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/).

Monoclonal gammopathy of renal significance: Early diagnosis is key / Gammapatía monoclonal de significado renal: la clave es el diagnóstico precoz

Monoclonal gammopathy of renal significance is a clinical–pathological entity grouping renal disorders secondary to the secretion of a monoclonal immunoglobulin synthesized by a B-cell-derived clone and/or plasma cells in a patient with no diagnostic criteria for multiple myeloma. This term applies to a concept recently introduced owing to the need to differentiate this entity from monoclonal gammopathy of undetermined significance, given the negative prognostic impact of its high morbidity and mortality resulting from both renal and systemic involvement, occasionally even progressing to advanced chronic kidney disease. The renal damage occurs via both direct pathogenic mechanisms, with the deposition of the monoclonal protein in different renal structures, as well as indirect mechanisms, acting as an autoantibody provoking dysregulation of the alternative complement pathway. The detection of this monoclonal protein and an early hematologic study are essential, as is the need for a kidney biopsy to establish the associated nephropathological diagnosis. Consequently, this then leads to the start of specific hematologic treatment to detain the production of the monoclonal protein and minimize renal and systemic injury. (AU)

La gammapatía monoclonal de significado renal es una entidad clínico-patológica que agrupa los trastornos renales secundarios a la secreción de una inmunoglobulina monoclonal sintetizada por un clon derivado de células B y/o células plasmáticas en un paciente sin criterios de diagnóstico de mieloma múltiple. Este término se aplica a un concepto introducido recientemente debido a la necesidad de diferenciar esta entidad de la gammapatía monoclonal de significado incierto, teniendo en cuenta el impacto pronóstico negativo de su alta morbilidad y mortalidad a causa de la afectación tanto renal como sistémica, llegando en ocasiones a progresar a una enfermedad renal crónica avanzada. El daño renal se produce tanto por mecanismos patogénicos directos, con el depósito de la proteína monoclonal en diferentes estructuras renales, como por mecanismos indirectos, actuando como un autoanticuerpo que provoca la desregulación de la vía alternativa del complemento. La detección de esta proteína monoclonal y un estudio hematológico precoz son imprescindibles, así como la necesidad de una biopsia renal para establecer el diagnóstico nefropatológico asociado. En consecuencia, esto lleva al inicio de un tratamiento hematológico específico para detener la síntesis de la proteína monoclonal y minimizar la lesión renal y sistémica. (AU)

¿Cuál es su diagnóstico? / What is your diagnosis?

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Monoclonal Gammopathy of Renal Significance and its Associated Experimental Models.

Monoclonal gammopathy of renal significance (MGRS) is a state of circulating monoclonal immunoglobulin (Ig) and light chains that cause kidney injury without definite evidence of multiple myeloma (MM). Although chemotherapy is used to treat many variants of MGRS and has been recently recommended, relatively limited clinical validation studies are available. A few transgenic models of MM reveal renal deposition of monoclonal Ig and light chains. We have demonstrated that the XBP1s-transgenic mouse model from early plasma cell dyscrasia to MM reveals monoclonal IgG/kappa deposition at the subendothelial spaces of the glomeruli, mimicking proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Inhibition of a key immune-modulator, gp96/grp94, genetically or pharmacologically results in a significant reduction of plasma cells within the bone marrow and reduced renal deposition of monoclonal IgG and kappa light chain. This article will review the emerging role of in vitro and animal models from plasma cell dyscrasia to MM in understanding the renal deposition of monoclonal Ig and light chains, along with its potential treatment strategies.

Classification of Plasma Cell Disorders by 21 Tesla Fourier Transform Ion Cyclotron Resonance Top-Down and Middle-Down MS/MS Analysis of Monoclonal Immunoglobulin Light Chains in Human Serum.

The current five-year survival rate for systemic AL amyloidosis or multiple myeloma is ∼51%, indicating the urgent need for better diagnosis methods and treatment plans. Here, we describe highly specific and sensitive top-down and middle-down MS/MS methods owning the advantages of fast sample preparation, ultrahigh mass accuracy, and extensive residue cleavages with 21 telsa FT-ICR MS/MS. Unlike genomic testing, which requires bone marrow aspiration and may fail to identify all monoclonal immunoglobulins produced by the body, the present method requires only a blood draw. In addition, circulating monoclonal immunoglobulins spanning the entire population are analyzed and reflect the selection of germline sequence by B cells. The monoclonal immunoglobulin light chain FR2-CDR2-FR3 was sequenced by database-aided de novo MS/MS and 100% matched the gene sequencing result, except for two amino acids with isomeric counterparts, enabling accurate germline sequence classification. The monoclonal immunoglobulin heavy chains were also classified into specific germline sequences based on the present method. This work represents the first application of top/middle-down MS/MS sequencing of endogenous human monoclonal immunoglobulins with polyclonal immunoglobulins background.

κ Light-chain monoclonal gammopathy and cast nephropathy in a horse with multiple myeloma.

CASE DESCRIPTION A 27-year-old Dutch Warmblood mare was evaluated because of a history of lethargy, reluctance to move, weight loss, persistent hyperproteinemia, and recurrent episodes of mild lameness. CLINICAL FINDINGS Hematologic evaluation revealed anemia (RBC concentration, 3.84 × 106 cells/µL), thrombocytopenia (47 × 103 thrombocytes/µL), and hyperproteinemia (total protein concentration, 11.2 g/dL) with hyperglobulinemia and hypoalbuminemia. Results of protein electrophoresis of serum and urine samples indicated a monoclonal gammopathy; the paraprotein was identified as a κ light chain. On abdominal ultrasonographic examination, hypoechoic nodules were visualized in the spleen. Results of cytologic examination of a splenic fine-needle aspirate and histologic examination of a bone marrow biopsy sample were consistent with plasma cell myeloma. TREATMENT AND OUTCOME Treatment was declined owing to the age of the horse and poor prognosis. The horse was discharged from the hospital, and the owner was given palliative care instructions. The horse was euthanized 2 weeks later because of recurrent episodes of lethargy, anorexia, and signs of colic. Necropsy confirmed the diagnosis of multiple (plasma cell) myeloma. Plasma cell aggregates in the liver, spleen, bone marrow, and kidney and the presence of cast nephropathy were identified on histologic examination. CLINICAL RELEVANCE Multiple myeloma is rarely reported in horses. A monoclonal peak on serum protein electrophoresis should raise the suspicion of neoplasia, specifically multiple myeloma. The findings for this patient confirmed the importance of considering neoplasia in horses with nonspecific clinical signs.

[Classification and therapeutic management of monoclonal gammopathies of renal significance]. / Classification et prise en charge thérapeutique des gammapathies monoclonales de signification rénale.

Two categories of renal disorders associated with monoclonal gammopathies are to be distinguished, according to the characteristics of the underlying B-cell clone. The first group of renal diseases always occurs in the setting of high tumor mass with production of large amounts of monoclonal immunoglobulins. The main complication is the so-called myeloma cast nephropathy, which almost invariably complicates high tumor mass myeloma. The second group includes all renal disorders caused by a monoclonal immunoglobulin secreted by a nonmalignant B-cell clone, and currently referred as a "monoclonal gammopathy of renal significance (MGRS)". This term was introduced to distinguish monoclonal gammopathies that are responsible for the development of kidney damage from those that are truly benign. The spectrum of renal diseases in MGRS is wide and its classification relies on the localization of renal lesions, either glomerular or tubular, and on the pattern of ultrastructural organization of immunoglobulin deposits. Physicochemical characteristics of the pathogenic monoclonal immunoglobulin are probably involved in their propensity to deposit or precipitate in the kidney, as illustrated by the high rate of recurrence of each specific type after kidney transplantation. Early diagnosis and efficient chemotherapy targeting the causal B-cell clone are mandatory to improve renal prognosis and patient survival.

The 2016 revision of the World Health Organization classification of lymphoid neoplasms.

A revision of the nearly 8-year-old World Health Organization classification of the lymphoid neoplasms and the accompanying monograph is being published. It reflects a consensus among hematopathologists, geneticists, and clinicians regarding both updates to current entities as well as the addition of a limited number of new provisional entities. The revision clarifies the diagnosis and management of lesions at the very early stages of lymphomagenesis, refines the diagnostic criteria for some entities, details the expanding genetic/molecular landscape of numerous lymphoid neoplasms and their clinical correlates, and refers to investigations leading to more targeted therapeutic strategies. The major changes are reviewed with an emphasis on the most important advances in our understanding that impact our diagnostic approach, clinical expectations, and therapeutic strategies for the lymphoid neoplasms.

[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.

Uveal effusion associated with an IgM lambda subtype monoclonal gammopathy.

CASE REPORT: A 68-year-old man was referred to the hospital with progressive decreased vision in the right eye over the past year. A moderate cataract and annular choroidal thickening were found. The diagnosis of uveal effusion was confirmed by ultrasound and fluorescein and indocyanine green angiography. Laboratory studies showed an IgM lambda subtype monoclonal gammopathy of undetermined significance. The patient underwent cataract surgery, and a sub-Tenon's triamcinolone injection with a satisfactory short-term outcome. CONCLUSION: This association has not been previously reported, and it shows that IgM lambda subtype monoclonal gammopathy of undetermined significance should be added to the list of disorders associated with uveal effusion.

Smoldering multiple myeloma requiring treatment: time for a new definition?

Smoldering multiple myeloma (SMM) bridges the gap between monoclonal gammopathy of undetermined significance (a mostly premalignant disorder) and active multiple myeloma (MM). Until recently, no interventional study in patients with SMM showed improved overall survival (OS) with therapy as compared with observation. A report from the PETHEMA-GEM (Programa Español de Tratamientos en Hematologica) group described both fewer myeloma-related events and better OS among patients with high-risk SMM who were treated with lenalidomide and dexamethasone. This unique study prompted us to review current knowledge about SMM and address the following questions: (1) Are there patients currently defined as SMM who should be treated routinely? (2) Should the definitions of SMM and MM be reconsidered? (3) Has the time come when not treating is more dangerous than treating? (4) Could unintended medical harm result from overzealous intervention? Our conclusion is that those patients with the highest-risk SMM (extreme bone marrow plasmacytosis, extremely abnormal serum immunoglobulin free light chain ratio, and multiple bone lesions detected only by modern imaging) should be reclassified as active MM so that they can receive MM-appropriate therapy and the paradigm of careful observation for patients with SMM can be preserved.

Systemic immunoglobulin G4 (IgG4) disease and idiopathic orbital inflammation; removing 'idiopathic' from the nomenclature?

The discovery of systemic disease related to raised tissue and serum immunoglobulin G4 (IgG4) is changing diagnostic and therapeutic practice in many medical specialties. Orbital inflammation remains a diverse and heterogeneous group of disorders that can pose a diagnostic and therapeutic challenge, but with improved understanding and corresponding diagnostic advances the previously expansive group of idiopathies is reducing. The recent discovery that IgG4 has a causative role in a subtype of, what is currently termed, idiopathic orbital inflammation is encouraging. The term 'idiopathic' can now be removed from the nomenclature for another subtype of orbital inflammation. IgG4 disease should be especially considered in patients with a bilateral dacryoadenitis and systemic features (eg, lung and gastrointestinal involvement). However, reports are emerging suggesting that IgG4 may be responsible for more diverse disease subtypes. The relationship between IgG4-related disease and lymphoma remains unknown but vigilance is required.

[Nosology and management of monoclonal gammapathy]. / Nosologie et prise en charge des gammapathies monoclonales.

Monoclonal gammapathy (MG) affects about 1% of the general population, and its prevalence is higher in elderly subjects. Monoclonal gammapathy of undetermined significance (MGUS), the most common disorder, is asymptomatic and associated with normal hemoglobin, calcium and creatinine levels and a monoclonal component of less than 15 g/l. A B cell neoplasm should be suspected in patients with clinical manifestations and/or abnormal hemoglobin, calcium or creatinine levels, and/or a monoclonal component >15 g/l. Multiple myeloma tends to be associated with IgG or IgA MG, and Waldenstrom's macroglobulinemia with IgM MG Patients with MGUS do not need treatment but only yearly follow-up (symptoms, protein electrophoresis, hemoglobin, calcium and creatinine assay), as the estimated annual risk of malignant transformation is about 1 %. Factors predictive of malignant transformation include the type of serum monoclonal protein, the monoclonal protein concentration, bone marrow plasmocytosis, and the serum free light chain ratio.

Inflammatory demyelinating neuropathies and neuropathies associated with monoclonal gammopathies: treatment update.

This review focuses on recent data regarding inflammatory demyelinating neuropathies and neuropathies associated with monoclonal gammopathies. We describe both acute and chronic inflammatory neuropathies, and we discuss conditions ranging from mostly cell-mediated to antibody-mediated disorders. These diseases are characterized by proximal and distal sensory motor involvement. Treatments are based on immune-modulation and/or immune-suppression. Work-up sequence and therapeutical modes are discussed in the light of recently published data, with a special interest on new treatment modalities.

Multiple myeloma and immunosecretory disorders: an update.

The immunosecretory disorders are a diverse group of diseases associated with proliferation of an abnormal clone of immunoglobulin (Ig)-synthesizing, terminally differentiated B cells. These disorders include multiple myeloma (MM) and its variants, plasmacytoma, Waldenstrom macroglobulinemia, monoclonal gammopathy of undetermined significance, and monoclonal Ig deposition diseases, the latter including primary amyloidosis and nonamyloidotic types. These disorders are histologically composed of plasma cells, or plasmacytoid cells which produce Ig that is synthesized and usually secreted and can be deposited in some diseases. The Ig can be complete or can be composed of either heavy or light chains and is termed M-(monoclonal) protein. In MM, this proliferation overwhelms the normal cellular counterparts that synthesize and secrete appropriate levels of Ig. Immunosecretory disorders have been classified in multiple schemes, mostly morphologic, to such a degree that the classification of these entities has become a challenge to pathologists. The World Health Organization classification in 2001 was helpful because it provided specific clinicopathologic criteria for diagnosis. However, terms such as "progressive" disease were not well defined. In 2003, the International Myeloma Group defined MM as a disease with related organ and tissue injury, serving to better explain progressive in terms of deterioration of organ (renal, bone, and bone marrow) function over time. Therefore, modern classification of immunosecretory diseases is based on integration of clinical, morphologic, laboratory, radiographic, and biologic (including molecular) parameters, which we review here.

The Schnitzler syndrome: chronic urticaria and monoclonal gammopathy--an autoinflammatory syndrome?

Schnitzler syndrome describes the simultaneous occurrence of monoclonal gammopathy and chronic urticaria with at least two additional minor symptoms (arthralgia, bone pain, fever of uncertain origin, hepato- or splenomegaly, lymphadenopathy, increased erythrocyte sedimentation rate, leukocytosis/thrombocytosis or increased bone density). Schnitzler syndrome is not wellknown and very likely under-recognized. Comprehensive diagnostic examinations are necessary to rule out other diseases, especially those of hematologic origin. Close interdisciplinary collaboration is mandatory. The etiology of Schnitzler syndrome is unclear, but the rapid response to the interleukin-1 receptor inhibitor anakinra underlines the pivotal role which the proinflammatory cytokine interleukin-1 may play in the pathophysiology of this potentially autoinflammatory disorder.