<i><scp>RAS</scp></i> mutation status and bortezomib therapy for relapsed multiple myeloma

Smith, Dean; Armenteros, Elena; Percy, Laura; Kumar, Madhu; Lach, Anna; Herledan, Gaëlle; Stubbs, Matthew; Downward, Julian; Yong, Kwee

doi:10.1111/bjh.13258

Cited by 20 publications

(19 citation statements)

References 9 publications

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“…Our sequencing approach in the study cohort of the DSMM XI trial confirmed the reported distribution of clonal and subclonal KRAS-mutations [9,19,20,22,34] and the results obtained by correlation of the KRAS-mutation profile with survival are in line with previous observations in bortezomib-treated patients at relapse [4,18]. KRAS-mutations did not have an influence on survival in bortezomib-treated patients at diagnosis.…”

Section: Discussionsupporting

confidence: 90%

“…After more than 30 years of research aimed at developing useful RAS inhibitors, AMG 510, an inhibitor specifically for p.G12C mutant KRAS, is now being tested in a clinical trial and is the first hope for targetting oncogenic KRAS therapeutically [1]. However, only a few studies exist in MM that investigated the clinical role of KRAS-mutations after the introduction of novel agents such as bortezomib and lenalidomide, which nowadays are routinely included in MM therapies [31], and all of these studies focused on the role of KRAS-mutations in relapsed/refractory disease [4,18]. Moreover, functional investigations on oncogenic KRAS in MM are rather limited.…”

Section: Discussionmentioning

confidence: 99%

“…The prognostic outcome of patients with RAS mutated MM has been assessed in several studies with contradicting conclusions, which may at least in part reflect the fact that different treatment regimens have been used [3,[12][13][14][15][16][17]. Of note, in trials treating relapsed/refractory patients with proteasome inhibitors, no significant difference in overall survival between RAS-mutant and RAS-WT patients was found [4,18].…”

Section: Introductionmentioning

confidence: 99%

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Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines

Weissbach

Heredia-Guerrero

Barnsteiner

et al. 2020

Cancers

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Approximately 20% of multiple myeloma (MM) cases harbor a point mutation in KRAS. However, there is still no final consent on whether KRAS-mutations are associated with disease outcome. Specifically, no data exist on whether KRAS-mutations have an impact on survival of MM patients at diagnosis in the era of novel agents. Direct blockade of KRAS for therapeutic purposes is mostly impossible, but recently a mutation-specific covalent inhibitor targeting KRASp.G12C entered into clinical trials. However, other KRAS hotspot-mutations exist in MM patients, including the less common exon-4 mutations. For the current study, the coding regions of KRAS were deep-sequenced in 80 newly diagnosed MM patients, uniformely treated with three cycles of bortezomib plus dexamethasone and cyclophosphamide (VCD)-induction, followed by high-dose chemotherapy and autologous stem cell transplantation. Moreover, the functional impact of KRASp.G12A and the exon-4 mutations p.A146T and p.A146V on different survival pathways was investigated. Specifically, KRASWT, KRASp.G12A, KRASp.A146T, and KRASp.A146V were overexpressed in HEK293 cells and the KRASWT MM cell lines JJN3 and OPM2 using lentiviral transduction and the Sleeping Beauty vector system. Even though KRAS-mutations were not correlated with survival, all KRAS-mutants were found capable of potentially activating MEK/ERK- and sustaining PI3K/AKT-signaling in MM cells.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines

Weissbach

Heredia-Guerrero

Barnsteiner

et al. 2020

Cancers

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“…Activating mutations are found in a number of genes in myeloma, with frequencies varying in different studies e.g. NRAS (20–30%) , KRAS (15–20%) , BRAF (5%) , CCND1 (12%), MYC (1%) and a number of genes in the nuclear factor‐кB pathway (6–17%) (Morgan et al , ; Smith et al , ; Walker et al , ). Mutations in TP53 are present in around one third of cases with del(17p) but are much less prevalent in patients without del(17p).…”

Section: Genetic Lesionsmentioning

confidence: 99%

“…There are conflicting reports regarding the prognostic significance of NRAS and KRAS mutations. Studies performed prior to the novel agent era reported the poor prognostic impact of KRAS mutations (Smith et al , ). Recently, results from the APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial suggested that NRAS mutations conferred resistance to single agent bortezomib in previously treated patients (Mulligan et al , ).…”

Section: Genetic Lesionsmentioning

confidence: 99%

Advances in understanding prognosis in myeloma

Smith

Yong

2016

Br J Haematol

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In the last two decades outcomes in multiple myeloma (myeloma) have greatly improved, due to the introduction of newer, more effective therapies. This improvement is not uniform. Response to treatment and survival remains heterogeneous, with some patients living for 1-2 years whilst others are alive and progression-free at 10 years. This variation in outcome is due to patient characteristics plus features intrinsic to the myeloma tumour. Alongside the introduction of novel therapies there has been a greater understanding of disease biology and mechanisms of resistance. This has led to an increase in the number of prognostic markers that can be used in myeloma. This is important not only for more accurate counselling of patients in terms of disease outcome, but also in paving the way for risk-adapted therapy. Both newer and traditional prognostic markers need to be used in the context of planned therapy. Indeed, the prognostic value of certain markers varies according to which therapy the patient receives. As such, these prognostic factors will require constant re-evaluation as agents with new mechanisms of action are added into the myeloma treatment algorithm. This article summarises current concepts of prognostic markers in myeloma.

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Plasma cell myeloma with RAS/BRAF mutations is frequently associated with a complex karyotype, advanced stage disease, and poorer prognosis

Lin

Zuo

et al. 2023

Cancer Medicine

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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.How to cite this article: Li N, Lin P, Zuo Z, et al. Plasma cell myeloma with RAS/BRAF mutations is frequently associated with a complex karyotype, advanced stage disease, and poorer prognosis.

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RAS mutation status and bortezomib therapy for relapsed multiple myeloma

Cited by 20 publications

References 9 publications

Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines

Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines

Advances in understanding prognosis in myeloma

Plasma cell myeloma with RAS/BRAF mutations is frequently associated with a complex karyotype, advanced stage disease, and poorer prognosis

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