(10):2581-2587
pubmed: 28961848
J Natl Compr Canc Netw. 2017 Feb;15(2):230-269
pubmed: 28188192
Mod Pathol. 2017 Oct;30(10):1378-1386
pubmed: 28664940
Cancer Med. 2023 Jul;12(13):14293-14304
pubmed: 37212518
J Clin Oncol. 2015 Sep 10;33(26):2863-9
pubmed: 26240224
J Immunol Res. 2018 Jan 17;2018:5376476
pubmed: 29577050
Nat Rev Clin Oncol. 2017 Feb;14(2):100-113
pubmed: 27531699
Blood Cancer J. 2022 Jan 31;12(1):21
pubmed: 35102148
Am J Clin Pathol. 2005 Apr;123(4):594-602
pubmed: 15743747
Blood Cancer J. 2015 Mar 20;5:e299
pubmed: 25794135
Appl Clin Genet. 2010 Jul 28;3:41-51
pubmed: 23776351