RESUMEN
Current guidelines recommend screening with serum M-protein and serum-free light chain analysis (S-FLC) when an M-protein-related disorder is suspected. Many patients with multiple myeloma will be overlooked if only serum M-protein is measured. Despite this, the general practitioners in some areas of Denmark cannot order S-FLC. This review aims to disseminate knowledge of the S-FLC analysis, its applicability, and limitations in the diagnostic workup for suspected monoclonal gammopathies.
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Cadenas Ligeras de Inmunoglobulina , Mieloma Múltiple , Humanos , Cadenas Ligeras de Inmunoglobulina/sangre , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/sangre , Paraproteinemias/diagnóstico , Paraproteinemias/sangre , Proteínas de Mieloma/análisisRESUMEN
BACKGROUND: Immunofixation electrophoresis (IFE) is the standard method for confirming the presence of a monoclonal protein (M-protein) at multiple myeloma (MM) diagnosis. IFE is also essential at assessment of complete response (CR) and stringent CR during treatment. As the CR assessment is influenced by daratumumab and isatuximab, HYDRASHIFT assays were developed. METHODS: Samples from patients under treatment that included daratumumab or isatuximab were tested and monitored by IFE on the HYDRASYS system using HYDRASHIFT assays (HYDRASYS/HYDRASHIFT) and by IFE on the Epalyzer2 system (Epalyzer). RESULTS: The IFE using HYDRASYS/HYDRASHIFT avoided a false positive caused by drug-related IgG-κ and contributed to accurate assessment of CR. Furthermore, HYDRASYS/HYDRASHIFT detected small M-proteins at early relapse and detected free light chains (FLCs) in patients with renal impairment exhibiting high serum FLCs despite being often missed on Epalyzer. CONCLUSION: Sensitivity and specificity of M-protein detection vary greatly depending on the IFE system and reagents used.
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Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Mieloma Múltiple , Proteínas de Mieloma , Humanos , Anticuerpos Monoclonales/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/sangre , Anticuerpos Monoclonales Humanizados/uso terapéutico , Proteínas de Mieloma/análisis , Femenino , Anciano , Masculino , Persona de Mediana Edad , Inmunoelectroforesis/métodos , Resultado del Tratamiento , Inmunoglobulina G/sangre , Cadenas kappa de Inmunoglobulina/sangre , Indicadores y ReactivosRESUMEN
BACKGROUND: Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare plasma cell (PC) neoplasm with associated paraneoplastic syndrome. According to the current diagnostic criteria, peripheral polyneuropathy and monoclonal PC proliferative disorder represent two mandatory criteria. CASE PRESENTATION: We report a 54-year-old male with peripheral neuropathy of bilateral lower limbs, sclerotic bone lesions, elevated vascular endothelial growth factor (VEGF) levels, splenomegaly, extravascular volume overload, endocrinopathy, and skin hemangiomas. Of note, serum and urine protein electrophoresis (PEP) and immunofixation electrophoresis (IFE) of this patient indicated undetectable M-protein and the normal ratio of free light chains κ and λ (FLC-R (κ/λ)). No monoclonal PCs were found in bone marrow examinations or biopsy of diseased bones. However, his clinical manifestations matched most of the diagnostic criteria. After excluding other diseases that are easily confused with POEMS syndrome, the diagnosis of variant POEMS syndrome with undetectable M-protein was proposed. The patient obtained clinically significant improvement and elevated VEGF returned to normal after 6 months of treatment with lenalidomide plus dexamethasone. CONCLUSIONS: Monoclonal PC dyscrasia (M-protein) while being a mandatory criterion for POEMS syndrome is undetectable in a considerable amount of patients that otherwise demonstrate typical symptoms. Here, we reported a case of variant POEMS syndrome with featured clinical manifestations, elevated VEGF levels, and good response to therapies targeting PCs but no evidence of M-protein. Therefore, negative results in M-protein and monoclonal PCs aren't enough to reject the diagnosis of POEMS syndrome. It is imperative to recognize the variant form of POEMS syndrome.
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Síndrome POEMS , Humanos , Síndrome POEMS/diagnóstico , Síndrome POEMS/patología , Masculino , Persona de Mediana Edad , Lenalidomida/uso terapéutico , Talidomida/uso terapéutico , Talidomida/análogos & derivados , Factor A de Crecimiento Endotelial Vascular , Dexametasona/uso terapéutico , Resultado del Tratamiento , Proteínas de Mieloma/análisisRESUMEN
ABSTRACT: Mass spectrometry (MS) can detect multiple myeloma-derived monoclonal proteins in the peripheral blood (PB) with high sensitivity, potentially serving as a PB assay for measurable residual disease (MRD). This study evaluated the significance of PB MS MRD negativity during posttransplant therapy in patients with newly diagnosed multiple myeloma. Serum samples from 138 patients treated in the phase 3 ATLAS trial of posttransplant maintenance with either carfilzomib, lenalidomide, and dexamethasone, or with lenalidomide alone were analyzed using EXENT MS methodology. We established feasibility of measuring MRD by MS in the PB in the posttransplant setting, despite unavailability of pretreatment calibration samples. There was high agreement between MRD by MS in the PB and paired bone marrow (BM) MRD results at the 10-5 threshold, assessed by either next-generation sequencing (NGS) or multiparameter flow cytometry (MFC) (70% and 67%, respectively). Agreement between PB MS and both BM MRD methods was lowest early after transplant and increased with time. MS negativity was associated with improved progression-free survival (PFS), which, in landmark analysis, reached statistical significance after 18 cycles after transplant. Combined PB/BM MRD negativity by MFC or NGS was associated with superior PFS compared with MRD negativity by only 1 modality. Sustained MS negativity carried similar prognostic performance to sustained BM MRD negativity at the 10-5 threshold. Overall, posttransplant MS assessment was feasible and provided additional prognostic information to BM MRD negativity. Further studies are needed to confirm the role and optimal timing of MS in disease evaluation algorithms. The ATLAS trial is registered at www.clinicaltrials.gov as #NCT02659293.
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Espectrometría de Masas , Mieloma Múltiple , Humanos , Mieloma Múltiple/sangre , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/terapia , Masculino , Femenino , Persona de Mediana Edad , Anciano , Espectrometría de Masas/métodos , Neoplasia Residual , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Lenalidomida/administración & dosificación , Lenalidomida/uso terapéutico , Proteínas de Mieloma/análisis , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Quimioterapia de Mantención , Adulto , Oligopéptidos/administración & dosificación , Oligopéptidos/uso terapéuticoRESUMEN
BACKGROUND: Isatuximab, an IgG-kappa (IgGκ) anti-cluster of differentiation 38 (CD38) monoclonal antibody approved for use in patients with relapsed or refractory multiple myeloma (MM), can potentially interfere with the visualization of endogenous monoclonal protein (M-protein) on standard immunofixation electrophoresis (IFE) and lead to inaccurate classification of a patient's response to therapy. The Hydrashift 2/4 isatuximab IFE assay (Hydrashift isatuximab assay) removes isatuximab interference from IFE. Using samples from patients enrolled in clinical trials of isatuximab-based therapy for MM, we demonstrate how the Hydrashift isatuximab assay improves the ability to detect residual M-protein and offer recommendations for when the assay is most useful. METHODS: Samples from 141 patients with a variety of known M-protein isotypes were selected and analyzed by standard IFE and the Hydrashift isatuximab assay. A positive control containing isatuximab was run on every standard IFE and Hydrashift gel. RESULTS: The Hydrashift isatuximab assay reliably shifted the migration of isatuximab in patient samples. Standard IFE was adequate for determining 104 patients' M-protein status, and the Hydrashift isatuximab assay confirmed these results. In samples from 37 patients with a history of IgGκ MM and a single IgGκ band visible on standard IFE near the isatuximab migration site, the Hydrashift isatuximab assay was able to separate isatuximab from endogenous M-protein, identifying residual M-protein in 17 samples and preventing false-positive interpretations of standard IFE in 20 samples. CONCLUSIONS: The Hydrashift isatuximab assay is most useful in patients with known IgGκ MM when a single IgGκ band appears near the isatuximab migration site on standard IFE during isatuximab-based therapy. CLINICALTRIALS.GOV REGISTRATION NUMBERS: NCT03275285 and NCT03319667.
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Anticuerpos Monoclonales Humanizados , Inmunoelectroforesis , Mieloma Múltiple , Proteínas de Mieloma , Humanos , Mieloma Múltiple/sangre , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/inmunología , Mieloma Múltiple/diagnóstico , Inmunoelectroforesis/métodos , Proteínas de Mieloma/análisis , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
OBJECTIVES: Multiple myeloma (MM) is a plasma cell malignancy characterized by a monoclonal expansion of plasma cells that secrete a characteristic M-protein. This M-protein is crucial for diagnosis and monitoring of MM in the blood of patients. Recent evidence has emerged suggesting that N-glycosylation of the M-protein variable (Fab) region contributes to M-protein pathogenicity, and that it is a risk factor for disease progression of plasma cell disorders. Current methodologies lack the specificity to provide a site-specific glycoprofile of the Fab regions of M-proteins. Here, we introduce a novel glycoproteogenomics method that allows detailed M-protein glycoprofiling by integrating patient specific Fab region sequences (genomics) with glycoprofiling by glycoproteomics. METHODS: Glycoproteogenomics was used for the detailed analysis of de novo N-glycosylation sites of M-proteins. First, Genomic analysis of the M-protein variable region was used to identify de novo N-glycosylation sites. Subsequently glycopeptide analysis with LC-MS/MS was used for detailed analysis of the M-protein glycan sites. RESULTS: Genomic analysis uncovered a more than two-fold increase in the Fab Light Chain N-glycosylation of M-proteins of patients with Multiple Myeloma compared to Fab Light Chain N-glycosylation of polyclonal antibodies from healthy individuals. Subsequent glycoproteogenomics analysis of 41 patients enrolled in the IFM 2009 clinical trial revealed that the majority of the Fab N-glycosylation sites were fully occupied with complex type glycans, distinguishable from Fc region glycans due to high levels of sialylation, fucosylation and bisecting structures. CONCLUSIONS: Together, glycoproteogenomics is a powerful tool to study de novo Fab N-glycosylation in plasma cell dyscrasias.
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Mieloma Múltiple , Humanos , Mieloma Múltiple/metabolismo , Mieloma Múltiple/genética , Mieloma Múltiple/diagnóstico , Glicosilación , Proteómica/métodos , Espectrometría de Masas en Tándem , Glicoproteínas/metabolismo , Cromatografía Liquida , Proteínas de Mieloma/metabolismo , Proteínas de Mieloma/análisisRESUMEN
BACKGROUND: To improve the early detection rate of multiple myeloma (MM), the M-protein screening system has been performed in the hospital population at Zhongshan Hospital Fudan University since 2014, with electrophoretic-based monoclonal immunoglobulin (M-protein) screening integrated into the blood biochemistry panel. This study updated 7-year follow-up findings of MM patients diagnosed by screening-driven and symptom-driven approaches. METHODS: The retrospective study compared the characteristics and outcomes of patients diagnosed through two patterns by reviewing the plasma cell disease database from January 2014 to October 2021. The screening-driven group included patients diagnosed through the screening system during workups of unrelated medical conditions or routine checkups. In contrast, patients who visited or were referred to the hematological department due to myeloma-related end-organ damage were categorized into the symptom-driven group. RESULTS: There were 3,110,218 serum protein electrophoresis (SPEP) tests performed during 7 years, with 1.95% (60,609) patients yielding positive SPEP results. Of 911 confirmed MM cases (excluding concurrent amyloidosis), 366 were assigned to the screening-driven group, while 545 were to the symptom-driven group. Compared to the symptom-driven group, the screening group had more IgG subtypes, earlier International Stage System stages, fewer disease-related symptoms, lower ECOG scores, less extramedullary disease, a lower percentage of bone marrow plasma cells, and a lower level of lactate dehydrogenase. Frontline response results of two groups were similar. Patients detected through screening had a significantly improved median progression-free survival (PFS) than the symptom-driven group (62.2 vs. 24.9 months, p < 0.001, HR: 2.12, 95% CIs: 1.69-2.65), with median follow-ups of 32.6 and 27.4 months. Furthermore, the median overall survival (OS) was significantly longer in patients of the screening group (not reached vs. 62.3 months, p < 0.001, HR: 2.49, 95% CIs: 1.81-3.41). After being adjusted for well-acknowledged myeloma prognostic factors, the screening-driven diagnostic pattern remained an independent prognostic factor indicating improved PFS and OS in MM patients. CONCLUSION: Routine M-protein screening for MM in the hospital population results in an earlier diagnosis and better patient outcomes.
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Detección Precoz del Cáncer , Mieloma Múltiple , Humanos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/sangre , Mieloma Múltiple/mortalidad , Masculino , Femenino , Persona de Mediana Edad , China/epidemiología , Estudios Retrospectivos , Anciano , Detección Precoz del Cáncer/métodos , Proteínas de Mieloma/análisis , Proteínas de Mieloma/metabolismo , Electroforesis de las Proteínas Sanguíneas , Adulto , Estudios de Seguimiento , Tamizaje Masivo/métodosRESUMEN
ABSTRACT: Plasma cell myeloma (PCM) is a monoclonal gammopathy (MGM) characterized by proliferation of abnormal clone of plasma cells infiltrating the bone marrow with consequent end organ damage. The clonal plasma cells secrete a single clone of immunoglobulins (Ig) leading to presence of M-protein in the serum and/or urine. The M-protein is appreciated as a discrete band on serum protein electrophoresis (SPE) in the gamma globulin region, also called the M-band. Biclonal gammopathy (BGM) occurs due to neoplastic transformation of a plasma cell clone undergoing Ig class switching or due to an independent neoplastic transformation event yielding proliferation of unrelated plasma cell clones, therefore resulting in two distinct M-bands on SPE. It is, however, vital to distinguish a true BGM from an apparent one (MGM presenting with two distinct bands on SPE) so as to make an accurate diagnosis. Hereby, we report a case of a 61-year-old man, diagnosed with PCM and presenting with two discrete bands on SPE (simulating a BGM) which turned out to be monoclonal in nature.
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Mieloma Múltiple , Humanos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/sangre , Mieloma Múltiple/patología , Masculino , Persona de Mediana Edad , Electroforesis de las Proteínas Sanguíneas/métodos , Células Plasmáticas/patología , Células Plasmáticas/metabolismo , Proteínas de Mieloma/análisis , Diagnóstico Diferencial , Paraproteinemias/diagnóstico , Paraproteinemias/sangreRESUMEN
Monoclonal gammopathy (MG) is common in autoimmune diseases (AID), but its progression to hematological neoplasm (HN) and the predictors for the progression are unclear. Patients diagnosed with AID and MG in our hospital from January 2010 to June 2017 were reviewed and followed. Cox proportional hazard regression analysis was applied. Of 160 patients with AID and MG, the most common AID was primary SjÓ§gren's syndrome (37, 23.1%). Thirty-nine (24.4%) patients developed HN during follow-up (median: 3.7 years, IQR: 0.3-5.5 years). The cumulative probability of HN progression was 21.8% at one year and 29.3% at six years after the finding of MG. High levels of monoclonal protein (> 14.35% of total serum protein) (HR 11.71, 95%CI: 5.37-25.54), significant weight loss (HR 6.24, 95%CI: 2.87-13.59), and reduction of other types of immunoglobulins (HR 3.02, 95%CI: 1.40-6.48) are independent risk indicators for HN whose presence warrants vigorous follow-up and monitoring.
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Enfermedades Autoinmunes/complicaciones , Neoplasias Hematológicas/etiología , Paraproteinemias/complicaciones , Adulto , Anciano , Enfermedades Autoinmunes/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Mieloma/análisis , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Atención Terciaria de SaludRESUMEN
PURPOSE: Elotuzumab plus pomalidomide/dexamethasone (E-Pd) demonstrated efficacy and safety in relapsed and refractory multiple myeloma (RRMM). The clinical pharmacology of elotuzumab [± lenalidomide/dexamethasone (Ld)] was characterized previously. These analyses describe elotuzumab population pharmacokinetics (PPK), the effect of Pd, and assess elotuzumab exposure-response relationships for efficacy and safety in patients with RRMM. METHODS: A previously established PPK model was updated with E-Pd data from the phase 2 ELOQUENT-3 study (NCT02654132). The dataset included 8180 serum concentrations from 440 patients with RRMM from 5 clinical trials. Elotuzumab PK parameter estimates were used to generate individual daily time-varying average concentrations (daily Cavg) for multi-variable time-to-event exposure-response analyses of progression-free survival (PFS) and time to the first occurrence of grade 3 + adverse events (AEs) in RRMM. RESULTS: Elotuzumab PK were well-described by a two-compartment model with parallel linear and Michaelis-Menten elimination from the central compartment (Vmax) and non-renewable target-mediated elimination from the peripheral compartment (Kint). Co-administration with Pd resulted in a 19% and 51% decrease in elotuzumab linear clearance and Kint, respectively, versus Ld; steady-state exposures were similar. Vmax increased with increasing serum M-protein. Hazard ratios (95% confidence intervals) for daily Cavg were 0.9983 (0.9969-0.9997) and 0.9981 (0.9964-0.9998) for PFS and grade 3 + AEs, respectively. CONCLUSIONS: The PPK model adequately described the data and was appropriate for determining exposures for exposure-response analyses. There were no clinically relevant differences in elotuzumab exposures between Pd and Ld backbones. In ELOQUENT-3, increasing elotuzumab daily Cavg prolonged PFS without increasing grade 3 + AEs.
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Anticuerpos Monoclonales Humanizados/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Dexametasona/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/patología , Proteínas de Mieloma/análisis , Recurrencia Local de Neoplasia/tratamiento farmacológico , Supervivencia sin Progresión , Talidomida/administración & dosificación , Talidomida/análogos & derivados , Resultado del TratamientoAsunto(s)
Citometría de Flujo/métodos , Cadenas Ligeras de Inmunoglobulina/sangre , Mieloma Múltiple/sangre , Neoplasia Residual/sangre , Espectrometría de Masa por Ionización de Electrospray/métodos , Médula Ósea/metabolismo , Médula Ósea/patología , Cromatografía Liquida/métodos , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Quimioterapia de Inducción/métodos , Quimioterapia de Mantención/métodos , Espectrometría de Masas/métodos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Proteínas de Mieloma/análisis , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodosAsunto(s)
Crioglobulinemia/etiología , Mieloma Múltiple/complicaciones , Vasculitis/etiología , Anciano , Bortezomib/uso terapéutico , Dexametasona/uso terapéutico , Humanos , Inmunoglobulina G/análisis , Masculino , Proteínas de Mieloma/análisis , Recurrencia , Ombligo , Vasculitis/tratamiento farmacológicoRESUMEN
BACKGROUND: Plasma cell disorders (PCDs) are typically characterized by excessive production of a single immunoglobulin, defined as a monoclonal protein (M-protein). Some patients have more than one identifiable M-protein, termed biclonal. Traditional immunofixation electrophoresis (IFE) cannot distinguish if two bands of the same isotype represent biclonal proteins or M-proteins with some other feature. A novel assay using immunoenrichment coupled to matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (Mass-Fix) was applied to determine whether two bands of the same isotype represented (1) monomers and dimers of a single M-protein, (2) an M-protein plus a therapeutic monoclonal antibody (t-mAb), (3) an M-protein with light chain glycosylation, or (4) two distinct biclonal M-proteins. METHODS: Patient samples with two bands of the same isotype identified by IFE were enriched using nanobodies against IgG, IgA, IgM, or κ and λ light chains then analyzed by Mass-Fix. Light chain masses were used to differentiate IgGκ M-proteins from t-mAbs. Mass differences between peaks were calculated to identify N-glycosylation or matrix adducts. High-resolution mass spectrometry was used as a comparator method in a subset of samples. RESULTS: Eighty-one residual samples were collected. For IgA, 93% (n = 25) were identified as monoclonal. For IgG, 67% (n = 24) were monoclonal, and 33% (n = 12) were truly biclonal. Among the monoclonal IgGs, the second band represented a glycosylated form for 21% (n = 5), while 33% (n = 8) had masses consistent with a t-mAb. 44% (n = 8) of IgM samples were biclonal, and 56% (n = 10) were monoclonal, of which one was glycosylated. CONCLUSIONS: We demonstrate the utility of mass spectrometry in the characterization of multiple IFE bands of the same isotype. Improved reporting accuracy of M-proteins is useful for monitoring of patients with PCDs.
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Anticuerpos Monoclonales/sangre , Inmunoelectroforesis/métodos , Proteínas de Mieloma/análisis , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/química , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/química , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Proteínas de Mieloma/química , Multimerización de Proteína , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
OBJECTIVE: Monoclonal protein (MP) exists in various diseases, and capillary electrophoresis (CE) has been widely used to detect MP. However, there is not much research on the application value of MP in the differential diagnosis of monoclonal gammopathies. This study aimed to explore MP's cutoff value for the differential diagnosis of multiple myeloma (MM) and other monoclonal gammopathies (MGs). METHODS: A retrospective analysis of 8167 cases was conducted. Serum MP was detected by CE, and the patients' clinical information was collected from the clinical database of our hospital. RESULTS: 985 cases had MP with high peaks, and 91.1% were diagnosed with malignant diseases. The MP showed small peaks in 471 cases, and only 24.4% were diagnosed with malignant diseases. Among the MPs, the IgG-κ type was the most common type, followed by the IgG-λ, IgA-κ, IgA-λ, free λ light chain, IgM-κ, free κ light chain, double clone, and IgM-λ types. Differences in the MP of the IgG, IgA, IgM, and FLC types between the MM group and MGUS group were statistically different (P<0.01). The MP of the IgG, IgA, and FLC types showed clear specificity and sensitivity in discriminating MM from other monoclonal gammopathies in ROC curve analysis. Serum IgM had statistical significance in the differential diagnosis between WM and other MGs (P<0.01). However, there was no statistical significance in the differential diagnosis between MM and other MGs (P=0.140). The cutoff values of the MP of the IgG, IgA, and FLC types were >18.67g/L, >13.86g/L, and >10.15g/L, respectively, for the differential diagnosis of MM and other MGs. The cutoff value of the MP of IgM for the WM diagnosis was >37.75 g/L. CONCLUSION: CE has good clinical application value in the diagnosis of monoclonal gammopathies, and MP can be used in the differential diagnosis of MM and other monoclonal gammopathies.
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Electroforesis Capilar/métodos , Cadenas Ligeras de Inmunoglobulina/sangre , Cadenas kappa de Inmunoglobulina/sangre , Cadenas lambda de Inmunoglobulina/sangre , Mieloma Múltiple/diagnóstico , Proteínas de Mieloma/análisis , Paraproteinemias/diagnóstico , Proteínas Sanguíneas/análisis , Proteínas Sanguíneas/inmunología , Diagnóstico Diferencial , Humanos , Cadenas Ligeras de Inmunoglobulina/inmunología , Cadenas kappa de Inmunoglobulina/inmunología , Cadenas lambda de Inmunoglobulina/inmunología , Mieloma Múltiple/sangre , Mieloma Múltiple/inmunología , Proteínas de Mieloma/inmunología , Paraproteinemias/sangre , Paraproteinemias/inmunología , Curva ROC , Estudios RetrospectivosRESUMEN
High-dose chemotherapy followed by autologous stem cell transplantation is a major component in the treatment of patients with multiple myeloma. As a prerequisite, the successful collection of a sufficient number of viable peripheral blood hematopoietic CD34+ cells is critical. A common standard protocol for mobilization is currently not defined and critically discussed especially in German-speaking Europe. In times of the Covid-19 pandemic, safe and effective strategies have to be chosen to minimize hospitalization times and severe courses. In this single-center retrospective analysis, safety and efficacy of cyclophosphamide plus etoposide (CE) and growth-factor support (n = 33) was compared to cyclophosphamide mono treatment and growth-factor support (n = 49) in 82 patients with multiple myeloma at first diagnosis. CE was superior to cyclophosphamide mono with a significantly higher number of collected CD34+ cells (15.46 × 106 CD34+ cells/kg vs. 9.92 × 106 CD34+ cells/kg), significantly faster engraftment of granulocytes after stem cell transplantation (day 10.5 vs. day 11.6), shorter duration of the inpatient stay (17.47 days vs. 19.16 days) and significantly less transfusions (8.82 % vs. 30.61 % patients receiving transfusions). The safety profile was comparable in both groups and in line with published data. We conclude that CE is a safe and highly effective mobilization protocol in patients with multiple myeloma at first diagnosis and appears to be superior to the commonly used cyclophosphamide mono regimen.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Ciclofosfamida/farmacología , Etopósido/farmacología , Movilización de Célula Madre Hematopoyética/métodos , Células Madre Hematopoyéticas/efectos de los fármacos , Mieloma Múltiple/terapia , Trasplante de Células Madre de Sangre Periférica/métodos , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , COVID-19 , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Factor Estimulante de Colonias de Granulocitos/farmacología , Humanos , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Mieloma Múltiple/sangre , Proteínas de Mieloma/análisis , Pandemias , Estudios Retrospectivos , SARS-CoV-2 , Trasplante AutólogoRESUMEN
Treatment benefit in multiple myeloma (MM) patients with high-risk cytogenetics remains suboptimal. The phase 3 ICARIA-MM trial (NCT02990338) showed that isatuximab plus pomalidomide-dexamethasone prolongs median progression-free survival (mPFS) in patients with relapsed/refractory MM (RRMM). This subgroup analysis of ICARIA-MM compared the benefit of isatuximab in high-risk [defined by the presence of del(17p), t(4;14) or t(14;16)] versus standard-risk patients. The efficacy of isatuximab in patients with gain(1q21) abnormality was also assessed in a retrospective subgroup analysis. In ICARIA-MM, 307 patients received isatuximab-pomalidomide-dexamethasone (n = 154) or pomalidomide-dexamethasone (n = 153). Isatuximab (10 mg/kg intravenously) was given weekly in the first 28-day cycle, and every other week thereafter. Standard pomalidomide-dexamethasone doses were given. Isatuximab-pomalidomide-dexamethasone improved mPFS (7·5 vs 3·7 months; HR, 0·66; 95% CI, 0·33-1·28) and overall response rate (ORR, 50·0% vs 16·7%) in high-risk patients. In patients with isolated gain(1q21), isatuximab addition improved mPFS (11·2 vs 4·6 months; HR, 0·50; 95% CI, 0·28-0·88) and ORR (53·6% vs 27·6%). More grade ≥3 adverse events occurred in high-risk patients receiving isatuximab (95·7%) versus the control group (67·6%); however, isatuximab did not increase events leading to discontinuation or treatment-related mortality. Isatuximab-pomalidomide-dexamethasone provides a consistent benefit over pomalidomide-dexamethasone treatment in RRMM patients regardless of cytogenetic risk.
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Ensayos Clínicos Fase III como Asunto/estadística & datos numéricos , Mieloma Múltiple/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Terapia Recuperativa , Cariotipo Anormal , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Cromosomas Humanos Par 1/genética , Dexametasona/administración & dosificación , Neutropenia Febril/inducido químicamente , Femenino , Humanos , Factores Inmunológicos/administración & dosificación , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , Proteínas de Mieloma/análisis , Neumonía/inducido químicamente , Recurrencia , Riesgo , Talidomida/administración & dosificación , Talidomida/análogos & derivados , TrisomíaRESUMEN
The MCRN-003/CCTGMYX.1 is a single arm phase II trial of weekly carfilzomib, cyclophosphamide and dexamethasone (wKCd), exploring a convenient immunomodulator (IMiD)-free regimen in relapsed myeloma. Weekly carfilzomib (20/70 mg/m2 ), dexamethasone 40 mg and cyclophosphamide 300 mg/m2 was delivered over 28-day cycles. The primary endpoint was overall response after four cycles. Secondary endpoints included toxicity, response depth, PFS and OS. Exploratory endpoints included the impact of cytogenetics, prior therapy exposure and serum free light chain (sFLC) escape; 76 patients were accrued. The ORR was 85% (68% ≥very good partial response [VGPR] and 29% ≥complete response [CR]). The median OS and PFS were 27 and 17 months respectively. High-risk cytogenetics conferred a worse ORR (75% vs. 97%, p = .013) and median OS (18 months vs. NR, p = .002) with a trend toward a worse median PFS (14 vs. 22 months, p = .06). Prior proteasome inhibitor (PI) or lenalidomide did not influence OS or PFS. The sFLC was noted in 15% of patients with a median PFS of 17 months when included as a progression event. The most common ≥ grade 3 non-hematologic adverse events were infectious (40%), vascular (17%) and cardiac (15%). The wKCD is a safe and effective regimen in relapse, especially for patients ineligible for lenalidomide-based therapies.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Enfermedades Cardiovasculares/inducido químicamente , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Esquema de Medicación , Disnea/inducido químicamente , Femenino , Enfermedades Hematológicas/inducido químicamente , Humanos , Infecciones/etiología , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Proteínas de Mieloma/análisis , Oligopéptidos/administración & dosificación , Oligopéptidos/efectos adversos , Selección de Paciente , Pronóstico , Supervivencia sin Progresión , Recurrencia , Terapia Recuperativa , Resultado del TratamientoRESUMEN
Daratumumab (DARA) is a human IgG-K monoclonal antibody (MoAb) targeting CD38 that is approved alone or in combination with bortezomib and dexamethasone or lenalidomide and dexamethasone for relapsed or refractory MM (RRMM) in patients previously exposed or double refractory to proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs). However, there are limited data on its clinical activity and tolerability in real-world patients. Therefore, in the present study, we aim to determine the efficacy and toxicity profile of daratumumab in a real-life setting. In this study, we report the experience of the multiple myeloma GIMEMA Lazio Group in 62 relapsed/refractory MM patients treated with daratumumab as monotherapy who had previously received at least two treatment lines including a PI and an IMiDs or had been double refractory. Patients received DARA 16 mg/kg intravenously weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks until disease progression or unacceptable toxicity. The overall response rate to daratumumab was 46%. Median progression-free survival (PFS) and overall survival reached 2.7 and 22.4 months, respectively. DARA was generally well tolerated; however, 2 patients interrupted their therapy due to adverse events. Present real-life experience confirms that DARA monotherapy is an effective strategy for heavily pre-treated and refractory patients with multiple myeloma, with a favorable safety profile.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/administración & dosificación , Ensayos Clínicos Fase II como Asunto/estadística & datos numéricos , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Estimación de Kaplan-Meier , Lenalidomida/administración & dosificación , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto/estadística & datos numéricos , Mieloma Múltiple/mortalidad , Mieloma Múltiple/terapia , Proteínas de Mieloma/análisis , Oligopéptidos/administración & dosificación , Supervivencia sin Progresión , Talidomida/administración & dosificación , Talidomida/análogos & derivadosRESUMEN
Plasma cell disorders (PCDs) are identified in the clinical lab by detecting the monoclonal immunoglobulin (M-protein) which they produce. Traditionally, serum protein electrophoresis methods have been utilized to detect and isotype M-proteins. Increasing demands to detect low-level disease and new therapeutic monoclonal immunoglobulin treatments have stretched the electrophoretic methods to their analytical limits. Newer techniques based on mass spectrometry (MS) are emerging which have improved clinical and analytical performance. MS is gaining traction into clinical laboratories, and has replaced immunofixation electrophoresis (IFE) in routine practice at one institution. The International Myeloma Working Group (IMWG) Mass Spectrometry Committee reviewed the literature in order to summarize current data and to make recommendations regarding the role of mass spectrometric methods in diagnosing and monitoring patients with myeloma and related disorders. Current literature demonstrates that immune-enrichment of immunoglobulins coupled to intact light chain MALDI-TOF MS has clinical characteristics equivalent in performance to IFE with added benefits of detecting additional risk factors for PCDs, differentiating M-protein from therapeutic antibodies, and is a suitable replacement for IFE for diagnosing and monitoring multiple myeloma and related PCDs. In this paper we discuss the IMWG recommendations for the use of MS in PCDs.
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Mieloma Múltiple/diagnóstico , Proteínas de Mieloma/análisis , Neoplasias de Células Plasmáticas/diagnóstico , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Cromatografía Liquida/métodos , Humanos , Cadenas Ligeras de Inmunoglobulina/análisisRESUMEN
Monoclonal gammopathy of undetermined significance (MGUS) is rare in young patients (age <40 years at diagnosis), with a prevalence of <0.3%, representing ~2% of all patients with MGUS. We hypothesized that MGUS detected in young patients may be associated with a higher risk of progression. We examined 249 patients with MGUS < 40 years old. Among these, 135 patients had immune-related conditions, including infections, autoimmune and inflammatory disorders at the time of diagnosis of MGUS. The risk of progression to multiple myeloma or a related disorder at 5 years and 10 years was 6.0% and 13.8%, respectively. The size of M protein was a significant risk factor for progression (HR 4.2, 95% CI 2.2-7.9). There was a trend that the risk of progression was higher in patients without immune-related conditions (HR 2.36, 95% CI 0.85-6.52, p = 0.088). The M protein resolved in 36 (14%) patients, with a greater likelihood of resolution in patients with immune-related conditions (RR 1.9, 95% CI 1.02-3.6). Young patients with MGUS have a similar risk of progression as older patients, 1.4% per year. Over 50% are diagnosed in the setting of immune-related disorders. Patients with immune-related disorders may have a lower risk of progression.