Lack of Awareness in Managment and Monitoring of Monoclonal Gammopathy of Undetermined Significance (MGUS) in Patients aged 60 years and more in Primary Health Care: Short Communication

Monoclonal gammopathy of undetermined significance (MGUS) presents a rare premalignant clonal plasma cell disorder, characterized by the presence of a monoclonal (M) protein, less than 10% of clonal plasma cells in the bone marrow and absence of multiple myeloma or related lymphoplasmacytic malignancies [1,2]. It is associated with a rate of progression to multiple myeloma or a related malignant condition of 1 percent per year or less [3]. The prevalence of monoclonal gammopathy of undetermined significance among persons 50 years of age or older has not been accurately determined [4]. In previous studies, the frequency of monoclonal immunoglobulins in serum from a normal population has been reported to be 0.5 to 3.6 percent among patients seen in community practice, and usually it was the coincidental finding of MGUS [5-7]. Previous reports expected that the number of living individuals diagnosed with MGUS will be well over a million in next 30 years [8]. Cause current practice guidelines do not recommend routine screening for MGUS in the general population because of the lack of proven benefit and absence of curative or preventive therapy. In this overview, we assume severe difficulities in managment of MGUS in patients aged 60 years and more in primary health care. Abstract


Introduction
Monoclonal gammopathy of undetermined significance (MGUS) presents a rare premalignant clonal plasma cell disorder, characterized by the presence of a monoclonal (M) protein, less than 10% of clonal plasma cells in the bone marrow and absence of multiple myeloma or related lymphoplasmacytic malignancies [1,2]. It is associated with a rate of progression to multiple myeloma or a related malignant condition of 1 percent per year or less [3]. The prevalence of monoclonal gammopathy of undetermined significance among persons 50 years of age or older has not been accurately determined [4]. In previous studies, the frequency of monoclonal immunoglobulins in serum from a normal population has been reported to be 0.5 to 3.6 percent among patients seen in community practice, and usually it was the coincidental finding of MGUS [5][6][7]. Previous reports expected that the number of living individuals diagnosed with MGUS will be well over a million in next 30 years [8]. Cause current practice guidelines do not recommend routine screening for MGUS in the general population because of the lack of proven benefit and absence of curative or preventive therapy. In this overview, we assume severe difficulities in managment of MGUS in patients aged 60 years and more in primary health care.

MGUS and Comorbidity
Comorbidity is defined as the co-occurence of more than one disorder in the same individual as result from many factors. One disorder may represent an early manifestation of another, and sometimes can overlap with many other disorders [9]. These conditions present a big challenge in family medicine practice, while comorbidities correlate with aging and make the elderly particularly vulnerable to toxicities of therapy [10]. Observations of comorbidity among populations may be extremely useful in informing the therapist's understanding of an individual patient, especially in family medicine practice [11]. For example, the presence of one disorder in a patient may make another condition more visible, even though it may be no more common than in a general population. Similarly, the presence of one disorder may influence the observations of clinicians and make them more likely to report the presence of another disorder. The conceptual and pragmatic logic of a generalist approach to the care of patients with chronic illness is compelling. The issue of comorbidity highlights the intricacy of primary care and the complexity of providing holistic care. Another challenge to medical generalism is the difficulty of measuring health status and clinical outcomes, especially in rare disorder. As usually chronic disease starts at age 50 and more, a monoclonal protein is often discovered incidentally on routine blood testing ( as part of an investigation for a clinical condition such as osteophorosis, rheumatological disorders, nephrotic syndrome, peripheral neuropathy, congestive heart failure, endocrine disorders) [12]. In those patients with comorbidities who present with anemia, back pain, renal insufficiency, osteolytic bone lesions, or unexplained peripheral neuropathy, they should be screened for the presence of an M-protein [13]. Routinely found laboratory small monoclonal abnormalities, low light chain monoclonal gammopathy of undetermined significance (LCMGUS) should be follow, eventhough it represents a relatively benign condition [14].

Low knowledge and awareness of MGUS among general practitioners
Clinical diagnosis and regular monitoring of the population at risk of chronic diseases is clinically and financially resourceintensive. Mining administrative data could be an effective alternative way to identify this high-risk cohort. Once, when an M protein is detected, the majority of patients will initially be under the care of their primary care physician ( GP) or a clinician outside haematology [15]. Due to M-findings, comprehensive history analysis, physical examination and laboratory tests (serum protein electrophoresis to quantify the protein, serum immunofixation, serum free light chains, complete blood cell count, calcium and creatinine) should be done, taking into consideration the differential diagnosis of monoclonal gammopathies. Nowadays, one of the biggest problem in every day clinical practice is early recognition of this rare medical condition. McShane CM et al. explored GP knowledge and awareness of MGUS and their perceived support needs to manage MGUS patients within primary care [16]. The results showed a lack of knowledge and awareness of MGUS among general practitioners and suggested multidisciplinary approach with support from haematology in providing these services. These findings are also in agreement with previous studies with MGUS patients and haematology healthcare professionals who reported low awareness of MGUS outside of haematology, which may be associated with no special education in this field and to burn out of GP-s [17,18]. Cause these patients usually present with no tipical symptoms, MGUS is classified as a 'hard to suspect' premalignat lesion [19].

Working groups involving primary care and haematology specialists in follow up
It is relatively easy to order serum protein electrophoresis (SPEP), serum immunofixation, and serum FLC assays, clinicians need to be more judicious when ordering these tests, given the consequences of a MGUS diagnosis. These tests should be performed only in patients in whom there is clear suspicion that could be associated with M-protein. After, when MGUS is confirmed, the patient should be risk-stratified to determine the need for bone marrow biopsy and to predict the risk of progression to more serious conditions. In patients with lowrisk MGUS who do not have any unexplained clinical concerns, skeletal imaging and bone marrow biopsy can be deferred. The Mayo Clinic risk stratification model is used with low-risk defined as having all of the following: serum M-protein ≤1.5 g/dL, IgG isotype, and normal FLC ratio [20,21]. Routine skeletal imaging and bone marrow biopsy in low-risk MGUS have a low yield. In these patients, a follow-up assessment of M-protein level in next 6 months will most likely identify any patient who needs further evaluation. While approximately 50% of MGUS patients are at low risk, avoiding skeletal imaging and bone marrow biopsy in these patients will minimize health care costs without adversely affecting clinical outcome [22]. Future research on biomarkers in the progression from MGUS to MM (multiple myeloma) will give more insight in the unknown pathogenesis of this hematological malignancy [22]. This would improve research by elucidating new pathways and potential therapeutic targets as well as clinical management by closer follow-up and earlier treatment of high-risk MGUS patients. Despite this, there is lack of increasing government and public demand for primary care to expand its role in cancer prevention, early detection and control, and management within the community especially in rare hematological disorder. Even though most patients diagnosed with monoclonal gammopathy of undetermined significance will never develop malignant disease, follow-up is needed to identify those patients at risk of progression [23].
The challenge therefore remains to increase GP awareness of MGUS, regular diagnostic approach and new biomarkers in laboratory work. Also, there is important role of GP-s in educating patients to report any new worrisome symptom (bone pain, fatigue, neuropathy, weight loss, night sweats) with previous detected MGUS, cause these could be a significant as predictor of disease progression and appropiate staging All these steps, may minimaze major complications and initate proper timely treatment [24]. Discontinuation of follow-up can be considered for patients with a life expectancy of <5 years and among those >80 years old, consistent with screening guidelines for other common yet potentially curable cancers (discontinuation of screening at >65 years of age for cervical cancer, >75 years for breast and colon cancers, and >80 years for lung cancer).

Conclusion
Current practice guidelines do not recommend routine screening for MGUS in the general population because of the lack of proven benefit and absence of curative or preventive therapy. Patients with more comorbidities may present severe difficulities in early detection and managment of MGUS, due to overlapping of symtomps. Follow-up is needed to identify those patients at risk of progression. Future research should offer better biomarkers in order to predict the risk of transformation to MM.