Management of smoldering myeloma: Recommendations of the Spanish Myeloma Group

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Len-dex: lenalidomida-dexametasona; MM: mieloma múltipe." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "María-Victoria Mateos, Joan Bladé, Juan-José Lahuerta, Jesús San-Miguel" "autores" => array:4 [ 0 => array:2 [ "nombre" => "María-Victoria" "apellidos" => "Mateos" ] 1 => array:2 [ "nombre" => "Joan" "apellidos" => "Bladé" ] 2 => array:2 [ "nombre" => "Juan-José" "apellidos" => "Lahuerta" ] 3 => array:2 [ "nombre" => "Jesús" "apellidos" => "San-Miguel" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2387020617303339" "doi" => "10.1016/j.medcle.2017.05.003" "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/S2387020617303339?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775317301537?idApp=UINPBA00004N" "url" => "/00257753/0000014800000011/v1_201705140041/S0025775317301537/v1_201705140041/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2387020617303352" "issn" => "23870206" "doi" => "10.1016/j.medcle.2017.01.023" "estado" => "S300" "fechaPublicacion" => "2017-06-07" "aid" => "3955" "copyright" => "Elsevier España, S.L.U." 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"documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Med Clin. 2017;148:511-6" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Cerebral magnetic resonance changes associated with fibromyalgia syndrome" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "511" "paginaFinal" => "516" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Cambios en la resonancia magnética cerebral asociados al síndrome de fibromialgia" ] ] "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" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3016 "Ancho" => 1736 "Tamanyo" => 370836 ] ] "descripcion" => array:1 [ "en" => "Magnetic resonance imaging (MRI) indicating whether the values for the referred metabolites are increased (in red) or decreased (in green). Creatinine is in bold as it is used as the reference value. (a) Coronal-slice MRI, indicating the values of the metabolites studied regarding both hippocampus. Note that in the left hippocampus, different authors give opposite values for choline. (b) Horizontal-slice MRI, indicating the values of the studied metabolites referred to the head of the caudate nucleus bilaterally and to the insula (anterior and posterior region). (c) Sagittal-slice MRI, indicating the values of the metabolites studied referred to the ventrolateral prefrontal cortex, and the anterior and posterior cortex of the cingulate gyrus. Cho: choline; Cr: creatine; GABA: gamma-aminobutyric acid; Gln: glutamine; Glu: glutamate; Glx: glutamate+glutamine; Lact: lactate; MI: myo-inositol; NAA: N-acetylaspartate; NAAG: N-acetylaspartate glutamate." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Iñigo Murga, Virginia Guillen, José-Vicente Lafuente" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Iñigo" "apellidos" => "Murga" ] 1 => array:2 [ "nombre" => "Virginia" "apellidos" => "Guillen" ] 2 => array:2 [ "nombre" => "José-Vicente" "apellidos" => "Lafuente" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775317301902" "doi" => "10.1016/j.medcli.2017.01.034" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775317301902?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020617303571?idApp=UINPBA00004N" "url" => "/23870206/0000014800000011/v1_201706250038/S2387020617303571/v1_201706250038/en/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "Special article" "titulo" => "Management of smoldering myeloma: Recommendations of the Spanish Myeloma Group" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "517" "paginaFinal" => "523" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "María-Victoria Mateos, Joan Bladé, Juan-José Lahuerta, Jesús San-Miguel" "autores" => array:4 [ 0 => array:4 [ "nombre" => "María-Victoria" "apellidos" => "Mateos" "email" => array:1 [ 0 => "mvmateos@usal.es" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Joan" "apellidos" => "Bladé" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 2 => array:3 [ "nombre" => "Juan-José" "apellidos" => "Lahuerta" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] 3 => array:3 [ "nombre" => "Jesús" "apellidos" => "San-Miguel" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "e" "identificador" => "aff0025" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Complejo Asistencial Universitario de Salamanca/Instituto Biosanitario de Salamanca (CAUSA/IBSAL), Salamanca, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Grupo Español de Mieloma (GEM)/PETHEMA, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Hospital Clinic i Provincial de Barcelona, Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Hospital 12 de Octubre, Madrid, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Clínica Universidad de Navarra, Pamplona, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento del mieloma múltiple asintomático: recomendaciones del Grupo Español de Mieloma" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1336 "Ancho" => 3343 "Tamanyo" => 246941 ] ] "descripcion" => array:1 [ "en" => "Time to progression (A) and overall survival (B) of patients with asymptomatic or smoldering multiple myeloma included in the trial of the Spanish group QuiRedex. Len-dex: lenalidomide-dexamethasone; MM: multiple myeloma." ] ] ] "textoCompleto" => "IntroductionAsymptomatic or smoldering multiple myeloma (SMM) was first defined in 1980 by Kyle and Greipp after observing the clinical course of 6 patients who met the criteria for multiple myeloma (MM) but experienced a painless course.<a class="elsevierStyleCrossRef" href="#bib0155">1</a>Based on data from the Swedish MM Registry, Kristinsson et al. reported that 14% of patients with newly diagnosed MM are SMM, equivalent to 0.44 new cases per 100,000 inhabitants/year.<a class="elsevierStyleCrossRef" href="#bib0160">2</a>The concept of SMM was updated by the International Myeloma Working Group (IMWG), agreeing on the following diagnostic criteria: serum monoclonal component (MC) ≥3g/dl, and/or between 10% and 60% of plasma cells (PC) in bone marrow (BM) without organic damage, that is, without CRAB (Calcium, Renal insufficiency, Anaemia or Bone lesions) symptoms. A subgroup of asymptomatic patients with a very high risk of progression (ultra-high risk) to MM (>80% at 2 years) who had one or more of the following biomarkers: (i) presence of 2 or more focal lesions on whole body or spine and pelvis magnetic resonance imaging (MRI); (ii) ratio of free light chains in serum over 100; or (iii) PC infiltration in BM ≥60% were excluded from this new definition of SMM.<a class="elsevierStyleCrossRef" href="#bib0165">3</a> These patients are now considered as MM and therefore need to start treatment.Differential diagnosis<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the criteria that define monoclonal gammopathy of undetermined significance, SMM and MM. Monoclonal gammopathy of undetermined significance is characterized by a MC <3g/dl and <10% of PC in BM, in the absence of organic damage data. On the contrary, the MM, as we have already pointed out, is defined by the presence of ≥10% clonal PCs in BM or in a bone or extramedullary plasmacytoma. However, for the diagnosis of MM, the presence of any CRAB symptomatology is essential, either that or the presence of one or more of the three biomarkers referred to above, which, in the absence of CRAB, are associated with an imminent risk of progression to MM.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Symptomatology, especially CRAB, should be carefully evaluated so as not to confuse it with concomitant diseases whose manifestations may mimic MM symptomatology; for example, nutritional anaemia, menopausal osteoporosis, impaired renal function due to hypertension or diabetes, hypercalcemia due to hyperparathyroidism, or an isolated single bone cyst.The diagnosis of SMM requires some additional examinations whose results should also be interpreted in the context of the clinical symptoms:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">(1)For the evaluation of bone lesions, the IMWG recommends the performance, according to availability, of a bone series or a CT scan of individual low dose or combined with a positron emission tomography (PET/CT) using 18F fluorodeoxyglucose as a tracer, although the latter 2 techniques are more sensitive. Low-dose CT is the most cost-effective technique to detect lesions in up to 30% of the cases in which the bone series was negative (the lytic lesion must measure at least 5mm to be considered as such). It is also necessary to perform a whole body or spine and pelvis MRI, since MM should be considered if there is more than one focal bone lesion. In this sense Hillengas et al. reported that the presence of more than one MRI focal lesion in patients with SMM is associated with a high risk of progression to MM (median time to progression [TTP]) of 13 months),<a class="elsevierStyleCrossRef" href="#bib0170">4</a> data confirmed by Kastritis et al.<a class="elsevierStyleCrossRef" href="#bib0175">5</a> in a small study in which 9 cases with more than one focal lesion were evaluated, with a 2-year risk of transformation of 69%.</li><li class="elsevierStyleListItem" id="lsti0010">(2)With regard to PC infiltration of BM, in a series of 651 patients with SMM of the Mayo Clinic, the median TTP in cases of one infiltration ≥60% was 7.7 months, with a 2-year progression risk of 95%.<a class="elsevierStyleCrossRef" href="#bib0180">6</a> This finding was corroborated in 2 other series, one of 96 patients, confirming the TTP of 15 months<a class="elsevierStyleCrossRef" href="#bib0185">7</a> and another of 121 patients identifying 6 (5%) cases with this biomarker and development of MM in all cases within 2 years.<a class="elsevierStyleCrossRef" href="#bib0190">8</a></li><li class="elsevierStyleListItem" id="lsti0015">(3)Serum free light chains (sFLC) quantification is required in the initial assessment. The Mayo Clinic group analyzed the value of the ratio between the affected and unaffected free light chains in serum in 586 patients with SMM and when the ratio was higher than 100, present in 15% of patients, the risk of progression to MM at 2 years was 71%.<a class="elsevierStyleCrossRef" href="#bib0195">9</a> The results of the Greek Myeloma Group confirmed these results in a series of 96 patients, detecting a progression rate of 80% in the first 24 months.<a class="elsevierStyleCrossRef" href="#bib0185">7</a> This biomarker is probably the most conflicting and, in fact, a recent analysis published by the Danish Myeloma Group on 321 patients with SMM has not confirmed the significant influence of abnormal sFLCr values on TTP.<a class="elsevierStyleCrossRef" href="#bib0200">10</a></li></ul>In summary, if after considering the above aspects, a patient meets SMM criteria (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>), this should be confirmed 2–3 months after the first evaluation and then the therapeutic approach should be determined by the risk to progress to MM.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Risk assessment in the patient with smoldering multiple myelomaThe annual risk of developing MM in a patient with SMM depends on the time elapsed since diagnosis: 10% per year for the first 5 years; 3% per year for the next 5 years and only 1% after the first 10 years.<a class="elsevierStyleCrossRef" href="#bib0205">11</a> Although most patients with SMM will develop MM, the risk is not homogeneous and is conditioned by the presence of biomarkers that have been used to create models aimed at evaluating the risk of each patient with SMM, in order to support an individualized management of this disease (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Monoclonal component in serum and bone marrow infiltrationThe Mayo Clinic group<a class="elsevierStyleCrossRef" href="#bib0205">11</a> identified 3 categories of patients: group 1, defined by a MC ≥3g/dl and ≥10% of PC in the BM, with a median TTP of 2 years; group 2, with ≤3g/dl of MC and ≥10% PC in BM, whose median TTP reached 8 years, and group 3, characterized by an M band ≥3g/dl but <10% of PC in the BM, with a median TTP of 19 years.Ratio of free light chains in serumAnother analysis performed at the Mayo Clinic in a series of 273 patients identified an increased risk of progression in patients with an abnormal ratio (<0.125 or >8) between the affected light chains versus those not affected (sFLCr). Combining this parameter with the previous model based on MC and percentage of PC in BM, the group of high risk patients with a TTP of 1.9 years was defined by a MC ≥3g/dl, a BM infiltration ≥10%, and an abnormal sFLCr.<a class="elsevierStyleCrossRef" href="#bib0210">12</a>Immunophenotype and immunoparesisFlow cytometry evaluates the immunophenotypic profile of PC and the Salamanca group identified that phenotypically normal and aberrant PC coexist in patients with SMM. Our group demonstrated that the presence of ≥95% of PC and/or immunoparesis are high risk factors, and a model can be established that identifies 3 risk groups: group 1 with a median TTP of 23 months when the 2 parameters are present; group 2, with a median TTP of 73 months when only one risk factor is present and group 3 with very low risk if none of the factors is present.<a class="elsevierStyleCrossRef" href="#bib0215">13</a>The Danish MM Group evaluated immunoparesis in its registry of SMM patients, confirming that its presence along with a MC ≥3g/dl was associated with a significantly higher risk of progression to MM (HR: 2.7; 95% CI [1.5; 4.7] p=0.001 and RH: 3.3; 95% CI [1.4; 7.8] p=0.002, respectively).<a class="elsevierStyleCrossRef" href="#bib0200">10</a>Circulating plasma cells in peripheral bloodThe Mayo Clinic Group has analyzed the value of pbPC to predict progression to MM, noting that 15% of patients with SMM present >5×106/l and/or >5% pbPC per 100 mononuclear cells (identified as clonal by immunofluorescence for cytoplasmic immunoglobulins); the median TTP in this group of patients was 2 years.<a class="elsevierStyleCrossRef" href="#bib0220">14</a> Data are being generated based on the quantification of pbPC by flow cytometry showing that patients with more than 150 pbPC have very high risk of transformation (median TTP of 9 months) and this parameter could be considered in the future to define patients with MM.Progression patterns of monoclonal component and haemoglobin together with bone marrow infiltrationIn a series of 207 patients with SMM, the Clinic Hospital group<a class="elsevierStyleCrossRef" href="#bib0225">15</a> identified a subgroup of patients with MC ≥3g/dl which increased by at least 10% in the following 6 months, or in the case of <3g/dl the increase was progressive in each yearly determination over a period of 3 years. These patients, with progressive SMM, accounted for 25% and the probability of progression to MM at 2 years was 45%. The median TTP in patients with non-progressive SMM was 19 years.<a class="elsevierStyleCrossRef" href="#bib0230">16</a> Recently, this progression pattern was validated in 191 patients of the Mayo Clinic and the progression profile was associated with a MM progression probability at 2 years of 64%. In addition, BM infiltration by PC >20% as well as the decrease in haemoglobin (at least 0.5g/dl in the first year) were included as independent factors that predicted risk of progression to MM within 2 years (48 and 65% in each case). A new model has been generated using these risk factors, capable of distinguishing SMM patients with TTP of 12.3; 4.2; 2.8 and 1 years according to the presence of none, one, two or all three risk factors. This model could be incorporated into the definition of early MM in the future.<a class="elsevierStyleCrossRef" href="#bib0235">17</a> Finally, the SWOG group described that the increase of MC values up to ≥3g/dl in the first 3 months from diagnosis was associated with a 50% progression probability in 2 years.Bence Jones proteinuriaThe Castilla y León gammopathies group evaluated IgG or IgA in SMM; the coincidence of Bence Jones proteinuria, regardless of its quantification, is associated with a TTP to MM of 22 months versus 83 months in Bence Jones negative patients and 7 months if Bence Jones >500mg/24h.<a class="elsevierStyleCrossRef" href="#bib0240">18</a>New imaging techniquesBoth MRI and PET/CT can help predict the risk of progressing to MM. New focal lesions detection on MRI or an increase in lesion diameter are associated with increased risk of progression.<a class="elsevierStyleCrossRef" href="#bib0245">19</a> Two recent studies<a class="elsevierStyleCrossRefs" href="#bib0250">20,21</a> evaluated PET/CT in SMM, confirming that the presence of hypermetabolic areas without underlying lytic lesions constitutes a risk of progression to MM of 48–56% in the first 2 years, respectively.Cytogenetic abnormalitiesThe presence of t (4; 14) and/or (17p) in SMM is associated with a median TTP of 2 years.<a class="elsevierStyleCrossRef" href="#bib0260">22</a> Neben et al. identified t (4; 14), 1q21 gains or hyperdiploidy as independent prognostic factors associated with risk of progression to MM (50% to 2 years).<a class="elsevierStyleCrossRef" href="#bib0265">23</a> Finally, the SWOG group identified a genetic signature to identify a subgroup whose risk of progression to MM in 2 years reaches 85.7%.<a class="elsevierStyleCrossRef" href="#bib0270">24</a>Management of patients with smoldering multiple myelomaThe initial step after the diagnosis of SMM is to identify the individual risk that the patient has to progress to MM. The next step would be to see which is the ideal model to use to assess that individual risk. The models described by both the Mayo Clinic and the Spanish Myeloma Group (SMG) have been validated in a randomized and prospective clinical trial. However, as shown in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>, new risk models have been proposed based on factors identified in multivariate analysis and, therefore, have prognostic value with independent value.<a class="elsevierStyleCrossRefs" href="#bib0190">8,10,11,13,15,23,25–27</a> It is important to insist that a patient with high-risk SMM does not have to manifest all the characteristics that define a high-risk SMM.<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Patients with SMM should be classified into one of 3 groups:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020">1.SMM with low risk of progression to MM: characterized by the absence of high risk biomarkers and a 5-year progression probability of 8% (Mayo Clinic and SMG models). These patients may have a MC ≥3g/dl but the infiltration of BM is <10%, and/or have no immunoparesis and the percentage of PC with aberrant phenotype does not exceed 95%. The follow-up of these patients may be annual, with confirmation of MC stability and absence of symptomatology in initial controls.</li><li class="elsevierStyleListItem" id="lsti0025">2.SMM with intermediate risk to progress to MM: in this group, the patients would be characterized by a MC <3g/dl, an infiltration by PC in BM ≥10%, or the presence of immunoparesis or a percentage of PC with aberrant phenotype ≥95%. These patients could be defined as the “true” SMM, in which the 5-year risk of progression reaches 42%.<a class="elsevierStyleCrossRefs" href="#bib0205">11,13</a> Follow-up may be spaced up to 6 months, except for the first year in which a quarterly evaluation will allow to check the stability of MC, haemoglobin, or non-involved immunoglobulins.</li><li class="elsevierStyleListItem" id="lsti0030">3.SMM with high risk of progression to MM: This group of patients is characterized by MC ≥3g/dl, PC in BM ≥10% or in the presence of only one of the above 2 factors suffering at the same time of immunoparesis plus a PC percentage of aberrant phenotype ≥95%. Half of these patients will progress to MM within 2 years, so they will require follow-up every 2–3 months. As there is no approved treatment for patients with high-risk SMM, these patients should be referred to specialist centres to, if possible, be included in clinical trials.</li></ul>In case no clinical trials are available or patients with high-risk SMM do not meet the inclusion and/or exclusion criteria, the Spanish Group of MM (PETHEMA/GEM) has performed a phase 3 randomized trial in a series of 119 patients with high-risk SMM, demonstrating that early treatment with lenalidomide and dexamethasone significantly slows the progression to MM versus lack of treatment and, in addition, significantly prolongs the overall survival (OS), therefore, this trial could be the rationale behind early treatment in this subgroup of patients with SMM. This study included 125 patients with high-risk SMM who progressed to MM, of whom 119 were finally considered evaluable for efficacy following a review by an external and independent review committee. This committee certified the high-risk classification of SMM patients included. The inclusion criteria chosen for defining SMM at high risk of progression to MM were those based on, either the Mayo Clinic group definition (PC in BM ≥10% and MC ≥3g/dl), or the PETHEMA/GEM group definition (≥95% PC with aberrant phenotype and immunoparesis in the presence of only one of the 2 factors of the Mayo Clinic).The control group was assigned to therapeutic abstention, the management standard, whereas the experimental group received an induction treatment with 9 cycles of lenalidomide and dexamethasone (Rd). Lenalidomide was given at doses of 25mg daily, orally, during days 1–21 of each cycle followed by one week of rest; dexamethasone (d) was given at low dose: 20mg on days 1–4 and 12–15 of each cycle (total dose per cycle of 160mg). After induction, the patients received maintenance with cycles of lenalidomide at 10mg daily between days 1 and 21 followed by a week of rest. Although maintenance was initially scheduled until progression from SMM to MM, an amendment in March 2011 limited the duration of treatment to 24 months, following news about the development of second primary neoplasms in patients undergoing maintenance with lenalidomide. This amendment also included the possibility of administering low doses of dexamethasone to patients in the experimental arm who underwent a biological progression in the maintenance phase with lenalidomide (increase of MC ≥25% without symptomatology).Lenalidomide is an immunomodulatory drug whose target is cereblon, which binds to the aiolos and ikaros proteins, which are lymphoid transcription factors, resulting in their ubiquitination and subsequent degradation, which produces cytotoxic and immunomodulatory effects. It is approved for first-line treatment of adult patients with MM who are not transplant candidates, and in combination with dexamethasone in the treatment of patients with MM who have received at least one prior treatment.There were 119 patients included, 57 assigned to the experimental arm and 62 to the control group. The recruitment took place in 19 Spanish sites and 3 Portuguese sites. The first analysis, performed in 2013 with a median follow-up of 40 months, showed that early treatment with Rd delayed progression to MM compared to the control group (HR: 0.18; 95% CI: 0.09–0.32, p<0.001), and a median TTP not reached in the experimental group in contrast to the median of 23 months in the control group, confirming both the efficacy of the early treatment and the real high risk of the selected population.<a class="elsevierStyleCrossRef" href="#bib0290">28</a> This benefit was maintained in the long-term follow-up analysis (75 months from inclusion in the study), confirming that early treatment with Rd had reduced the probability of progression to MM by 76% with respect to therapeutic abstention (HR: 0, 24; 95% CI: 0.14–0.41; p<0.001). At the time of the first analysis, none of the groups had reached the median OS, although in the experimental arm the 3-year survival rate was 94% as opposed to 80% in the control arm (HR: 0.31; 95% CI: 0.10–0.91; p=0.03). This advantage is maintained in the last update, confirming the benefit not only in TTP but also in OS (HR: 0.43; 95% CI: 0.20–0.90; p=0.02) (OS: 94 vs 64% at 7 years) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A and 1B). 10 patients died (18%) in the experimental arm, compared to 22 (36%) in the control arm, all of them after progression to MM and, in most cases, after several treatment lines. The rescue treatments received by the patients in both groups were evaluated and it was verified that there were no significant differences neither in the treatment schemes nor in the response rates reached, as well as that the treatments received were adequate for the characteristics of the patients at the time of progression.<a class="elsevierStyleCrossRef" href="#bib0295">29</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>In the experimental arm, during maintenance with lenalidomide, 15 patients had biological progression and received low doses of dexamethasone, as specified in the protocol. This strategy controlled the disease again in all of them. In fact, the OS of this group was similar to the group of patients who remained progression-free. In both cases, OS is statistically superior (95% of patients alive at 6 years) than those who progressed directly to MM (50% at 6 years).On the other hand, considering the absence of OS differences between the control and experimental groups from the time of progression (p=0.50), it can be stated that early treatment with Rd did not induce a selection of more resistant-to-relapse clones.The toxicity profile was acceptable with most adverse events being grade 1 and 2. In the experimental arm, 4 patients (6%) had infections and grade-3 asthenia, 3 grade-3 neutropenia and 2 rashes. In the control arm, 26% of patients had grade 1–2 infections probably because of the immunosuppressive status associated with SMM. Only one death from pneumonia was recorded in the experimental arm in the induction phase. The frequency of second primary neoplasms was slightly higher in the experimental arm (6 [10%] vs 1 [2%]) but the cumulative and adjusted exposure risk was similar (p=0.07).QuiRedex is the first clinical trial with a high power of evidence that has demonstrated a significant benefit of early treatment in high-risk SMM in both TTP and OS, which is a milestone in the management of patients with SMM, until now simply monitored without any possibility of delaying or eliminating the transformation to MM. The results of this study would justify early treatment in these patients, at least with Rd.At present, other clinical trials are evaluating early treatment in high-risk SMM using lenalidomide alone without corticosteroids, combinations of elotuzumab plus Rd, daratumumab, or even combinations such as carfilzomib plus Rd: the latter has achieved complete response in almost all cases as a preliminary regimen in 12 patients, plus being associated to negative minimal residual disease.<a class="elsevierStyleCrossRef" href="#bib0300">30</a> These results have served as rationale for the development of more intensive therapeutic strategies as the one selected for the new phase II PETHEMA/GEM trial for high-risk SMMs up to 70 years of age, which evaluates the effect of a 6-cycle induction based on carfilzomib plus Rd, followed by autogenous transplantation, double consolidation and maintenance with the aim to “cure” before SMM progression to MM.ConclusionsIn the past, the treatment philosophy of MM has focused on MM patients, which is different from what is planned in other oncological diseases, such as breast, colon, in which early treatment is essential when it comes to increase survival and achieve recovery. However, this philosophy was logical in the case of MM since the alkylators were the only effective therapeutic agents and also because the trials initially performed with melphalan and even thalidomide showed no benefit for early treatment. In addition, all types of SMM were included in these studies without discrimination based on the risk of progression.Fortunately, there have been important advances in the knowledge of the biology of SMM and today we can identify in each patient the individual risk of progression to MM. Moreover, we know that if there is an imminent risk of progressing to MM (80% at 2 years), these patients should already be considered MM and start receiving treatment. However, the positive results of the SMG/QuiRedex study justify the early treatment of patients with high-risk SMM (50–80% transformation in the first 2 years) without waiting for extreme risk criteria or MM occurrence.The next discussion would be whether high-risk SMMs should receive only Rd, as in the QuiRedex trial, or, on the contrary, whether a more intense strategy would be justified in order to achieve recovery in these early stages. The SMG, for the time being, supports Rd for transplant candidates and non-candidates based on the results obtained, and works on the development of more intensive therapeutic strategies especially in young patients in whom recovery is perceived as an attainable goal.Conflict of interestsM.V. Mateos, J. Bladé, J.J. Lahuerta and J. San Miguel have received fees for conferences and participation in Celgene's advisory meetings." "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Differential diagnosis" ] 2 => array:3 [ "identificador" => "sec0015" "titulo" => "Risk assessment in the patient with smoldering multiple myeloma" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Monoclonal component in serum and bone marrow infiltration" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Ratio of free light chains in serum" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Immunophenotype and immunoparesis" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Circulating plasma cells in peripheral blood" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Progression patterns of monoclonal component and haemoglobin together with bone marrow infiltration" ] 5 => array:2 [ "identificador" => "sec0045" "titulo" => "Bence Jones proteinuria" ] 6 => array:2 [ "identificador" => "sec0050" "titulo" => "New imaging techniques" ] 7 => array:2 [ "identificador" => "sec0055" "titulo" => "Cytogenetic abnormalities" ] ] ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "Management of patients with smoldering multiple myeloma" ] 4 => array:2 [ "identificador" => "sec0065" "titulo" => "Conclusions" ] 5 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflict of interests" ] 6 => array:2 [ "identificador" => "xack287342" "titulo" => "Acknowledgements" ] 7 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-02-03" "fechaAceptado" => "2017-02-15" "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Mateos M-V, Bladé J, Lahuerta J-J, San-Miguel J. Tratamiento del mieloma múltiple asintomático: recomendaciones del Grupo Español de Mieloma. Med Clin (Barc). 2017;148:517–523." ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1336 "Ancho" => 3343 "Tamanyo" => 246941 ] ] "descripcion" => array:1 [ "en" => "Time to progression (A) and overall survival (B) of patients with asymptomatic or smoldering multiple myeloma included in the trial of the Spanish group QuiRedex. Len-dex: lenalidomide-dexamethasone; MM: multiple myeloma." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "PC: plasma cells; CRAB: Calcium, Renal insufficiency, Anaemia or Bone lesions; MDE: myeloma defining episodes; MGUS: monoclonal gammopathy of undetermined significance; MM: multiple myeloma; SMM: smoldering multiple myeloma; BM: bone marrow." "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="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristic \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">MGUS \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">SMM \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">MM \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">Serum M protein \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><3g/dl, and \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">≥3g/dl and/or \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \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">Clonal infiltration by PC in BM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><10% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10–60% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">≥10% or plasmacytoma evidenced on biopsy \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">Symptomatology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Absence of CRAB<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Absence of MDE<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> or amyloidosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Presence of MDE** \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1447607.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "CRAB symptomatology includes (1) hypercalcemia: serum calcium >0.25mmol/l (>1mg/dl) above the upper limit of normal or >2.75mmol/l (>11mg/dl); (2) renal failure: serum creatinine >177μmol/l (2mg/dl) or creatinine clearance <40ml/min; (3) anaemia: haemoglobin >2g/dl below the low limit of normal, or haemoglobin <10g/dl; (4) bone lesions: one or more lytic lesions evidenced by conventional radiology, CT, or PET-CT." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Events that define myeloma and include the CRAB symptoms described above or one or more of the following biomarkers that predict progression to MM: ≥60% clonal plasma cells in the bone marrow; ratio of free light chains in serum affected/unaffected ≥100; >1 focal lesion in MRI studies." ] ] ] "descripcion" => array:1 [ "en" => "Differential diagnosis between monoclonal gammopathy of undetermined significance, smoldering multiple myeloma and multiple myeloma." ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "LDH: lactate dehydrogenase; PET-CT: positron emission tomography using 18F-fluorodeoxyglucose as tracer; MRI: magnetic resonance imaging; sFLC: Serum Free light chain; CT: computed tomography." "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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Clinical history and physical examination \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">Blood count \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">Biochemical studies, including serum and calcium creatinine; beta2-microglobulin, LDH and albumin \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">Protein studies \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">Total serum proteins and electrophoresis (monoclonal component) \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">Protein electrophoresis in 24h urine sample (urine monoclonal component or Bence Jones proteinuria) \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">Immunofixation in serum and urine \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">Ratio of free light chains in serum (sFLC ratio) \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">Aspirate±bone marrow biopsy: clonal plasma cell infiltration, flow cytometry and In situ fluorescence hybridization in selected plasma cells \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">Bone series, CT, or PET-CT \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">MRI of the spine and pelvis, although, ideally, it should be whole-body MRI \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1447608.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Tests performed at the time of smoldering multiple myeloma diagnosis." ] ] 3 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "BM: bone marrow; PET-CT: positron emission tomography using 18F-fluorodeoxyglucose as tracer; MRI: magnetic resonance imaging." "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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tumour mass \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">≥10% clonal plasma cells in BM plus \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">≥3g/dl of monoclonal component and serum free light chains ratio <0.125 or >8 \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">Positive Bence Jones proteinuria in 24h urine \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">Circulating plasma cells in peripheral blood >5×106/l \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">Circulating plasma cells in peripheral blood by cytometry ≥150 \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">Immunophenotypic characterization and immunoparesis \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">≥95% of aberrant plasma cells by cytometry in the BM plasma cells plus \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">Immunoparesis (>25% decrease in one or both immunoglobulins not affected with respect to the low level of normality) \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">Cytogenetic abnormalities \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">Presence of t (4; 14) \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">Presence of del17p \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">1q24 gain \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">Hyperdiploidy \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">Score >−0.26 by gene expression profile \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">Monoclonal component and haemoglobin progression pattern \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">Type in progression: if monoclonal component ≥3g/dl, increase of at least 10% during the first 6 months. If monoclonal component <3g/dl, annual increase over 3 years \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">Increase of monoclonal component up to ≥3g/dl during the 3 months following the previous determination \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">Decreased haemoglobin in ≥0.50g/dl in the first year since diagnosis \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">Imaging techniques \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">MRI: progressive disease by MRI when new focal lesions are detected or the diameter of the existing lesion increases (if previously detected) or progressive diffuse 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">Positive PET/CT without osteolytic lesions \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1447605.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Smoldering multiple myeloma: factors that predict progression to multiple myeloma. Characteristics to identify high-risk smoldering multiple myeloma (approximately 50% in 2 years)." ] ] 4 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "C: cytogenetics; FCM: flow cytometry; PC: plasma cells; GEP: gene expression profile; BM: bone marrow; TM: tumour mass; sFLC: Serum free light chain; TTP: time to progression." "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="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk model \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk of progression to multiple myeloma</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">Mayo Clinic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Median TTP \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">≥10% PC in BM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 risk factor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 years \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">≥3g/dl of monoclonal component \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 risk factors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 years \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">sFLC ratio <0.125 or >8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 risk factors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.9 years \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">Spanish group \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Median TTP \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">≥95% of aberrant PC by FCM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 risk factors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not reached \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">Immunoparesis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 risk factor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 years \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 risk factors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.9 years \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">Heidelberg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3-year TTP \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">Tumour mass as per Mayo Clinic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low TM+low risk C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15% \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">t (4; 14), del17p, or +1q \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low TM+high risk C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">42% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">High TM plus low risk C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">64% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">High TM+high risk C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">55% \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">SWOG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2-year TTP \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">Monoclonal component ≥2g/dl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 risk factors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30% \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">Affected FLC >25mg/dl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 risk factor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">29% \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">GEP >−0.26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">≥2 risk factors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">71% \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">Penn \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2-year TTP \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">≥40% PC in BM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 risk factors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16% \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">sFLC ratio ≥50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 risk factor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">44% \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">Albumin ≤3.5mg/dl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">≥2 risk factors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">81% \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">Japanese \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2-year TTP \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">Beta 2-microglobulin ≥2.5mg/l \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 risk factors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">67.5% \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">Monoclonal component increase rate >1mg/dl/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \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">Czech & Heidelberg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2-year TTP \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">Immunoparesis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 risk factors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.3% \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">Monoclonal component ≥2.3g/dl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 risk factor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.5% \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">Affected/unaffected sFLC ratio >30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 risk factors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">44.8% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 risk factors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">81.3% \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">Barcelona \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2-year TTP \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">Progression pattern=2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 points \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.4% \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">Monoclonal component ≥3g/dl=1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 point \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">31% \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">Immunoparesis=1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 points \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">52% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 points \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">80% \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">Mayo Clinic progression model \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \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">Monoclonal component under progression \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \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">Haemoglobin under progression \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 points \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12.3 years \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">≥20% PC in BM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 point \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.2 years \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 points \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.8 years \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 points \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 year \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">Danish \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3-year TTP \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">Monoclonal component ≥3g/dl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 risk factors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5% \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">Immunoparesis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 risk factor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Twenty-one% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 risk factors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50% \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1447606.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Risk models for the stratification of smoldering multiple myeloma." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:30 [ 0 => array:3 [ "identificador" => "bib0155" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Smoldering multiple myeloma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "R.A. 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Javier López (Hospital Ramón y Cajal, Madrid, Spain); José-María Arguiñano (Hospital Complex of Navarra, Pamplona, Spain); Jose M. Hernández Martín (General Hospital of Segovia, Segovia, Spain); Ana López de la Guía (Hospital La Paz, Madrid, Spain); Adrian Alegre Amor (Hospital La Princesa, Madrid, Spain); Ana Isabel Teruel Casasús (Clinical Hospital of Valencia, Valencia, Spain); Jose Luis Guzmán Zamudio (Hospital Jerez of the Border, Cadiz, Spain); María Luz Martino Galiana (University Hospital Virgen del Rocio, Seville, Spain); Mário Mariz (Portuguese Oncology Institute of Oporto, Porto, Portugal); Joanna Parreira (Instituto Portugés de Oncologia, Lisbon, Portugal); Graça Esteves (Hospital of Santa Maria, Lisbon, Portugal); as well as members of the Spanish Myeloma Group who have participated in regional advisory meetings to consolidate the recommendations set out in this study and which in some cases have also participated in the QuiRedex study: Miguel Hernández (University Hospital of Canarias), Joan Bargay (Sont Llatzer Hospital of Palma de Mallorca), Luis Palomera (Lozano Blesa Hospital of Zaragoza), Felipe de Arriba (Morales Messeguer Hospital of Murcia), Jose Mariano Hernández (Segovia General Hospital), Rafael Ríos (Virgen de las Nieves University Hospital of Granada), María Casanova (Costa del Sol Hospital of Marbella) and Ana Pilar González (Central Hospital of Asturias)." 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Management of smoldering myeloma: Recommendations of the Spanish Myeloma Group

Tratamiento del mieloma múltiple asintomático: recomendaciones del Grupo Español de Mieloma

María-Victoria Mateosa,b,

Corresponding author

mvmateos@usal.es

Corresponding author.

, Joan Bladéb,c, Juan-José Lahuertab,d, Jesús San-Miguelb,e

a Complejo Asistencial Universitario de Salamanca/Instituto Biosanitario de Salamanca (CAUSA/IBSAL), Salamanca, Spain

b Grupo Español de Mieloma (GEM)/PETHEMA, Spain

c Hospital Clinic i Provincial de Barcelona, Barcelona, Spain

d Hospital 12 de Octubre, Madrid, Spain

e Clínica Universidad de Navarra, Pamplona, Spain

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agreeing on the following diagnostic criteria&#58; serum monoclonal component &#40;MC&#41; &#8805;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl&#44; and&#47;or between 10&#37; and 60&#37; of plasma cells &#40;PC&#41; in bone marrow &#40;BM&#41; without organic damage&#44; that is&#44; without CRAB &#40;<span class="elsevierStyleItalic">Calcium&#44; Renal insufficiency&#44; Anaemia or Bone lesions</span>&#41; symptoms&#46; A subgroup of asymptomatic patients with a very high risk of progression &#40;ultra-high risk&#41; to MM &#40;&#62;80&#37; at 2 years&#41; who had one or more of the following biomarkers&#58; &#40;i&#41; presence of 2 or more focal lesions on whole body or spine and pelvis magnetic resonance imaging &#40;MRI&#41;&#59; &#40;ii&#41; ratio of free light chains in serum over 100&#59; or &#40;iii&#41; PC infiltration in BM &#8805;60&#37; were excluded from this new definition of SMM&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> These patients are now considered as MM and therefore need to start treatment&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Differential diagnosis</span><p id="par0020" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the criteria that define monoclonal gammopathy of undetermined significance&#44; SMM and MM&#46; Monoclonal gammopathy of undetermined significance is characterized by a MC &#60;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl and &#60;10&#37; of PC in BM&#44; in the absence of organic damage data&#46; On the contrary&#44; the MM&#44; as we have already pointed out&#44; is defined by the presence of &#8805;10&#37; clonal PCs in BM or in a bone or extramedullary plasmacytoma&#46; However&#44; for the diagnosis of MM&#44; the presence of any CRAB symptomatology is essential&#44; either that or the presence of one or more of the three biomarkers referred to above&#44; which&#44; in the absence of CRAB&#44; are associated with an imminent risk of progression to MM&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Symptomatology&#44; especially CRAB&#44; should be carefully evaluated so as not to confuse it with concomitant diseases whose manifestations may mimic MM symptomatology&#59; for example&#44; nutritional anaemia&#44; menopausal osteoporosis&#44; impaired renal function due to hypertension or diabetes&#44; hypercalcemia due to hyperparathyroidism&#44; or an isolated single bone cyst&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The diagnosis of SMM requires some additional examinations whose results should also be interpreted in the context of the clinical symptoms&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#40;1&#41;</span><p id="par0035" class="elsevierStylePara elsevierViewall">For the evaluation of bone lesions&#44; the IMWG recommends the performance&#44; according to availability&#44; of a bone series or a CT scan of individual low dose or combined with a positron emission tomography &#40;PET&#47;CT&#41; using <span class="elsevierStyleSup">18</span>F fluorodeoxyglucose as a tracer&#44; although the latter 2 techniques are more sensitive&#46; Low-dose CT is the most cost-effective technique to detect lesions in up to 30&#37; of the cases in which the bone series was negative &#40;the lytic lesion must measure at least 5<span class="elsevierStyleHsp" style=""></span>mm to be considered as such&#41;&#46; It is also necessary to perform a whole body or spine and pelvis MRI&#44; since MM should be considered if there is more than one focal bone lesion&#46; In this sense Hillengas et al&#46; reported that the presence of more than one MRI focal lesion in patients with SMM is associated with a high risk of progression to MM &#40;median time to progression &#91;TTP&#93;&#41; of 13 months&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> data confirmed by Kastritis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a> in a small study in which 9 cases with more than one focal lesion were evaluated&#44; with a 2-year risk of transformation of 69&#37;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#40;2&#41;</span><p id="par0040" class="elsevierStylePara elsevierViewall">With regard to PC infiltration of BM&#44; in a series of 651 patients with SMM of the Mayo Clinic&#44; the median TTP in cases of one infiltration &#8805;60&#37; was 7&#46;7 months&#44; with a 2-year progression risk of 95&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a> This finding was corroborated in 2 other series&#44; one of 96 patients&#44; confirming the TTP of 15 months<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> and another of 121 patients identifying 6 &#40;5&#37;&#41; cases with this biomarker and development of MM in all cases within 2 years&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a></p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#40;3&#41;</span><p id="par0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Serum free light chains</span> &#40;sFLC&#41; quantification is required in the initial assessment&#46; The Mayo Clinic group analyzed the value of the ratio between the affected and unaffected free light chains in serum in 586 patients with SMM and when the ratio was higher than 100&#44; present in 15&#37; of patients&#44; the risk of progression to MM at 2 years was 71&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a> The results of the Greek Myeloma Group confirmed these results in a series of 96 patients&#44; detecting a progression rate of 80&#37; in the first 24 months&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> This biomarker is probably the most conflicting and&#44; in fact&#44; a recent analysis published by the Danish Myeloma Group on 321 patients with SMM has not confirmed the significant influence of abnormal sFLCr values on TTP&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a></p></li></ul></p><p id="par0050" class="elsevierStylePara elsevierViewall">In summary&#44; if after considering the above aspects&#44; a patient meets SMM criteria &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; this should be confirmed 2&#8211;3 months after the first evaluation and then the therapeutic approach should be determined by the risk to progress to MM&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Risk assessment in the patient with smoldering multiple myeloma</span><p id="par0055" class="elsevierStylePara elsevierViewall">The annual risk of developing MM in a patient with SMM depends on the time elapsed since diagnosis&#58; 10&#37; per year for the first 5 years&#59; 3&#37; per year for the next 5 years and only 1&#37; after the first 10 years&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> Although most patients with SMM will develop MM&#44; the risk is not homogeneous and is conditioned by the presence of biomarkers that have been used to create models aimed at evaluating the risk of each patient with SMM&#44; in order to support an individualized management of this disease &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Monoclonal component in serum and bone marrow infiltration</span><p id="par0060" class="elsevierStylePara elsevierViewall">The Mayo Clinic group<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> identified 3 categories of patients&#58; group 1&#44; defined by a MC &#8805;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl and &#8805;10&#37; of PC in the BM&#44; with a median TTP of 2 years&#59; group 2&#44; with &#8804;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl of MC and &#8805;10&#37; PC in BM&#44; whose median TTP reached 8 years&#44; and group 3&#44; characterized by an M band &#8805;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl but &#60;10&#37; of PC in the BM&#44; with a median TTP of 19 years&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Ratio of free light chains in serum</span><p id="par0065" class="elsevierStylePara elsevierViewall">Another analysis performed at the Mayo Clinic in a series of 273 patients identified an increased risk of progression in patients with an abnormal ratio &#40;&#60;0&#46;125 or &#62;8&#41; between the affected light chains versus those not affected &#40;sFLCr&#41;&#46; Combining this parameter with the previous model based on MC and percentage of PC in BM&#44; the group of high risk patients with a TTP of 1&#46;9 years was defined by a MC &#8805;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl&#44; a BM infiltration &#8805;10&#37;&#44; and an abnormal sFLCr&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Immunophenotype and immunoparesis</span><p id="par0070" class="elsevierStylePara elsevierViewall">Flow cytometry evaluates the immunophenotypic profile of PC and the Salamanca group identified that phenotypically normal and aberrant PC coexist in patients with SMM&#46; Our group demonstrated that the presence of &#8805;95&#37; of PC and&#47;or immunoparesis are high risk factors&#44; and a model can be established that identifies 3 risk groups&#58; group 1 with a median TTP of 23 months when the 2 parameters are present&#59; group 2&#44; with a median TTP of 73 months when only one risk factor is present and group 3 with very low risk if none of the factors is present&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The Danish MM Group evaluated immunoparesis in its registry of SMM patients&#44; confirming that its presence along with a MC &#8805;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl was associated with a significantly higher risk of progression to MM &#40;HR&#58; 2&#46;7&#59; 95&#37; CI &#91;1&#46;5&#59; 4&#46;7&#93; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001 and RH&#58; 3&#46;3&#59; 95&#37; CI &#91;1&#46;4&#59; 7&#46;8&#93; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Circulating plasma cells in peripheral blood</span><p id="par0080" class="elsevierStylePara elsevierViewall">The Mayo Clinic Group has analyzed the value of pbPC to predict progression to MM&#44; noting that 15&#37; of patients with SMM present &#62;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span>&#47;l and&#47;or &#62;5&#37; pbPC per 100 mononuclear cells &#40;identified as clonal by immunofluorescence for cytoplasmic immunoglobulins&#41;&#59; the median TTP in this group of patients was 2 years&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a> Data are being generated based on the quantification of pbPC by flow cytometry showing that patients with more than 150 pbPC have very high risk of transformation &#40;median TTP of 9 months&#41; and this parameter could be considered in the future to define patients with MM&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Progression patterns of monoclonal component and haemoglobin together with bone marrow infiltration</span><p id="par0085" class="elsevierStylePara elsevierViewall">In a series of 207 patients with SMM&#44; the Clinic Hospital group<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a> identified a subgroup of patients with MC &#8805;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl which increased by at least 10&#37; in the following 6 months&#44; or in the case of &#60;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl the increase was progressive in each yearly determination over a period of 3 years&#46; These patients&#44; with progressive SMM&#44; accounted for 25&#37; and the probability of progression to MM at 2 years was 45&#37;&#46; The median TTP in patients with non-progressive SMM was 19 years&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">16</span></a> Recently&#44; this progression pattern was validated in 191 patients of the Mayo Clinic and the progression profile was associated with a MM progression probability at 2 years of 64&#37;&#46; In addition&#44; BM infiltration by PC &#62;20&#37; as well as the decrease in haemoglobin &#40;at least 0&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;dl in the first year&#41; were included as independent factors that predicted risk of progression to MM within 2 years &#40;48 and 65&#37; in each case&#41;&#46; A new model has been generated using these risk factors&#44; capable of distinguishing SMM patients with TTP of 12&#46;3&#59; 4&#46;2&#59; 2&#46;8 and 1 years according to the presence of none&#44; one&#44; two or all three risk factors&#46; This model could be incorporated into the definition of early MM in the future&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a> Finally&#44; the SWOG group described that the increase of MC values up to &#8805;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl in the first 3 months from diagnosis was associated with a 50&#37; progression probability in 2 years&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Bence Jones proteinuria</span><p id="par0090" class="elsevierStylePara elsevierViewall">The Castilla y Le&#243;n gammopathies group evaluated IgG or IgA in SMM&#59; the coincidence of Bence Jones proteinuria&#44; regardless of its quantification&#44; is associated with a TTP to MM of 22 months versus 83 months in Bence Jones negative patients and 7 months if Bence Jones &#62;500<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">New imaging techniques</span><p id="par0095" class="elsevierStylePara elsevierViewall">Both MRI and PET&#47;CT can help predict the risk of progressing to MM&#46; New focal lesions detection on MRI or an increase in lesion diameter are associated with increased risk of progression&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a> Two recent studies<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">20&#44;21</span></a> evaluated PET&#47;CT in SMM&#44; confirming that the presence of hypermetabolic areas without underlying lytic lesions constitutes a risk of progression to MM of 48&#8211;56&#37; in the first 2 years&#44; respectively&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Cytogenetic abnormalities</span><p id="par0100" class="elsevierStylePara elsevierViewall">The presence of t &#40;4&#59; 14&#41; and&#47;or &#40;17p&#41; in SMM is associated with a median TTP of 2 years&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> Neben et al&#46; identified t &#40;4&#59; 14&#41;&#44; 1q21 gains or hyperdiploidy as independent prognostic factors associated with risk of progression to MM &#40;50&#37; to 2 years&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a> Finally&#44; the SWOG group identified a genetic signature to identify a subgroup whose risk of progression to MM in 2 years reaches 85&#46;7&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a></p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Management of patients with smoldering multiple myeloma</span><p id="par0105" class="elsevierStylePara elsevierViewall">The initial step after the diagnosis of SMM is to identify the individual risk that the patient has to progress to MM&#46; The next step would be to see which is the ideal model to use to assess that individual risk&#46; The models described by both the Mayo Clinic and the Spanish Myeloma Group &#40;SMG&#41; have been validated in a randomized and prospective clinical trial&#46; However&#44; as shown in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#44; new risk models have been proposed based on factors identified in multivariate analysis and&#44; therefore&#44; have prognostic value with independent value&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">8&#44;10&#44;11&#44;13&#44;15&#44;23&#44;25&#8211;27</span></a> It is important to insist that a patient with high-risk SMM does not have to manifest all the characteristics that define a high-risk SMM&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Patients with SMM should be classified into one of 3 groups&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">1&#46;</span><p id="par0115" class="elsevierStylePara elsevierViewall">SMM with low risk of progression to MM&#58; characterized by the absence of high risk biomarkers and a 5-year progression probability of 8&#37; &#40;Mayo Clinic and SMG models&#41;&#46; These patients may have a MC &#8805;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl but the infiltration of BM is &#60;10&#37;&#44; and&#47;or have no immunoparesis and the percentage of PC with aberrant phenotype does not exceed 95&#37;&#46; The follow-up of these patients may be annual&#44; with confirmation of MC stability and absence of symptomatology in initial controls&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">2&#46;</span><p id="par0120" class="elsevierStylePara elsevierViewall">SMM with intermediate risk to progress to MM&#58; in this group&#44; the patients would be characterized by a MC &#60;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl&#44; an infiltration by PC in BM &#8805;10&#37;&#44; or the presence of immunoparesis or a percentage of PC with aberrant phenotype &#8805;95&#37;&#46; These patients could be defined as the &#8220;true&#8221; SMM&#44; in which the 5-year risk of progression reaches 42&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">11&#44;13</span></a> Follow-up may be spaced up to 6 months&#44; except for the first year in which a quarterly evaluation will allow to check the stability of MC&#44; haemoglobin&#44; or non-involved immunoglobulins&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">3&#46;</span><p id="par0125" class="elsevierStylePara elsevierViewall">SMM with high risk of progression to MM&#58; This group of patients is characterized by MC &#8805;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl&#44; PC in BM &#8805;10&#37; or in the presence of only one of the above 2 factors suffering at the same time of immunoparesis plus a PC percentage of aberrant phenotype &#8805;95&#37;&#46; Half of these patients will progress to MM within 2 years&#44; so they will require follow-up every 2&#8211;3 months&#46; As there is no approved treatment for patients with high-risk SMM&#44; these patients should be referred to specialist centres to&#44; if possible&#44; be included in clinical trials&#46;</p></li></ul></p><p id="par0130" class="elsevierStylePara elsevierViewall">In case no clinical trials are available or patients with high-risk SMM do not meet the inclusion and&#47;or exclusion criteria&#44; the Spanish Group of MM &#40;PETHEMA&#47;GEM&#41; has performed a phase 3 randomized trial in a series of 119 patients with high-risk SMM&#44; demonstrating that early treatment with lenalidomide and dexamethasone significantly slows the progression to MM versus lack of treatment and&#44; in addition&#44; significantly prolongs the overall survival &#40;OS&#41;&#44; therefore&#44; this trial could be the rationale behind early treatment in this subgroup of patients with SMM&#46; This study included 125 patients with high-risk SMM who progressed to MM&#44; of whom 119 were finally considered evaluable for efficacy following a review by an external and independent review committee&#46; This committee certified the high-risk classification of SMM patients included&#46; The inclusion criteria chosen for defining SMM at high risk of progression to MM were those based on&#44; either the Mayo Clinic group definition &#40;PC in BM &#8805;10&#37; and MC &#8805;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl&#41;&#44; or the PETHEMA&#47;GEM group definition &#40;&#8805;95&#37; PC with aberrant phenotype and immunoparesis in the presence of only one of the 2 factors of the Mayo Clinic&#41;&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The control group was assigned to therapeutic abstention&#44; the management standard&#44; whereas the experimental group received an induction treatment with 9 cycles of lenalidomide and dexamethasone &#40;Rd&#41;&#46; Lenalidomide was given at doses of 25<span class="elsevierStyleHsp" style=""></span>mg daily&#44; orally&#44; during days 1&#8211;21 of each cycle followed by one week of rest&#59; dexamethasone &#40;d&#41; was given at low dose&#58; 20<span class="elsevierStyleHsp" style=""></span>mg on days 1&#8211;4 and 12&#8211;15 of each cycle &#40;total dose per cycle of 160<span class="elsevierStyleHsp" style=""></span>mg&#41;&#46; After induction&#44; the patients received maintenance with cycles of lenalidomide at 10<span class="elsevierStyleHsp" style=""></span>mg daily between days 1 and 21 followed by a week of rest&#46; Although maintenance was initially scheduled until progression from SMM to MM&#44; an amendment in March 2011 limited the duration of treatment to 24 months&#44; following news about the development of second primary neoplasms in patients undergoing maintenance with lenalidomide&#46; This amendment also included the possibility of administering low doses of dexamethasone to patients in the experimental arm who underwent a biological progression in the maintenance phase with lenalidomide &#40;increase of MC &#8805;25&#37; without symptomatology&#41;&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Lenalidomide is an immunomodulatory drug whose target is cereblon&#44; which binds to the aiolos and ikaros proteins&#44; which are lymphoid transcription factors&#44; resulting in their ubiquitination and subsequent degradation&#44; which produces cytotoxic and immunomodulatory effects&#46; It is approved for first-line treatment of adult patients with MM who are not transplant candidates&#44; and in combination with dexamethasone in the treatment of patients with MM who have received at least one prior treatment&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">There were 119 patients included&#44; 57 assigned to the experimental arm and 62 to the control group&#46; The recruitment took place in 19 Spanish sites and 3 Portuguese sites&#46; The first analysis&#44; performed in 2013 with a median follow-up of 40 months&#44; showed that early treatment with Rd delayed progression to MM compared to the control group &#40;HR&#58; 0&#46;18&#59; 95&#37; CI&#58; 0&#46;09&#8211;0&#46;32&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; and a median TTP not reached in the experimental group in contrast to the median of 23 months in the control group&#44; confirming both the efficacy of the early treatment and the real high risk of the selected population&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a> This benefit was maintained in the long-term follow-up analysis &#40;75 months from inclusion in the study&#41;&#44; confirming that early treatment with Rd had reduced the probability of progression to MM by 76&#37; with respect to therapeutic abstention &#40;HR&#58; 0&#44; 24&#59; 95&#37; CI&#58; 0&#46;14&#8211;0&#46;41&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; At the time of the first analysis&#44; none of the groups had reached the median OS&#44; although in the experimental arm the 3-year survival rate was 94&#37; as opposed to 80&#37; in the control arm &#40;HR&#58; 0&#46;31&#59; 95&#37; CI&#58; 0&#46;10&#8211;0&#46;91&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;03&#41;&#46; This advantage is maintained in the last update&#44; confirming the benefit not only in TTP but also in OS &#40;HR&#58; 0&#46;43&#59; 95&#37; CI&#58; 0&#46;20&#8211;0&#46;90&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;02&#41; &#40;OS&#58; 94 vs 64&#37; at 7 years&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A and 1B&#41;&#46; 10 patients died &#40;18&#37;&#41; in the experimental arm&#44; compared to 22 &#40;36&#37;&#41; in the control arm&#44; all of them after progression to MM and&#44; in most cases&#44; after several treatment lines&#46; The rescue treatments received by the patients in both groups were evaluated and it was verified that there were no significant differences neither in the treatment schemes nor in the response rates reached&#44; as well as that the treatments received were adequate for the characteristics of the patients at the time of progression&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">In the experimental arm&#44; during maintenance with lenalidomide&#44; 15 patients had biological progression and received low doses of dexamethasone&#44; as specified in the protocol&#46; This strategy controlled the disease again in all of them&#46; In fact&#44; the OS of this group was similar to the group of patients who remained progression-free&#46; In both cases&#44; OS is statistically superior &#40;95&#37; of patients alive at 6 years&#41; than those who progressed directly to MM &#40;50&#37; at 6 years&#41;&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">On the other hand&#44; considering the absence of OS differences between the control and experimental groups from the time of progression &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;50&#41;&#44; it can be stated that early treatment with Rd did not induce a selection of more resistant-to-relapse clones&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">The toxicity profile was acceptable with most adverse events being grade 1 and 2&#46; In the experimental arm&#44; 4 patients &#40;6&#37;&#41; had infections and grade-3 asthenia&#44; 3 grade-3 neutropenia and 2 rashes&#46; In the control arm&#44; 26&#37; of patients had grade 1&#8211;2 infections probably because of the immunosuppressive status associated with SMM&#46; Only one death from pneumonia was recorded in the experimental arm in the induction phase&#46; The frequency of second primary neoplasms was slightly higher in the experimental arm &#40;6 &#91;10&#37;&#93; vs 1 &#91;2&#37;&#93;&#41; but the cumulative and adjusted exposure risk was similar &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;07&#41;&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">QuiRedex is the first clinical trial with a high power of evidence that has demonstrated a significant benefit of early treatment in high-risk SMM in both TTP and OS&#44; which is a milestone in the management of patients with SMM&#44; until now simply monitored without any possibility of delaying or eliminating the transformation to MM&#46; The results of this study would justify early treatment in these patients&#44; at least with Rd&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">At present&#44; other clinical trials are evaluating early treatment in high-risk SMM using lenalidomide alone without corticosteroids&#44; combinations of elotuzumab plus Rd&#44; daratumumab&#44; or even combinations such as carfilzomib plus Rd&#58; the latter has achieved complete response in almost all cases as a preliminary regimen in 12 patients&#44; plus being associated to negative minimal residual disease&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a> These results have served as rationale for the development of more intensive therapeutic strategies as the one selected for the new phase II PETHEMA&#47;GEM trial for high-risk SMMs up to 70 years of age&#44; which evaluates the effect of a 6-cycle induction based on carfilzomib plus Rd&#44; followed by autogenous transplantation&#44; double consolidation and maintenance with the aim to &#8220;cure&#8221; before SMM progression to MM&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusions</span><p id="par0175" class="elsevierStylePara elsevierViewall">In the past&#44; the treatment philosophy of MM has focused on MM patients&#44; which is different from what is planned in other oncological diseases&#44; such as breast&#44; colon&#44; in which early treatment is essential when it comes to increase survival and achieve recovery&#46; However&#44; this philosophy was logical in the case of MM since the alkylators were the only effective therapeutic agents and also because the trials initially performed with melphalan and even thalidomide showed no benefit for early treatment&#46; In addition&#44; all types of SMM were included in these studies without discrimination based on the risk of progression&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Fortunately&#44; there have been important advances in the knowledge of the biology of SMM and today we can identify in each patient the individual risk of progression to MM&#46; Moreover&#44; we know that if there is an imminent risk of progressing to MM &#40;80&#37; at 2 years&#41;&#44; these patients should already be considered MM and start receiving treatment&#46; However&#44; the positive results of the SMG&#47;QuiRedex study justify the early treatment of patients with high-risk SMM &#40;50&#8211;80&#37; transformation in the first 2 years&#41; without waiting for extreme risk criteria or MM occurrence&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">The next discussion would be whether high-risk SMMs should receive only Rd&#44; as in the QuiRedex trial&#44; or&#44; on the contrary&#44; whether a more intense strategy would be justified in order to achieve recovery in these early stages&#46; The SMG&#44; for the time being&#44; supports Rd for transplant candidates and non-candidates based on the results obtained&#44; and works on the development of more intensive therapeutic strategies especially in young patients in whom recovery is perceived as an attainable goal&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflict of interests</span><p id="par0190" class="elsevierStylePara elsevierViewall">M&#46;<span class="elsevierStyleSmallCaps">V</span>&#46; Mateos&#44; J&#46; Blad&#233;&#44; J&#46;J&#46; Lahuerta and J&#46; San Miguel have received fees for conferences and participation in Celgene&#39;s advisory meetings&#46;</p></span></span>"
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              "titulo" => "Monoclonal component in serum and bone marrow infiltration"
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              "titulo" => "Circulating plasma cells in peripheral blood"
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          "titulo" => "Management of patients with smoldering multiple myeloma"
        ]
        4 => array:2 [
          "identificador" => "sec0065"
          "titulo" => "Conclusions"
        ]
        5 => array:2 [
          "identificador" => "sec0070"
          "titulo" => "Conflict of interests"
        ]
        6 => array:2 [
          "identificador" => "xack287342"
          "titulo" => "Acknowledgements"
        ]
        7 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2017-02-03"
    "fechaAceptado" => "2017-02-15"
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; Mateos M-V&#44; Blad&#233; J&#44; Lahuerta J-J&#44; San-Miguel J&#46; Tratamiento del mieloma m&#250;ltiple asintom&#225;tico&#58; recomendaciones del Grupo Espa&#241;ol de Mieloma&#46; Med Clin &#40;Barc&#41;&#46; 2017&#59;148&#58;517&#8211;523&#46;</p>"
      ]
    ]
    "multimedia" => array:5 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
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        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Time to progression &#40;A&#41; and overall survival &#40;B&#41; of patients with asymptomatic or smoldering multiple myeloma included in the trial of the Spanish group QuiRedex&#46; Len-dex&#58; lenalidomide-dexamethasone&#59; MM&#58; multiple myeloma&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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        "detalles" => array:1 [
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          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">PC&#58; plasma cells&#59; CRAB&#58; <span class="elsevierStyleItalic">Calcium&#44; Renal insufficiency&#44; Anaemia or Bone lesions</span>&#59; MDE&#58; myeloma defining episodes&#59; MGUS&#58; monoclonal gammopathy of undetermined significance&#59; MM&#58; multiple myeloma&#59; SMM&#58; smoldering multiple myeloma&#59; BM&#58; bone marrow&#46;</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="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristic&nbsp;\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">MGUS&nbsp;\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">SMM&nbsp;\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">MM&nbsp;\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">Serum M protein&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl&#44; and&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8805;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl and&#47;or&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\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">Clonal infiltration by PC in BM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;10&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#8211;60&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8805;10&#37; or plasmacytoma evidenced on biopsy&nbsp;\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">Symptomatology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Absence of CRAB<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Absence of MDE<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> or amyloidosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Presence of MDE<span class="elsevierStyleSup">&#42;&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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          "notaPie" => array:2 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">CRAB symptomatology includes &#40;1&#41; hypercalcemia&#58; serum calcium &#62;0&#46;25<span class="elsevierStyleHsp" style=""></span>mmol&#47;l &#40;&#62;1<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41; above the upper limit of normal or &#62;2&#46;75<span class="elsevierStyleHsp" style=""></span>mmol&#47;l &#40;&#62;11<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41;&#59; &#40;2&#41; renal failure&#58; serum creatinine &#62;177<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;l &#40;2<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41; or creatinine clearance &#60;40<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#59; &#40;3&#41; anaemia&#58; haemoglobin &#62;2<span class="elsevierStyleHsp" style=""></span>g&#47;dl below the low limit of normal&#44; or haemoglobin &#60;10<span class="elsevierStyleHsp" style=""></span>g&#47;dl&#59; &#40;4&#41; bone lesions&#58; one or more lytic lesions evidenced by conventional radiology&#44; CT&#44; or PET-CT&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Events that define myeloma and include the CRAB symptoms described above or one or more of the following biomarkers that predict progression to MM&#58; &#8805;60&#37; clonal plasma cells in the bone marrow&#59; ratio of free light chains in serum affected&#47;unaffected &#8805;100&#59; &#62;1 focal lesion in MRI studies&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Differential diagnosis between monoclonal gammopathy of undetermined significance&#44; smoldering multiple myeloma and multiple myeloma&#46;</p>"
        ]
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        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">LDH&#58; lactate dehydrogenase&#59; PET-CT&#58; positron emission tomography using <span class="elsevierStyleSup">18</span>F-fluorodeoxyglucose as tracer&#59; MRI&#58; magnetic resonance imaging&#59; sFLC&#58; <span class="elsevierStyleItalic">Serum Free light chain&#59;</span> CT&#58; computed tomography&#46;</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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Clinical history and physical examination</span>&nbsp;\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"><span class="elsevierStyleItalic">Blood count</span>&nbsp;\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"><span class="elsevierStyleItalic">Biochemical studies&#44; including serum and calcium creatinine&#59; beta2-microglobulin&#44; LDH and albumin</span>&nbsp;\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"><span class="elsevierStyleItalic">Protein studies</span>&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Total serum proteins and electrophoresis &#40;monoclonal component&#41;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Protein electrophoresis in 24<span class="elsevierStyleHsp" style=""></span>h urine sample &#40;urine monoclonal component or Bence Jones proteinuria&#41;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Immunofixation in serum and urine&nbsp;\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"><span class="elsevierStyleItalic">Ratio of free light chains in serum &#40;sFLC ratio&#41;</span>&nbsp;\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"><span class="elsevierStyleItalic">Aspirate</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#177;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">bone marrow biopsy&#58; clonal plasma cell infiltration&#44; flow cytometry and</span> In situ <span class="elsevierStyleItalic">fluorescence hybridization in selected plasma cells</span>&nbsp;\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"><span class="elsevierStyleItalic">Bone series&#44; CT&#44; or PET-CT</span>&nbsp;\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"><span class="elsevierStyleItalic">MRI of the spine and pelvis&#44; although&#44; ideally&#44; it should be whole-body MRI</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Tests performed at the time of smoldering multiple myeloma diagnosis&#46;</p>"
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      3 => array:8 [
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        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">BM&#58; bone marrow&#59; PET-CT&#58; positron emission tomography using <span class="elsevierStyleSup">18</span>F-fluorodeoxyglucose as tracer&#59; MRI&#58; magnetic resonance imaging&#46;</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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Tumour mass</span>&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>&#8805;10&#37; clonal plasma cells in BM plus&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>&#8805;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl of monoclonal component and serum free light chains ratio &#60;0&#46;125 or &#62;8&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Positive Bence Jones proteinuria in 24<span class="elsevierStyleHsp" style=""></span>h urine&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Circulating plasma cells in peripheral blood &#62;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span>&#47;l&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Circulating plasma cells in peripheral blood by cytometry &#8805;150&nbsp;\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"><span class="elsevierStyleItalic">Immunophenotypic characterization and immunoparesis</span>&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>&#8805;95&#37; of aberrant plasma cells by cytometry in the BM plasma cells plus&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Immunoparesis &#40;&#62;25&#37; decrease in one or both immunoglobulins not affected with respect to the low level of normality&#41;&nbsp;\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"><span class="elsevierStyleItalic">Cytogenetic abnormalities</span>&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Presence of t &#40;4&#59; 14&#41;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Presence of del17p&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>1q24 gain&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Hyperdiploidy&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Score &#62;&#8722;0&#46;26 by gene expression profile&nbsp;\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"><span class="elsevierStyleItalic">Monoclonal component and haemoglobin progression pattern</span>&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Type in progression&#58; if monoclonal component &#8805;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl&#44; increase of at least 10&#37; during the first 6 months&#46; If monoclonal component &#60;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl&#44; annual increase over 3 years&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Increase of monoclonal component up to &#8805;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl during the 3 months following the previous determination&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Decreased haemoglobin in &#8805;0&#46;50<span class="elsevierStyleHsp" style=""></span>g&#47;dl in the first year since diagnosis&nbsp;\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"><span class="elsevierStyleItalic">Imaging techniques</span>&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>MRI&#58; progressive disease by MRI when new focal lesions are detected or the diameter of the existing lesion increases &#40;if previously detected&#41; or progressive diffuse infiltration&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Positive PET&#47;CT without osteolytic lesions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Smoldering multiple myeloma&#58; factors that predict progression to multiple myeloma&#46; Characteristics to identify high-risk smoldering multiple myeloma &#40;approximately 50&#37; in 2 years&#41;&#46;</p>"
        ]
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      4 => array:8 [
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        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">C&#58; cytogenetics&#59; FCM&#58; flow cytometry&#59; PC&#58; plasma cells&#59; GEP&#58; gene expression profile&#59; BM&#58; bone marrow&#59; TM&#58; tumour mass&#59; sFLC&#58; <span class="elsevierStyleItalic">Serum free light chain&#59;</span> TTP&#58; time to progression&#46;</p>"
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                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="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk model&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk of progression to multiple myeloma</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"><span class="elsevierStyleItalic">Mayo Clinic</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Median TTP&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>&#8805;10&#37; PC in BM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 risk factor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 years&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>&#8805;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl of monoclonal component&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 risk factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 years&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>sFLC ratio &#60;0&#46;125 or &#62;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 risk factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;9 years&nbsp;\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"><span class="elsevierStyleItalic">Spanish group</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Median TTP&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>&#8805;95&#37; of aberrant PC by FCM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 risk factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not reached&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Immunoparesis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 risk factor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 risk factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;9 years&nbsp;\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"><span class="elsevierStyleItalic">Heidelberg</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3-year TTP&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Tumour mass as per Mayo Clinic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low TM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>low risk C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15&#37;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>t &#40;4&#59; 14&#41;&#44; del17p&#44; or &#43;1q&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low TM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>high risk C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">42&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">High TM plus low risk C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">64&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">High TM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>high risk C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">55&#37;&nbsp;\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"><span class="elsevierStyleItalic">SWOG</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2-year TTP&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Monoclonal component &#8805;2<span class="elsevierStyleHsp" style=""></span>g&#47;dl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 risk factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30&#37;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Affected FLC &#62;25<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 risk factor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">29&#37;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>GEP &#62;&#8722;0&#46;26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8805;2 risk factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">71&#37;&nbsp;\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"><span class="elsevierStyleItalic">Penn</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2-year TTP&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>&#8805;40&#37; PC in BM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 risk factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16&#37;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>sFLC ratio &#8805;50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 risk factor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">44&#37;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Albumin &#8804;3&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8805;2 risk factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">81&#37;&nbsp;\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"><span class="elsevierStyleItalic">Japanese</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2-year TTP&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Beta 2-microglobulin &#8805;2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 risk factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">67&#46;5&#37;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Monoclonal component increase rate &#62;1<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\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"><span class="elsevierStyleItalic">Czech &#38; Heidelberg</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2-year TTP&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Immunoparesis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 risk factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#46;3&#37;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Monoclonal component &#8805;2&#46;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 risk factor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#46;5&#37;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Affected&#47;unaffected sFLC ratio &#62;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 risk factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">44&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 risk factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">81&#46;3&#37;&nbsp;\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"><span class="elsevierStyleItalic">Barcelona</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2-year TTP&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Progression pattern<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 points&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;4&#37;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Monoclonal component &#8805;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 point&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">31&#37;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Immunoparesis<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 points&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">52&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 points&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">80&#37;&nbsp;\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"><span class="elsevierStyleItalic">Mayo Clinic progression model</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Monoclonal component under progression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Haemoglobin under progression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 points&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#46;3 years&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>&#8805;20&#37; PC in BM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 point&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#46;2 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 points&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;8 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 points&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 year&nbsp;\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"><span class="elsevierStyleItalic">Danish</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3-year TTP&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Monoclonal component &#8805;3<span class="elsevierStyleHsp" style=""></span>g&#47;dl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 risk factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#37;&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Immunoparesis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 risk factor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Twenty-one&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 risk factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Risk models for the stratification of smoldering multiple myeloma&#46;</p>"
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        "texto" => "<p id="par0195" class="elsevierStylePara elsevierViewall">The authors wish to thank all the researchers who participated in the QuiRedex study&#58; Miguel-Teodoro Hern&#225;ndez &#40;University Hospital of the Canary Islands&#44; Tenerife&#44; Spain&#41;&#59; Pilar Giraldo &#40;Miguel Servet Hospital&#44; Zaragoza&#44; Spain&#41;&#59; Javier de la Rubia &#40;La Fe University Hospital&#44; Valencia&#44; Spain&#41;&#59; Felipe de Arriba &#40;Morales Messeguer Hospital&#44; Murcia&#44; Spain&#41;&#59; Luc&#237;a L&#243;pez Corral &#40;University Hospital of Salamanca&#44; Institute of Biomedical Research of Salamanca &#40;IBSAL&#41;&#44; Salamanca&#44; Spain&#41;&#59; Laura Rosi&#241;ol &#40;Hospital Clinic&#44; August Pi i Sunyer Biomedical Research Institute &#40;IDIBAPS&#41;&#44; Barcelona&#44; Spain&#41;&#59; Bruno Paiva &#40;Clinical University of Navarra&#44; Center for Applied Medical Research &#40;CIMA&#41;&#44; Pamplona&#44; Spain&#41;&#59; Luis Palomera &#40;Lozano Blesa Hospital&#44; Zaragoza&#44; Spain&#41;&#59; Joan Bargay &#40;Sont Llatzer Hospital&#44; Palma de Mallorca&#44; Spain&#41;&#59; Albert Oriol &#40;Germans Trias i Pujol Hospital&#44; Badalona&#44; Spain&#41;&#59; Felipe Prosper &#40;Clinical University of Navarra&#44; Center for Applied Medical Research &#40;CIMA&#41;&#44; Pamplona&#44; Spain&#41;&#46; Javier L&#243;pez &#40;Hospital Ram&#243;n y Cajal&#44; Madrid&#44; Spain&#41;&#59; Jos&#233;-Mar&#237;a Argui&#241;ano &#40;Hospital Complex of Navarra&#44; Pamplona&#44; Spain&#41;&#59; Jose M&#46; Hern&#225;ndez Mart&#237;n &#40;General Hospital of Segovia&#44; Segovia&#44; Spain&#41;&#59; Ana L&#243;pez de la Gu&#237;a &#40;Hospital La Paz&#44; Madrid&#44; Spain&#41;&#59; Adrian Alegre Amor &#40;Hospital La Princesa&#44; Madrid&#44; Spain&#41;&#59; Ana Isabel Teruel Casas&#250;s &#40;Clinical Hospital of Valencia&#44; Valencia&#44; Spain&#41;&#59; Jose Luis Guzm&#225;n Zamudio &#40;Hospital Jerez of the Border&#44; Cadiz&#44; Spain&#41;&#59; Mar&#237;a Luz Martino Galiana &#40;University Hospital Virgen del Rocio&#44; Seville&#44; Spain&#41;&#59; M&#225;rio Mariz &#40;Portuguese Oncology Institute of Oporto&#44; Porto&#44; Portugal&#41;&#59; Joanna Parreira &#40;Instituto Portug&#233;s de Oncologia&#44; Lisbon&#44; Portugal&#41;&#59; Gra&#231;a Esteves &#40;Hospital of Santa Maria&#44; Lisbon&#44; Portugal&#41;&#59; as well as members of the Spanish Myeloma Group who have participated in regional advisory meetings to consolidate the recommendations set out in this study and which in some cases have also participated in the QuiRedex study&#58; Miguel Hern&#225;ndez &#40;University Hospital of Canarias&#41;&#44; Joan Bargay &#40;Sont Llatzer Hospital of Palma de Mallorca&#41;&#44; Luis Palomera &#40;Lozano Blesa Hospital of Zaragoza&#41;&#44; Felipe de Arriba &#40;Morales Messeguer Hospital of Murcia&#41;&#44; Jose Mariano Hern&#225;ndez &#40;Segovia General Hospital&#41;&#44; Rafael R&#237;os &#40;Virgen de las Nieves University Hospital of Granada&#41;&#44; Mar&#237;a Casanova &#40;Costa del Sol Hospital of Marbella&#41; and Ana Pilar Gonz&#225;lez &#40;Central Hospital of Asturias&#41;&#46;</p>"
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