A nationwide study of patients with monoclonal gammopathy of undetermined significance with a 10-year follow-up in South Korea

In clinical practice, most patients with monoclonal gammopathy of undetermined significance (MGUS) undergo long-term follow-up without disease progression. There is insufficient real-world data about how closely and whether anything other than disease progression should be monitored. Herein, we performed a nationwide study of 470 patients with MGUS with a 10-year follow-up to determine the patterns of disease progression and other comorbidities. During the follow-up period, 158 of 470 patients with MGUS (33.62%) progressed to symptomatic monoclonal gammopathies. Most of these were multiple myeloma (134/470 patients, 28.51%), and those diagnosed within 2 years after diagnosis of MGUS was high. Approximately 30–50% of patients with MGUS had hypertension, diabetes, hyperlipidemia, and osteoarthritis at the time of diagnosis, and these comorbidities were newly developed during the follow-up period in approximately 50% of the remaining patients with MGUS. Approximately 20–40% of patients with MGUS have acute or chronic kidney failure, thyroid disorders, disc disorders, peripheral neuropathy, myocardial infarction, stroke, and heart failure during the follow-up period. Altogether, when MGUS is diagnosed, close follow-up of the possibility of progression to multiple myeloma is required, especially within 2 years after diagnosis; simultaneously, various comorbidities should be considered and monitored during the follow-up of patients with MGUS. Continuous research is needed to establish appropriate follow-up guidelines.

Clinical endpoints. We aimed to confirm the prevalence of MGUS in South Korea and to determine the occurrence patterns of disease progression and other comorbidities during the 10-year follow-up period.
The prevalence of MGUS was calculated by dividing the number of patients with MGUS by the mid-year population (Table 1 and Supplementary Table 2). The HIRA only provides claim data for the patient population that the researcher intends to study (HIRA policy due to database serving capacity limitations). Instead, information on the number of patients with specific diseases (excluding details about that population) is disclosed to the general public as public data. In this study, we analyzed the claims data extracted from January 1, 2007, to August 31, 2019, for patients who were diagnosed with MGUS from January 1, 2007, to August 31, 2009. To present the number of patients with MGUS from 2007 to 2019, the number of patients with MGUS in 2007 and 2008 was derived from the HIRA database, and the data after 2009 were derived from the public data provided by HIRA (Fig. 1).
Disease progression was defined as the occurrence of MM, PCL, plasmacytoma, WM, amyloidosis, and any lymphoproliferative disease or hematologic malignancies after the date of diagnosis of MGUS. The incidence of disease progression was presented as the number of new patients in the year normalized to the number of patients with MGUS in this study. The prevalence was presented as the number of total patients in the year normalized to the number of patients MGUS in this study.
Comorbidities included chronic diseases known to be common in South Korea 23 or diseases commonly associated with patients with MGUS in existing studies [11][12][13]16 . For solid malignancies, the seven most common cancers in South Korea were selected 24 . The prevalence of comorbidities at the diagnosis of MGUS was defined as comorbidities diagnosed from January 1, 2007, to the date of MGUS diagnosis. Newly developed comorbidities were defined as newly developed diseases in patients with MGUS who did not have any comorbidities at the time of MGUS diagnosis. As mentioned above, the HIRA provided claims data for patients who were diagnosed with MGUS from January 1, 2007, to August 31, 2009. To determine the prevalence of comorbidities in patients with MGUS compared to the entire population, the prevalence data for each comorbidity in the entire population (determined from public data from the HIRA database) were presented as reference data. The prevalence calculation method for each comorbidity in the entire population is presented as a figure legend in Supplementary    31,2009, was 0.37-0.50 overall and 1.11-1.52 in those aged 50 years or older. The prevalence of MGUS was higher in individuals aged 50 years and older and in men ( Table 1). The prevalence has been shown to increase annually, and from around 2015, the trend of increase has become steeper ( Fig. 1).
The occurrence patterns of disease progression during the follow-up period of MM, PCL, extramedullary plasmacytoma, solitary plasmacytoma, WM, and amyloidosis are shown in Fig. 2. In the case of MM, WM, and amyloidosis, the probability of occurrence within 2 years of initial diagnosis of MGUS tended to be high. PCL, extramedullary plasmacytoma, and solitary plasmacytoma showed a tendency to occur sporadically throughout the follow-up period. In patients who progressed to MM, the median duration from the date of diagnosis of MGUS to the date of diagnosis of MM was 2.  Tables 3 and 4. Population-wide prevalence data for each comorbidity are presented as reference data in Table 3. The prevalence calculation method for each comorbidity is presented as a figure legend in Supplementary Figure 1 (Fig. 3). Solid malignancies occurred in 5% of the patients during the follow-up period.

Discussion
In this study, the prevalence rate of MGUS was 1. The prevalence of MGUS in those older than 50 years has been reported to be 3.6-3.9% in Western countries 10,25 and 0.8-3.3% in Eastern countries [26][27][28] . In this study, the prevalence rate per 100,000 was 0.37-0.50 overall and 1.11-1.52 in those aged 50 years or older in South Korea between January 1, 2007, and August 31,2009. Considering that the world standardized incidence rate for MGUS was 3.76 ± 0.26 per 100,000 inhabitants reported in a population-based study in France 29 , the prevalence of MGUS in South Korea between January 1, 2007, and August 31,2009, is thought to be relatively low compared to other countries. However, it is difficult to directly compare the prevalence of previous studies with those of the present study. In this study, we calculated the period prevalence by dividing the total number of patients with MGUS by the mid-year population. In other words, this study determined prevalence using the claim data for MGUS as a numerator and the mid-year population as the denominator, which is an arbitrary number representing the population. During the recruitment period, asymptomatic cases or cases in which the individual did not receive treatment could not be captured by this method; thus, the prevalence of MGUS could be somewhat underreported. In addition, since the mid-year population could be larger than the actual population, there is a possibility that the prevalence of MGUS in this study was somewhat underreported. In contrast, previous studies conducted screening tests for M-protein in all subjects regardless of symptoms, and these studies were conducted in limited participant groups recruited in community practices, hospitals, or regions, rather than the entire population.
It should be noted that the number of patients with MGUS is increasing every year compared to the patient registration period of this study (January 1, 2007, to August 31, 2009). This trend has not only been seen in South Korea, but also in other Asian countries, including Japan, Taiwan, and Hong Kong 27,28,30 . The reasons for this increase could be related to rapid industrialization and increased life span, which are common trends among Asian countries. Since aging is associated with the incidence of MGUS, increased life span may have increased the prevalence of MGUS. Alternatively, as interest in MGUS and diseases related to MGUS increases, more cases are assessed for MGUS, which may lead to greater detection of MGUS cases. Additionally, the prevalence of MGUS decreased in those over 80 years of age in this study, contrary to what it has been widely demonstrated in previous studies that indicated that prevalence of MGUS increases with increasing age 10,25 . Considering that this study was based on analysis of insurance claims data, it is possible that people in this age group had more passive hospital visits and treatment compared to younger people. Alternatively, this trend may be due to limited access to medical services in older patients. , and amyloidosis (2.13%) during a 10-year follow-up period. MM, WM, and amyloidosis showed a tendency to occur within 2 years after the initial diagnosis of MGUS; in contrast, PCL, extramedullary plasmacytoma, and solitary plasmacytoma occurred sporadically throughout the follow-up period. The molecular basis of MGUS progression to symptomatic monoclonal gammopathy remains poorly understood; however, several genetic aberrations may be involved in its mechanism. Taking this into account, the genetic factors involved in the mechanism of progression of symptomatic monoclonal gammopathy may differ from each other, which may have led to the above epidemiological pattern 3,31-34 . The 10-year cumulative probability of progression to MM in this study was higher than previously known (approximately 10%) 1,7,18,35 , which may also be due to racial and genetic differences. Alternatively, it could be due to insufficient work-up to exclude symptomatic monoclonal gammopathy at the time of diagnosis of MGUS in the real world because routine bone marrow examination or CT in all patients with MGUS was a controversial guideline in 2010 4,6,7,36 . In fact, in the present study, bone marrow examination, spinal CT, and spinal MRI were performed in only 20.2%, 1.5%, and 0.9% of 470 patients with MGUS, respectively. In addition, approximately 50% of patients progressed to MM within 3 months from the date of MGUS diagnosis. Based on the results of this study, it can be suggested that when diagnosing patients with MGUS, sufficient tests should be performed to differentiate symptomatic monoclonal gammopathy, especially MM. If sufficient testing is not performed, close follow-up within three months of diagnosis is necessary. Another important consideration is that since this study selected patients with MGUS based on insurance claims data, patients without symptoms or specific clinical abnormalities may have been excluded. Therefore, the higher 10-year cumulative probability of progression reported in this study may have been due to the under-diagnosis of low-risk cases of MGUS with a low risk of disease progression.

Baseline characteristics
Interestingly, approximately 30-50% of patients with MGUS had HTN, DM, HLD, and OA at the time of diagnosis of MGUS, and these comorbidities were newly developed during the follow-up period in approximately 50% of patients who did not have any comorbidities at the time of diagnosis of MGUS. According to data from the Korean National Health and Nutrition Examination Survey, the prevalence of HTN, DM, HLD, and OA in the population aged 50 years and older in South Korea is reported to be approximately 35%, 15%, 50%, and 35%, respectively [37][38][39][40][41] . Although direct comparison is impossible, it is deemed a significant number, considering that out of the total 470 patients with MGUS, the probability of already having or someday having these comorbidities is up to 80%. This may be because MGUS might be associated with the pathophysiology of HTN, DM, HLD, and OA. Alternatively, it may have been found that the chances of visiting the hospital and undergoing tests increased during the follow-up period for MGUS, considering the high incidence of these comorbidities within 5 years of MGUS diagnosis (Fig. 3). Conversely, a population that has already been diagnosed with HTN, DM, HLD, OA or belonging to a high-risk group that could proceed to these conditions have higher healthcare utilization and are therefore more likely to be tested for MGUS, that may have led to the results of this study.
Monitoring for kidney disease in patients with MGUS is important because it is one of the end-organ damages that can be caused by disease progression. In contrast, monoclonal gammopathy of renal significance (MGRS), in which one or more kidney lesions related to the produced monoclonal immunoglobulin occur without disease progression 42 . In this study, approximately 30% of 470 patients with MGUS had existing or newly developed acute or chronic kidney disease. This is a fairly high number compared to the pooled incidence of acute kidney disease in the general hospitalized population, which is 19.4% in Eastern Asia according to KDIGO-equivalent criteria 43 . The total prevalence estimate of chronic kidney disease in adults aged over 20 years in South Korea was 8.2% 44 . Supplementary Figures 3 and 4 present cases of newly occurring acute or chronic kidney disease in patients with MGUS divided according to disease progression. In this study, 15/470 patients (3.19%) and 13/470 patients (2.77%) were diagnosed with acute or chronic kidney disease, respectively, several months before disease progression. Additionally, 52/470 patients (11.06%) and 63/470 patients (13.40%) were diagnosed with acute or chronic kidney disease, respectively, without evidence of disease progression. These patients may have had MGRS. MGRS-associated kidney diseases do not respond well to the immunosuppressive regimens, and may necessitate clone-directed therapy. Affected patients have an approximately 90% recurrence after kidney transplantation www.nature.com/scientificreports/ if monoclonal gammopathy is not eliminated before or immediately after transplantation [45][46][47] . Therefore, it is necessary to raise awareness for these patients and actively consider kidney biopsy if MGRS is suspected. In addition, approximately 20-40% of all MGUS patients in this study had pre-existing or newly diagnosed comorbidities such as thyroid disorders, disc disorders, peripheral neuropathy, myocardial infarction, stroke, and heart failure. These prevalence and incidence rates are higher than previously known [48][49][50][51][52][53][54] . However, it is difficult to conclude whether MGUS or underlying comorbidities may be risk factors for these diseases. Nevertheless, according to the results of this study, it is considered necessary to monitor not only disease progression but also the comorbidities mentioned above in the follow-up of patients with MGUS. In the case of solid malignancies, less than 5% of patients with MGUS were newly identified within the follow-up period. This is similar to the previously known average risk [55][56][57][58][59] ; therefore, it is reasonable to perform cancer screening in MGUS patients in the same manner as in the general population.
This study analyzed claims data using the HIRA database; therefore, the present study has several limitations. First, because information on risk factors, including individual patient's type of MGUS and blood test at the time of diagnosis cannot be identified, detailed risk groups cannot be classified. Second, it was impossible to directly analyze the risk compared to the matched general population because HIRA only provided data concerning the population with MGUS claims data rather than the entire population (HIRA policy due to database capacity limitations). For example, this study showed that the prevalence of the aforementioned comorbidities in patients with MGUS was higher than the prevalence data for each comorbidity in the entire population provided by the public HIRA database (2010). However, it was not possible to determine whether this was due to MGUS or other combined comorbidities, as the comparison was not made with the general population, which was corrected for several factors that could influence these results. Third, we defined the prevalence of comorbidities at diagnosis of MGUS as comorbidities from January 1, 2007, to the date of diagnosis with MGUS, and newly developed comorbidities were defined as newly developed diseases in MGUS patients who did not have any comorbidities at the time of diagnosis of MGUS. There is a limitation in that the follow-up period, according to the date of diagnosis of MGUS, differed in determining the prevalence of comorbidities or the number of newly developed cases in this study. Although the distribution of the date of diagnosis with MGUS was relatively even except for January 2007, and the median follow-up duration for the definition of prevalence was 15.61 months, which was close to the average patient enrollment period (Supplementary Figure 5), it is necessary to be cautious in interpreting the prevalence of comorbidities or newly developed diseases presented in this study. Nevertheless, it is considered to be important because this study presented the prevalence of MGUS in South Korea and information on the occurrence patterns of disease progression and comorbidities during a 10-year follow-up period of patients with MGUS in the real world.
In conclusion, in this study, 33.62% of the patients with MGUS experienced disease progression to symptomatic monoclonal gammopathies during a 10-year follow-up in the real world. Most patients had MM, and the incidence rate was high within 2 years of the diagnosis of MGUS. In addition, approximately 80% of patients with MGUS were diagnosed with HTN, DM, HLD, and OA at the time of diagnosis or during the follow-up period. Taken together, when MGUS is diagnosed, close follow-up of the possibility of progression to MM is required, especially within 2 years after diagnosis; at the same time, various comorbidities should be considered and monitored during the follow-up of patients with MGUS, especially HTN, DM, HLD, and OA. Since this study was performed by analyzing insurance claims data, it must be taken into account that the prevalence of MGUS and its correlative comorbidities could have been underestimated from the actual prevalence, and more studies are needed to transition from the current disease progression detection-centered guidelines to those that can improve overall patient care.