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
Plasma cell myeloma (PCM) is a multifocal neoplastic proliferation of plasma cells in the bone marrow (BM) [1]. Karyotype abnormalities are the main drivers of PCM, including hyperdiploidy characterized by trisomies of chromosomes 3, 5, 7, 9 11, 15, 19, and 21, and rearrangements involving the immunoglobulin heavy locus (
Recent studies have expanded the genetic spectrum of PCM regarding genetic mutations. The RAS pathway is the most frequently mutated pathway in PCM, with about 20% of newly diagnosed patients with PCM having driver mutations in
In this study, we analyzed the
We explored 50 patients who were newly diagnosed with PCM between 2009 and 2012 at Seoul St. Mary’s Hospital. We selected available BM samples of inpatients who were previously performed with a BM study and were treated for PCM. We analyzed the data in April 2020. This study was performed according to the Declaration of Helsinki and approval for this study was obtained from the Institutional Review Board of Seoul St. Mary’s Hospital, The Catholic University of Korea (KC12SISE0594).
Genomic DNA from BM aspirates were isolated using a Wizard Genomic DNA Purification kit (Promega, Madison, WI, USA). Pyrosequencing was carried out using a PCR primer mix for
We performed additional
Comparisons of clinical and laboratory parameters at diagnosis between patient subgroups were done with the Mann-Whitney test or Fisher’s exact test, respectively. Stages were classified according to the International Staging System for multiple myeloma [16]. Treatment response was evaluated according to the International Myeloma Working Group (IMWG) criteria [17]. Events for progression-free survival (PFS) were indicated as the first progression after frontline treatment or any cause of death. Overall survival (OS) was indicated as the time from initiation of frontline treatment to death (from any cause) or the date of the last follow-up. OS and PFS were determined using the Kaplan-Meier method and compared using a log-rank test. Variables with
The patient demographics, clinical, and laboratory characteristics are summarized in Table 1. The median age of patients was 66 years (range, 31–82). The most frequent type of myeloma was IgG (54%, 27/50), followed by IgA (20%), light chain (18%), IgD (6%), and IgM (2%). Karyotype analyses and interphase FISH were performed using diagnostic BM aspirates with the same methods used in a previous study [18]. Results were classified and described according to the 2016 International System for Human Cytogenetic Nomenclature (ISCN) guidelines [19]. Of the 50 patients, 31 (62%) harbored abnormal karyotypes. Hyperdiploidy (≥47 chromosomes) and hypodiploidy (≤45 chromosomes) were observed in 18 (36%) and 6 patients (12%), respectively. Sixteen patients presented with
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.
RAS mutations were detected in 16% patients (8/50), including four
In the total cohort, there was an overall response rate of 98% (49 of 50 patients) through frontline treatment: 23 patients (46%) with complete response, 13 patients (26%) with very good partial response, and 13 patients (26%) with partial response. The remaining patient showed stable disease despite 6 cycles of treatment with bortezomib-melphalan-prednisolone, finishing her frontline treatment early due to unacceptable peripheral neuropathy. RAS/RAF mutations did not provide a significant impact on either complete response rate or the achievement of partial response of any degree (Table 2).
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
With a respective median PFS of 23.5 months (95% CI, 16.5–25.6) and median OS of 105.7 months (95% CI, 63.7–not estimable) (Supplementary Fig. 1), RAS/RAF mutations were significantly associated with poor median PFS [24.0 mo (95% CI, 16.5–49.3) vs. 18.2 mo (3.6–24.2),
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
In this study, we identified 14 patients with PCM and RAS/RAF mutations (28%).
From a clinical perspective, the prognostic significance of RAS/RAF mutations in PCM is controversial. The application of novel therapeutic agents has changed the influence of these mutations. One study showed that RAS mutations appeared to be significantly associated with a favorable outcome [26]. Another study showed that functional activation of the RAS pathway was observed in 75% of patients with relapsed/refractory PCM and about half had RAS/RAF mutations [27]. In this study, we demonstrated that RAS/RAF mutations were associated with poor outcomes, such as a shorter PFS. Aside from RAS/RAF mutations, a subgroup with
Our study has several limitations. This is a retrospective study using selected BM samples of inpatients considered to be in a more severe condition with a high disease burden. Thus, the proportion of karyotype abnormalities and ISS stage II were relatively higher compared to a previous study in Asian patients [35]. There is also a possibility that the prevalence of
Consequently, this study 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 outcomes and their potential as a therapeutic target.
This study was supported by a grant from the Korea Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A120175).
No potential conflicts of interest relevant to this article were reported.
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
Plasma cell myeloma (PCM) is a multifocal neoplastic proliferation of plasma cells in the bone marrow (BM) [1]. Karyotype abnormalities are the main drivers of PCM, including hyperdiploidy characterized by trisomies of chromosomes 3, 5, 7, 9 11, 15, 19, and 21, and rearrangements involving the immunoglobulin heavy locus (
Recent studies have expanded the genetic spectrum of PCM regarding genetic mutations. The RAS pathway is the most frequently mutated pathway in PCM, with about 20% of newly diagnosed patients with PCM having driver mutations in
In this study, we analyzed the
We explored 50 patients who were newly diagnosed with PCM between 2009 and 2012 at Seoul St. Mary’s Hospital. We selected available BM samples of inpatients who were previously performed with a BM study and were treated for PCM. We analyzed the data in April 2020. This study was performed according to the Declaration of Helsinki and approval for this study was obtained from the Institutional Review Board of Seoul St. Mary’s Hospital, The Catholic University of Korea (KC12SISE0594).
Genomic DNA from BM aspirates were isolated using a Wizard Genomic DNA Purification kit (Promega, Madison, WI, USA). Pyrosequencing was carried out using a PCR primer mix for
We performed additional
Comparisons of clinical and laboratory parameters at diagnosis between patient subgroups were done with the Mann-Whitney test or Fisher’s exact test, respectively. Stages were classified according to the International Staging System for multiple myeloma [16]. Treatment response was evaluated according to the International Myeloma Working Group (IMWG) criteria [17]. Events for progression-free survival (PFS) were indicated as the first progression after frontline treatment or any cause of death. Overall survival (OS) was indicated as the time from initiation of frontline treatment to death (from any cause) or the date of the last follow-up. OS and PFS were determined using the Kaplan-Meier method and compared using a log-rank test. Variables with
The patient demographics, clinical, and laboratory characteristics are summarized in Table 1. The median age of patients was 66 years (range, 31–82). The most frequent type of myeloma was IgG (54%, 27/50), followed by IgA (20%), light chain (18%), IgD (6%), and IgM (2%). Karyotype analyses and interphase FISH were performed using diagnostic BM aspirates with the same methods used in a previous study [18]. Results were classified and described according to the 2016 International System for Human Cytogenetic Nomenclature (ISCN) guidelines [19]. Of the 50 patients, 31 (62%) harbored abnormal karyotypes. Hyperdiploidy (≥47 chromosomes) and hypodiploidy (≤45 chromosomes) were observed in 18 (36%) and 6 patients (12%), respectively. Sixteen patients presented with
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..
RAS mutations were detected in 16% patients (8/50), including four
In the total cohort, there was an overall response rate of 98% (49 of 50 patients) through frontline treatment: 23 patients (46%) with complete response, 13 patients (26%) with very good partial response, and 13 patients (26%) with partial response. The remaining patient showed stable disease despite 6 cycles of treatment with bortezomib-melphalan-prednisolone, finishing her frontline treatment early due to unacceptable peripheral neuropathy. RAS/RAF mutations did not provide a significant impact on either complete response rate or the achievement of partial response of any degree (Table 2).
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
With a respective median PFS of 23.5 months (95% CI, 16.5–25.6) and median OS of 105.7 months (95% CI, 63.7–not estimable) (Supplementary Fig. 1), RAS/RAF mutations were significantly associated with poor median PFS [24.0 mo (95% CI, 16.5–49.3) vs. 18.2 mo (3.6–24.2),
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
In this study, we identified 14 patients with PCM and RAS/RAF mutations (28%).
From a clinical perspective, the prognostic significance of RAS/RAF mutations in PCM is controversial. The application of novel therapeutic agents has changed the influence of these mutations. One study showed that RAS mutations appeared to be significantly associated with a favorable outcome [26]. Another study showed that functional activation of the RAS pathway was observed in 75% of patients with relapsed/refractory PCM and about half had RAS/RAF mutations [27]. In this study, we demonstrated that RAS/RAF mutations were associated with poor outcomes, such as a shorter PFS. Aside from RAS/RAF mutations, a subgroup with
Our study has several limitations. This is a retrospective study using selected BM samples of inpatients considered to be in a more severe condition with a high disease burden. Thus, the proportion of karyotype abnormalities and ISS stage II were relatively higher compared to a previous study in Asian patients [35]. There is also a possibility that the prevalence of
Consequently, this study 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 outcomes and their potential as a therapeutic target.
This study was supported by a grant from the Korea Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A120175).
No potential conflicts of interest relevant to this article were reported.
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