Blood Res 2020; 55(3):
Published online September 30, 2020
https://doi.org/10.5045/br.2020.2020137
© The Korean Society of Hematology
Correspondence to : Myungshin Kim, M.D., Ph.D.
Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea
E-mail: microkim@catholic.ac.kr
This is an Open Access article distributed unAcute myeloid leukemia, New FDA approvalsder the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background
Plasma cell myeloma (PCM) is a genetically heterogeneous disease. The genetic spectrum of PCM has been expanded to mutations such as KRAS, NRAS, and BRAF genes in the RAS-RAF-MAPK pathway. In this study, we have evaluated the frequency of these mutations and their significance, including baseline characteristics and clinical outcomes.
Methods
We explored 50 patients who were newly diagnosed with PCM between 2009 and 2012 at a single Korean institute. Clinical and laboratory parameters were gathered through careful review of medical records. Mutation analysis was carried out using DNA from the bone marrow at the time of diagnosis. Pyrosequencing was performed to detect KRAS G12V, KRAS G13D, and NRAS G61R. BRAF V600E was analyzed by allele-specific real- time PCR. Comparison of clinical and laboratory parameters was carried out according to those mutations.
Results
We identified 14 patients (28%) with activating mutations in the RAS-RAF-MAPK pathway (RAS/RAF mutations): KRAS (N=3), NRAS (N=4), BRAF (N=7), and both KRAS and BRAF (N=1). RAS/RAF mutations were more frequently observed in patients with complex karyotypes and showed poorer progression free survival (PFS). Specifically, the BRAF V600E mutation had a significantly negative impact on median PFS.
Conclusion
We first showed the frequency of RAS/RAF mutations in Korean patients with PCM. Screening of these mutations could be considered as a routine clinical test at the time of diagnosis and follow-up due to their influence on clinical outcome, as well as its potential as a therapeutic target.
Keywords KRAS, NRAS, BRAF, Plasma cell myeloma
Blood Res 2020; 55(3): 159-168
Published online September 30, 2020 https://doi.org/10.5045/br.2020.2020137
Copyright © The Korean Society of Hematology.
Yonggoo Kim1,2, Sung-Soo Park3, Chang-Ki Min3, Gun Dong Lee2, Jungok Son2, Sung Jin Jo1, Eunhee Han1,2, Kyungja Han1, Myungshin Kim1,2
1Department of Laboratory Medicine, 2Catholic Genetic Laboratory Center, Seoul St. Mary’s Hospital, 3Department of Hematology, Leukemia Research Institute, Seoul St. Mary's Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
Correspondence to:Myungshin Kim, M.D., Ph.D.
Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea
E-mail: microkim@catholic.ac.kr
This is an Open Access article distributed unAcute myeloid leukemia, New FDA approvalsder the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background
Plasma cell myeloma (PCM) is a genetically heterogeneous disease. The genetic spectrum of PCM has been expanded to mutations such as KRAS, NRAS, and BRAF genes in the RAS-RAF-MAPK pathway. In this study, we have evaluated the frequency of these mutations and their significance, including baseline characteristics and clinical outcomes.
Methods
We explored 50 patients who were newly diagnosed with PCM between 2009 and 2012 at a single Korean institute. Clinical and laboratory parameters were gathered through careful review of medical records. Mutation analysis was carried out using DNA from the bone marrow at the time of diagnosis. Pyrosequencing was performed to detect KRAS G12V, KRAS G13D, and NRAS G61R. BRAF V600E was analyzed by allele-specific real- time PCR. Comparison of clinical and laboratory parameters was carried out according to those mutations.
Results
We identified 14 patients (28%) with activating mutations in the RAS-RAF-MAPK pathway (RAS/RAF mutations): KRAS (N=3), NRAS (N=4), BRAF (N=7), and both KRAS and BRAF (N=1). RAS/RAF mutations were more frequently observed in patients with complex karyotypes and showed poorer progression free survival (PFS). Specifically, the BRAF V600E mutation had a significantly negative impact on median PFS.
Conclusion
We first showed the frequency of RAS/RAF mutations in Korean patients with PCM. Screening of these mutations could be considered as a routine clinical test at the time of diagnosis and follow-up due to their influence on clinical outcome, as well as its potential as a therapeutic target.
Keywords: KRAS, NRAS, BRAF, Plasma cell myeloma
Table 1 . Baseline characteristics of the patients..
Characteristics | Total (N=50) |
---|---|
Age years, median (range) | 66 (31–82) |
Gender, male, N (%) | 27 (54%) |
Type of myeloma, N (%) | |
Ig G | 25 (50%) |
Ig A | 10 (20%) |
Ig M | 1 (2%) |
Ig D | 3 (6%) |
Light chain disease | 11 (22%) |
Clonality of Light chain, N (%) | |
kappa | 33 (66%) |
Lambda | 17 (34%) |
Extramedullary disease | |
Yes, N (%) | 8 (16%) |
No, N (%) | 42 (84%) |
Lactate dehydrogenase | |
>Upper limit of normal | 19 (38%) |
Normal | 31 (62%) |
Median renal function (creatinine clearance) before transplant, mL/min, (range) | 58.8 (5.73–110.8) |
>60, N (%) | 24 (48%) |
≥30 to <60, N (%) | 16 (32%) |
<30, N (%) | 10 (20%) |
ISS stage at diagnosis | |
I, N (%) | 6 (12%) |
II, N (%) | 16 (32%) |
III, N (%) | 26 (52%) |
Unknown, N (%) | 2 (4%) |
Frontline treatment | |
Bortezomib-melphalan-prednisolone with transplant | 11 (22%) |
Bortezomib-melphalan-prednisolone without transplant | 36 (72%) |
Others with transplant | 3 (6%) |
Eligibility of autologous stem cell transplantation | |
Eligible, N (%) | 14 (28%) |
Not-eligible, N (%) | 36 (72%) |
Best response of frontline treatment | |
CR or better | 23 (46%) |
VGPR | 13 (26%) |
PR | 13 (26%) |
SD | 1 (2%) |
Median PFS of frontline treatment, months, median (95% CI) | 23.5 (16.5–25.6) |
Median OS, months, median (95% CI) | 105.7 (63.7-not available) |
Abbreviations: CI, confidence interval; CR, complete response; OS, Overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease; VGPR, very good partial response..
Table 2 . Characteristics of patients with any
Characteristics | RAS/RAF(+) | RAS/RAF(-) |
---|---|---|
Age years, median (range) | 69 (64–82) | 66 (32–80) |
Gender, male, N (%) | 9 (64%) | 18 (50%) |
Cytogenetics | ||
Abnormal | 12 | 19 |
Complex (≥3) | 10 | 13 |
ISS stage at diagnosis | ||
I, N (%) | 0 (0%) | 6 (17%) |
II, N (%) | 5 (36%) | 11 (31%) |
III, N (%) | 9 (64%) | 17 (47%) |
Unknown, N (%) | 2 (6%) | |
Frontline treatment | ||
Bortezomib-melphalan-prednisolone with transplant | 2 (14%) | 9 (25%) |
Bortezomib-melphalan-prednisolone without transplant | 12 (86%) | 24 (67%) |
Others with transplant | 0 (0%) | 3 (8%) |
Best response of frontline treatment | ||
CR or better | 5 (36%) | 18 (50%) |
VGPR | 4 (29%) | 9 (25%) |
PR | 5 (36%) | 8 (22%) |
SD | 0 (0%) | 1 (3%) |
Abbreviations: CR, complete response; PR, partial response; RAS/RAF(+), presence of any
Table 3 . Univariable and multivariable analysis for progression-free survival..
Variables (N=50) | N | Univariate analysis | Multivariable analysis | |||
---|---|---|---|---|---|---|
Median PFS, mo (95% CI) | Hazard ratio (95% CI) | |||||
Patient age (yr) | 0.837 | - | ||||
<66 | 19 | 23.9 (15.4–51.3) | - | |||
≥66 | 31 | 18.9 (12.6–29) | - | |||
Sex | 0.496 | - | ||||
Male | 27 | 23.9 (15.4–31.4) | - | |||
Female | 23 | 18.9 (12.6–24.9) | - | |||
Type of myeloma | 0.605 | - | ||||
IgG | 25 | 24.2 (15.4–49.3) | - | |||
Non-IgG | 25 | 18.9 (12.6–24.9) | - | |||
Type of light chain | 0.649 | - | ||||
Kappa | 33 | 18.9 (15.4–25.5) | - | |||
Lambda | 17 | 24.6 (8.5–51.3) | - | |||
Lactate dehydrogenase | 0.373 | - | ||||
>Upper limit of normal | 31 | 23.9 (16.3–31.4) | - | |||
Normal | 19 | 22.2 (8.5–26) | - | |||
ISS stage at diagnosis | 0.826 | - | ||||
I or II | 22 | 24.2 (18.2–31.4) | - | |||
III | 26 | 16.5 (8.8–51.3) | - | |||
Unknown | 2 | - | ||||
Cytogenetic status | 0.536 | - | ||||
Standard risk | 26 | 23.9 (16.3–31.2) | - | |||
High risk | 13 | 23.5 (8.5–51.3) | - | |||
Unknown | 11 | - | ||||
Extramedullary disease | 0.925 | - | ||||
Present | 8 | 25.1 (6–52.8) | - | |||
None | 42 | 22.2 (14.8-25.6) | - | |||
Transplant eligibility | 0.601 | - | ||||
No | 36 | 18.9 (12.6–24.9) | - | |||
Yes | 14 | 26.5 (15.4–51.3) | - | |||
0.04 | 0.623 | |||||
No | 43 | 23.9 (16.5–31.2) | 1 | |||
Yes | 7 | 18.2 (1.8–24.2) | 1.32 (0.44–3.98) | |||
RAS/RAF mutation | 0.015 | 0.018 | ||||
No | 36 | 24.0 (16.5–49.3) | 1 | |||
Yes | 14 | 18.2 (3.6–24.2) | 2.28 (1.15–4.5) |
Abbreviations: CI, confidence interval; PFS, progression free survival; RAS/RAF, any of
Hanah Kim, Hee-Won Moon, Mina Hur, Yeo-Min Yun, Chul-Min Park, and Mark Hong Lee
Korean J Hematol 2011; 46(2): 135-138