Abstract
Background
KRAS, NRAS, and BRAF (RAS/RAF) genes mutations play a role in the pathogenesis of multiple myeloma (MM). We conducted this study to investigate whether RAS/RAF genes mutations have a prognostic value in patients with MM.
Material and methods
117 newly diagnosed MM patients underwent the FISH technique to detect high-risk cytogenetic abnormalities and next-generation sequencing (NGS) to detect KRAS, NRAS, BRAF and TP53 mutations.
Results
In the study patient group, patients with the KRAS mutation had significantly longer OS and PFS compared to those with the TP53 mutation; patients with the BRAF mutation had significantly longer OS compared to those with the TP53 mutation. In the patient without high-risk cytogenetics based on FISH, patients with the KRAS mutation had significantly longer OS and PFS compared to those with the TP53 mutation. Conversely, in the patients with high-risk cytogenetics based on FISH, no difference in survival time has been observed among patient groups harboring different gene mutations.
Conclusions
RAS/RAF gene mutations may have important prognostic implications for MM but should be considered in conjunction with other abnormalities, such as chromosomal abnormalities and TP53 mutations.
Keywords: KRAS, NRAS, BRAF, Gene mutations, Multiple myeloma
1. Introduction
Multiple myeloma (MM) is a malignant hematological disease characterized by proliferation and long lifespan of monoclonal plasma cells. The accumulation of genetic aberrations, as well as the interaction between malignant plasma cells and the bone marrow microenvironment, play an important role in the pathogenesis of MM [1]. Primary or clonal genetic events included immunoglobulin (IgH) translocations (translocations involving chromosome 14) and hyperdiploidy. These IgH translocations lead to the dysregulation of a d-group cyclin and the G1 to S phase. Secondary or subclonal genetic events included del(17p13), gain(1q21), del(1p32), del(13q14) and tumor protein P53 (TP53), which are involved in the nuclear factor kappa light chain enhancer of activated B (NF-κB) activation, G1 to S cell cycle, and RNA processing. These processes are associated with the development and progression of MM. Cytogenetic abnormalities, including t(4;14), t(14;16), t(14;20), del(17p13), gain(1q21) and del(1p32); and mutation of the TP53 gene, were recognized as high-risk cytogenetics [2,3]. Furthermore, there are many other gene mutations associated with MM progression; however, only a few mutations have a high rate above 5%, such as RAS mutations, including Kirsten rat sarcoma virus oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), and proto-oncogene B-Raf also known as v-Raf murine sarcoma viral oncogene homolog B (BRAF). KRAS, NRAS, and BRAF through the Rat sarcoma/Rapidly accelerated fibrosarcoma/Mitogen-activated protein kinase/Extracellular signal-regulated kinase (RAS/RAF/MEK/ERK) signaling pathway, are involved in cell proliferation, migration, survival, and angiogenesis in multiple myeloma [[2], [3], [4], [5]]. The detection of KRAS, NRAS, and BRAF mutations with high rates in patients with relapsed / refractory MM has raised questions about whether these gene mutations have poor prognostic significance for MM [2,5]. There have been some studies conducted to demonstrate the prognostic role of these genes in MM; however, the conclusions remain controversial. Therefore, we conducted this study to investigate whether mutations in the RAS/RAF gene mutations have prognostic value in patients with MM.
2. Materials and methods
Patients: This cohort study was conducted at the Hematology and Blood Transfusion Center of Bach Mai Hospital, Hanoi, Vietnam. From March 2023 to February 2025, all newly diagnosed MM patients who received chemotherapy were consecusively recruited into this study. These patients were followed until March 2026. Treatment regimens included VRD (bortezomib, lenalidomide, and dexamethasone), VTD (bortezomib, thalidomide, and dexamethasone) and VCD (bortezomib, cyclophosphamide, and dexamethasone). Overall survival (OS) and progression-free survival (PFS) were estimated over a 3-year period. This study protocol was approved by the Institutional Review Board of Hanoi Medical University (no.1159/GCN—HMUIRB). All patients were informed and consented to participate in the study.
Cytogenetic and gene mutations analysis: At the time of diagnosis, chromosomal abnormalities were detected by fluorescence in situ hybridization (FISH) technique, including t(4;14), t(11;14), t(14;16), t(14;20), del(17p13), gain(1q21), del(1p32) and del (13q14).
Next-generation sequencing (NGS) was performed to detect mutations in the KRAS, NRAS, BRAF, and TP53 genes. The technical method employed was whole-exome sequencing (WES). Sequencing was performed on the Genolab M Dx system (GeneMind Biosciences) using a panel of 120 genes. The panel was presented in Supplementary 1, Table S1. Sequencing depth was 3000X, limit of dectection (LOD) with variant allele frequency (VAF) ≥0.5%, sequencing quality score was Q30.
Definitions. The MM diagnosis was based on criteria of the 2014 International Myeloma Working Group (IMWG) [6,7]. Chromosomal abnormalities, including t(4;14), t(14;16), t(14;20), del(17p13), gain(1q21) and del (1p32), were considered high-risk cytogenetics based on FISH [6,7]. Double hit or triple hit was identified based on whether a patient had two or three of the following abnormalities: t(4;14), t(14;16), t(14;20), del(17p13), gain(1q21), del(1p32) and TP53 mutations [1]. OS was evaluated from the time of diagnosis to death or the last follow-up. PFS was calculated from the beginning of treatment to relapse, death, or the last follow-up.
Statistical analysis: Quantitative data are expressed as mean values and ranges. Qualitative data is presented as frequencies and percentages. Depending on the presence of gene mutations (KRAS, NRAS, BRAF, and TP53), patients were divided into the following groups: without mutations, KRAS, NRAS, BRAF, KRAS+NRAS, RAS+RAF (BRAF + any KRAS or NRAS), TP53, TP53 + KRAS, TP53 + NRAS, TP53 + BRAF, TP53 + KRAS + NRAS and TP53+RAS+RAF. The Kaplan-Meier method with log-rank tests was used to analyze differences in OS and PFS among these patient groups. Statistical analyzes were performed with SPSS (version 25; IBM Corp.). A Bonferroni correction was performed to adjust the p-value. Adjusted P-value =Original P-value x m, with m = k(k-1)/2, m: total number of pairs comparíons, k: total number of groups. Adjusted P-value <0.05 was considered to indicate a statistically significant difference.
3. Results
3.1. Patient data included chromosomal abnormalities and gene mutations
There were 117 patients with a new diagnosis of MM, including 65 men (55.6%) and 52 women (44.4%). The mean age of the patients was 61.83 years (range 32–79 years). The proportions of patients with IgG, IgA, and light chains types were 55.6% (65 patients), 24.8% (29 patients), and 19.6% (23 patients); respectively. There were 73 patients with an R-ISS II, accounting for 62.4%, 44 patients with an R-ISS III, accounting for 37.6%. No patients with R-ISS I was observed. The majority of patients were treated with the VRD regimen (87 patients with 74.3%), the remaining (30 patients with 35.7%) were treated with other regimens (VTD, VCD). No patients underwent stem cell transplantation. Table 1 presents laboratory indices and results of chromosomal abnormalities and gene mutations. Among high-risk chromosomal abnormalities, gain(1q21) has the highest incidence (31.6%) and del(17p13) has the lowest incidence (4.3%). The triple hit accounts for 3.4%, while the double hit accounts for 10.3% (Table 1). The proportion of KRAS mutation was the highest (31.6%), followed by the NRAS, BRAF, and TP53 mutation (12.0%, 6.8% and 6.8%; respectively). The simultaneous occurrence of 2 or 3 of these gene mutations was infrequent, only 1 to 3 cases (Table 1). Specific mutation variants for KRAS, NRAS, BRAF, TP53 and their VAF was presented in Supplementary 2, Table S2.
Table 1.
Laboratory index and genetics abnormalities of 117 patients with newly diagnosed multiple myeloma.
| Laboratory index | Mean | Min-max |
|---|---|---|
| Hemoglobin (g/l), (Mean ± SD) | 87.68 | 44–132 |
| WBC, (x109/l), (Median) | 7.95 | 2.03–59.00 |
| Platelet count, (x109/l), (Median) | 213 | 44–508 |
| Bone marrow count, (x109/l), (Median) | 56 | 8.6–207 |
| Bone marrow plasma cell percentage, (%), (Median) | 26 | 1–84 |
| Calcium (mmol/l), (Median) | 2.48 | 1.62–4.00 |
| Creatinine (µmol/l), (Median) | 198 | 33–1237 |
| Albumin (g/l), (Median) | 31.95 | 14.60–49.90 |
| β2M (mg/l), (Median) | 14.00 | 2.34–102.59 |
| LDH (U/l), (Median) | 258 | 73–898 |
| Cytogenetics abnormalities | Frequency | Percentage |
|---|---|---|
| t(4;14) | 13 | 11.1 |
| t(11;14) | 7 | 6.0 |
| del(17p13) | 5 | 4.3 |
| gain(1q21) | 37 | 31.6 |
| del(1p32) | 6 | 5.1 |
| del(13q14) | 50 | 42.7 |
| Double hit | 12 | 10.3 |
| Triple hit | 4 | 3.4 |
| Gene mutations | Frequency | Percentage |
|---|---|---|
| KRAS | 37 | 31.6 |
| NRAS | 14 | 12.0 |
| BRAF | 8 | 6.8 |
| TP53 | 8 | 6.8 |
| Types of gene mutation combinations | Frequency | Percentage |
|---|---|---|
| No mutation | 58 | 49.6 |
| KRAS (sole) | 31 | 26.5 |
| NRAS (sole) | 11 | 9.4 |
| BRAF (sole) | 6 | 5.1 |
| TP53 (sole) | 3 | 2.6 |
| KRAS+NRAS (combined) | 2 | 1.7 |
| RAS+RAF (combined) | 1 | 0.9 |
| TP53+KRAS (combined) | 3 | 2.6 |
| TP53+NRAS (combined) | 0 | 0 |
| TP53+BRAF (combined) | 1 | 0.9 |
| TP53+KRAS+NRAS (combined) | 1 | 0.9 |
| TP53+RAS+RAF (combined) | 0 | 0 |
Note: WBC: white blood count, LDH: Lactate Dehydrogenase, β2M: Beta 2 microglobulin.
3.2. Association between gene mutations and survival time
The median of follow-up time, OS, and PFS was 24.4, 25.5, and 22.4 months; respectively. Number of events in OS, and PFS were 39, and 50; respectively. Number of censored patients in OS, and PFS were 78, and 67; respectively. Analysis in the study patient group, Kaplan–Meier curve analysis and log-rank test demonstrated that patients with the KRAS mutation had significantly longer OS and PFS compared to those with the TP53 mutation (28.11 vs 4.0, and 24.11 vs 1.0 months p < 0.001; respectively) (Fig. 1, Table 2); patients with the BRAF mutation had significantly longer OS compared to those with the TP53 mutation (25.66 vs 4.0 months p = 0.045) (Fig. 2, Table 2). In the patient without high-risk cytogenetics based on FISH, patients with the KRAS mutation had significantly longer OS and PFS compared to those with TP53 mutation (31.18 vs 4.5 months p = 0.001; 27.31 vs 3.5 months p = 0.045; respectively) (Fig. 3, Table 2). Conversely, in the patients with high-risk cytogenetics based on FISH, no difference in survival time has been observed among patient groups harboring different gene mutations (Table 2).
Fig. 1.
A. Overall survival according to KRAS and TP53 mutations in patients with newly diagnosed multiple myeloma. B. Progression-free survival according to KRAS and TP53 mutations in patients with newly diagnosed multiple myeloma.
Table 2.
Analysis survival time of 117 patients with newly diagnosed multiple myeloma according to presence of gene mutations.
|
Study patients (n = 117) | ||||
|---|---|---|---|---|
| Gene mutations | Overall survival (OS) |
Progression-free survival (PFS) |
||
| Estimate Months | Plogrank | Estimate Months | Plogrank | |
| No mutations (1) | 24.47 |
P2.7 < 0.001 P4.7 = 0.045 P Others>0.05 |
22.04 |
P2.7 < 0.001 P Others>0.05 |
| KRAS (2) | 28.11 | 24.11 | ||
| NRAS (3) | 19.82 | 15.91 | ||
| BRAF(4) | 25.66 | 21.17 | ||
| KRAS+NRAS (5) | Not reached | Not reached | ||
| RAS+RAF (6) | 2.00 | 1.00 | ||
| TP53 (7) | 4.00 | 1.00 | ||
| TP53+KRAS (8) | 11.67 | 11.33 | ||
| TP53+BRAF (9) | Not reached | Not reached | ||
| TP53+KRAS+NRAS (10) | 2.00 | 3.00 | ||
|
Patients without high-risk cytogenetics based on FISH (n = 60) | ||||
|---|---|---|---|---|
| Gene mutations | Overall survival (OS) |
Progression-free survival (PFS) |
||
| Estimate Months | Plogrank | Estimate Months | Plogrank | |
| No mutations (1) | 23.83 |
P2.7 = 0.045 P Others>0.05 |
22.39 |
P2.7 = 0.045 P Others>0.05 |
| KRAS (2) | 31.18 | 27.31 | ||
| NRAS (3) | 18.86 | 17.86 | ||
| BRAF(4) | 24.80 | 23.00 | ||
| KRAS+NRAS (5) | Not reached | Not reached | ||
| RAS+RAF (6) | 2.00 | 1.00 | ||
| TP53 (7) | 4.50 | 3.50 | ||
| TP53+KRAS (8) | Not reached | Not reached | ||
| TP53+BRAF (9) | Not reached | Not reached | ||
| TP53+KRAS+NRAS (10) | No patients | No patients | ||
|
Patients with high-risk cytogenetics based on FISH (n = 47) | ||||
|---|---|---|---|---|
| Gene mutations | Overall survival (OS) |
Progression-free survival (PFS) |
||
| Estimate Months | Plogrank | Estimate Months | Plogrank | |
| No mutations (1) | 24.34 | All P > 0.05 | 20.24 | All P > 0.05 |
| KRAS (2) | 24.30 | 20.27 | ||
| NRAS (3) | 17.50 | 12.50 | ||
| BRAF(4) | Not reached | 12.00 | ||
| KRAS+NRAS (5) | Not reached | Not reached | ||
| RAS+RAF (6) | No patients | No patients | ||
| TP53 (7) | 3.0 | 2.0 | ||
| TP53+KRAS (8) | 2.5 | 1.5 | ||
| TP53+BRAF (9) | No patients | No patients | ||
| TP53+KRAS+NRAS (10) | 2.0 | 1.0 | ||
Note:.
The P-values presented in the table were adjusted P-values.
Adjusted P- value =original P -value x m, with m = k(k-1)/2 = 10(10–1)/2 = 45, m: total number of pairs comparíons, k: total number of groups.
FISH: Fluorescence in situ hybridization.
P1.2: between no mutation group and KRAS mutation group.
P1.3: between no mutation group and NRAS mutation group.
P1.4: between no mutation group and BRAF mutation group.
P1.5: between no mutation group and KRAS+NRAS mutations group.
P1.6: between no mutation group and RAS+RAF mutations group.
P1.7: between no mutation group and TP53 mutation group.
P1.8: between no mutation group and TP53+KRAS mutations group.
P1.9: between no mutation group and TP53+BRAF mutations group.
P1.10: between no mutation group and TP53+KRAS+NRAS mutations group.
P2.3: between KRAS mutation group and NRAS mutation group.
P2.4: between KRAS mutation group and BRAF mutation group.
P2.5: between KRAS mutation group and KRAS+NRAS mutations group.
P2.6: between KRAS mutation group and RAS+RAF mutations group.
P2.7: between KRAS mutation group and TP53 mutation group.
P2.8: between KRAS mutation group and TP53+KRAS mutations group.
P2.9: between KRAS mutation group and TP53+BRAF mutations group.
P2.10: between KRAS mutation group and TP53+KRAS+NRAS mutations group.
P3.4: between NRAS mutation group and BRAF mutation group.
P3.5: between NRAS mutation group and KRAS+NRAS mutations group.
P3.6: between NRAS mutation group and RAS+RAF mutations group.
P3.7: between NRAS mutation group and TP53 mutation group.
P3.8: between NRAS mutation group and TP53+KRAS mutations group.
P3.9: between NRAS mutation group and TP53+BRAF mutations group.
P3.10: between NRAS mutation group and TP53+KRAS+NRAS mutations group.
P4.5: between BRAF mutation group and KRAS+NRAS mutations group.
P4.6: between BRAF mutation group and RAS+RAF mutations group.
P4.7: between BRAF mutation group and TP53 mutation group.
P4.8: between BRAF mutation group and TP53+KRAS mutations group.
P4.9: between BRAF mutation group and TP53+BRAF mutations group.
P4.10: between BRAF mutation group and TP53+KRAS+NRAS mutations group.
P5.6: between KRAS+NRAS mutations group and RAS+RAF mutations group.
P5.7: between KRAS+NRAS mutations group and TP53 mutation group.
P5.8: between KRAS+NRAS mutations group and TP53+KRAS mutations group.
P5.9: between KRAS+NRAS mutations group and TP53+BRAF mutations group.
P5.10: between KRAS+NRAS mutations group and TP53+KRAS+NRAS mutations group.
P6.7: between RAS+RAF mutations group and TP53 mutation group.
P6.8: between RAS+RAF mutations group and TP53+KRAS mutations group.
P6.9: between RAS+RAF mutations group and TP53+BRAF mutations group.
P6.10: between RAS+RAF mutations group and TP53+KRAS+NRAS mutations group.
P7.8: between TP53 mutation group and TP53+KRAS mutations group.
P7.9: between TP53 mutation group and TP53+BRAF mutations group.
P7.10: between TP53 mutation group and TP53+KRAS+NRAS mutations group.
P8.9: between TP53+KRAS mutations group and TP53+BRAF mutations group.
P8.10: between TP53+KRAS mutations group and TP53+KRAS+NRAS mutations group.
P9.10: between TP53+BRAF mutations group and TP53+KRAS+NRAS mutations group.
Fig. 2.
Overall survival according to BRAF and TP53 mutations in patients with newly diagnosed multiple myeloma.
Fig. 3.
A. Overall survival according to KRAS and TP53 mutations in multiple myeloma patients without high-risk cytogenetics based on FISH. B. Progression-free survival according to KRAS and TP53 mutations in multiple myeloma patients without high-risk cytogenetics based on FISH.
4. Discussion
In MM, genetic mutations, and the interaction between plasma cells and the bone marrow microenvironment lead to the activation of signaling pathways that promote the growth of malignant cell lines, while also stimulating angiogenesis and osteoclastogenesis, which are essential factors supporting tumor cell growth. Overregulated or deregulated signaling pathways involved in the development of MM include the RAS/RAF/MEK/ERK [also known as Rat sarcoma/Mitogen-activated protein kinase (RAS/MAPK)], NF-κB, phosphatidylinositol 3-kinase/Protein Kinase B/Mechanistic Target of Rapamycin (PI3K/AKT/mTOR), Janus Kinase/Signal Transducer and transcription activator (JAK/STAT), Wingless-related integration site (WNT/β-catenin), transforming growth factor beta (TGFβ), and Hedgehog-Notch pathways. Among these pathways, the RAS/MAPK signaling pathway plays a crucial role due to its influence on cell proliferation, survival, and differentiation [4,5]. On the other hand, the proportion of patients exhibiting mutations related to the RAS/MAPK pathway was high [2,5]. In our study, the proportions of KRAS, NRAS and BRAF were 31.6, 12.0, and 6.8%; respectively. This result is also similar to that of other authors [[6], [7], [8], [9], [10]]. RAS (NRAS, KRAS) activates RAF- kinases, leading to the phosphorylation of MEK and ultimately ERK- kinase, which in turn activates genes responsible for cell division and growth [4,5]. Some studies indicated that RAS/RAF mutations appear in the early stages of MM such as MGUS and SMM, but they have a high incidence in relapse/refractory MM [2,5]. Therefore, there is reason to believe that RAS/RAF is associated with disease progression and early relapse. However, previous studies have yielded contradictory results.
Although Li et al. showed that only KRAS negatively affects OS, Kim et al. and Shehab et al. indicated that only BRAF was associated with shorter PFS [[11], [12], [13]]. Shehab et al. with univariate analysis also demonstrated that BRAF was also a poor predictor of OS [11]. On the other hand, more authors supported the prognostic role of NRAS. Mulligan et al. indicated that patients with NRAS had a worse outcome with bortezomid monotherapy, while Sergeeva et al. showed that patients with NRAS had a low complete remission rate even with chemotherapy regimens such as PAD (doxorubicin, dexamethasone, and bortezomib) or VCD (bortezomib, cyclophosphamide and dexamethasone) [14,15]. Furthermore, Mishima et al. suggested that NRAS is a poor predictor of PFS [7]. In addition, Perroud et al. and Soloveva et al. suggested that RAS/RAF was a poor prognostic factor in MM [8.9]. However, in a recent study, Wang et al. refuted the prognostic value of KRAS and NRAS for MM [10].
The differences in the results of these studies are evidence of the complexity in the pathogenesis of MM, which involves a combination of various mechanisms with different genetic mutations. Therefore, it is difficult to assess the prognostic role of gene mutations individually. In MM, as mentioned in the introduction, the role of primary genetic events such as IgH transcalotions, of secondary genetic events such as del(17), gain(1q21), del(1p32) and the TP53 mutation is extremely important. Therefore, it is perhaps necessary to assess the prognostic significance of RAS/RAF in relation to these genetic abnormalities. In our study, the results of the survival time analysis indicated that patients with KRAS and with BRAF had a better survival time than those with TP53. However, this difference was not observed in the group of patients with high-risk cytogenetics based on FISH. Thus, is the role of RAS/RAF mutations limited to multiple myeloma patients without high-risk chromosomal abnormalities? Further studies involving larger patient cohorts are needed to answer this question.
Although the role of RAS/RAF in the pathogenesis of MM through the RAS/MAPK pathway has been acknowledged, which is the basis for research and clinical trials of drugs targeting the MAPK pathway, which promise to improve treatment outcomes for MM [4,5]. However, the true prognostic importance of RAS/RAF in MM likely requires further research to clarify.
Limitation of study: This is a preliminary study. The number of patients in each subgroup according to the presence of specific gene mutations remains small, while the interplay of gene mutations in the prognosis of multiple myeloma is highly complex. We hope to expand this study with larger patients population to further elucidate the role of RAS/RAF genes in the prognosis of multiple myeloma.
Conclusions RAS/RAF gene mutations may have important prognostic implications for MM but should be considered in conjunction with other abnormalities, such as chromosomal abnormalities and TP53 mutations.
Ethics declaration
Written informed consent to take part in the study and to publish the article has been obtained from all participants or their legal representatives. The privacy rights of participants have been observed.
This study was performed in compliance with relevant laws, regulatory frameworks and guidelines where the research took place. This study was approved by the Institutional Review Board of Hanoi Medical University. (Approval No. no.1159/GCN—HMUIRB)
Ethics approval and consent to participate
This study was approved by the Institutional Review Board of Hanoi Medical University (no. 1159/GCN—HMUIRB). All patients were informed about this study and their informed consent was received.
Financial disclosure statement
No financial support was received for this study.
Use of large language models, AI, and machine learning tool
No
CRediT authorship contribution statement
Phuong Thao Pham: Writing – original draft, Methodology, Investigation, Formal analysis, Data curation. Hoang Viet Nguyen: Writing – original draft, Methodology, Formal analysis. Minh Phuong Vu: Writing – review & editing, Writing – original draft, Methodology, Formal analysis, Data curation, Conceptualization.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
No applicable
Footnotes
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.lrr.2026.100615.
Appendix. Supplementary materials
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