Monoclonal gammopathy of uncertain significance | Medicina Clínica (English Edition)

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ClCr: aclaramiento de creatinina; CLL: cadenas ligeras libres; CM: componente monoclonal; GMSI: gammapatía monoclonal de significado incierto; TAP: toraco-abomino-pélvico. *Definido por la estadificación de la Clínica Mayo: CM≤1,5g/dL, isotipo IgG y ratio CLL normal. **Ver <a class="elsevierStyleCrossRef" href="#tbl0015">tabla 3</a>." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Elena Alejo, Borja Puertas, María-Victoria Mateos" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Elena" "apellidos" => "Alejo" ] 1 => array:2 [ "nombre" => "Borja" "apellidos" => "Puertas" ] 2 => array:2 [ "nombre" => "María-Victoria" "apellidos" => "Mateos" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2387020623003364" "doi" => "10.1016/j.medcle.2023.05.011" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020623003364?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775323002890?idApp=UINPBA00004N" "url" => "/00257753/0000016100000005/v3_202312011048/S0025775323002890/v3_202312011048/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2387020623003327" "issn" => "23870206" "doi" => "10.1016/j.medcle.2023.04.023" "estado" => "S300" "fechaPublicacion" => "2023-09-08" "aid" => "6287" "copyright" => "Elsevier España, S.L.U." 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CrCl, creatinine clearance; FLC, free light chains; MC, monoclonal component; MGUS, monoclonal gammopathy of uncertain significance; TAP, Thorax, Abdomen and Pelvis; *Defined by Mayo Clinic staging: MC ≤ 1.5 g/dL, IgG isotype and normal FLC ratio. **See <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>." ] ] ] "textoCompleto" => "Introduction: definition and classificationPlasma cell (PC) dyscrasias, dysproteinaemias or monoclonal gammopathies are a heterogeneous group of entities characterised by clonal proliferation of PCs and secretion of an aberrant immunoglobulin detectable in blood and/or urine, paraprotein or monoclonal component (MC).Monoclonal gammopathy of uncertain significance (MGUS) was first described in 1960 by Dr. Jan Waldeström as benign gammopathy or essential hypergammaglobulinemia. In 1978, Dr. Kyle defined MGUS as the detection of a MC without being associated with signs and/or symptoms of multiple myeloma (MM), amyloidosis (AL), macroglobulinemia or other lymphoproliferative syndromes.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> According to the latest 2014 International Myeloma Working Group (IMWG) diagnostic criteria for gammopathies,<a class="elsevierStyleCrossRef" href="#bib0010">2</a> all of the following criteria are required to diagnose a patient with MGUS: serum MC of less than 3 g/dl, bone marrow (BM) infiltration of less than 10% of PCs, and the absence of myeloma-defining events (MDEs). MDEs comprise classic CRAB symptomatology (hypercalcaemia, renal failure, anaemia and lytic lesions), and the 3 biomarkers of malignancy (infiltration ≥60% of PCs in BM, free light chain involved/uninvolved ratio ≥100, or more than one focal lesion ≥5 mm on whole body or spine MRI study). Patients with a MC ≥ 3 g/dl and/or ≥500 mg/24 h in urine and/or 10–60% of PCs in the BM without MDEs are diagnosed with quiescent multiple myeloma (QMM). Multiple myeloma (MM) is the paradigm of monoclonal gammopathies and is defined by the presence of ≥10% of PCs in the BM or plasmacytoma and MDEs. The detection of MC is not essential to make the diagnosis of MM, so patients who meet criteria for this gammopathy without the identification of MC or immunofixation abnormalities in serum or urine constitute the subgroup of non-secretory myelomas (<5% of newly diagnosed MM).MGUS is the most common PC dyscrasia, accounting for around 50–60% of the total.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> It is generally asymptomatic and its premalignant nature is widely accepted, being a preliminary and necessary stage for the development of other gammopathies.<a class="elsevierStyleCrossRefs" href="#bib0020">4,5</a> Its clinical course and progression will be determined by the type of immunoglobulin involved, with three types of MGUS being differentiated: IgM, non-IgM and light chain.<a class="elsevierStyleCrossRefs" href="#bib0030">6,7</a> The most common are IgG (≈70%), followed by IgM (15%), IgA (12%), biclonal (3%) and light chain (<1%).<a class="elsevierStyleCrossRefs" href="#bib0015">3,8</a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> describes the diagnostic criteria for the different subtypes of MGUS and their risk of progression.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>EpidemiologyThe importance of MGUS lies in its high prevalence, occurring in 3.2% of patients over 50 years of age. Moreover, its prevalence increases progressively with age, being higher than 5 and 7% in patients older than 70 and 85 years, respectively.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> However, the Iceland screens, treats or prevents multiple myeloma (iStopMM) study recently conducted in Iceland with more than 75,000 patients shows that the prevalence of IgA MGUS subtype does not increase with age.<a class="elsevierStyleCrossRef" href="#bib0045">9</a>MGUS is significantly more common in men than in women as demonstrated in a study involving more than 20,000 patients over the age of 50. In this study, a prevalence of 4.0% was observed in men and 2.9% in women (p < 0.001), and these differences were maintained regardless of age at diagnosis.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> Other population-based studies highlight its racial association, with differences not only in prevalence, but also in age at presentation, type and amount of paraprotein. African Americans are up to 3 times more likely to be diagnosed with MGUS than Caucasians, with younger patients, lower paraprotein levels, and less common IgM. However, no differences are observed in terms of progression to MM.<a class="elsevierStyleCrossRefs" href="#bib0040">8,10–13</a> In contrast, MGUS is less often detected in Asian patients, especially in women, as reported in a study in the Nagasaki population.<a class="elsevierStyleCrossRef" href="#bib0070">14</a>With the introduction of more sensitive techniques for MC detection, such as mass spectrometry (MS), MGUSs are more commonly detected. MS confers greater specificity for detecting the presence of small amounts of paraprotein and is also capable of detecting light chain glycosylation, which has been shown to be a risk factor for the development of PC dyscrasias.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> A recent study in the American population has shown that, in high-risk patients over 50 years of age, the prevalence of MGUS in the black population, analysed by MS, is up to 17%, with no significant differences found in those with a family history of gammopathy.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>AetiopathogenesisDifferent authors agree that the PC responsible for MGUS is a post-germline one, because there are several sequencing studies of segment VH of the immunoglobulin heavy chain (IGH) gene which show a large number of mutations, but with an absence of intraclonal variation.<a class="elsevierStyleCrossRefs" href="#bib0025">5,17</a> Classically, it is thought that the first genetic alteration favouring the development of MGUS occurs after abnormal DNA repair during somatic hypermutation and isotype switching recombination of immunoglobulins. Following repair of this break, abnormal rearrangements involving oncogenes can occur, conferring an evolutionary advantage to these post-germline B cells. Subsequently in the BM, the clonal PC will interact with the microenvironment favouring its survival, leading to the accumulation of second genetic events and possible progression to other entities (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bib0085">17</a> However, this instructive multi-stage natural history form of MGUS is being challenged by increased knowledge of plasma cell biology and the demonstration of clonal heterogeneity in patients with PC dyscrasia.<a class="elsevierStyleCrossRef" href="#bib0090">18</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Genetic predispositionAs with other diseases, familial aggregation in the development of MGUS has been reported. Two independent studies have shown that people with a first-degree family history of MGUS have up to a 3-fold increased risk of developing MGUS compared to the general population.<a class="elsevierStyleCrossRefs" href="#bib0095">19,20</a>Recent genome-wide association studies (GWAS) have identified more than 30 polymorphisms associated with an increased risk of developing MGUS. However, the effect of these polymorphisms on the eventual progression to MM, AL or other diseases is currently unknown.<a class="elsevierStyleCrossRefs" href="#bib0105">21,22</a>Toxic exposureSeveral retrospective population-based studies have identified radiation exposure as a risk factor, with the risk being 1.7 times higher in a retrospective study of 1945 atomic bomb survivors.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> Other studies point to exposure to pesticides, herbicides or fungicides as a risk factor for this entity, increasing the risk by 2–4 times compared to non-exposed individuals.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> A causal relationship has also been established between smoking or air pollution and MGUS.<a class="elsevierStyleCrossRefs" href="#bib0125">25,26</a>Diseases and monoclonal gammopathy of uncertain significanceClassically, previous history of bacterial and viral infections and/or autoimmune diseases have been positively associated as a risk factor for MGUS. A Swedish population-based study reported that the prevalence of MGUS in individuals with a history of significant infections (meningitis, pneumonia, septicaemia, pericarditis, endocarditis…) or autoimmune diseases was 1.5–2 times higher than in a population without such a history.<a class="elsevierStyleCrossRefs" href="#bib0120">24,25</a> Similar results were published in an American study. Both associations are supported by the theory of chronic antigenic stimulation. According to this theory, persistent stimulation and activation of the immune system would favour the development and proliferation of PCs that can acquire a genetic event and favour the development of a monoclonal gammopathy.In contrast, in the prospective iStopMM study, no association between MGUS and autoimmune diseases was observed.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> Prior to the start of the study, it had been established in the Icelandic population that patients with autoimmune diseases were twice as likely to develop MGUS. However, the results of the study show no relationship between the two entities, which casts doubt on the biological correlation reported in previous studies.Metabolic syndrome, and especially obesity, has also been associated with an increased risk of developing MGUS and its progression to MM.<a class="elsevierStyleCrossRefs" href="#bib0140">28,29</a> However, being a patient-dependent modifiable factor, the results of studies that have analysed this association are inconsistent.<a class="elsevierStyleCrossRefs" href="#bib0125">25,28,29</a> However, it appears that adequate metabolic control plays a role in the eventual progression of MGUS, as noted in a retrospective study in which metformin use in diabetic patients reduced progression to MM by more than 50%.<a class="elsevierStyleCrossRef" href="#bib0150">30</a>Genomic alterationsMGUS is a very heterogeneous entity from a genetic perspective. Primary genetic events comprising alterations involved in the genesis of the disease, and secondary genetic events responsible for clonal expansion and progression to MM or other diseases have been described.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Although patients with MGUS have been shown to have genomic alterations in common with QMM or MM, the genetic complexity of MGUS is significantly lower.<a class="elsevierStyleCrossRefs" href="#bib0155">31–33</a> A study by the Salamanca group demonstrated this statement in a very visual way: only 48% of patients with MGUS had more than one chromosomal alteration detected by fluorescence in situ hybridisation (FISH) compared to more than 70% in QMM and MM. In addition, all detected chromosomal alterations were present in a lower percentage of PCs in patients with MGUS.<a class="elsevierStyleCrossRef" href="#bib0160">32</a>Copy number variations are the most common genome alteration in MGUS patients, being detected in 60% of patients, and include gains of 1q, 3p, 6p, 9p,11q, 19p and 21q or deletions of 1p,13q, 16q,17p or 22q.<a class="elsevierStyleCrossRefs" href="#bib0155">31–33</a> The 1q gain is the most prevalent and is detected in 30% of patients. Other copy number variations traditionally analysed in MM are also detected in MGUS, such as 13q deletion (≈20%), 17p deletion (1%).<a class="elsevierStyleCrossRef" href="#bib0160">32</a> A copy number variation characteristic of Waldeström macroglobulinemia (WM) is the 6q deletion but is not detected in IgM MGUS, so this would be a late genetic event related to the progression of the gammopathy.<a class="elsevierStyleCrossRef" href="#bib0170">34</a>One of the most commonly detected genome alterations in patients with MGUS is the IGH gene translocation (≈40–50%).<a class="elsevierStyleCrossRef" href="#bib0175">35</a> The prevalence of the different IGH translocations is lower compared to MM, with the prevalence of t (11;14) and t (4;14) being 10 and 5%, respectively.<a class="elsevierStyleCrossRefs" href="#bib0160">32,35</a> The MYC translocation is not usually detected in MGUS patients, but is present in 15% of MM patients, indicating that it may be a late genetic event favouring clonal expansion.<a class="elsevierStyleCrossRef" href="#bib0155">31</a>Somatic mutations are also detected in patients with MGUS. In non-IgM MGUS, the most commonly detected are those affecting the MAPK (N-RAS) or NF-ĸB (LTB) metabolic pathways, although less common than in MM patients.<a class="elsevierStyleCrossRefs" href="#bib0155">31,35</a> IgM MGUS has a spectrum of different somatic mutations including MYD88 (L265 P), CXCR4 and KMT2D mutation, present in 60, 9 and 5% of patients, respectively.<a class="elsevierStyleCrossRef" href="#bib0180">36</a> The TP53 mutation has not been detected in patients with MGUS, so it would be a genetic alteration related to MGUS progression.<a class="elsevierStyleCrossRef" href="#bib0155">31</a>Tumour microenvironmentThe marrow microenvironment consists of cellular elements such as B cells, T cells, natural killer (NK) cells, myeloid cells, stromal cells, osteoblasts and osteoclasts, and non-cellular elements such as the extracellular matrix. Quantitative and qualitative differences have been described in the immune system of patients with MGUS compared to healthy individuals, such as the expansion of myeloid suppressor cells and regulatory T cells or the inactivation of effector T cells. The bidirectional interaction of clonal PCs with elements of the microenvironment through cytokines and growth factors and the immunosuppressive environment will favour clonal survival and expansion and eventual progression of MGUS to other diseases such as MM.<a class="elsevierStyleCrossRef" href="#bib0185">37</a>Dysregulation of the microenvironment is closely related to the production of the osteolytic lesions characteristic of MM by altering bone homeostasis, and to immunoparesis by decreasing the production of normal PCs in favour of pathological PCs.Natural history of monoclonal gammopathy of undetermined significance and risk factors associated with progressionA US study involving 1,384 patients diagnosed with MGUS was reported in 2018. After a median follow-up of more than 15 years, the annual risk of progression of MGUS to other diseases was 1%: 10% at 10 years, 18% at 20 years, 28% at 30 years and 36% at 40 years. Of the 147 patients who progressed to other entities, 97 (7%) progressed to MM, 19 (1.4%) to non-Hodgkin's lymphoma (NHL), 14 (1%) to AL, 13 (1%) to WM, 3 (0.2%) to chronic lymphocytic leukaemia (FLC) and one (0.07%) to plasmacytoma.<a class="elsevierStyleCrossRef" href="#bib0190">38</a>Baseline value, type and progressive increase of the monoclonal componentAccording to a study by Kyle et al., the baseline monoclonal component is the most important predictor of progression and the risk of progression is directly related to the baseline concentration of a MC.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> Those patients diagnosed with a MC ≥ 1.5 and ≥2.5 g/dl were 2 and 5 times more likely to progress to other disease compared to patients with a MC below 0.5 g/dl at diagnosis, respectively. The predictive value of baseline paraprotein concentration has also been tested by other working groups.<a class="elsevierStyleCrossRefs" href="#bib0200">40,41</a>IgG type MGUS have the lowest risk of progression compared to IgA or IgM MGUS.<a class="elsevierStyleCrossRefs" href="#bib0195">39,40</a> Furthermore, the above-mentioned American study<a class="elsevierStyleCrossRef" href="#bib0190">38</a> reported that patients with IgM MGUS had an annual risk of progression of 2% during the first ten years and 1% thereafter. In contrast, those with non-IgM MGUS were constant at 1% per year. Light chain MGUS have an annual progression risk of 0.3%.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>In addition to the type and value of MC, it is important to know the paraprotein dynamics. Following a study by the Hospital Clinic, the term evolving was coined to refer to patients with MGUS who progressively and annually increased their paraprotein levels over a follow-up of at least 3 years.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> The risk of progression at 10 and 20 years for evolving patients was 55% and 80%, compared to 10% and 13% for non-evolving patients, respectively.Free light chain ratioThe free light chain (FLC) ratio is an independent predictor of progression in MGUS. A Mayo Clinic study reported that patients with an abnormal free light chain ratio were 3.5 times more likely to progress to other diseases.<a class="elsevierStyleCrossRef" href="#bib0210">42</a>Aberrant plasma cellsThe percentage of MPC infiltration and the risk of progression in patients with MGUS have been related. Univariate analysis of a study including 359 patients showed that patients with MGUS and an infiltration ≥5% had a higher risk of progression than patients with a lower infiltration.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> However, PC infiltration did not independently demonstrate its impact in the multivariate analysis.Predictors of transformation were analysed in more than 400 patients with MGUS in a study by the Spanish Myeloma Group (GEM). The presence of ≥95% aberrant PCs in the BM and DNA aneuploidy of the PCs were identified as independent factors for progression. With a median time to progression of 107 months, the risk of progression for patients with MGUS was fivefold higher in those with ≥95% aberrant PCs in the BM (24 vs. 4%).Risk stratification of monoclonal gammopathy of unclear significanceThe clinical course of MGUS is heterogeneous, so attempts have been made to establish prognostic indices to identify patients at higher risk of progression and to tailor further testing and follow-up. The most widely used prognostic index is the one developed by the Mayo Clinic group that includes the baseline concentration and type of paraprotein and the FLC ratio.<a class="elsevierStyleCrossRef" href="#bib0210">42</a> Also of note is the prognostic index developed by the GEM based on immunophenotype and DNA ploidy of clonal PCs (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Clinical features and differential diagnosisAlthough numerous associations between MGUS and more than 100 different diseases have been described over the years, most cases have been found to be incidental findings given the high prevalence of MGUS in the population.<a class="elsevierStyleCrossRef" href="#bib0215">43</a>There are a number of pathological conditions associated with MGUS that can cause damage to various organs without meeting MM criteria. All these disorders, which are becoming increasingly common, constitute a new clinical entity known as clinically significant monoclonal gammopathy (MGCS). In these cases, the paraprotein causes organ damage through different mechanisms, such as tissue deposition, autoantibodies or through interactions with the complement system. Early detection of these diseases is essential to prevent progression and advanced organ damage.<a class="elsevierStyleCrossRef" href="#bib0220">44</a> Among the clinical entities most commonly associated with MGUS are monoclonal gammopathies of renal significance (MGRS), peripheral neuropathies (PNs), cutaneous and ocular entities, as well as acquired von Willebrand disease.MGRS comprises a group of relatively rare renal diseases characterised by the deposition of immunoglobulins (Igs) secreted by a clone of B cells. They include glomerulopathies with fibrillar deposits (heavy chain AL and light and heavy chain immunoglobulin), microtubular (cryoglobulinaemia types I and II, immunotactoid glomerulopathy) or unorganised deposits (monoclonal Ig deposition disease); and also tubular diseases, such as Fanconi syndrome.<a class="elsevierStyleCrossRef" href="#bib0230">46</a>The prevalence of MGUS in PN varies between 3 and 10% and is much more commonly associated with the IgM type. Generally, IgM MGUS-associated PN presents as a symmetrical demyelinating neuropathy resulting in sensory ataxia and, although less common, may also cause a mild distal predominant motor deficit. Since a causal relationship between non-IgM MGUS and neuropathy has not yet been demonstrated, IgG or IgA type MGUS can be observed in a wide spectrum of neuropathies, from sensory axonal peripheral neuropathy slowly progressing to a motor deficit to the classic chronic inflammatory demyelinating polyradiculopathy.<a class="elsevierStyleCrossRef" href="#bib0235">47</a> Other entities to consider in the differential diagnosis of PN are AL and POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes).ScreeningThere are currently no established recommendations on when to screen for MGUS in asymptomatic individuals. Due to its high prevalence in the elderly population, screening is not routinely recommended.<a class="elsevierStyleCrossRef" href="#bib0240">48</a>It is usually performed when a patient has signs and symptoms suggestive of MM, AL, WM or lymphoproliferative syndromes, such as NHL or FLC. However, most signs and symptoms are non-specific, so they are often attributed to other entities, with the finding of MGUS being considered incidental.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>Initial evaluation includes serum protein electrophoresis and immunofixation and quantification of free light chains. Once a MC is detected, 24 h urine electrophoresis and immunofixation is performed, in addition to a complete blood count and serum creatinine, creatinine clearance and calcium.Although MGUS requires by definition the presence of <3 g/dl serum paraprotein, <10% of PCs in the BM and the absence of MM-defining events, not all MGUS will require further testing (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<a class="elsevierStyleCrossRef" href="#bib0245">49</a> In patients with low-risk MGUS according to Mayo Clinic staging, BM aspirate/biopsy and imaging may be deferred. Mangiavalli et al.<a class="elsevierStyleCrossRef" href="#bib0240">48</a> conducted a study of 1,217 patients, showing that the probability of having >10% PCs in the BM in those with IgG MGUS and a MC ≤ 1.5 g/dl was only 4.7% and the probability of having lytic lesions was 2.5%.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Since IgM MGUS is associated in most cases with WM, and it is rare for this entity to produce lytic lesions, imaging is not necessary in the absence of symptomatology, as well as BM if the MC ≤ 1.5 g/dl. Despite the lack of evidence in the management of light chain MGUS, imaging and BM are not routinely recommended if the FLC ratio is low (<8), although cardiac markers and urine protein should be requested at diagnosis given the risk of association with AL.<a class="elsevierStyleCrossRef" href="#bib0220">44</a>In all other patients with MGUS, both BM and imaging (preferably low-dose chest-abdomen-pelvis computed tomography [CT]) are indicated at the time of diagnosis.Follow-upThe aim of follow-up is to detect progression at an early stage, thereby reducing complications and improving survival. However, there is no evidence to support routine follow-up in these patients, with differences in recommendations between guidelines.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> A study by Bianchi et al.<a class="elsevierStyleCrossRef" href="#bib0245">49</a> showed that most patients with MGUS, including high-risk patients, who experience disease progression, are diagnosed incidentally.Taking into account the latest recommendations of the European Myeloma Network from 2014,<a class="elsevierStyleCrossRef" href="#bib0240">48</a> with a risk-adapted approach based on the Mayo Clinic stratification model, we recommend that all patients with MGUS should be reassessed at 6 months (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). Thereafter, low-risk MGUS should be followed every 1−2 years. In selected cases, follow-up could be discontinued if the disease remains stable and resumed if symptoms appear, as the risk of progression in these patients is very low at less than 5% at 20 years. In patients with intermediate or high risk MGUS, after the first assessment at 6 months, annual follow-up should be performed. This follow-up could be interrupted in patients with a life expectancy of less than 5 years. Generally speaking, these are patients who will need regular lifelong follow-up.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>An increase in MC or FLC should alert us to the suspicion of progression; however, this only occurs in about half of patients with MGUS.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> The onset of signs or symptoms unexplained by other causes (anaemia, hypercalcaemia, renal failure, bone fractures or lytic lesions, hyperviscosity, nephrotic syndrome, macroglossia, etc.) should raise the possibility of progression. In all these cases, the appropriate complementary tests should be requested to detect progression and thus establish treatment as soon as possible.Clinical approachAlthough the optimal treatment for MGCS patients is currently unknown, there are two therapeutic strategies. The first is based on anti-myeloma regimens capable of destroying the clonal plasma cell and the second is based on immunosuppressive or immunomodulatory agents.<a class="elsevierStyleCrossRef" href="#bib0225">45</a>In the case of MGRS, once the diagnosis is confirmed by renal biopsy, joint management with nephrologists is essential to choose the most appropriate treatment, taking into account the subtype and the risk of progression to end-stage chronic kidney disease. Despite the lack of evidence on the best treatment, different strategies include anti-myeloma regimens followed or not by autologous transplant, with the aim of eliminating the PC clone. Bortezomib-based regimens have been shown to be effective in these situations.<a class="elsevierStyleCrossRef" href="#bib0250">50</a> Milani et al.<a class="elsevierStyleCrossRef" href="#bib0255">51</a> demonstrated the efficacy of daratumumab in patients with refractory MGRS, being able to achieve early and significant haematological responses. Although further studies are needed, this anti-CD38 monoclonal antibody seems to be a promising therapeutic option in relapsed disease. Moreover, its use at earlier stages could lead to more significant responses and prevent the onset of end-stage renal failure.A complete physical examination together with an electromyographic and neuromuscular study are essential in patients with MGUS and associated neuropathy to determine the degree of neuropathy, as well as to rule out other possible causes of peripheral neuropathy, such as POEMS syndrome or AL.Unfortunately, there is little evidence on the treatment of MGUS-associated peripheral neuropathy. Since the association between neuropathy and IgA/IgG MGUS has been found to be uncommon on most occasions, it is thought that treatment may not be beneficial. When considering therapy, the likelihood of neuropathy secondary to MGUS must be high. In addition, it must be severe and progressive enough to warrant initiation of treatment. Generally, in IgM neuropathy, Igs or rituximab are used as first line, while plasma exchange, Igs or glucocorticoids are normally used in non-IgM neuropathy.<a class="elsevierStyleCrossRef" href="#bib0235">47</a>ConclusionMGUS is a premalignant and asymptomatic entity, which increases the risk of developing other diseases. Although progression rates are low, we must perform a thorough work-up at diagnosis to distinguish MGUS from other paraprotein-associated clinical entities. Follow-up of these patients should be based on the risk of progression, to prevent end-stage damage to the affected organs. Despite major advances in the understanding of the pathophysiology and biology of these entities, further studies are needed to identify patients who would benefit from early intervention.Ethical considerationsNot applicable, no sensitive patient data is involved.FundingWe have not received any funding for this manuscript.Conflict of interestNone of the 3 authors have any conflict of interest to declare in conducting this review." "textoCompletoSecciones" => array:1 [ "secciones" => array:18 [ 0 => array:3 [ "identificador" => "xres2081577" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1775776" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2081578" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1775775" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction: definition and classification" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Epidemiology" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Aetiopathogenesis" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Genetic predisposition" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Toxic exposure" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Diseases and monoclonal gammopathy of uncertain significance" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Genomic alterations" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Tumour microenvironment" ] ] ] 7 => array:3 [ "identificador" => "sec0045" "titulo" => "Natural history of monoclonal gammopathy of undetermined significance and risk factors associated with progression" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Baseline value, type and progressive increase of the monoclonal component" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Free light chain ratio" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Aberrant plasma cells" ] ] ] 8 => array:2 [ "identificador" => "sec0065" "titulo" => "Risk stratification of monoclonal gammopathy of unclear significance" ] 9 => array:2 [ "identificador" => "sec0070" "titulo" => "Clinical features and differential diagnosis" ] 10 => array:2 [ "identificador" => "sec0075" "titulo" => "Screening" ] 11 => array:2 [ "identificador" => "sec0080" "titulo" => "Follow-up" ] 12 => array:2 [ "identificador" => "sec0085" "titulo" => "Clinical approach" ] 13 => array:2 [ "identificador" => "sec0090" "titulo" => "Conclusion" ] 14 => array:2 [ "identificador" => "sec0095" "titulo" => "Ethical considerations" ] 15 => array:2 [ "identificador" => "sec0100" "titulo" => "Funding" ] 16 => array:2 [ "identificador" => "sec0105" "titulo" => "Conflict of interest" ] 17 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-03-08" "fechaAceptado" => "2023-05-24" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1775776" "palabras" => array:3 [ 0 => "Monoclonal gammopathy of uncertain significance" 1 => "Screening" 2 => "Prognosis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1775775" "palabras" => array:3 [ 0 => "Gammapatía monoclonal de significado incierto" 1 => "Screening" 2 => "Pronóstico" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Monoclonal gammopathy of uncertain significance is a premalignant plasma cell neoplasm with a high prevalence in the population over 50 years of age and an annual risk of progression of 1%. Multiple recent studies have led to advances in understanding both the pathogenesis of these disorders and their risk of progression to other diseases. Patients require lifelong follow-up, and a multidisciplinary and risk-adapted approach is essential. In recent years, an increasing number of entities associated with a paraprotein, known as clinically significant monoclonal gammopathies, have been recognized." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La gammapatía monoclonal de significado incierto es una neoplasia de células plasmáticas premaligna, con una elevada prevalencia en la población mayor de 50 años y un riesgo anual de progresión del 1%. Numerosos estudios recientes han permitido un avance en la compresión de la patogenia de estos trastornos y su riesgo de progresión a otras enfermedades. Los pacientes requieren un seguimiento de por vida, siendo fundamental un enfoque multidisciplinar y adaptado al riesgo. En los últimos años, cada vez se reconocen más entidades asociadas a la presencia de una paraproteína, conocidas como gammapatías monoclonales de significado clínico." ] ] "multimedia" => array:5 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1599 "Ancho" => 2508 "Tamanyo" => 343602 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Aetiopathogenesis of monoclonal gammopathy of uncertain significance and its progression to multiple myeloma. MGUS, monoclonal gammopathy of uncertain significance; MM, multiple myeloma; PCL, plasma cell leukaemia; QMM, quiescent multiple myeloma." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1487 "Ancho" => 2508 "Tamanyo" => 195966 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Diagnostic algorithm and follow-up of monoclonal gammopathies of uncertain significance. CrCl, creatinine clearance; FLC, free light chains; MC, monoclonal component; MGUS, monoclonal gammopathy of uncertain significance; TAP, Thorax, Abdomen and Pelvis; *Defined by Mayo Clinic staging: MC ≤ 1.5 g/dL, IgG isotype and normal FLC ratio. **See <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>." ] ] 2 => array:9 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: Rajkumar et al.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>" "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AL, amyloidosis; BM, bone marrow; LPS, lymphoproliferative syndrome; MC, monoclonal component; MDE, myeloma-defining event; MGUS, monoclonal gammopathy of uncertain significance; MM, multiple myeloma; PCs, plasma cells." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type of MGUS \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Diagnostic criteria \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Risk of progression \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Disease progressing to \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IgM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Serum IgM <3 g/dlInfiltration <10% of lymphoplasmacytes in BMNo evidence of anaemia, constitutional syndrome, lymphadenopathy, visceromegaly attributed to LPS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1,5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Waldeström's Macroglobulinemia. Rarely AL or MM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Non-IgM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MC not IgM <3 g/dlInfiltration <10% of PCs in BMAbsence of MDE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MM, solitary plasmacytoma or AL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Light chains \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Abnormal light chain ratio (<0.26 or >1.65) with increase of the involved light chainNon-detection of immunoglobulin heavy chain by immunofixationMC in urine <500 mg/24 hInfiltration <10% of PCs in BMAbsence of MDE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0,3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MM, solitary plasmacytoma, AL \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3447083.png" ] ] ] ] "descripcion" => array:1 [ "en" => "MGUS diagnostic criteria and risk of progression (IMWG 2014)." ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "DNA, deoxyribonucleic acid; FLC, free light chains; MGUS, monoclonal gammopathy of uncertain significance; PCs, plasma cells." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Risk factors \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Risk group(Number of factorsrisk) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Risk of progression (%)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mayo Clinic</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><1,5 g/dlIgG MGUS Altered FLC ratio</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low: 0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intermediate-Low: 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intermediate-High: 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High: 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">27 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Spanish Myeloma Group</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≥95% of aberrant PCs in BMAneuploid DNA</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low: 0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Risk: 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High: 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3447081.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Risk of progression at 20 and 5 years for the Mayo Clinic and Spanish Myeloma Group indexes, respectively." ] ] ] "descripcion" => array:1 [ "en" => "Prognostic indices of MGUS." ] ] 4 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0025" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "MGUS, monoclonal gammopathy of uncertain significance." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Low risk \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Intermediate or high risk \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Light chains \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Follow-up \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">At 6 months, and if stable every 1−2 yearsor discontinue and restart if symptoms of progression are present \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">At 6 months, and annually thereafter \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">At 6 months, and annually thereafter \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Recommended tests \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Complete blood count, electrophoresis and immunofixation in blood and urine, free light chains, calcium and serum creatinine.</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NT-proBNP, troponin T, albuminuria and as recommended in the rest of MGUS \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3447082.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Recommendations in the follow-up of MGUS." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:51 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "The International Myeloma Working Group" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Br J Haematol" "fecha" => "2003" "volumen" => "121" "paginaInicial" => "749" "paginaFinal" => "757" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.V. Rajkumar" 1 => "M.A. Dimopoulos" 2 => "A. Palumbo" 3 => "J. Blade" 4 => "G. Merlini" 5 => "M.V. Mateos" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1470-2045(14)70442-5" "Revista" => array:6 [ "tituloSerie" => "Lancet Oncol." "fecha" => "2014" "volumen" => "15" "paginaInicial" => "e538" "paginaFinal" => "48" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25439696" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Monoclonal gammopathy of undetermined significance" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "R.A. Kyle" 1 => "S. Vincent Rajkumar" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2141.2006.06235.x" "Revista" => array:6 [ "tituloSerie" => "Br J Haematol." 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Monoclonal gammopathy of uncertain significance

Gammapatía monoclonal de significado incierto

Elena Alejo, Borja Puertas, María-Victoria Mateos

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mvmateos@usal.es

Corresponding author.

Hospital Universitario de Salamanca/Instituto de Investigación Biomédica de Salamanca (IBSAL)/Centro Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

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amyloidosis &#40;AL&#41;&#44; macroglobulinemia or other lymphoproliferative syndromes&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> According to the latest 2014 International Myeloma Working Group &#40;IMWG&#41; diagnostic criteria for gammopathies&#44;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> all of the following criteria are required to diagnose a patient with MGUS&#58; serum MC of less than 3&#8239;g&#47;dl&#44; bone marrow &#40;BM&#41; infiltration of less than 10&#37; of PCs&#44; and the absence of myeloma-defining events &#40;MDEs&#41;&#46; MDEs comprise classic <span class="elsevierStyleItalic">CRAB</span> symptomatology &#40;hypercalcaemia&#44; renal failure&#44; anaemia and lytic lesions&#41;&#44; and the 3 biomarkers of malignancy &#40;infiltration &#8805;60&#37; of PCs in BM&#44; free light chain involved&#47;uninvolved ratio &#8805;100&#44; or more than one focal lesion &#8805;5&#8239;mm on whole body or spine MRI study&#41;&#46; Patients with a MC&#8239;&#8805;&#8239;3&#8239;g&#47;dl and&#47;or &#8805;500&#8239;mg&#47;24&#8239;h in urine and&#47;or 10&#8211;60&#37; of PCs in the BM without MDEs are diagnosed with quiescent multiple myeloma &#40;QMM&#41;&#46; Multiple myeloma &#40;MM&#41; is the paradigm of monoclonal gammopathies and is defined by the presence of &#8805;10&#37; of PCs in the BM or plasmacytoma and MDEs&#46; The detection of MC is not essential to make the diagnosis of MM&#44; so patients who meet criteria for this gammopathy without the identification of MC or immunofixation abnormalities in serum or urine constitute the subgroup of non-secretory myelomas &#40;&#60;5&#37; of newly diagnosed MM&#41;&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">MGUS is the most common PC dyscrasia&#44; accounting for around 50&#8211;60&#37; of the total&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> It is generally asymptomatic and its premalignant nature is widely accepted&#44; being a preliminary and necessary stage for the development of other gammopathies&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a> Its clinical course and progression will be determined by the type of immunoglobulin involved&#44; with three types of MGUS being differentiated&#58; IgM&#44; non-IgM and light chain&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> The most common are IgG &#40;&#8776;70&#37;&#41;&#44; followed by IgM &#40;15&#37;&#41;&#44; IgA &#40;12&#37;&#41;&#44; biclonal &#40;3&#37;&#41; and light chain &#40;&#60;1&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;8</span></a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> describes the diagnostic criteria for the different subtypes of MGUS and their risk of progression&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Epidemiology</span><p id="par0020" class="elsevierStylePara elsevierViewall">The importance of MGUS lies in its high prevalence&#44; occurring in 3&#46;2&#37; of patients over 50 years of age&#46; Moreover&#44; its prevalence increases progressively with age&#44; being higher than 5 and 7&#37; in patients older than 70 and 85 years&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> However&#44; the <span class="elsevierStyleItalic">Iceland screens&#44; treats or prevents multiple myeloma</span> &#40;iStopMM&#41; study recently conducted in Iceland with more than 75&#44;000 patients shows that the prevalence of IgA MGUS subtype does not increase with age&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">MGUS is significantly more common in men than in women as demonstrated in a study involving more than 20&#44;000 patients over the age of 50&#46; In this study&#44; a prevalence of 4&#46;0&#37; was observed in men and 2&#46;9&#37; in women &#40;p&#8239;&#60;&#8239;0&#46;001&#41;&#44; and these differences were maintained regardless of age at diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Other population-based studies highlight its racial association&#44; with differences not only in prevalence&#44; but also in age at presentation&#44; type and amount of paraprotein&#46; African Americans are up to 3 times more likely to be diagnosed with MGUS than Caucasians&#44; with younger patients&#44; lower paraprotein levels&#44; and less common IgM&#46; However&#44; no differences are observed in terms of progression to MM&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;10&#8211;13</span></a> In contrast&#44; MGUS is less often detected in Asian patients&#44; especially in women&#44; as reported in a study in the Nagasaki population&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">With the introduction of more sensitive techniques for MC detection&#44; such as mass spectrometry &#40;MS&#41;&#44; MGUSs are more commonly detected&#46; MS confers greater specificity for detecting the presence of small amounts of paraprotein and is also capable of detecting light chain glycosylation&#44; which has been shown to be a risk factor for the development of PC dyscrasias&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> A recent study in the American population has shown that&#44; in high-risk patients over 50 years of age&#44; the prevalence of MGUS in the black population&#44; analysed by MS&#44; is up to 17&#37;&#44; with no significant differences found in those with a family history of gammopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Aetiopathogenesis</span><p id="par0035" class="elsevierStylePara elsevierViewall">Different authors agree that the PC responsible for MGUS is a post-germline one&#44; because there are several sequencing studies of segment V<span class="elsevierStyleInf">H</span> of the immunoglobulin heavy chain <span class="elsevierStyleItalic">&#40;IGH&#41;</span> gene which show a large number of mutations&#44; but with an absence of intraclonal variation&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;17</span></a> Classically&#44; it is thought that the first genetic alteration favouring the development of MGUS occurs after abnormal DNA repair during somatic hypermutation and isotype switching recombination of immunoglobulins&#46; Following repair of this break&#44; abnormal rearrangements involving oncogenes can occur&#44; conferring an evolutionary advantage to these post-germline B cells&#46; Subsequently in the BM&#44; the clonal PC will interact with the microenvironment favouring its survival&#44; leading to the accumulation of second genetic events and possible progression to other entities &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> However&#44; this instructive multi-stage natural history form of MGUS is being challenged by increased knowledge of plasma cell biology and the demonstration of clonal heterogeneity in patients with PC dyscrasia&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Genetic predisposition</span><p id="par0040" class="elsevierStylePara elsevierViewall">As with other diseases&#44; familial aggregation in the development of MGUS has been reported&#46; Two independent studies have shown that people with a first-degree family history of MGUS have up to a 3-fold increased risk of developing MGUS compared to the general population&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;20</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Recent genome-wide association studies &#40;GWAS&#41; have identified more than 30 polymorphisms associated with an increased risk of developing MGUS&#46; However&#44; the effect of these polymorphisms on the eventual progression to MM&#44; AL or other diseases is currently unknown&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;22</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Toxic exposure</span><p id="par0050" class="elsevierStylePara elsevierViewall">Several retrospective population-based studies have identified radiation exposure as a risk factor&#44; with the risk being 1&#46;7 times higher in a retrospective study of 1945 atomic bomb survivors&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Other studies point to exposure to pesticides&#44; herbicides or fungicides as a risk factor for this entity&#44; increasing the risk by 2&#8211;4 times compared to non-exposed individuals&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> A causal relationship has also been established between smoking or air pollution and MGUS&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25&#44;26</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Diseases and monoclonal gammopathy of uncertain significance</span><p id="par0055" class="elsevierStylePara elsevierViewall">Classically&#44; previous history of bacterial and viral infections and&#47;or autoimmune diseases have been positively associated as a risk factor for MGUS&#46; A Swedish population-based study reported that the prevalence of MGUS in individuals with a history of significant infections &#40;meningitis&#44; pneumonia&#44; septicaemia&#44; pericarditis&#44; endocarditis&#8230;&#41; or autoimmune diseases was 1&#46;5&#8211;2 times higher than in a population without such a history&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;25</span></a> Similar results were published in an American study&#46; Both associations are supported by the theory of chronic antigenic stimulation&#46; According to this theory&#44; persistent stimulation and activation of the immune system would favour the development and proliferation of PCs that can acquire a genetic event and favour the development of a monoclonal gammopathy&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">In contrast&#44; in the prospective iStopMM study&#44; no association between MGUS and autoimmune diseases was observed&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Prior to the start of the study&#44; it had been established in the Icelandic population that patients with autoimmune diseases were twice as likely to develop MGUS&#46; However&#44; the results of the study show no relationship between the two entities&#44; which casts doubt on the biological correlation reported in previous studies&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Metabolic syndrome&#44; and especially obesity&#44; has also been associated with an increased risk of developing MGUS and its progression to MM&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;29</span></a> However&#44; being a patient-dependent modifiable factor&#44; the results of studies that have analysed this association are inconsistent&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25&#44;28&#44;29</span></a> However&#44; it appears that adequate metabolic control plays a role in the eventual progression of MGUS&#44; as noted in a retrospective study in which metformin use in diabetic patients reduced progression to MM by more than 50&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Genomic alterations</span><p id="par0070" class="elsevierStylePara elsevierViewall">MGUS is a very heterogeneous entity from a genetic perspective&#46; Primary genetic events comprising alterations involved in the genesis of the disease&#44; and secondary genetic events responsible for clonal expansion and progression to MM or other diseases have been described&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Although patients with MGUS have been shown to have genomic alterations in common with QMM or MM&#44; the genetic complexity of MGUS is significantly lower&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#8211;33</span></a> A study by the Salamanca group demonstrated this statement in a very visual way&#58; only 48&#37; of patients with MGUS had more than one chromosomal alteration detected by fluorescence in situ hybridisation &#40;FISH&#41; compared to more than 70&#37; in QMM and MM&#46; In addition&#44; all detected chromosomal alterations were present in a lower percentage of PCs in patients with MGUS&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Copy number variations are the most common genome alteration in MGUS patients&#44; being detected in 60&#37; of patients&#44; and include gains of 1q&#44; 3p&#44; 6p&#44; 9p&#44;11q&#44; 19p and 21q or deletions of 1p&#44;13q&#44; 16q&#44;17p or 22q&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#8211;33</span></a> The 1q gain is the most prevalent and is detected in 30&#37; of patients&#46; Other copy number variations traditionally analysed in MM are also detected in MGUS&#44; such as 13q deletion &#40;&#8776;20&#37;&#41;&#44; 17p deletion &#40;1&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> A copy number variation characteristic of Waldestr&#246;m macroglobulinemia &#40;WM&#41; is the 6q deletion but is not detected in IgM MGUS&#44; so this would be a late genetic event related to the progression of the gammopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">One of the most commonly detected genome alterations in patients with MGUS is the <span class="elsevierStyleItalic">IGH</span> gene translocation &#40;&#8776;40&#8211;50&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> The prevalence of the different <span class="elsevierStyleItalic">IGH</span> translocations is lower compared to MM&#44; with the prevalence of t &#40;11&#59;14&#41; and t &#40;4&#59;14&#41; being 10 and 5&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;35</span></a> The <span class="elsevierStyleItalic">MYC</span> translocation is not usually detected in MGUS patients&#44; but is present in 15&#37; of MM patients&#44; indicating that it may be a late genetic event favouring clonal expansion&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Somatic mutations are also detected in patients with MGUS&#46; In non-IgM MGUS&#44; the most commonly detected are those affecting the MAPK &#40;<span class="elsevierStyleItalic">N-RAS</span>&#41; or NF-&#312;B <span class="elsevierStyleItalic">&#40;LTB&#41;</span> metabolic pathways&#44; although less common than in MM patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#44;35</span></a> IgM MGUS has a spectrum of different somatic mutations including <span class="elsevierStyleItalic">MYD88</span> &#40;L265&#8239;P&#41;&#44; <span class="elsevierStyleItalic">CXCR4</span> and <span class="elsevierStyleItalic">KMT2D</span> mutation&#44; present in 60&#44; 9 and 5&#37; of patients&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> The <span class="elsevierStyleItalic">TP53</span> mutation has not been detected in patients with MGUS&#44; so it would be a genetic alteration related to MGUS progression&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Tumour microenvironment</span><p id="par0090" class="elsevierStylePara elsevierViewall">The marrow microenvironment consists of cellular elements such as B cells&#44; T cells&#44; <span class="elsevierStyleItalic">natural killer</span> &#40;NK&#41; cells&#44; myeloid cells&#44; stromal cells&#44; osteoblasts and osteoclasts&#44; and non-cellular elements such as the extracellular matrix&#46; Quantitative and qualitative differences have been described in the immune system of patients with MGUS compared to healthy individuals&#44; such as the expansion of myeloid suppressor cells and regulatory T cells or the inactivation of effector T cells&#46; The bidirectional interaction of clonal PCs with elements of the microenvironment through cytokines and growth factors and the immunosuppressive environment will favour clonal survival and expansion and eventual progression of MGUS to other diseases such as MM&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Dysregulation of the microenvironment is closely related to the production of the osteolytic lesions characteristic of MM by altering bone homeostasis&#44; and to immunoparesis by decreasing the production of normal PCs in favour of pathological PCs&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Natural history of monoclonal gammopathy of undetermined significance and risk factors associated with progression</span><p id="par0100" class="elsevierStylePara elsevierViewall">A US study involving 1&#44;384 patients diagnosed with MGUS was reported in 2018&#46; After a median follow-up of more than 15 years&#44; the annual risk of progression of MGUS to other diseases was 1&#37;&#58; 10&#37; at 10 years&#44; 18&#37; at 20 years&#44; 28&#37; at 30 years and 36&#37; at 40 years&#46; Of the 147 patients who progressed to other entities&#44; 97 &#40;7&#37;&#41; progressed to MM&#44; 19 &#40;1&#46;4&#37;&#41; to non-Hodgkin&#39;s lymphoma &#40;NHL&#41;&#44; 14 &#40;1&#37;&#41; to AL&#44; 13 &#40;1&#37;&#41; to WM&#44; 3 &#40;0&#46;2&#37;&#41; to chronic lymphocytic leukaemia &#40;FLC&#41; and one &#40;0&#46;07&#37;&#41; to plasmacytoma&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Baseline value&#44; type and progressive increase of the monoclonal component</span><p id="par0105" class="elsevierStylePara elsevierViewall">According to a study by Kyle et al&#46;&#44; the baseline monoclonal component is the most important predictor of progression and the risk of progression is directly related to the baseline concentration of a MC&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Those patients diagnosed with a MC&#8239;&#8805;&#8239;1&#46;5 and &#8805;2&#46;5&#8239;g&#47;dl were 2 and 5 times more likely to progress to other disease compared to patients with a MC below 0&#46;5&#8239;g&#47;dl at diagnosis&#44; respectively&#46; The predictive value of baseline paraprotein concentration has also been tested by other working groups&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40&#44;41</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">IgG type MGUS have the lowest risk of progression compared to IgA or IgM MGUS&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39&#44;40</span></a> Furthermore&#44; the above-mentioned American study<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> reported that patients with IgM MGUS had an annual risk of progression of 2&#37; during the first ten years and 1&#37; thereafter&#46; In contrast&#44; those with non-IgM MGUS were constant at 1&#37; per year&#46; Light chain MGUS have an annual progression risk of 0&#46;3&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">In addition to the type and value of MC&#44; it is important to know the paraprotein dynamics&#46; Following a study by the Hospital Clinic&#44; the term <span class="elsevierStyleItalic">evolving</span> was coined to refer to patients with MGUS who progressively and annually increased their paraprotein levels over a follow-up of at least 3 years&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> The risk of progression at 10 and 20 years for <span class="elsevierStyleItalic">evolving</span> patients was 55&#37; and 80&#37;&#44; compared to 10&#37; and 13&#37; for <span class="elsevierStyleItalic">non-evolving patients</span>&#44; respectively&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Free light chain ratio</span><p id="par0120" class="elsevierStylePara elsevierViewall">The free light chain &#40;FLC&#41; ratio is an independent predictor of progression in MGUS&#46; A Mayo Clinic study reported that patients with an abnormal free light chain ratio were 3&#46;5 times more likely to progress to other diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Aberrant plasma cells</span><p id="par0125" class="elsevierStylePara elsevierViewall">The percentage of MPC infiltration and the risk of progression in patients with MGUS have been related&#46; Univariate analysis of a study including 359 patients showed that patients with MGUS and an infiltration &#8805;5&#37; had a higher risk of progression than patients with a lower infiltration&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> However&#44; PC infiltration did not independently demonstrate its impact in the multivariate analysis&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Predictors of transformation were analysed in more than 400 patients with MGUS in a study by the Spanish Myeloma Group &#40;GEM&#41;&#46; The presence of &#8805;95&#37; aberrant PCs in the BM and DNA aneuploidy of the PCs were identified as independent factors for progression&#46; With a median time to progression of 107 months&#44; the risk of progression for patients with MGUS was fivefold higher in those with &#8805;95&#37; aberrant PCs in the BM &#40;24 vs&#46; 4&#37;&#41;&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Risk stratification of monoclonal gammopathy of unclear significance</span><p id="par0135" class="elsevierStylePara elsevierViewall">The clinical course of MGUS is heterogeneous&#44; so attempts have been made to establish prognostic indices to identify patients at higher risk of progression and to tailor further testing and follow-up&#46; The most widely used prognostic index is the one developed by the Mayo Clinic group that includes the baseline concentration and type of paraprotein and the FLC ratio&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> Also of note is the prognostic index developed by the GEM based on immunophenotype and DNA ploidy of clonal PCs &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Clinical features and differential diagnosis</span><p id="par0140" class="elsevierStylePara elsevierViewall">Although numerous associations between MGUS and more than 100 different diseases have been described over the years&#44; most cases have been found to be incidental findings given the high prevalence of MGUS in the population&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">There are a number of pathological conditions associated with MGUS that can cause damage to various organs without meeting MM criteria&#46; All these disorders&#44; which are becoming increasingly common&#44; constitute a new clinical entity known as clinically significant monoclonal gammopathy &#40;MGCS&#41;&#46; In these cases&#44; the paraprotein causes organ damage through different mechanisms&#44; such as tissue deposition&#44; autoantibodies or through interactions with the complement system&#46; Early detection of these diseases is essential to prevent progression and advanced organ damage&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> Among the clinical entities most commonly associated with MGUS are monoclonal gammopathies of renal significance &#40;MGRS&#41;&#44; peripheral neuropathies &#40;PNs&#41;&#44; cutaneous and ocular entities&#44; as well as acquired von Willebrand disease&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">MGRS comprises a group of relatively rare renal diseases characterised by the deposition of immunoglobulins &#40;Igs&#41; secreted by a clone of B cells&#46; They include glomerulopathies with fibrillar deposits &#40;heavy chain AL and light and heavy chain immunoglobulin&#41;&#44; microtubular &#40;cryoglobulinaemia types I and II&#44; immunotactoid glomerulopathy&#41; or unorganised deposits &#40;monoclonal Ig deposition disease&#41;&#59; and also tubular diseases&#44; such as Fanconi syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The prevalence of MGUS in PN varies between 3 and 10&#37; and is much more commonly associated with the IgM type&#46; Generally&#44; IgM MGUS-associated PN presents as a symmetrical demyelinating neuropathy resulting in sensory ataxia and&#44; although less common&#44; may also cause a mild distal predominant motor deficit&#46; Since a causal relationship between non-IgM MGUS and neuropathy has not yet been demonstrated&#44; IgG or IgA type MGUS can be observed in a wide spectrum of neuropathies&#44; from sensory axonal peripheral neuropathy slowly progressing to a motor deficit to the classic chronic inflammatory demyelinating polyradiculopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> Other entities to consider in the differential diagnosis of PN are AL and POEMS syndrome &#40;Polyneuropathy&#44; Organomegaly&#44; Endocrinopathy&#44; Monoclonal gammopathy&#44; and Skin changes&#41;&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Screening</span><p id="par0160" class="elsevierStylePara elsevierViewall">There are currently no established recommendations on when to screen for MGUS in asymptomatic individuals&#46; Due to its high prevalence in the elderly population&#44; screening is not routinely recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">It is usually performed when a patient has signs and symptoms suggestive of MM&#44; AL&#44; WM or lymphoproliferative syndromes&#44; such as NHL or FLC&#46; However&#44; most signs and symptoms are non-specific&#44; so they are often attributed to other entities&#44; with the finding of MGUS being considered incidental&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Initial evaluation includes serum protein electrophoresis and immunofixation and quantification of free light chains&#46; Once a MC is detected&#44; 24&#8239;h urine electrophoresis and immunofixation is performed&#44; in addition to a complete blood count and serum creatinine&#44; creatinine clearance and calcium&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Although MGUS requires by definition the presence of &#60;3&#8239;g&#47;dl serum paraprotein&#44; &#60;10&#37; of PCs in the BM and the absence of MM-defining events&#44; not all MGUS will require further testing &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> In patients with low-risk MGUS according to Mayo Clinic staging&#44; BM aspirate&#47;biopsy and imaging may be deferred&#46; Mangiavalli et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> conducted a study of 1&#44;217 patients&#44; showing that the probability of having &#62;10&#37; PCs in the BM in those with IgG MGUS and a MC&#8239;&#8804;&#8239;1&#46;5&#8239;g&#47;dl was only 4&#46;7&#37; and the probability of having lytic lesions was 2&#46;5&#37;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0180" class="elsevierStylePara elsevierViewall">Since IgM MGUS is associated in most cases with WM&#44; and it is rare for this entity to produce lytic lesions&#44; imaging is not necessary in the absence of symptomatology&#44; as well as BM if the MC&#8239;&#8804;&#8239;1&#46;5&#8239;g&#47;dl&#46; Despite the lack of evidence in the management of light chain MGUS&#44; imaging and BM are not routinely recommended if the FLC ratio is low &#40;&#60;8&#41;&#44; although cardiac markers and urine protein should be requested at diagnosis given the risk of association with AL&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">In all other patients with MGUS&#44; both BM and imaging &#40;preferably low-dose chest-abdomen-pelvis computed tomography &#91;CT&#93;&#41; are indicated at the time of diagnosis&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Follow-up</span><p id="par0190" class="elsevierStylePara elsevierViewall">The aim of follow-up is to detect progression at an early stage&#44; thereby reducing complications and improving survival&#46; However&#44; there is no evidence to support routine follow-up in these patients&#44; with differences in recommendations between guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> A study by Bianchi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> showed that most patients with MGUS&#44; including high-risk patients&#44; who experience disease progression&#44; are diagnosed incidentally&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Taking into account the latest recommendations of the <span class="elsevierStyleItalic">European Myeloma Network</span> from 2014&#44;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> with a risk-adapted approach based on the Mayo Clinic stratification model&#44; we recommend that all patients with MGUS should be reassessed at 6 months &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Thereafter&#44; low-risk MGUS should be followed every 1&#8722;2 years&#46; In selected cases&#44; follow-up could be discontinued if the disease remains stable and resumed if symptoms appear&#44; as the risk of progression in these patients is very low at less than 5&#37; at 20 years&#46; In patients with intermediate or high risk MGUS&#44; after the first assessment at 6 months&#44; annual follow-up should be performed&#46; This follow-up could be interrupted in patients with a life expectancy of less than 5 years&#46; Generally speaking&#44; these are patients who will need regular lifelong follow-up&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0200" class="elsevierStylePara elsevierViewall">An increase in MC or FLC should alert us to the suspicion of progression&#59; however&#44; this only occurs in about half of patients with MGUS&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The onset of signs or symptoms unexplained by other causes &#40;anaemia&#44; hypercalcaemia&#44; renal failure&#44; bone fractures or lytic lesions&#44; hyperviscosity&#44; nephrotic syndrome&#44; macroglossia&#44; etc&#46;&#41; should raise the possibility of progression&#46; In all these cases&#44; the appropriate complementary tests should be requested to detect progression and thus establish treatment as soon as possible&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Clinical approach</span><p id="par0205" class="elsevierStylePara elsevierViewall">Although the optimal treatment for MGCS patients is currently unknown&#44; there are two therapeutic strategies&#46; The first is based on anti-myeloma regimens capable of destroying the clonal plasma cell and the second is based on immunosuppressive or immunomodulatory agents&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">In the case of MGRS&#44; once the diagnosis is confirmed by renal biopsy&#44; joint management with nephrologists is essential to choose the most appropriate treatment&#44; taking into account the subtype and the risk of progression to end-stage chronic kidney disease&#46; Despite the lack of evidence on the best treatment&#44; different strategies include anti-myeloma regimens followed or not by autologous transplant&#44; with the aim of eliminating the PC clone&#46; Bortezomib-based regimens have been shown to be effective in these situations&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> Milani et al&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> demonstrated the efficacy of daratumumab in patients with refractory MGRS&#44; being able to achieve early and significant haematological responses&#46; Although further studies are needed&#44; this anti-CD38 monoclonal antibody seems to be a promising therapeutic option in relapsed disease&#46; Moreover&#44; its use at earlier stages could lead to more significant responses and prevent the onset of end-stage renal failure&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">A complete physical examination together with an electromyographic and neuromuscular study are essential in patients with MGUS and associated neuropathy to determine the degree of neuropathy&#44; as well as to rule out other possible causes of peripheral neuropathy&#44; such as POEMS syndrome or AL&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Unfortunately&#44; there is little evidence on the treatment of MGUS-associated peripheral neuropathy&#46; Since the association between neuropathy and IgA&#47;IgG MGUS has been found to be uncommon on most occasions&#44; it is thought that treatment may not be beneficial&#46; When considering therapy&#44; the likelihood of neuropathy secondary to MGUS must be high&#46; In addition&#44; it must be severe and progressive enough to warrant initiation of treatment&#46; Generally&#44; in IgM neuropathy&#44; Igs or rituximab are used as first line&#44; while plasma exchange&#44; Igs or glucocorticoids are normally used in non-IgM neuropathy&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conclusion</span><p id="par0225" class="elsevierStylePara elsevierViewall">MGUS is a premalignant and asymptomatic entity&#44; which increases the risk of developing other diseases&#46; Although progression rates are low&#44; we must perform a thorough work-up at diagnosis to distinguish MGUS from other paraprotein-associated clinical entities&#46; Follow-up of these patients should be based on the risk of progression&#44; to prevent end-stage damage to the affected organs&#46; Despite major advances in the understanding of the pathophysiology and biology of these entities&#44; further studies are needed to identify patients who would benefit from early intervention&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Ethical considerations</span><p id="par0230" class="elsevierStylePara elsevierViewall">Not applicable&#44; no sensitive patient data is involved&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Funding</span><p id="par0235" class="elsevierStylePara elsevierViewall">We have not received any funding for this manuscript&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflict of interest</span><p id="par0240" class="elsevierStylePara elsevierViewall">None of the 3 authors have any conflict of interest to declare in conducting this review&#46;</p></span></span>"
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          "titulo" => "Introduction&#58; definition and classification"
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          "titulo" => "Natural history of monoclonal gammopathy of undetermined significance and risk factors associated with progression"
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              "titulo" => "Baseline value&#44; type and progressive increase of the monoclonal component"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Monoclonal gammopathy of uncertain significance is a premalignant plasma cell neoplasm with a high prevalence in the population over 50 years of age and an annual risk of progression of 1&#37;&#46; Multiple recent studies have led to advances in understanding both the pathogenesis of these disorders and their risk of progression to other diseases&#46; Patients require lifelong follow-up&#44; and a multidisciplinary and risk-adapted approach is essential&#46; In recent years&#44; an increasing number of entities associated with a paraprotein&#44; known as clinically significant monoclonal gammopathies&#44; have been recognized&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">La gammapat&#237;a monoclonal de significado incierto es una neoplasia de c&#233;lulas plasm&#225;ticas premaligna&#44; con una elevada prevalencia en la poblaci&#243;n mayor de 50 a&#241;os y un riesgo anual de progresi&#243;n del 1&#37;&#46; Numerosos estudios recientes han permitido un avance en la compresi&#243;n de la patogenia de estos trastornos y su riesgo de progresi&#243;n a otras enfermedades&#46; Los pacientes requieren un seguimiento de por vida&#44; siendo fundamental un enfoque multidisciplinar y adaptado al riesgo&#46; En los &#250;ltimos a&#241;os&#44; cada vez se reconocen m&#225;s entidades asociadas a la presencia de una paraprote&#237;na&#44; conocidas como gammapat&#237;as monoclonales de significado cl&#237;nico&#46;</p></span>"
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Diagnostic algorithm and follow-up of monoclonal gammopathies of uncertain significance&#46; CrCl&#44; creatinine clearance&#59; FLC&#44; free light chains&#59; MC&#44; monoclonal component&#59; MGUS&#44; monoclonal gammopathy of uncertain significance&#59; TAP&#44; Thorax&#44; Abdomen and Pelvis&#59;</p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">&#42;Defined by Mayo Clinic staging&#58; MC&#8239;&#8804;&#8239;1&#46;5&#8239;g&#47;dL&#44; IgG isotype and normal FLC ratio&#46;</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">&#42;&#42;See <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46;</p>"
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">AL&#44; amyloidosis&#59; BM&#44; bone marrow&#59; LPS&#44; lymphoproliferative syndrome&#59; MC&#44; monoclonal component&#59; MDE&#44; myeloma-defining event&#59; MGUS&#44; monoclonal gammopathy of uncertain significance&#59; MM&#44; multiple myeloma&#59; PCs&#44; plasma cells&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type of MGUS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Diagnostic criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Risk of progression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Disease progressing to&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IgM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serum IgM &#60;3&#8239;g&#47;dlInfiltration &#60;10&#37; of lymphoplasmacytes in BMNo evidence of anaemia&#44; constitutional syndrome&#44; lymphadenopathy&#44; visceromegaly attributed to LPS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Waldestr&#246;m&#39;s Macroglobulinemia&#46; Rarely AL or MM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Non-IgM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MC not IgM &#60;3&#8239;g&#47;dlInfiltration &#60;10&#37; of PCs in BMAbsence of MDE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MM&#44; solitary plasmacytoma or AL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Light chains&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Abnormal light chain ratio &#40;&#60;0&#46;26 or &#62;1&#46;65&#41; with increase of the involved light chainNon-detection of immunoglobulin heavy chain by immunofixationMC in urine &#60;500&#8239;mg&#47;24&#8239;hInfiltration &#60;10&#37; of PCs in BMAbsence of MDE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#44;3&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MM&#44; solitary plasmacytoma&#44; AL&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Risk group&#40;Number of factorsrisk&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">Low&#58; 0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Intermediate-Low&#58; 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Intermediate-High&#58; 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">High&#58; 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="3" align="left" valign="\n
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                  \t\t\t\t">Spanish Myeloma Group</td><td class="td" title="\n
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                  \t\t\t\t  " rowspan="3" align="left" valign="\n
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                  \t\t\t\t">&#8805;95&#37; of aberrant PCs in BMAneuploid DNA</td><td class="td" title="\n
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                  \t\t\t\t">Low&#58; 0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">High&#58; 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">46&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Follow-up&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">At 6 months&#44; and if stable every 1&#8722;2 yearsor discontinue and restart if symptoms of progression are present&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">At 6 months&#44; and annually thereafter&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">At 6 months&#44; and annually thereafter&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Recommended tests&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Complete blood count&#44; electrophoresis and immunofixation in blood and urine&#44; free light chains&#44; calcium and serum creatinine&#46;</td><td class="td" title="\n
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                  \t\t\t\t">NT-proBNP&#44; troponin T&#44; albuminuria and as recommended in the rest of MGUS&nbsp;\t\t\t\t\t\t\n
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                          "autores" => array:6 [
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