The Current Role of the Heavy/Light Chain Assay in the Diagnosis, Prognosis and Monitoring of Multiple Myeloma: An Evidence-Based Approach.

Despite tremendous progress being made in recent years, multiple myeloma (MM) remains a challenging disease. The laboratory plays a critical role in the overall management of patients. The diagnosis, prognosis, clinical monitoring and evaluation of the response are key moments in the clinical care process. Conventional laboratory methods have been and continue to be the basis of laboratory testing in monoclonal gammopathies, along with the serum free light chain test. However, more accurate methods are needed to achieve new and more stringent clinical goals. The heavy/light chain assay is a relatively new test which can overcome some of the limitations of the conventional methods for the evaluation of intact immunoglobulin MM patients. Here, we report an update of the evidence accumulated in recent years on this method regarding its use in MM.

HLC Pair Suppression as a Risk Factor for Bacterial Bloodstream Infections and Early Mortality in Newly Diagnosed Intact Immunoglobulin Multiple Myeloma Patients.

Despite the outstanding progresses in Multiple Myeloma treatment options in the last decades, it remains an incurable disease nowadays. Infectious events are a complication due to an impaired immune system associated with MM, sometimes a life-threatening one, particularly on the first months after the diagnosis. Both the underlying disease and treatment can contribute to the infection risk, so a biomarker that assess this risk could be highly relevant for a more tailored management of the patient. The measurement of the heavy+light chain (HLC) pairs of immunoglobulins in serum allows the quantification of both the monoclonal component and the non-monoclonal immunoglobulin of the same isotype. This approach has demonstrated high sensitivity for the detection of the clonality and prognostic value for MM. HLC pair suppression itself has prognostic power and it has been proposed to be a reflection of the immune system' attempt to control the tumor. In this study we evaluated the impact of the HLC pair suppression on the rate of bloodstream infections (BSI) and early death in 115 newly diagnosed MM patients. Twenty-one percent of the patients suffered a BSI in the first 6 months after diagnosis, of which 58% died within this period, accounting to 67% of the early deaths in global and highlighting the major impact of infections on MM patients in a "real world" setting. Severe HLC pair suppression identified patients with a higher risk of early BSI (HR: 6,97, p=0,009), and extreme HLC pair suppression together with BSI event and age >65 were independent risk factors for early death (p<0,001). Based on these factors, a stratification model was generated to allow identify patients at a higher risk of early death and poorer OS, with an apparently better performance than the ISS on the early death context. In conclusion, HLC pair suppression associates with both a higher risk of life-threatening early infection and early death in newly diagnosed MM patients. Patients older than 65 with extreme HLC pair suppression and BSI are at a high risk of early death, and thus patients presenting with these criteria have a very adverse prognosis.

Asociación del epítopo compartido, el tabaquismo y la interacción entre ambos con la presencia de autoanticuerpos (anti-PCC y FR) en pacientes con artritis reumatoide en un hospital de Sevilla, España / Association of the shared epitope, smoking and the interaction between the two with the presence of autoantibodies (Anti-CCP and RF) in patients with rheumatoid arthritis in a hospital in Seville, Spain

OBJETIVO: Evaluar la asociación del epítopo compartido, el tabaquismo y la interacción entre ambos sobre la presencia de autoanticuerpos (antipéptidos cíclicos citrulinados [anti-PCC] y factor reumatoide) en pacientes con artritis reumatoide en nuestra área geográfica. MÉTODOS: Estudio descriptivo y transversal realizado en una cohorte de 106 pacientes diagnosticados de artritis reumatoide. Análisis estadístico univariante y multivariante mediante regresión logística ordinal. Se calcularon odds ratios (OR) con un intervalo de confianza del 95% [IC95%] y se considero significativo un valor de p < 0,05. RESULTADOS: En el análisis univariante, el epítopo compartido (OR=2,68; IC95% 1,11-6,46), el hábito tabáquico (OR=2,79; IC95% 1,12-6,97) y un índice de tabaquismo en paquetes-año alto (>20 paquetes/año) (OR=8,93; IC95% 1,95-40,82) se asociaron con la presencia de anti-PCC positivos. Para el factor reumatoide, la asociación solo fue significativa con el hábito tabáquico (OR=3,89; IC95% 1,06-14,28) y el índice de tabaquismo (OR=8,33; IC95% 1,05-66,22). Mediante análisis de regresión logística ordinal se identificó asociación con títulos elevados de anti-PCC (>200 U/mL) en mestizos latinoamericanos, ser homocigoto para el epítopo compartido, tener factor reumatoide positivo y ser gran fumador. CONCLUSIONES: El ser mestizo latinoamericano, tener epítopo compartido, factor reumatoide y un índice de tabaquismo>20 paquetes/año son factores de riesgo independientes para el desarrollo de artritis reumatoide con anti-PCC positivos a títulos elevados (>200U/mL). En los pacientes portadores del epítopo compartido, la intensidad del consumo de tabaco se asocia más fuertemente que el hábito de fumar con un riesgo incrementado de anti-PCC positivos, observándose una interacción entre ambos factores

OBJECTIVES: To evaluate the association of shared epitope, smoking and their interaction on the presence of autoantibodies (anti-cyclic citrullinated peptide [CCP] antibodies and rheumatoid factor) in patients with rheumatoid arthritis in our geographical area. METHODS: A descriptive and cross-sectional study was carried out in a cohort of 106 patients diagnosed with RA. Odds ratios (OR) for antibody development were calculated for shared epitope, tobacco exposure and smoking dose. Statistical analysis was performed with univariate and multivariate statistics using ordinal logistic regression. Odds ratios were calculated with 95% confidence interval (95% CI) and a value of P<.05 was considered significant. RESULTS: In univariate analysis, shared epitope (OR=2.68; 95% CI: 1.11-6.46), tobacco exposure (OR=2.79; 95% CI: 1.12-6.97) and heavy smoker (>20 packs/year) (OR=8.93; 95% CI: 1.95-40.82) were associated with the presence of anti-CCP antibodies. For rheumatoid factor, the association was only significant for tobacco exposure (OR=3.89; 95% CI: 1.06-14.28) and smoking dose (OR=8.33; 95% CI: 1.05-66.22). By ordinal logistic regression analysis, an association with high titers of anti-CCP (>200U/mL) was identified with South American mestizos, patients with homozygous shared epitope, positive FR and heavy smokers. CONCLUSIONS: Being a South American mestizo, having a shared epitope, rheumatoid factor positivity and a smoking dose>20 packs/year are independent risk factors for the development of rheumatoid arthritis with a high titer of anti-CCP (>200U/mL). In shared epitope-positive rheumatoid arthritis patients, the intensity of smoking is more strongly associated than tobacco exposure with an increased risk of positive anti-CCP

Association of the Shared Epitope, Smoking and the Interaction Between the Two With the Presence of Autoantibodies (Anti-CCP and RF) in Patients With Rheumatoid Arthritis in a Hospital in Seville, Spain. / Asociación del epítopo compartido, el tabaquismo y la interacción entre ambos con la presencia de autoanticuerpos (anti-PCC y FR) en pacientes con artritis reumatoide en un hospital de Sevilla, España.

OBJECTIVES: To evaluate the association of shared epitope, smoking and their interaction on the presence of autoantibodies (anti-cyclic citrullinated peptide [CCP] antibodies and rheumatoid factor) in patients with rheumatoid arthritis in our geographical area. METHODS: A descriptive and cross-sectional study was carried out in a cohort of 106 patients diagnosed with RA. Odds ratios (OR) for antibody development were calculated for shared epitope, tobacco exposure and smoking dose. Statistical analysis was performed with univariate and multivariate statistics using ordinal logistic regression. Odds ratios were calculated with 95% confidence interval (95% CI) and a value of P<.05 was considered significant. RESULTS: In univariate analysis, shared epitope (OR=2.68; 95% CI: 1.11-6.46), tobacco exposure (OR=2.79; 95% CI: 1.12-6.97) and heavy smoker (>20 packs/year) (OR=8.93; 95% CI: 1.95-40.82) were associated with the presence of anti-CCP antibodies. For rheumatoid factor, the association was only significant for tobacco exposure (OR=3.89; 95% CI: 1.06-14.28) and smoking dose (OR=8.33; 95% CI: 1.05-66.22). By ordinal logistic regression analysis, an association with high titers of anti-CCP (>200U/mL) was identified with South American mestizos, patients with homozygous shared epitope, positive FR and heavy smokers. CONCLUSIONS: Being a South American mestizo, having a shared epitope, rheumatoid factor positivity and a smoking dose>20 packs/year are independent risk factors for the development of rheumatoid arthritis with a high titer of anti-CCP (>200U/mL). In shared epitope-positive rheumatoid arthritis patients, the intensity of smoking is more strongly associated than tobacco exposure with an increased risk of positive anti-CCP.

Validation and meta-analysis of kappa index biomarker in multiple sclerosis diagnosis.

The importance of studying the cerebrospinal fluid (CSF) in Multiple Sclerosis (MS) is included in the last McDonald criteria (2018). The study of oligoclonal IgG bands (OCGB) assay is strongly recommended in some situations in which MS diagnosis is uncertain. New biomarkers are developed during the last years. Kappa free light chains (FLC) can predict conversion to MS in patients with Clinically Isolated Syndrome (CIS). The aim of this work is to validate the clinical usefulness of the kappa index, and to establish the actual state of knowledge for kappa index as a biomarker of conversion in CIS patients by a meta-analysis. Kappa index seems more relevant than the mere concentration of kappa FLC in CSF. In the validation study, 334 patients were included; in which 100 were CIS patients. Patients were divided in two groups according kappa index cut-off of 10.62: group 1 (kappa index>10.62); group 2 (kappa index<10.62). In group 1 more patients had positive OCGB, IgG index>0.56 and fulfilled magnetic resonance imaging (MRI) criteria. In contrast, in group 2, more patients showed negative OCGB, IgG index<0.56 and did not fulfilled MRI criteria. While 67.6% of patients from group 1 converted to MS, only 12.5% of patients from group 2 converted to MS. An HR of 6.02 was obtained in the Kaplan-Meier analysis. In the meta-analysis, 8 studies were finally included. The SROC curve revealed a high diagnostic performance for the kappa index as a MS diagnostic biomarker. Despite heterogeneity found between studies, the global OR revealed a good discriminatory capacity of kappa index. In conclusion, kappa index has a great clinical sensitivity and specificity as a support in MS diagnosis. High kappa index increase the probability of CIS to MS conversion. A correct sample processing in the preanalytical stage is key to obtain right results and to allow establishing comparison between laboratories.

Serum free light chains in the evaluation of the response to treatment and biological progression in primary amyloidosis / Cadenas ligeras libres séricas en la evaluación de la respuesta al tratamiento y progresión biológica en Amiloidosis Primaria

Primary amyloidosis is a rare condition characterised by the deposition of free light chains in different tissues and organs (e.g. kidney, heart, liver, gastrointestinal system). The aim of the therapy in patients with primary amyloidosis is to suppress the monoclonal plasma cells that produce the amyloidogenic free light chains and to preserve the organ function. Thus, the new criteria for the haematological disease response include the measurement of serum free light chains concentrations. The case is presented on a patient diagnosed with primary amyloidosis, where the difference between bound and free serum free light chains (dFLC) was used to evaluate the haematological response to the treatment, as well as any biological progression. In contrast to dFLC, Bence Jones Protein in urine was positive but ineffective to evaluate the response to the treatment (AU)

La amiloidosis primaria es una entidad rara caracterizada por el depósito de cadenas ligeras libres en diferentes tejidos y órganos (riñón, corazón, hígado, aparato gastrointestinal). El objetivo en la terapia de los pacientes con amiloidosis primaria consiste en suprimir las células plasmáticas monoclonales que producen las cadenas ligeras libres amiloidogénicas y preservar la función de los órganos afectados. Así, los nuevos criterios de respuesta hematológica de la enfermedad incorporan la medida de las concentraciones séricas de cadenas ligeras libres. Presentamos el caso de una paciente a quien se diagnosticó amiloidosis primaria y en la cual la diferencia de concentración en suero entre la cadena ligera libre monoclonal implicada y la no implicada (dFLC) nos permitió evaluar la respuesta hematológica al tratamiento y la presencia de progresión biológica. En contraste a la dFLC, la proteinuria de Bence Jones fue positiva pero ineficaz en la evaluación de la respuesta al tratamiento (AU)

Mieloma múltiple IgD: reporte de 5 casos clínicos / IgD multiple myeloma. A report of five cases

El Mieloma Múltiple (MM) IgD es una entidad compleja que representa menos del 2% de los casos de pacientes con MM. En este estudio describimos las características clínicas y analíticas de una serie de cinco pacientes diagnosticados con MM IgD en nuestro área geográfica destacando la importancia de los hallazgos del laboratorio clínico en el estudio de estos pacientes. La serie de pacientes se caracterizó por una prevalencia del género masculino, con una edad comprendida entre 50 y 83 años y un predominio de la cadena ligera monoclonal lambda. Al diagnóstico, todos los pacientes presentaron fallo renal agudo y lesiones óseas características de la enfermedad (AU)

IgD Multiple Myeloma (MM) is a rare entity that affects less than 2% of patients with MM. The aim of this study is to describe the clinical and analytical findings in five patients diagnosed with IgD MM in our geographic area. Furthermore, the relevance of clinical laboratory findings in the diagnostic protocol for these patients is demonstrated. The majority of patients studied were males, with ages ranging from 50 to 83 years, and a predominance of lambda light chain. At diagnosis, all the patients were shown to have impaired renal function and bone lesions characteristic of the disease (AU)

Carcinoma de células pequeñas mixto: un desafío diagnóstico / A rare case of combined small-cell lung carcinoma: a challenging diagnosis

Los síndromes neurológicos paraneoplásicos constituyen un conjunto de manifestaciones neurológicas asociadas a la existencia de una tumor oculto no diagnosticado en un paciente. Los síndromes neurológicos paraneoplásicos están producidos por mecanismos inmunológicos donde tiene lugar una respuesta inmunológica frente a antígenos compartidos por el tumor y el tejido neuronal del paciente. La detección serológica de los anticuerpos onconeuronales (Hu, Yo, Ri, Ma-2, anfifisina, etc.) es de utilidad en el diagnóstico de los síndromes neurológicos paraneoplásicos asociados. Presentamos el caso de una paciente que acude a Urgencias por presentar alteraciones neurológicas y donde los resultados obtenidos por el laboratorio clínico permiten orientar el estudio diagnóstico de la paciente hacía la búsqueda de un tumor oculto de estirpe microcítica mixta (AU)

Paraneoplastic neurological syndromes are a set of neurological manifestations associated with the existence of a hidden tumour in a patient. Paraneoplastic neurological syndromes are produced by immunological mechanisms where an immune response occurs against antigens shared between tumour and neuronal tissue of the patient. Serological detection of onconeural antibodies (Hu, Yo, Ri, Ma-2, amphiphysin, etc.) is useful in the diagnosis of associated paraneoplastic neurological syndromes. The case is presented of a patient who was admitted to emergency room due to neurological disorders. With the results of the clinical laboratory, the study was oriented towards the search for a hidden tumour of microcytic mixed lineage (AU)

Prognostic Value of Serum Free Light Chains Measurements in Multiple Myeloma Patients.

BACKGROUND: The outcome for patients with Multiple Myeloma (MM) is highly variable, therefore, the existence of robust and easy to determine prognostic markers is extremely important for an efficient management of these patients. Presently, there is a debate about the role of the serum free light chains (sFLC) in the prognosis of MM patients both at diagnosis and after treatment. The aim of this study is to evaluate in a cohort of newly diagnosed MM patients from the Southern area of Spain, the prognostic value of sFLC both at baseline and after treatment. MATERIALS AND METHODS: 180 patients with a median age of 69 years were followed-up for a median time of 35 (18-61) months. The sFLC ratio (sFLCR) was calculated using the monoclonal sFLC as numerator. Patients were divided in two groups according to a sFLCR cut-off based on ROC analysis. The primary endpoints were the Overall Survival (OS) and the Progression-free Survival (PFS). Additionally, thirty-six MM patients treated with novel agents (Bortezomib/Dexamethasone) that achieved Complete Response (CR) or stringent CR (sCR) before autologous stem cell transplantation were studied to assess the impact of sCR in Disease Free Survival (DFS) and OS. RESULTS: During follow-up there were 72 disease-related deaths. The 5-years OS for the whole group was 51%. However, separate analysis of patients with sFLCR above (group "high") or below (groups "low") the cut-off value of 47 shows an OS of 23% and 73%, respectively (HR = 5.03, 95%CI 2.99-8.50, p<0.001). In addition, analysis by ISS stage, showed that the presence of high sFLCR was always significantly associated with a worse OS. Multivariate analysis identified sFLCR (HR = 4.42, 95%CI 2.57-7.60, p<0.001) and beta-2-microglobulin (B2M) (HR = 3.04, 95%IC 1.75-5.31, p<0.001) as independent risk factors for adverse outcome. A new risk stratification model based on sFLCR≥47 and B2M>3.5 mg/L provided a statistically more significant result for this cohort when compared with the conventional ISS system. The HR for the new model were 2.84 (95% CI, 1.39-5.79, p = 0.004) for patients in stage 2 and 15.39 (95% CI, 6.35-37.33, p<0.001) for those in stage 3. Finally, in the group of patients reaching CR (19/36) or sCR (17/36) after induction, the median DFS for CR patients was 29 months, and NR for sCR patients (HR = 3.73; 95% CI 1.15-12.13, p = 0.03). Importantly, achieving sCR also translated into a significantly longer OS (5y-OS: sCR-89% versus CR-49%; p = 0.003; OS: sCR-NR versus CR-52 months). CONCLUSIONS: Our findings confirm the observations that the sFLCR has a major role in the survival of MM patients. A cut-off of sFLCR≥47 was shown to have an independent prognostic value at diagnosis, and a proposed "New Staging System" allows an accurate and simple method to risk stratify MM patients. Furthermore, because achievement of sCR was shown to represent a response state deeper than conventional CR resulting in greater OS and DFS, our study supports the continuity of sFLC ratio as part of the response criteria for MM patients.