Special article
Laboratory guidelines for the diagnosis and follow-up of patients with monoclonal gammopathies
Guía de laboratorio para el diagnóstico y seguimiento de pacientes con gammapatías monoclonales
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En todos los casos se reveló con un anticuerpo específico; M: perfil de migración de la IgM.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M. Bravo García-Morato, B. Padilla-Merlano, P. Nozal, M. Espiño, C. Juárez, L.M. Villar, M. López-Trascasa" "autores" => array:8 [ 0 => array:2 [ "nombre" => "M." "apellidos" => "Bravo García-Morato" ] 1 => array:2 [ "nombre" => "B." "apellidos" => "Padilla-Merlano" ] 2 => array:2 [ "nombre" => "P." "apellidos" => "Nozal" ] 3 => array:2 [ "nombre" => "M." "apellidos" => "Espiño" ] 4 => array:2 [ "nombre" => "C." "apellidos" => "Juárez" ] 5 => array:2 [ "nombre" => "L.M." "apellidos" => "Villar" ] 6 => array:2 [ "nombre" => "M." "apellidos" => "López-Trascasa" ] 7 => array:1 [ "colaborador" => "en nombre del grupo de Inmunoquímica de la Sociedad Española de Inmunología" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2254887415001046" "doi" => "10.1016/j.rceng.2015.10.004" "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/S2254887415001046?idApp=WRCEE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256515002271?idApp=WRCEE" "url" => "/00142565/0000021600000003/v1_201604010057/S0014256515002271/v1_201604010057/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2254887415001174" "issn" => "22548874" "doi" => "10.1016/j.rceng.2015.11.003" "estado" => "S300" "fechaPublicacion" => "2016-04-01" "aid" => "1197" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI)" "documento" => "article" "crossmark" => 1 "subdocumento" => "ssu" "cita" => "Rev Clin Esp. 2016;216:135-45" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 3 "PDF" => 3 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Obstetric antiphospholipid syndrome" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "135" "paginaFinal" => "145" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Síndrome antifosfolipídico obstétrico" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 2460 "Ancho" => 3451 "Tamanyo" => 897898 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Various scenarios in terms of aFL, SAF and SAFO. Abbreviations: aPL: antiphospholipid antibodies; APS: antiphospholipid syndrome; OAPS: obstetric antiphospholipid syndrome.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "E. Esteve-Valverde, R. Ferrer-Oliveras, J. Alijotas-Reig" "autores" => array:3 [ 0 => array:2 [ "nombre" => "E." "apellidos" => "Esteve-Valverde" ] 1 => array:2 [ "nombre" => "R." "apellidos" => "Ferrer-Oliveras" ] 2 => array:2 [ "nombre" => "J." 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"apellidos" => "López-Trascasa" "email" => array:1 [ 0 => "mltrascasa@salud.madrid.org" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 7 => array:2 [ "colaborador" => "on behalf of grupo de Inmunoquímica de la Sociedad Española de Inmunología" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">◊</span>" "identificador" => "fn0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Unidad de Inmunología, Hospital Universitario La Paz, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Inmunología, Hospital Ramón y Cajal, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Inmunología, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Guía de laboratorio para el diagnóstico y seguimiento de pacientes con gammapatías monoclonales" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1928 "Ancho" => 3146 "Tamanyo" => 204713 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Algorithm of laboratory tests when faced with suspected monoclonal gammopathy. <span class="elsevierStyleItalic">Abbreviation</span>: MC, monoclonal component.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Monoclonal gammopathies encompass a collection of disorders associated with uncontrolled proliferation of plasma cell clones that, with the exception of nonsecretory myeloma, produce immunoglobulin molecules or their fragments, which are known as monoclonal components (MCs).</p><p id="par0010" class="elsevierStylePara elsevierViewall">There is a diverse spectrum of diseases grouped within monoclonal gammopathies, which is reflected in the clinical manifestations and their prognosis. These diseases are classified as malignant or nonmalignant.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The nonmalignant types include monoclonal gammopathy of undetermined significance (MGUS). In MGUS, the amount of plasma cells detected in bone marrow biopsies is less than 10%, and serum MC levels are less than 30<span class="elsevierStyleHsp" style=""></span>g/L. MGUS represents 60% of all monoclonal gammopathies and is present in 3.2% of the population around the age of 50 years. MGUS is characterized as benign (lack of anemia, renal failure, hypercalcemia, bone lesions or amyloidosis attributable to plasma cell dyscrasia) and asymptomatic, with an annual risk of progression to multiple myeloma (MM) of 0.5–1%. The risk factors for progression to MM include the MC concentration, the type of monoclonal protein, the light chain ratio, bone marrow plasmacytosis, the proportion of cells with the myelomatous phenotype in the total plasma cell count and the presence of immunoparesis.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">MGUS can present in isolation or associated with other underlying diseases: autoimmune (cryoglobulinemia, Sjögren's syndrome, IgA vasculitis), post-transplant immunodeficiencies, liver disease (chronic hepatitis, primary biliary cirrhosis, hepatitis C virus infection), rheumatism (rheumatoid arthritis, systemic lupus erythematosus), hemopathies (purpura fulminans), endocrinopathies (thymoma, Hashimoto's thyroiditis, myxedema), infectious diseases (human immunodeficiency virus infection, septic arthritis, pneumonia) and others (pyoderma gangrenosum).</p><p id="par0025" class="elsevierStylePara elsevierViewall">There are four types of MGUS<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a>:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1)</span><p id="par0030" class="elsevierStylePara elsevierViewall">IgM MGUS. Some 1–5% of cases progress to Waldenstrom macroglobulinemia or amyloidosis (light chain [AL], heavy chain [AH] or light and heavy chain [AHL]). Less frequently, cases can progress to IgM-secretory MM (abnormal proliferation of IgM-secretory plasma cells located in the bone marrow).</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2)</span><p id="par0035" class="elsevierStylePara elsevierViewall">Non-IgM MGUS. One percent of cases progress annually to MM. They can also progress to solitary bone plasmacytoma or amyloidosis (AL, AH and AHL).</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3)</span><p id="par0040" class="elsevierStylePara elsevierViewall">Light-chain MGUS. This condition is defined by an increase in involved free light chain levels, an abnormal light chain ratio and a lack of organ damage. The risk of progression to light-chain secretory MM can reach 3% annually, which can also progress to amyloidosis.</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4)</span><p id="par0045" class="elsevierStylePara elsevierViewall">Secondary MGUS. This type refers to the development of a new monoclonal protein in the course of a MM and that has an isotype (heavy and/or light chain) different from the original clone (e.g., IgM MGUS in a patient with IgG MM). This condition is more common in patients who have undergone hematopoietic stem cell transplantation and is associated with longer survival.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">3</span></a></p></li></ul></p><p id="par0050" class="elsevierStylePara elsevierViewall">The malignant monoclonal gammopathies include.<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">a)</span><p id="par0055" class="elsevierStylePara elsevierViewall">MM Represents 1% of all malignancies and 13% of hematological malignancies.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a> Bone marrow plasmacytosis ≥10% or the presence of a plasmacytoma (bone or extramedullary) are characteristics of MM. The presence of a monoclonal protein is not a requirement for diagnosis, because in the so-called nonsecretory myelomas the monoclonal protein is not detected in serum or urine, but its presence or absence is useful for classifying the myelomas. MM is also characterized by the presence of organ damage secondary to the clonal proliferation, which results in the defining events of MM (hypercalcemia, renal failure, anemia and bone lesions), and by the presence of one or more malignancy markers such as ≥60% bone marrow infiltration by plasma cells, ≥100 involved/uninvolved free light chains in serum (FLCs) ratio, or ≥0.1<span class="elsevierStyleHsp" style=""></span>g/L involved FLCs or more than one focal lesion in magnetic resonance imaging (each lesion must be ≥5<span class="elsevierStyleHsp" style=""></span>mm).<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">5</span></a></p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">b)</span><p id="par0060" class="elsevierStylePara elsevierViewall">Smoldering MM (SMM). This condition is an intermediate stage between MGUS and MM. The risk of progression to MM is approximately 10% annually during the first 5 years. SMM is defined by the presence of ≥30<span class="elsevierStyleHsp" style=""></span>g/L serum MC (IgG or IgA) levels, ≥500<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h urinary monoclonal protein levels or a 10–60% plasma cells in bone marrow, in the absence of organ damage.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">5,6</span></a></p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">c)</span><p id="par0065" class="elsevierStylePara elsevierViewall">Nonsecretory MM. Represents approximately 3% of MMs. This condition is an MM that is symptomatic and in which the MC is undetectable by immunofixation, both in serum and urine. The percentage of plasma cells in the bone marrow is greater than 10% or there is a plasmacytoma. Many of these cases require confirmation by biopsy.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">6–8</span></a></p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">d)</span><p id="par0070" class="elsevierStylePara elsevierViewall">Oligosecretory MM. Five to 10% of patients with MM have a oligosecretory MM at the time of diagnosis,<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">9</span></a> as defined by the presence of <0.1<span class="elsevierStyleHsp" style=""></span>g/L serum monoclonal protein levels or <200<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h urine monoclonal protein levels. As with nonsecretory MM, these patients need to be monitored by imaging studies and bone marrow tests, especially if the baseline FLC levels are <0.1<span class="elsevierStyleHsp" style=""></span>g/L or there are questions about the reliability of the results.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">6,9</span></a></p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">e)</span><p id="par0075" class="elsevierStylePara elsevierViewall">Light-chain MM. In this condition, monoclonal plasma cells secrete only light-chain immunoglobulins.</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">f)</span><p id="par0080" class="elsevierStylePara elsevierViewall">Primary amyloidosis. This condition is manifested as a systemic syndrome secondary to the deposit of amyloid proteins in various organs (kidneys, liver, heart, gastrointestinal tract and peripheral nerves), which entails the loss of organ structure and function. AL is diagnosed by positive Congo red staining in the histology of any organ (fat aspirate, bone marrow aspirate and organ biopsy) and by the presence of monoclonal plasma cells in light-chain fragment producing bone marrow, predominantly lambda.<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">10,11</span></a></p></li></ul></p><p id="par0085" class="elsevierStylePara elsevierViewall">Other malignant gammopathies include solitary bone plasmacytoma, extramedullary plasmacytoma, multiple plasmacytoma, Waldenstrom macroglobulinemia, lymphoproliferative syndromes (non-Hodgkin's lymphoma 3–4%, chronic lymphocytic leukemia 5%), immunoglobulin storage diseases, POEMS syndrome and plasma cell leukemia. The main characteristics of these diseases are listed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Diagnosis of monoclonal gammopathies</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Monoclonal component detection</span><p id="par0090" class="elsevierStylePara elsevierViewall">The suspicion of monoclonal gammopathy is established by the patient's symptoms, except for those MGUS that are found fortuitously in routine proteinograms. The regimen of tests to be performed after identifying the symptoms (anemia, lytic bone lesions, hyperviscosity and renal failure) is indicated in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">Electrophoresis of serum and urine proteins (proteinogram) provides electrophoretic separation of serum proteins in well-differentiated fractions (albumin, α1, α2, β and γ), which are quantified by spectrophotometry or densitometry. The MCs usually migrate primarily in the γ region of the electrophoretic gel, although they can migrate in the β region and less frequently in the α region. Protein electrophoresis should be performed both in serum and urine, which in the latter case provides information on renal involvement resulting from the possible monoclonal gammopathy. The technique has a lower limit of detection of 0.2–0.5<span class="elsevierStyleHsp" style=""></span>g/L, with a sensitivity of 82%.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">12</span></a> Additionally, the proteinogram profile provides for MC quantification. <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a> shows various proteinogram images.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Monoclonal component characterization</span><p id="par0100" class="elsevierStylePara elsevierViewall">Characterization is achieved by immunofixation in both serum and urine. The technique analyzes the electrophoretic migration in agarose gel of various immunoglobulins or fractions thereof, followed by precipitation of these immunoglobulins with specific antibodies (anti-IgG, IgA, IgM). For complete immunoglobulin paraproteins, the correlation between the electrophoretic movement of heavy and light chains provides an unequivocal characterization. If light chains are observed without an associated heavy chain, it is advisable to explore the possibility of a class IgD, IgE or FLC MC and, if the monoclonality of IgD or IgE is confirmed, these immunoglobulins should be quantified.</p><p id="par0105" class="elsevierStylePara elsevierViewall">Immunofixation is indicated for (a) patients with proteinograms that show an MC and (b) patients with no detectable MC in the proteinogram and clinical suspicion of MM, because the presence of a monoclonal band in the immunofixation with a normal proteinogram is a common finding in nonsecretory, oligosecretory and light-chain MM. This technique's detection limit is 0.2<span class="elsevierStyleHsp" style=""></span>g/L in serum and 0.04<span class="elsevierStyleHsp" style=""></span>g/L in urine.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">6</span></a> Similarly, urine protein tests at diagnosis are performed if a MC is previously found in serum<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">13</span></a> and when there is a significant suspicion of amyloidosis or light-chain MM.</p><p id="par0110" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a> shows 4 immunofixation images corresponding to samples from patients with monoclonal peaks.</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Serum immunoglobulin quantification</span><p id="par0115" class="elsevierStylePara elsevierViewall">This is usually performed through nephelometry, although this does not allow for an assessment of monoclonality, because increased serum immunoglobulin levels can correspond to both polyclonal and monoclonal increases. Clonality should therefore be established by immunofixation.</p><p id="par0120" class="elsevierStylePara elsevierViewall">Immunoglobulin quantification is a useful supplement to the proteinogram for the follow-up of patients with MM to assess treatment response. In certain situations, immunoglobulin levels can be more useful than the proteinogram, such as (a) when the MC migrates close to the β position (generally IgA), it can overlap with other proteins that migrate in this fraction and (b) when the monoclonal peak is so tall (>40<span class="elsevierStyleHsp" style=""></span>g/L) and narrow that the proteinogram underestimates the actual immunoglobulin level (in more than 15<span class="elsevierStyleHsp" style=""></span>g/L), due to the test's technical properties.<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">14,15</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Monoclonal component quantification</span><p id="par0125" class="elsevierStylePara elsevierViewall">If the presence of a monoclonal band is confirmed, it is advisable to quantify the MC to determine the patient's disease progression. This can be performed using the proteinogram or immunofixation (especially when the MC migrates in the β fraction).</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Free light-chain measurement</span><p id="par0130" class="elsevierStylePara elsevierViewall">This technique measures (by turbidimetry or nephelometry) the serum FLCs concentrations (<span class="elsevierStyleItalic">κ</span>/<span class="elsevierStyleItalic">λ</span>). Normal serum light-chain levels are kappa (0.33–1.94<span class="elsevierStyleHsp" style=""></span>g/L), lambda (0.57–2.6<span class="elsevierStyleHsp" style=""></span>g/L) and kappa/lambda ratio (0.26–1.65). For values less than 0.26 and the presence of a monoclonal <span class="elsevierStyleItalic">λ</span> peak in the immunofixation, <span class="elsevierStyleItalic">λ</span> clonality is considered. For values greater than 1.65 and the presence of a monoclonal <span class="elsevierStyleItalic">κ</span> peak, <span class="elsevierStyleItalic">κ</span> clonality is considered. For patients with renal failure, it is recommended that the results of the <span class="elsevierStyleItalic">κ</span>/<span class="elsevierStyleItalic">λ</span> ratio be interpreted with a modified range of 0.37–3.1.</p><p id="par0135" class="elsevierStylePara elsevierViewall">Serum FLCs quantification is a useful method in various conditions<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">16</span></a>: (a) diagnosis and follow-up of patients with nonsecretory, oligosecretory, light-chain or complete immunoglobulin MM and amyloidosis; (b) risk prediction for progression of MGUS, SMM, bone plasmacytoma and complete immunoglobulin MM<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">16–18</span></a>; and (c) in those cases in which MC is not observed in electrophoresis (proteinogram) or by immunofixation and in those cases in which the <span class="elsevierStyleItalic">κ</span>/<span class="elsevierStyleItalic">λ</span> ratio is normal, with no associated symptoms, allowing for monoclonal gammopathy to be ruled out of the diagnosis.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Hevylite</span><p id="par0140" class="elsevierStylePara elsevierViewall">The Hevylite assay<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">19</span></a> is also currently available but is not yet included in the international guidelines for the follow-up of monoclonal gammopathies. The assay separately quantifies (by nephelometry or turbidimetry) the specific pairs of heavy/light chains of each of the immunoglobulin isotypes (IgG<span class="elsevierStyleItalic">κ</span>/IgG<span class="elsevierStyleItalic">λ</span>, IgA<span class="elsevierStyleItalic">κ</span>/IgA<span class="elsevierStyleItalic">λ</span>, IgM<span class="elsevierStyleItalic">κ</span>/IgM<span class="elsevierStyleItalic">λ</span>). This assay enables the calculation of the ratios in a manner analogous to that of light chains, which can identify the monoclonal protein differentiating it from the polyclonal of the same class.</p><p id="par0145" class="elsevierStylePara elsevierViewall">The assay's main usefulness is in MC quantification in cases in which it is difficult to perform quantification by other methods and the assessment of both full remission and early risk of relapse. It has also been reported that abnormal ratios in the involved pair have prognostic value.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Follow-up of patients with monoclonal gammopathy</span><p id="par0150" class="elsevierStylePara elsevierViewall">Once the diagnosis has been established, the follow-up of these patients should consist of monitoring the MC (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>), following the following regimen, as long as this component is present at diagnosis in the proteinogram.</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">As a first step, electrophoresis of serum proteins (proteinogram) is performed to assess the disease progression and its response to treatment. This can result in 2 situations: persistence or lack of a monoclonal peak. If the monoclonal peak persists, we proceed to a) immunoglobulin quantification, b) MC quantification, and c) FLC quantification, which, in the case of an SMM, could help in assessing the possible progression to MM. For other cases, calculating the <span class="elsevierStyleItalic">κ</span>/<span class="elsevierStyleItalic">λ</span> ratio might be advisable, although this quantification is not necessary. The ratio's tendency to normalize will indicate the treatment response. In the second situation in which there is no monoclonal peak, immunoglobulin and FLC quantification and immunofixation are performed (to confirm the disappearance of the MC).</p><p id="par0160" class="elsevierStylePara elsevierViewall">If there were no monoclonal peaks in the proteinogram during diagnosis, as is the case for nonsecretory, oligosecretory and light-chain MM and amyloidosis, the same tests performed during the diagnosis are repeated.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Influence of monoclonal antibody therapy on laboratory data</span><p id="par0165" class="elsevierStylePara elsevierViewall">The therapeutic use of monoclonal antibodies in various diseases has undergone an exponential increase in recent years. As immunoglobulins, they are potentially detectable in the serum of treated patients, but due to the low dose used and its mechanism of action, they do not usually reach sufficiently high concentrations to be detected. Nevertheless, the sample with which the proteinogram or immunofixation will be performed should be distanced in time from the infusion of the medicinal product. That step is especially relevant for patients with hypogammaglobulinemia or agammaglobulinemia, in whom the drug could be identified as MC. For MM, treatment with monoclonal antibodies is still in the trial phase. The assessment of the complete treatment response using FLC immunofixation or quantification should be performed after the drug clearance period to avoid interference.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflict of interests</span><p id="par0170" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres624504" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec637907" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres624505" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec637908" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Diagnosis of monoclonal gammopathies" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Monoclonal component detection" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Monoclonal component characterization" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Serum immunoglobulin quantification" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Monoclonal component quantification" ] ] ] 6 => array:2 [ "identificador" => "sec0035" "titulo" => "Free light-chain measurement" ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Hevylite" ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Follow-up of patients with monoclonal gammopathy" ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Influence of monoclonal antibody therapy on laboratory data" ] 10 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflict of interests" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-06-08" "fechaAceptado" => "2015-09-02" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec637907" "palabras" => array:8 [ 0 => "Myeloma" 1 => "Monoclonal gammopathy" 2 => "Immunofixation" 3 => "Light chains" 4 => "Immunoglobulins" 5 => "Plasma cells" 6 => "Amyloidosis" 7 => "Monoclonal component" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec637908" "palabras" => array:8 [ 0 => "Mieloma" 1 => "Gammapatía monoclonal" 2 => "Inmunofijación" 3 => "Cadenas ligeras" 4 => "Inmunoglobulinas" 5 => "Células plasmáticas" 6 => "Amiloidosis" 7 => "Componente monoclonal" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">We present guidelines from the Immunochemistry group of the Spanish Society for Immunology that are designed to provide a practical tool for the diagnosis and follow-up of monoclonal gammopathies. We review the clinical and analytical features of various monoclonal gammopathies, international consensus guidelines and techniques used to detect and follow-up monoclonal components.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Se presenta una guía elaborada por el grupo de Inmunoquímica de la Sociedad Española de Inmunología con el objetivo de proporcionar una herramienta práctica para el diagnóstico y seguimiento de las gammapatías monoclonales.</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Se revisan las características clínicas y analíticas de los diferentes tipos de gammapatía monoclonal, las guías de consenso internacionales y las técnicas utilizadas para la detección y seguimiento del componente monoclonal.</p></span>" ] ] "NotaPie" => array:2 [ 0 => array:3 [ "etiqueta" => "◊" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">There is more information on the members of the Immunochemistry Group of the Spanish Society of Immunology in <a class="elsevierStyleCrossRef" href="#sec0060">Appendix 1</a>.</p>" "identificador" => "fn0005" ] 1 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as: Bravo García-Morato M, Padilla-Merlano B, Nozal P, Espiño M, Juárez C, Villar LM, et al. Guía de laboratorio para el diagnóstico y seguimiento de pacientes con gammapatías monoclonales. Rev Clin Esp. 2016;216:128–134.</p>" ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<p id="par0175" class="elsevierStylePara elsevierViewall">Carmen Cámara. Department of Immunology, Clinical Analysis Laboratory Hospital San Pedro de Alcantara, Caceres, Spain</p> <p id="par0180" class="elsevierStylePara elsevierViewall">Nieves Fernández. Department of Immunology, Regional University Hospital Carlos Haya, Malaga, Spain.</p> <p id="par0185" class="elsevierStylePara elsevierViewall">Joana Ferrer Balaguer. Immunology, University Hospital Son Espases, Palma de Mallorca, Spain.</p> <p id="par0190" class="elsevierStylePara elsevierViewall">Rosa García Delgado. Immunology, Jiménez Díaz-Capio Foundation, Madrid, Spain.</p> <p id="par0195" class="elsevierStylePara elsevierViewall">José Marcos García Pacheco. Department of Immunology, University Hospital Virgin de la Arrixaca, El Palmar, Murcia, Spain.</p> <p id="par0200" class="elsevierStylePara elsevierViewall">Manuel Hernández. Immunology, University Hospital Vall d’Hebron Barcelona, Spain.</p> <p id="par0205" class="elsevierStylePara elsevierViewall">Carmen Jiménez Garófano. Immunology, Central Hospital of Defense Gómez Ulla, Madrid, Spain.</p> <p id="par0210" class="elsevierStylePara elsevierViewall">Juana Jiménez Jiménez. Biochemical Laboratory, Immunoproteins, Autoimmunity and Allergies Section, Hospital Severo Ochoa, Leganes, Madrid, Spain.</p> <p id="par0215" class="elsevierStylePara elsevierViewall">Marcos López Hoyos. Department of Immunology, University Hospital Marqués de Valdecilla, Santander.</p> <p id="par0220" class="elsevierStylePara elsevierViewall">Eva M. Martínez Cáceres, University Hospital Germans Trias i Pujol Badalona, Barcelona, Spain.</p> <p id="par0225" class="elsevierStylePara elsevierViewall">Esther Moga Naranjo. Immunology, Hospital of la Santa Creu i de Sant Pau Barcelona, Spain.</p> <p id="par0230" class="elsevierStylePara elsevierViewall">Francisco Morandeira. Department of Immunology, University Hospital of Bellvitge L’Hospitalet de Llobregat Barcelona, Spain.</p> <p id="par0235" class="elsevierStylePara elsevierViewall">Cecilia Muñoz Calleja. Department of Immunology, Hospital de La Princesa, Madrid, Spain.</p> <p id="par0240" class="elsevierStylePara elsevierViewall">Joaquín Navarro Caspistegui. Department of Immunology, General University Hospital Gregorio Marañón, Madrid, Spain.</p> <p id="par0245" class="elsevierStylePara elsevierViewall">Esther Ocaña Pérez. Department of Clinical Analysis Immunology Laboratory, Hospital Complex of Jaen, Jaen, Spain.</p> <p id="par0250" class="elsevierStylePara elsevierViewall">Francisco Pujalte. Catlab, Park Logistic de Salut, Viladecavalls, Barcelona, Spain.</p> <p id="par0255" class="elsevierStylePara elsevierViewall">Juan José Rodríguez Molina. Department of Immunology, General University Hospital Gregorio Marañón, Madrid, Spain.</p> <p id="par0260" class="elsevierStylePara elsevierViewall">Pilar Sánchez Mozo. Immunology Laboratory, University Hospital Complex A Coruña La Coruña.</p> <p id="par0265" class="elsevierStylePara elsevierViewall">Aina Teniente Serra. University Hospital Germans Trias i Pujol Badalona, Barcelona, Spain.</p> <p id="par0270" class="elsevierStylePara elsevierViewall">Silvina Torio Gómez. Immunology Laboratory, University Hospital Complex A Coruña La Coruña.</p> <p id="par0275" class="elsevierStylePara elsevierViewall">Isabel Tovar. Department of Immunology, Clinical Analysis Laboratory Hospital San Pedro de Alcantara, Caceres, Spain.</p> <p id="par0280" class="elsevierStylePara elsevierViewall">Jordi Yagüe Ribes. Department of Immunology, CDB-Clinic Hospital. Barcelona, Spain.</p>" "etiqueta" => "Appendix 1" "titulo" => "Immunochemistry group of the Spanish Society of Immunology" "identificador" => "sec0060" ] ] ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1928 "Ancho" => 3146 "Tamanyo" => 204713 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Algorithm of laboratory tests when faced with suspected monoclonal gammopathy. <span class="elsevierStyleItalic">Abbreviation</span>: MC, monoclonal component.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1314 "Ancho" => 1658 "Tamanyo" => 113492 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Examples of proteinogram in serum.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1516 "Ancho" => 1682 "Tamanyo" => 122129 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Examples of immunofixation in samples from 4 patients with various gammopathies. <span class="elsevierStyleItalic">Abbreviations</span>: A, IgA migration profile; ELP, reference profile of total protein electrophoretic migration (after staining with a protein fixing solution); G, IgG migration profile; K, kappa light chain migration profile; L, lambda light chain migration profile. In all cases a specific antibody was revealed; M, IgM migration profile.</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 855 "Ancho" => 1565 "Tamanyo" => 94239 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Algorithm of laboratory tests during the follow-up of patients with monoclonal gammopathy. <span class="elsevierStyleItalic">Abbreviations</span>: MC, monoclonal component; Igs, immunoglobulins.</p>" ] ] 4 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>: MGUS, monoclonal gammopathy of undetermined significance; MC, monoclonal component; BM, bone marrow; FLCs, free light chains; MM, multiple myeloma; PA, primary amyloidosis.</p>" "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="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Tissue lesions/symptoms \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">MC \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">BM cells \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">MGUS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Absent \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgM, IgG, IgA, IgD.<br>MC <30<span class="elsevierStyleHsp" style=""></span>g/L (this concentration is directly related to the risk of malignization) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Clonal plasma cells in BM <10% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Waldenstrom macroglobulinemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Blood hyperviscosity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgM (any concentration) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lymphoplasmacytic lymphoma infiltration \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">MM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">One or more defining events of myeloma:<br>Hypercalcemia<br>Renal failure<br>Anemia<br>Bone lesions (>1 focal lesion MRI<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MC (IgG, IgM, IgA, IgD)<br>Ratio of FLCs involved: not involved ≥100<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Clonal plasma cells ≥10% or ≥60%<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a><br>Bone or extramedullary plasmacytoma \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Asymptomatic myeloma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Absence of defining events of MM or PA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MC (IgG, IgA) ≥30<span class="elsevierStyleHsp" style=""></span>g/L or 500<span class="elsevierStyleHsp" style=""></span>mg of MC in 24-h urine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Clonal plasma cells BM 10–60% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Light chain myeloma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Renal failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Abnormal <span class="elsevierStyleItalic">λ</span>/<span class="elsevierStyleItalic">κ</span> ratio<br>Absence of heavy chains \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Light chain-secreting clonal plasma cells <10% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nonsecretory/oligosecretory myeloma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypercalcemia<br>Renal failure<br>Anemia<br>Bone lesions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Undetectable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Clonal plasma cells ≥10% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Carpal tunnel syndrome, neuropathies, macroglossia, renal failure, cardiomyopathy. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Abnormal <span class="elsevierStyleItalic">λ</span>/<span class="elsevierStyleItalic">κ</span> ratio<br>Positive Congo red staining in organs or tissue.<br>MC in serum or urine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Clonal plasma cells \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1024394.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Biomarker of malignancy.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Main characteristics of monoclonal gammopathies.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:19 [ 0 => array:3 [ "identificador" => "bib0100" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Guidelines for the investigation of newly detected M-proteins and the management of monoclonal gammopathy of undetermined significance (MGUS)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. 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| Year/Month | Html | Total | |
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| 2023 March | 4 | 3 | 7 |
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