Gammapatía monoclonal de significado incierto / Monoclonal gammopathy of uncertain significance

La gammapatía monoclonal de significado incierto es una neoplasia de células plasmáticas premaligna, con una elevada prevalencia en la población mayor de 50 años, y un riesgo anual de progresión del 1%. Numerosos estudios recientes han permitido un avance en la compresión de la patogenia de estos trastornos y su riesgo de progresión a otras enfermedades. Los pacientes requieren un seguimiento de por vida, siendo fundamental un enfoque multidisciplinar y adaptado al riesgo. En los últimos años, cada vez se reconocen más entidades asociadas a la presencia de una paraproteína, conocidas como gammapatías monoclonales de significado clínico (AU)

Monoclonal gammopathy of uncertain significance is a premalignant plasma cell neoplasm with a high prevalence in the population over 50 years of age and an annual risk of progression of 1%. Multiple recent studies have led to advances in understanding both the pathogenesis of these disorders and their risk of progression to other diseases. Patients require lifelong follow-up, and a multidisciplinary and risk-adapted approach is essential. In recent years, an increasing number of entities associated with a paraprotein, known as clinically significant monoclonal gammopathies, have been recognized (AU)

[Monoclonal gammopathy of uncertain significance]. / Gammapatía monoclonal de significado incierto.

Monoclonal gammopathy of uncertain significance is a premalignant plasma cell neoplasm with a high prevalence in the population over 50 years of age and an annual risk of progression of 1%. Multiple recent studies have led to advances in understanding both the pathogenesis of these disorders and their risk of progression to other diseases. Patients require lifelong follow-up, and a multidisciplinary and risk-adapted approach is essential. In recent years, an increasing number of entities associated with a paraprotein, known as clinically significant monoclonal gammopathies, have been recognized.

Emergence of proteinase 3-antineutrophil cytoplasmic antibody-associated glomerulonephritis with mesangial immune deposition during the clinical course of IgG λ monoclonal gammopathy of uncertain significance.

Patients with monoclonal gammopathy of uncertain significance (MGUS) is sometimes associated with renal diseases, usually due to the deposition of secreted monoclonal immunoglobulin or a fragment thereof, a condition which is defined as monoclonal gammopathy of renal significance. Patients with MGUS appear to be at increased risk for various autoimmune conditions. We report the case of a 68-year-old man developed nephritic syndrome and mild renal insufficiency during the course of IgG λ MGUS. Laboratory findings showed hypocomplementemia, cryoglobulinemia, proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA) positivity and monoclonal proteins (λ light chain and λ-Bence-Jones protein) in the urine. A kidney biopsy revealed crescentic glomerulonephritis with mesangial immune deposits without paraproteins. Treatment with prednisolone for ANCA-associated glomerulonephritis, normalized urinalysis and decreased PR3-ANCA but MGUS persisted. This is a rare case of PR3-ANCA-associated glomerulonephritis with comorbid IgG λ MGUS with various pathological paraproteins. We highlight it as a clinical example with diagnostic and therapeutic implications.

Role of FDG PET in the staging of multiple myeloma.

18F-Fluorodeoxyglucose (FDG) PET has been used for staging of hematologic malignancies for years. In multiple myeloma, this imaging modality can be used in many different scenarios, including initial staging, evaluation of treatment response, and investigation of residual disease or early relapse. FDG PET-CT has excellent diagnostic performance, similar to other advanced imaging modalities such as whole-body CT and MRI, and it is particularly helpful for the assessment of extramedullary disease. It also offers important prognostic information on survival and risk of relapse, both at baseline and after therapy. This review will cover the main applications, advantages, and limitations of FDG PET-CT in multiple myeloma and related clonal plasma cell proliferative disorders, such as smoldering multiple myeloma and plasmacytoma.

Resolution of Laryngeal Oedema in a Patient with Acquired C1-Inhibitor Deficiency. a Case Report.

INTRODUCTION: Laryngeal oedema caused by acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) is a life-threatening condition. The swelling is bradykinin mediated and will not respond to the usual treatment with antihistamines, corticosteroids, or epinephrine. Instead, kallikrein-bradykinin-targeted therapies should be used promptly to prevent asphyxiation. CASE PRESENTATION: A 43 years old female presented at the Hereditary Angioedema Centre reporting a one-year history of peripheral, facial, and neck oedema. Treatment with antihistamines and corticosteroids had been ineffective. Laboratory results showed complement level deficiencies and monoclonal gammopathy characterised as immunoglobulin M. An abdominal ultrasound revealed splenomegaly. A bone marrow biopsy was normal. Based on these data, the diagnosis of C1-INH-AAE associated with monoclonal gammopathy of uncertain significance (MGUS) was made. As C1-INH-AAE can present with life-threatening, standard treatment-resistant laryngeal oedema, an emergency care treatment plan was proposed, and the patient was advised to present to the emergency department (ED) with this medical letter. Based on these recommendations, three laryngeal attacks were successfully treated in the ED with recombinant human C1-inhibitor (two attacks) and fresh frozen plasma (one attack). After these episodes, the patient was prescribed prophylactic treatment with antifibrinolytics. No further angioedema attacks were reported by the patient at the 18 months follow-up visit. CONCLUSIONS: Because angioedema of the upper airways is a life-threatening condition, recognising the specific type of swelling by the emergency physician is critical in providing immediate and effective treatment to reduce the associated risk of asphyxiation. C1-INH-AAE being a rare disorder, patients should have available an emergency care treatment plan with recommendations of acute treatment possibilities.

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)

Monoclonal gammopathy of renal significance: Early diagnosis is key.

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.

Crystalglobulinemia manifested as acute renal failure and thrombotic vasculopathy.

Crystalglobulinemia is an extremely rare pathology that is associated in most cases with plasma cell dyscrasia, mainly multiple myeloma. In most cases, it may be the manifestation of incipient gammopathy or it manifests shortly after diagnosis. We report a patient with ischemic lesions of thrombotic origin in lower limbs. Subsequently, renal involvement occurs, in view of this involvement, it is suspected that the patient may have an associated vasculitis. After performing the biopsy and with the subsequent diagnosis of monoclonal gammopathy of uncertain significance, the diagnosis is made. We review the most recent bibliography of patients who have been diagnosed with crystalglobulinemia associated with plasma dyscrasia focusing in those with thrombotic vasculopathy or acute renal failure. In our case, in addition to being associated with monoclonal gammopathy of undetermined significance that is less frequent, the debut of the symptoms is years before the detection of the monoclonal peak. This could speak of patients with a low peak of monoclonal component (not detected by immunoelectrophoresis) who could have kidney and vascular damage.

Bone tissue quality in patients with monoclonal gammopathy of uncertain significance.

INTRODUCTION: Monoclonal gammopathy of uncertain significance (MGUS) is highly prevalent in older adults and affects bone structure, with osteoporosis and increased risk of fractures in up to 14% of affected patients. Dual-energy X-ray absorptiometry (DXA), the standard technique for diagnosing osteoporosis, is ineffective to reveal microstructure and bone quality in this disease. MATERIALS AND METHODS: We conducted a cross-sectional study of patients with MGUS, recruited consecutively from the Hematology and Internal Medicine Departments of Hospital del Mar, Barcelona, between January 2011 and January 2018. Medical records, clinical results and spinal X-ray images were collected. Bone mineral density (BMD) at hip and spine was measured by DXA and Bone Material Strength index (BMSi) by impact microindentation on the tibial mid-shaft. RESULTS: Thirty-nine patients with MGUS and 65 age-matched controls without previous fractures were included. In the MGUS group, 11 (28.2%) patients had prevalent fractures, nearly half of them vertebral (n = 5, 45.45%). Compared to controls, MGUS patients had significantly lower BMSi, a mean (SD) of 70.72 (9.70) vs. 78.29 (8.70), p = 0.001, and lower spinal BMD values (0.900 [0.159] vs. 1.003 [0.168], respectively, p = 0.012), but no significant differences at femoral neck and total hip. No association was observed between BMSi and DXA. Bone remodeling markers (procollagen type-1 N propeptide, bone-alkaline phosphatase and C-terminal telopeptide of type I collagen) did not differ between the two groups. CONCLUSIONS: Spinal BMD and mechanical properties of bone tissue, as measured by impact microindentation, were impaired in patients with MGUS. These changes in bone tissue mechanical resistance were independent of DXA levels.

A Middle-Aged Man Presenting With Progressive Heart Failure, Myopathy, and Monoclonal Gammopathy of Uncertain Significance.

A 48-year-old man presented with rapidly progressive heart failure and monoclonal gammopathy of uncertain significance. No specific cause was detected on endomyocardial biopsy. As the heart failure worsened, he also developed progressive skeletal myopathy. This provided the clue to the diagnosis, and cardiac function recovered rapidly with cause-directed therapy. (Level of Difficulty: Intermediate.).

Risk of mature B-cell neoplasms and precursor conditions after joint replacement: A report from the Haematological Malignancy Research Network.

Associations between previous joint replacement and B-cell lymphoid malignancies have been reported, but despite numerous reports, associations with the disease subtypes have received little attention. Using a UK-based register of haematological malignancies and a matched general population-based cohort, joint replacements from linked hospital inpatient records were examined. Cases diagnosed 2009-2015 who were aged 50 years or more were included; 8,013 mature B-cell neoplasms comprising myeloma (n = 1,763), diffuse large B-cell lymphoma (DLBCL, n = 1,676), chronic lymphocytic leukaemia (CLL, n = 1,594), marginal zone lymphoma (MZL, n = 957), follicular lymphoma (FL, n = 725) and classical Hodgkin lymphoma (CHL, n = 255), together with monoclonal gammopathy of uncertain significance (MGUS, n = 2,138) and monoclonal B-cell lymphocytosis (MBL, n = 632). Odds ratios (OR) and 95% confidence intervals (95%CI) were calculated relative to 10 age- and sex-matched controls using conditional logistic regression. Having had a joint replacement before diagnosis was associated with myeloma (OR = 1.3, 95% CI 1.1-1.5, p = 0.008) and MGUS (OR = 1.3, 95% CI 1.1-1.5, p < 0.001). Excluding replacements in the year before diagnosis, the MGUS risk remained, elevated where two or more joints were replaced (OR = 1.5, 95% CI 1.2-2.0, p = 0.001), with hip (OR = 1.2, 95% CI 1.0-1.5, p = 0.06) or knee replacements (OR = 1.5, 95% CI 1.2-1.8, p < 0.001). Associations with CHL and two or more replacements (OR = 2.7, 95% CI 1.3-5.6, p = 0.005) or hip replacements (OR = 1.9, 95% CI 1.0-3.4, p = 0.04); and between DLBCL and knee replacements (OR = 1.3, 95% CI 1.0-1.6, p = 0.04) were also observed. Our study reports for the first time a relationship between joint replacements and MGUS; while absolute risks of disease are low and not of major public health concern, these findings warrant further investigation.

[Monoclonal gammopathy of uncertain significance (MGUS) and occupational risk factors: criteria to carry out the health surveillance]. / Gammopatia monoclonale di incerto significato (MGUS) e fattori occupazionali di rischio: criteri di attuazione della sorveglianza sanitaria.

SUMMARY: Monoclonal gammopathy of uncertain significance (MGUS) identifies a clinically asymptomatic and laboratory-based situation characterized by a modest monoclonal component (MC). In a limited percentage of cases, on a probabilistic basis, the asymptomatic genepremalignant stage could lead to multiple myeloma (MM). Materials and Methods. Based on literature data and available Guidelines on the subject, the diagnostic criteria and a methodological path are here suggested to the Occupational Physician to formulate a judgment of suitability for the task with exposure risk to RI or pesticides. Results. Some studies have evaluated the prevalence of MGUS in subjects exposed professionally to pesticides. Numerous other studies conducted on the survivors of the atomic bombing of Hiroshima and Nagasaki have highlighted a possible association with exposure to ionizing radiation (IR). The guidelines relating to the diagnosis and management of MGUS cases (with respect to the potential evolution in MM allow) to draw important operational indications for the competent/authorized physician. Conclusions. The routinely use of laboratory tests for subjects exposed to the studied risk factors is generally indicated starting from the worker's 50 years of age. The finding of a MGUS in the absence of further laboratory alterations represents the situation most frequently and does not require further measures, other than those of foreseeing even blood controls at least every two years. In this situation, there are no justified restrictions on work activities with exposure risks to IR or pesticides. If alterations suggestive for an increased risk of evolution in a neoplastic way could be identified, a close periodicity - every 3-6 months - of haematological checks is recommended. In these cases, it appears justified an abstention from activities involving exposure to ionizing radiation for a period of time that will be evaluated based on the evolution of the framework and by the progress of laboratory tests in the monitored period.

Saposin C is a frequent target of paraproteins in Gaucher disease-associated MGUS/multiple myeloma.

Patients with Gaucher disease (GD) have an increased risk of monoclonal gammopathies for which antigenic targets might play a role in their pathogenesis. Here we report the identification of saposin C (sapC) as high-titre (1:1 000 000) target structure of 7/16 GD-associated paraproteins. Anti-sapC immunoglobulin (Ig) showed identity with the paraprotein Ig type and subclass in each patient that showed anti-sapC immunoreactivity. Absorption and depletion studies completely removed the paraprotein from the sera of GD patients. No immunoreactivity against sapC was detected in healthy donors and in other plasma cell dyscrasias, demonstrating that anti-sapC reactivity is highly restricted to GD. Several uncharacterized forms of post-translational modified sapC were detected but their role in the pathogenesis is not clear. We confirm the frequent presence of low-titre (1:250) anti-lysolipid reactivities in the sera of GD patients but we could show that this immunoreactivity is not mediated by the paraprotein and is not restricted to GD patients.

The presence of monoclonal gammopathy in Ph-negative myeloproliferative neoplasms is associated with a detrimental effect on outcomes.

Many case reports have indicated the occurrence of monoclonal gammopathy of uncertain significance (MGUS) or multiple myeloma (MM) in patients with Ph-negative myeloproliferative neoplasms (MPN), but few cohorts of patients have been published. This study concerns 667 patients newly diagnosed with polycythemia vera (PV) or essential thrombocythemia (ET) who were tested for monoclonal (M) protein at diagnosis (13.9% of patients). The overall survival of patients with M protein was dramatically lower than that of patients without M protein (12.7 versus 22.4 years; p = .0132). Univariate analysis identified the presence of M protein as a potential risk factor for the secondary occurrence of myelofibrosis (p = .02), myelodysplastic syndrome (p = .043), and MM/Waldenstrom macroglobulinemia (p < .0001). Our cohort shows that the presence of M proteins in patients with PV or ET leads to a poor prognosis. We believe that testing for M protein could help practicians to identify such patients.

Ultrasound of the nerves - An appropriate addition to nerve conduction studies to differentiate paraproteinemic neuropathies.

OBJECTIVE: To investigate the use of peripheral nerve ultrasound (PNUS) in addition to nerve conduction studies (NCS) in the diagnosis of paraproteinemic neuropathies (PN). METHODS: PNUS/NCS of predefined peripheral nerves and the 5th/6th cervical roots were performed in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) (+/-paraprotein), patients with anti-MAG neuropathy, and patients with neuropathy and multiple myeloma or monoclonal gammopathy of uncertain significance (MGUS) - summarized as M-protein associated neuropathies (MPAN) and compared to controls (+/-paraprotein). RESULTS: 39 patients and 27 age-matched controls were included. Nerve enlargement was most marked in patients with CIDP, while in anti-MAG neuropathies enlargement was significant in the legs. In MPAN, no nerve enlargement is found regularly. However, in two cases, the diagnostic steps were influenced by the finding of multiple enlarged nerves and finally immunotherapy response was successfully initiated. By the use of the ultrasound pattern sum score (UPSS), differentiation of PN can be simplified. DISCUSSION: Due to the heterogeneous findings in NCS, correct diagnosis of PN, and straightforward therapeutic decisions often may be controversial. Particularly in cases of M-protein related neuropathy, the finding of multiple nerve enlargements facilitates the decision for therapeutic approaches or nerve biopsy. The UPSS enables the distinction of different PN from each other. CONCLUSION: The use of an ultrasound quantification tool in addition to NCS facilitates a differentiation of PN.

Monoclonal gammopathy: The good, the bad and the ugly.

Monoclonal gammopathy of undetermined significance (MGUS) is a condition characterized by the presence of a monoclonal gammopathy (MG) in which the clonal mass has not reached a predefined state in which the condition is considered malignant. It is a precursor to conditions such as multiple myeloma or lymphoma at a rate of ~1%/year. Thus, from a hematologic standpoint, MGUS is a fairly benign condition. However, it is now recognized that organ damage resulting from just the MG without the need MM or lymphoma can occur. One of the most recognized is nephropathy secondary to monoclonal gammopathy of renal significance (MGRS). Other well-recognized conditions include neuropathies, oculopathies and dermopathies. Some conditions such as autoimmune diseases and coagulopathies are less common and recognized. Finally, systemic involvement of multiple organs is well described in several entities. In all of these conditions, the role of the MG is no longer insignificant. Thus, the term MGUS should be avoided when describing these entities.

Flow cytometric differentiation of abnormal and normal plasma cells in the bone marrow in patients with multiple myeloma and its precursor diseases.

Flow cytometric (FC) enumeration of abnormal plasma cells (APCs) for diagnosis and prognostication of plasma cell dyscrasias (PCD) is challenging. We studied antigen expression in normal plasma cells (NPC) (N = 34) and APC in a series of unselected PCD (N = 59). NPC subpopulations often demonstrated CD19(-), CD20(+), CD45(-) or dim and CD56(+), an immunophenotype observed in PCD. However abnormal CD81 was only observed in APCs (APC detection sensitivity 95%; specificity 100%). We evaluated differences in antigen expression patterns among MGUS (N = 14), SMM (N = 35) and MM (N = 10), finding the combination of CD45 and CD56 helpful in differentiating MGUS from SMM and MM (p = 0.0002).