Accurate classification of plasma cell dyscrasias is achieved by combining artificial intelligence and flow cytometry.

Monoclonal gammopathy of unknown significance (MGUS), smouldering multiple myeloma (SMM), and multiple myeloma (MM) are very common neoplasms. However, it is often difficult to distinguish between these entities. In the present study, we aimed to classify the most powerful markers that could improve diagnosis by multiparametric flow cytometry (MFC). The present study included 348 patients based on two independent cohorts. We first assessed how representative the data were in the discovery cohort (123 MM, 97 MGUS) and then analysed their respective plasma cell (PC) phenotype in order to obtain a set of correlations with a hypersphere visualisation. Cluster of differentiation (CD)27 and CD38 were differentially expressed in MGUS and MM (P < 0·001). We found by a gradient boosting machine method that the percentage of abnormal PCs and the ratio PC/CD117 positive precursors were the most influential parameters at diagnosis to distinguish MGUS and MM. Finally, we designed a decisional algorithm allowing a predictive classification ≥95% when PC dyscrasias were suspected, without any misclassification between MGUS and SMM. We validated this algorithm in an independent cohort of PC dyscrasias (n = 87 MM, n = 41 MGUS). This artificial intelligence model is freely available online as a diagnostic tool application website for all MFC centers worldwide (https://aihematology.shinyapps.io/PCdyscrasiasToolDg/).

Prospective study of prognostic factors in asymptomatic patients with B-cell chronic lymphocytic leukemia-like lymphocytosis: the cut-off of 11 × 10(9)/L monoclonal lymphocytes better identifies subgroups with different outcomes.

The arbitrary threshold of 5 × 10(9)/L chronic lymphocytic leukemia (CLL)-like lymphocytes differentiates monoclonal B lymphocytosis (MBL) from CLL. There are no prospective studies that search for the optimal cut-off of monoclonal lymphocytes able to predict outcome and simultaneously analyze the prognostic value of classic, immunophenotypic, and cytogenetic variables in patients with asymptomatic clonal CLL lymphocytosis (ACL), which includes MBL plus Rai 0 CLL patients. From 2003 to 2010, 231 ACL patients were enrolled in this study. Patients with 11q deletion and atypical lymphocyte morphology at diagnosis had shorter progression-free survival (PFS) (p = 0.007 and p = 0.015, respectively) and treatment-free survival (TFS) (p = 0.009 and p = 0.017, respectively). Elevated beta-2 microglobulin (B2M) also correlated with worse TFS (p = 0.002). The optimal threshold of monoclonal lymphocytes independently correlated with survival was 11 × 10(9)/L (p = 0.000 for PFS and p = 0.016 for TFS). As conclusion, monoclonal lymphocytosis higher than 11 × 10(9)/L better identifies two subgroups of patients with different outcomes than the standard cut-off value of 5 × 10(9)/L. Atypical lymphocyte morphology, 11q deletion and elevated B2M had a negative impact on the survival in ACL patients.

[Skin disorders associated with monoclonal gammopathies]. / Huidafwijkingen bij monoklonale gammopathieën.

A monoclonal gammopathy is a condition in which a monoclonal immunoglobulin (M-protein, formerly known as paraprotein) produced by a clonal proliferation of plasma cells is present in the blood. The spectrum of monoclonal gammopathies includes monoclonal gammopathy of uncertain significance (MGUS), multiple myeloma, Waldenström disease, plasmacytoma and primary amyloidosis. Various skin diseases are associated with monoclonal gammopathies. These are often rare skin diseases which are not easily recognised. This association is important to be known, in order to screen these patients for M-proteins and if necessary refer them to a haematologist. We present a 62-year-old male with cryoglobulinaemia and MGUS, a 64-year-old male with lichen myxoedematosus and MGUS and a 74-year-old male with necrobiotic xanthogranuloma and probably MGUS.

[Pitfalls of monoclonal gammopathy]. / Les pièges des gammapathies monoclonales.

Monoclonal gammopathy of undetermined significance (MGUS) is a frequent condition affecting at least 3% of the general population over 50 years. Usually, the diagnosis of MGUS is made accidentally during a biological assessment for other conditions. Although MGUS is most frequently a benign and asymptomatic disorder, it has well been described that MGUS could be a premalignant status and that the risk of transformation into myeloma or other lymphoproliferative disorders is estimated at 1% per year. MGUS can also be associated with other diseases than malignant disorders such as Infections, autoimmune diseases. In some case it could reflect rare but severe disorders that will be crucial not to miss the diagnosis.

MicroRNA expression in multiple myeloma is associated with genetic subtype, isotype and survival.

BACKGROUND: MicroRNAs are small RNA species that regulate gene expression post-transcriptionally and are aberrantly expressed in many cancers including hematological malignancies. However, the role of microRNAs in the pathogenesis of multiple myeloma (MM) is only poorly understood. We therefore used microarray analysis to elucidate the complete miRNome (miRBase version 13.0) of purified tumor (CD138+) cells from 33 patients with MM, 5 patients with monoclonal gammopathy of undetermined significance (MGUS) and 9 controls. RESULTS: Unsupervised cluster analysis revealed that MM and MGUS samples have a distinct microRNA expression profile from control CD138+ cells. The majority of microRNAs aberrantly expressed in MM (109/129) were up-regulated. A comparison of these microRNAs with those aberrantly expressed in other B-cell and T-cell malignancies revealed a surprising degree of similarity (~40%) suggesting the existence of a common lymphoma microRNA signature. We identified 39 microRNAs associated with the pre-malignant condition MGUS. Twenty-three (59%) of these were also aberrantly expressed in MM suggesting common microRNA expression events in MM progression. MM is characterized by multiple chromosomal abnormalities of varying prognostic significance. We identified specific microRNA signatures associated with the most common IgH translocations (t(4;14) and t(11;14)) and del(13q). Expression levels of these microRNAs were distinct between the genetic subtypes (by cluster analysis) and correctly predicted these abnormalities in > 85% of cases using the support vector machine algorithm. Additionally, we identified microRNAs associated with light chain only myeloma, as well as IgG and IgA-type MM. Finally, we identified 32 microRNAs associated with event-free survival (EFS) in MM, ten of which were significant by univariate (logrank) survival analysis. CONCLUSIONS: In summary, this work has identified aberrantly expressed microRNAs associated with the diagnosis, pathogenesis and prognosis of MM, data which will prove an invaluable resource for understanding the role of microRNAs in this devastating disease.

[Contribution of whole-body magnetic resonance in the diagnostics of monoclonal gammopathy of undetermined significance, multiple myeloma, and the assessment of Durie-Salmon Plus staging system]. / Prínos celotelové magnetické rezonance v diagnostice monoklonální gamapatie nejistého výnamu, mnohocetného myelomu a stanovení stadia pokrocilosti nemoci s pomocí systému Durie-Salmon Plus.

BACKGROUND: The aim of the study was to assess the contribution of the whole body MRI (WB-MRI) in the diagnostics of monoclonal gammopathy of undetermined significance (MGUS) and initial, asymptomatic form of multiple myeloma (MM), as well as the evaluation of practical usefulness of the Durie-Salmon Plus staging system (D-S Plus). MATERIALS AND METHODS: The analyzed 86-patient cohort consisted of 28 patients with MGUS and 54 patients with newly diagnosed multiple myeloma and 4 patients with solitary plasmocytoma (SP). WB-MRI was evaluated using Magnetom Avanto 1.5 T with the use of virtual whole body coil with sequential acquisition on 7 levels and 2 sequentions--T2 STIR and T1. Based on the number of lesions and the degree of diffuse involvement we assessed the D-S Plus stage, and compared it to the results of standard staging systems according to Durie Salmon (D-S) and International Staging System (ISS). Statistical estimation was done using the Cohen kappa test and McNemara-Bowker test at p < 0.05. RESULTS: In the group of 28 individuals with MGUS, there were 17 (61%) patients fulfilling the IMWG criteria and/orWB-MRI criteria of incipient MM. In 4/17 (23%) patients we described a more advanced stage when comparing D-S Plus to D-S. Nine out of fourteen (64%) patients with MGUS transforming into MM with negative radiological assessment had positive findings on WB-MRI. The character of WB-MRI findings lead in 9/17 (53%) of the patients to the initiation of induction treatment. Stratification according to D-S Plus divided the 54 newly diagnosed patients with MM into stage 1 (16.7%), stage 2 (33.3%) and stage 3 (50%). In 22% there was a shift into a higher stage using DS-Plus in comparison with D-S, in 9% of the patients the shift lead to downstaging. When comparing the results of ISS vs D-S Plus we found that the system based on WB-MRI showed in 41% of the patients higher stage and only in 9% of the patients lower stage. In 13% of MM patients we described extramedulary masses of the tumor, especially in paraspinal region. In 1 of the 4 SP patients the WB-MRI changed the diagnosis into multifocal plasmocytoma. CONCLUSION: WB-MRI is a very contributive imaging method with substantially higher resolution than conventional radiography. It is able to evaluate the grade and the extent of myeloma bone disease. It improves the diagnostic approach in the differentiation of stable MGUS from the phase of malignant transformation into MM. The D-S Plus system proved to be contributive and is competent to become a routine part of diagnostic and stratification algorithms in MGUS and MM.

Monoclonal gammopathy in systemic lupus erythematosus.

We studied the prevalence, type and associated features of monoclonal gammopathy in patients with systemic lupus erythematosus (SLE). Patients included in the University of Toronto Lupus Database with an abnormal band on serum electropheresis were identified. Monoclonal gammopathy patients were matched with two controls each from the same database by age at SLE diagnosis, sex and disease duration. Of 1083 patients followed at the Lupus Clinic 59 (5.4%) were identified with monoclonal gammopathy. The gammopathies included 32 with IgG, 14 IgM and 12 IgA, one undefined. Nine (15.3%) malignancies were detected in monoclonal gammopathy and 12 (10.1%) in the controls during the entire course of their disease (P = 0.13). None had multiple myeloma. There was no difference between patients with monoclonal gammopathy and their controls with respect to disease activity, damage, or dose of steroids. The mean ESR and gammaglobulin levels in the monoclonal gammopathy patients were higher than the controls at last visit. We conclude that monoclonal gammopathy is more frequent in SLE patients than in the general population and has a benign course in patients with SLE. There were no differences in disease manifestations, treatment approaches, or malignancies between SLE patients with and those without monoclonal gammopathy.

Immunoglobulin M monoclonal gammopathies of undetermined significance and indolent Waldenstrom's macroglobulinemia recognize the same determinants of evolution into symptomatic lymphoid disorders: proposal for a common prognostic scoring system.

PURPOSE: To evaluate the clinicohematologic variables at diagnosis that are prognostically related to neoplastic progression in patients with immunoglobulin M (IgM) monoclonal gammopathies of undetermined significance (MGUS), and indolent Waldenström's macroglobulinemia (IWM), and propose a scoring system to identify subsets of patients at different risk. PATIENTS AND METHODS: We evaluated 217 patients with IgM MGUS and 201 with IWM (male-female ratio, 131:86 and 117:84; mean age, 63.7 and 63.6 years, respectively) diagnosed on the basis of serum monoclonal component (MC) levels and bone marrow lymphoplasmacytic infiltration degree. The variables selected by univariate analyses were multivariately investigated; on the basis of their individual relative hazards, a scoring system was devised to identify subsets of patients at different risk of evolution. RESULTS: After a median follow-up of 56.1 and 60.2 months, 15 of 217 MGUS and 45 of 201 IWM patients, respectively, required chemotherapy for symptomatic WM (13 and 36), non-Hodgkin's lymphoma (2 and 6) and amyloidosis (0 and 3). The median time to evolution (TTE) was not reached for MGUS and was 141.5 months for IWM. The variables adversely related to evolution were qualitatively the same in both groups: MC levels, Hb concentrations and sex. A scoring system based on these parameters identified three risk groups with highly significant differences in TTE in both groups (P < .0001). CONCLUSION: MGUS and IWM identify disease entities with different propensities for symptomatic neoplastic evolution. As both have the same prognostic determinants of progression, we propose a practical scoring system that, identifying different risks of malignant evolution, may allow an individualized clinical approach.

Incidencia de gammopatías monoclonales en pacientes infectados por HIV-1 / Incidence of monoclonal gammopathies in HIV-1 infected patients

Se estudió la incidencia de gammopatías monoclonales (GM) en pacientes infectados por HIV-1 y su posible asociación con neoplasias malignas. Se estudiaron 236 pacientes reactivos a la prueba de detección de anticuerpos anti-HVI-1, siguiendo con los criterios para el diagnóstico clínico y serológico propuestos por el CDC (Atlanta). Se observó GM en 24 casos (10,2%). Se clasificaron en GM de baja conc.: menor de 1 g/dl de suero (92%); de mediana conc.: entre 1-2 g/dl (0,4%) y de elevada conc.: mayor de 2 g/dl (0,4%). Los isotipos de las cadenas pesadas fueron identificados como IgG (94,5%) e IgM (5,5%). Del total de pacientes, en seis se diagnosticó Sarcoma de Kaposi y de éstos dos presentaron GM. Las GM que se describen en este trabajo deberían considerarse de significado incierto. Su hallazgo, la identificación, la purificación y el estudio de la actividad de anticuerpos de las mismas, serían de utilidad para dilucidar aspectos de la fisiopatología de este síndrome y para la mejor comprensión de procesos neoplásicos malignos asociados

Incidencia de gammopatías monoclonales en pacientes infectados por HIV-1 / Incidence of monoclonal gammopathies in HIV-1 infected patients

Se estudió la incidencia de gammopatías monoclonales (GM) en pacientes infectados por HIV-1 y su posible asociación con neoplasias malignas. Se estudiaron 236 pacientes reactivos a la prueba de detección de anticuerpos anti-HVI-1, siguiendo con los criterios para el diagnóstico clínico y serológico propuestos por el CDC (Atlanta). Se observó GM en 24 casos (10,2%). Se clasificaron en GM de baja conc.: menor de 1 g/dl de suero (92%); de mediana conc.: entre 1-2 g/dl (0,4%) y de elevada conc.: mayor de 2 g/dl (0,4%). Los isotipos de las cadenas pesadas fueron identificados como IgG (94,5%) e IgM (5,5%). Del total de pacientes, en seis se diagnosticó Sarcoma de Kaposi y de éstos dos presentaron GM. Las GM que se describen en este trabajo deberían considerarse de significado incierto. Su hallazgo, la identificación, la purificación y el estudio de la actividad de anticuerpos de las mismas, serían de utilidad para dilucidar aspectos de la fisiopatología de este síndrome y para la mejor comprensión de procesos neoplásicos malignos asociados

Age-related monoclonal gammapathies: clinical lessons from the aging C57BL mouse.

In this article the long-held notion that benign monoclonal gammapathy (BMG) is a premalignant stage in the development of multiple myeloma (MM) is attacked. Jiri Radl argues that clinical and experimental observations indicate that they are separate entities which may be distinguished in the laboratory and which should be managed in radically different ways.

Monoclonal gammopathy and multiple myeloma in the elderly.

The term 'benign monoclonal gammopathy' indicates the presence of a monoclonal protein in persons without evidence of multiple myeloma, macroglobulinaemia, amyloidosis, lymphoproliferative disease, or other related disorders. The term 'monoclonal gammopathy of undetermined significance' (MGUS) is preferable because it is not known at diagnosis whether an M-protein will remain stable and benign or develop into symptomatic multiple myeloma or related disorders. Immunoelectrophoresis and immunofixation of the serum and urine are necessary to determine the presence and type of M-protein. At the Mayo Clinic, follow-up data have been gathered for more than 13 years on 241 patients with an initial benign monoclonal gammopathy. Nineteen per cent of these patients developed multiple myeloma, macroglobulinaemia, amyloidosis, or related diseases during the follow-up period. There is no reliable technique for differentiating a patient with a benign monoclonal gammopathy from one who will subsequently develop a serious disease. It is necessary to follow these patients indefinitely. Important in the complete understanding of the elderly patient with monoclonal gammopathy are the following: clinical manifestations, laboratory findings, and differential diagnosis of multiple myeloma; the course and prognosis and the induction therapy and treatment of multiple myeloma; newer therapeutic approaches; and the management of complications such as hypercalcaemia, hyperuricaemia, renal failure, bacterial infections, skeletal disease, and neurological problems.

Application of the immunoperoxidase technic to bone marrow trephine biopsies in the classification of patients with monoclonal gammopathies.

This study evaluated the utility of the immunoperoxidase method as applied to bone marrow sections in the diagnosis of patients with monoclonal gammopathies. Intracellular immunoglobulin light chains were identified in fixed, decalcified bone marrow biopsy sections from 66 patients with monoclonal proteins, using an avidin-biotin-peroxidase complex immunoperoxidase method. In all cases the predominant light chain identified in the bone marrow biopsy correlated with the monoclonal light chain identified in the serum. In addition, a light chain ratio was defined that correlated with the clinical diagnoses. The light chain ratios were highest in patients with multiple myeloma and were significantly different from those with monoclonal gammopathy of undetermined significance. There was no correlation between level of serum monoclonal protein and light chain ratios. The ratios were also high in patients with macroglobulinemia, primary amyloidosis, and renal disease secondary to monoclonal proteins but without overt myeloma. Determination of light chain ratios differentiated patients with multiple myeloma from those with monoclonal gammopathy of undetermined significance and helped identify patients with end organ damage secondary to monoclonal proteins but without overt myeloma.