Serum-free light chains in the evaluation of M-component disease.

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.

[Chinese expert consensus on the application of flow cytometry for the detectin of circulating plasma cells in plasma cell disorders (2024)].

Flow cytometry plays an important role in the diagnosis and treatment of plasma cell diseases, particularly in the detection of circulating plasma cells (CPCs) in the peripheral blood. A consensus about the normalized use of flow cytometry in detection of CPCs in peripheral blood in clinical practice has been achieved. This consensus is founded on evidence-based principles, which elucidates the timing and value of flow cytometry for the detection of CPCs in the monoclonal gammopathy of undetermined significance, smoldering myeloma, multiple myeloma, and plasma cell leukemia and standardizes flow cytometry in the detection of CPCs in plasma cell diseases.

Monoclonal gammopathy of clinical signifi cance with osteosclerotic lesions - a case report and a literature review.

INTRODUCTION: Multiple myeloma is a common plasma cell neoplasia usually accompanied by the formation of osteolytic foci, whereas osteosclerotic myeloma is a very rare form of plasma cell dyscrasia. When osteosclerotic myeloma is detected, osteosclerotic foci are usually part of the POEMS syndrome. Osteosclerotic myeloma without other manifestations of the POEMS syndrome is an unusual finding. CASE DESCRIPTION: In a 46-year-old woman, osteosclerotic changes of the temporoparietal region caused soft tissue induration over this lesion, which initiated further investigation. Imaging studies subsequently showed multiple osteosclerotic foci in the skull. Examination of blood proteins revealed 8 g/L of IgG-lambda monoclonal immunoglobulin, subclass IgG1. In search of the cause of the osteosclerotic changes, FDG-PET/CT was performed, which revealed no FDG accumulation, i.e., no other tumor (breast or stomach cancer). Low-dose CT showed irregular bone structure, but not significant osteolytic or osteosclerotic foci. To map the extent of osteosclerotic changes, NaF-PET/CT imagination followed, which revealed multiple spots with high fluoride accumulation. A parietal bone biopsy showed osteosclerosis with minor clonal plasma cell infiltration. Trepanobioptic bone marrow sampling revealed an infiltration of bone marrow with atypical plasma cells in 8%. Flow-cytometric examination of bone marrow showed 0,37% of plasma cells, however predominantly (91%) clonal with lambda expression. MRI of the brain identified asymptomatic meningeal thickening. There was no evidence of POEMS syndrome in the patient; thus, we concluded the diagnosis as monoclonal gammopathy of clinical significance with osteosclerosis which was previously termed osteosclerotic multiple myeloma. CONCLUSION: Monoclonal gammopathy of clinical significance (MGCS) with osteosclerotic skeletal changes, documented on CT and multiple foci with intensive osteoneogenesis, documented on NaF-PET/CT without evidence of POEMS syndrome, is an extremely rare form of plasma cell dyscrasia. This publication documents the unique clinical manifestations of IgG-lambda type plasma cell proliferation without signs of POEMS syndrome and the role of NaF-PET/CT imaging. Classification of this disease as MGSC with osteosclerotic manifestations is more consistent with the indolent nature of the disease with a significantly better prognosis, compared with multiple myeloma.

Elevated polyclonal IgG4 mimicking a monoclonal gammopathy in IgG4-related disease-a case-based review.

IgG4-related diseases (IgG-RDs) are a group of fibroinflammatory diseases that affect a variety of tissues, resulting in tumour-like effects and/or organ dysfunction. Monoclonal gammopathies (MGPs) are a group of disorders characterized by clonal proliferation of plasma cells or lymphoid cells resulting in the secretion of a monoclonal immunoglobulin. Cases of MGPs in IgG4-RDs coexisting with plasma cell dyscrasias and lymphoid neoplasms have been reported over the past few years. Therefore, the results of examinations of M protein in IgG4-RD patients should be interpreted with caution. Herein, we report the case of a 58-year-old male with a history of type 2 diabetes who presented with submandibular masses, anosmia, swollen lymph nodes, proteinuria, and renal impairment. Laboratory tests revealed hyperglobulinemia and elevated levels of IgG4 (124 g/L) and serum-free light chains (sFLCs). Serum protein electrophoresis (SPEP) revealed an M spike of 5.6 g/dL, and immunofixation electrophoresis (IPE) revealed biclonal IgG-κ and IgG-λ. The patient underwent bone marrow, lymph node, and kidney biopsy, which ruled out plasma cell disorders and lymphoma. He was finally diagnosed with an IgG4-RD comorbid with diabetic nephropathy. The findings in this case highlight that significant activation of B cells in IgG4-RD patients, especially those with multiorgan involvement can lead to significant hyperglobulinemia and high sFLC and IgG4 levels, which are more pronounced in the setting of renal impairment. Relatively high concentrations of polyclonal IgG4 can give rise to a focal band bridging the ß and γ fractions, which may mimic the appearance of a monoclonal band on SPEP and monoclonal gammaglobulinemia in IFE. The patient experienced considerable improvement in his symptoms after rituximab combined with glucocorticoid therapy, and a monoclonal immunoglobulin was not detected.

Paraprotein-Mediated Glomerular Diseases.

Paraproteinemias are a group of complex diseases associated with an overproduction of a monoclonal immunoglobulin that can cause a diversity of kidney disorders and end-organ damage. In this review, we focus on paraprotein-mediated glomerular diseases. Kidney biopsy plays a crucial role in diagnosing these disorders, enabling the identification of specific histological patterns. These lesions are categorized into organized (such as amyloidosis, immunotactoid glomerulopathy, fibrillary glomerulonephritis, cryoglobulinemic glomerulonephritis, and monoclonal crystalline glomerulopathies) and nonorganized deposits (such as monoclonal Ig deposition disease and proliferative glomerulonephritis with monoclonal Ig deposits) based on the characteristics of immunofluorescence findings and the ultrastructural appearance of deposits on electron microscopy. This review aims to provide an update, highlight, and discuss clinicopathological aspects such as definition, epidemiology, clinical manifestations, mechanisms of kidney injury, histological features, and diagnostic procedures.

Renal impairment in monoclonal gammopathies and multiple myeloma.

The incidence of monoclonal gammopathy (MG) increases with age. In individuals over 80 years of age, we can diagnose the presence of monoclonal immunoglobulin (MIg) in up to 10 % of cases. Not only malignant diseases such as multiple myeloma (MM), but also benign forms such as MGUS (monoclonal gammopathy of undetermined significance) can lead to renal involvement. The light chains of immunoglobulins (LC) are the most damaging to the kidneys, as they are freely filtered into the urine due to their molecular weight. Detection of MIg relies mainly on a combination of immunofixation electrophoresis of serum (IELFO) and urine and determination of free light chains (FLC) of kappa and lambda and their ratio (κ/λ) in serum. The combination of these tests will detect the presence of MIg with 99 % sensitivity. Renal damage in MG may be caused by direct deposition of MIg in the glomeruli (e.g. AL amyloidosis, LC deposition disease) or tubules (in the distal tubule as a myeloma kidney or in the proximal tubule as Fanconi syndrome or proximal tubulopathy). Typical urinary findings in these diseases are moderate or severe proteinuria or nephrotic syndrome. Acute kidney injury (AKI) can be expected especially when serum FLC is >500 mg/l. Renal biopsy is crucial to establish an accurate diagnosis and thus initiate the correct treatment. Treatment of these types of renal damage involves the same treatment regimens used in the treatment of MM, including proteasome inhibitors or daratumumab.

Paraproteinaemic keratopathy simulating a crystalline keratopathy.

BACKGROUND: Paraproteinemic keratopathy is a rare disorder characterized by the bilateral accumulation of polychromatic deposits diffusely in all corneal layers together or not with diffuse or patchy pseudo lipid deposits. We present an atypical case of paraproteinemic keratopathy which lead to an initial misdiagnosis of infectious crystalline keratopathy. CASE PRESENTATION: a 69-year-old woman with an asymptomatic keratopathy detected during a cataract intervention. Slit-lamp examination revealed several hyper refringent subepithelial foci with fern-shaped branches, resembling crystalline keratopathy, in her left eye. Anterior segment optical coherence tomography revealed exclusively subepithelial hyperreflective lesions limited to the anterior stroma. The progressive bilateralization and progression of the condition prompted us to include other entities with crystalline corneal deposits in our differential diagnosis. Hematological analysis showed a high number of free Kappa light chains. Despite the typical clinical appearance of crystalline keratopathy, the atypical evolution and test results led us to consider that monoclonal gammopathy could be the cause of this entity. CONCLUSIONS: Paraproteinemic keratopathy may present in its early stages as a unilateral subepithelial crystalline keratopathy. Thus, it must always be taken into account in the differential diagnosis of any crystalline keratopathy, particularly when there are no predisposing factors for an infectious crystalline keratopathy. Early recognition of this rare entity is important to address the associated potentially serious systemic disease.

Monoclonal gammopathy-associated peripheral neuropathies: Uncovering pearls and challenges.

Monoclonal gammopathy-related peripheral neuropathies encompass a spectrum of clinical presentations in which the monoclonal protein directly damages the tissues, including the peripheral nervous system. Given the prevalence of both peripheral neuropathy and monoclonal gammopathy in the general population, these conditions may overlap in clinical practice, posing a challenge for clinicians in determining causality. Therefore, a comprehensive understanding of primary clinical syndromes and their neurophysiological patterns is of great importance for accurate differential diagnoses and effective treatment strategies. In this article, we examine the main forms of monoclonal gammopathies that affect the peripheral nerve. We explore the clinical and electrophysiological aspects and their correlation with each syndrome's corresponding monoclonal protein type. This knowledge is essential for healthcare professionals to diagnose better and manage patients presenting with monoclonal gammopathy-related peripheral nervous system involvement.

Massive arterial and venous thrombosis from smouldering multiple myeloma: further evidence for monoclonal gammopathy of thrombotic significance.

A man in his 40s presented to the emergency department after 2 weeks of abdominal pain and bloating. Radiological investigations revealed multiple unusual sites of thrombosis, including large thrombi in his portal and mesenteric veins, and a left ventricular thrombus with resultant embolic infarcts to his spleen, kidneys, coronary arteries and brain. Standard causes of underlying thrombophilia were excluded. A serum protein electrophoresis and serum-free light chains, with subsequent bone marrow biopsy, lead to the diagnosis of smouldering multiple myeloma (sMM), albeit an unusual presentation with severe clinical sequelae. Although sMM is known to be associated with an increased risk of venous thromboembolism, it is not recognised to cause thrombosis in both venous and arterial vascular beds simultaneously. Physicians encountering patients with multiple thrombi in unusual vascular beds without clear aetiology should consider an underlying monoclonal gammopathy in their list of differentials.

[Pulmonary light chain deposition disease from a respiratory physician's perspective].

Pulmonary light chain deposition disease (PLCDD) is a rare monoclonal immunoglobulin deposition disease characterized by the deposition of specific immunoglobulin light chains in lung tissue. In its early stages, PLCDD presents with mild clinical symptoms, while pulmonary imaging shows multiple nodules and thin-walled cysts. Pathologically, there is a deposition of eosinophilic amorphous protein-like material in the tissues, which stains negative for Congo red. The exact pathological mechanism of PLCDD remains unclear, and its clinical presentation lacks specificity. Challenges associated with this condition include difficulties in diagnosis, selection and evaluation of treatment options, lack of clear monitoring criteria, and standards for prognosis assessment. Further research is needed to elucidate the pathogenesis of PLCDD, to establish standardized diagnostic and therapeutic protocols, and to evaluate treatment efficacy and prognostic factors.

Association of routine hematological parameters with the development of monoclonal gammopathies: a case-control study of 134,740 patients : Resubmitted to annals of Hematology 26 March 2024.

The diagnosis of multiple myeloma requires detection of paraproteinemia and confirmation of monoclonal bone marrow infiltration, along with signs of end-organ damage. Despite the increasing prevalence, serum paraproteinemia is not routinely measured. We examined the relationship between alterations in routine hematological parameters and the development of paraproteinemia in a case-control study. Data was retrieved from a laboratory database in the capital region of Denmark between 01/01/2012 and 31/12/2022. Patients were included if they had a test for paraproteinemia (n = 134,740) and at least one prior hematological parameter (white blood cells, hemoglobin and platelet count) with a minimum follow-up of 1 year.Between 96,999 and 103,590 patients were included in each of the three hematological groups. We found white blood cell count and the presence of paraproteinemia followed an inverse J-shaped curve, with the highest presence below 3 × 109/L and above > 9 × 109/L. The adjusted OR below and above the nadir of 4 × 109/L was 1.61 (95% CI 1.25; 2.08, p < 0.0001) and 1.03 (95% CI 1.03; 1.04, p < 0.0001). Hemoglobin levels were inversely associated the presence of paraproteinemia, with the highest association below 6 mmol/L with an OR of 1.30 (95% CI 1.28; 1.32, p < 0.0001) adjusted for age and gender. Platelet count followed a U-shaped curve with the highest association at < 100 × 109/L. The adjusted OR below and above the nadir of 250 × 109/L was 1.13 (95% CI 1.10; 1.17, p < 0.0001) and 1.10 (95% CI 1.08; 1.12, p < 0.0001) respectively. In conclusion, all three parameters showed significant association with later paraproteinemia.

Double Hit of Hydroxichloroquine and Amiodarone Induced Renal Phospholipidosis in a Patient with Monoclonal Gammopathy and Sclerodermiform Syndrome: A Case Report and Review of the Literature.

Phospholipidosis is a rare disorder which consists of an excessive intracellular accumulation of phospholipids and the appearance of zebra bodies or lamellar bodies when looking at them using electron microscopy. This disease is associated with certain genetic diseases or is secondary to drugs or toxins. Drug-induced phospholipidosis encompasses many types of pharmaceuticals, most notably chloroquine, amiodarone or ciprofloxacin. Clinically and histologically, renal involvement can be highly variable, with the diagnosis not being made until the zebra bodies are seen under an electron microscope. These findings may require genetic testing to discount Fabry disease, as its histological findings are indistinguishable. Most of the chemicals responsible are cationic amphiphilic drugs, and several mechanisms have been hypothesized for the formation of zebra bodies and their pathogenic significance. However, the relationship between drug toxicity and phospholipid accumulation, zebra bodies and organ dysfunction remains enigmatic, as do the renal consequences of drug withdrawal. We present, to our knowledge, the first case report of acute renal injury with a monoclonal gammopathy of renal significance, lesions, and sclerodermiform syndrome, with zebra bodies that were associated with the initiation of a hydroxychloroquine and amiodarone treatment, as an example of drug-induced-phospholipidosis.

Monoclonal gammopathy in the setting of Pyoderma gangrenosum.

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterized by ulcerative painful lesions with violaceous undermined borders. Up to 75% of PG cases develop in association with an underlying systemic disease. Monoclonal gammopathy is reportedly a concomitant condition with PG, with studies indicating immunoglobulin (Ig) A gammopathy as the most common. Whether gammopathy is associated with PG or is an incidental finding has been debated. We sought to investigate the association and characteristics of gammopathy in patients with PG. We retrospectively identified PG patients at our institution from 2010 to 2022 who were screened for plasma cell dyscrasia. Of 106 patients identified, 29 (27%) had a gammopathy; subtypes included IgA (41%), IgG (28%), and biclonal (IgA and IgG) (14%). Mean age was similar between those with and without gammopathy (60.7 vs. 55.9 years; P = .26). In addition, hematologic or solid organ cancer developed in significantly more patients with vs. without gammopathy (8/29 [28%] vs. 5/77 [6%]; P = .003). Among the subtypes of gammopathy, IgG monoclonal gammopathy had the highest proportion of patients with subsequent cancer development (4 of 8 patients, 50%). Study limitations include a retrospective, single-institution design with a limited number of patients. Overall, our data show a high prevalence of gammopathy in patients with PG; those patients additionally had an increased incidence of cancer, especially hematologic cancer.

Paraproteinemic neuropathies.

The diagnostic evaluation of a peripheral neuropathy includes testing for the presence of monoclonal gammopathy, which can be found in about 10% of patients with peripheral neuropathy. Our role, as physicians, is to determine whether the neuropathy is directly related to the gammopathy or whether the co-occurrence of these two disorders is purely coincidental. The evaluating physician needs to be familiar with the different types of neuropathies associated with monoclonal gammopathies, their clinical and electrodiagnostic characteristics, and their appropriate diagnostic evaluation and management. Testing for monoclonal protein disorders includes serum protein electrophoresis (SPEP) and immunofixation of blood, and in some cases of urine, as well as measurement of free light chains and quantitative immunoglobulins. Specific antibody testing is directed by paraprotein type and neuropathy phenotype. Patients with abnormal free light chains in association with sensory and autonomic neuropathy should be evaluated for AL amyloidosis. When a lambda monoclonal protein is identified together with a clinical phenotype of chronic inflammatory demyelinating neuropathy (CIDP), a diagnosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS) syndrome should be considered. Patients with IgM paraprotein associated neuropathy should be assessed for distal acquired demyelinating sensorimotor (DADS) neuropathy, with or without anti myelin associated glycoprotein (MAG) antibody or CANOMAD syndrome. In many cases, a monoclonal gammopathy of uncertain significance (MGUS) is incidental and unrelated to the neuropathy. Collaboration with oncology is critical in evaluating patients with monoclonal proteins to assess for underlying plasma cell neoplasms or B cell lymphomas.

Monoclonal immunoglobulin crystalline nephropathies.

Monoclonal Ig crystalline nephropathies are rare lesions resulting from precipitation of monoclonal Igs in the kidney as crystalline inclusions. They can be categorized into lesions with predominant intracellular crystals (light chain [LC] proximal tubulopathy, LC crystal-storing histiocytosis, and LC crystalline podocytopathy) and lesions with predominant extracellular crystals (crystalglobulin-induced nephropathy and crystalline variant of LC cast nephropathy). The majority of these lesions are associated with low tumor burden lymphoproliferative disorders, with the exception of crystalline variant of LC cast nephropathy. Extrarenal involvement (e.g., skin and cornea) is frequent. Kidney biopsy is the cornerstone for diagnosis, which often requires electron microscopy and antigen retrieval. A thorough hematologic workup and evaluation of extrarenal involvement is mandatory for management. Treatment of these lesions is with clone-directed therapy, with the goal of achieving hematologic very good partial response or complete response, which preserves or improves kidney function. In vitro and in vivo studies, animal models, and novel sequencing techniques have been invaluable tools to understand the pathogenesis of LC proximal tubulopathy and can be used to increase our limited knowledge of the pathogenesis of the other monoclonal Ig crystalline nephropathies. This review provides an update on the pathology, renal and hematologic characteristics, extrarenal manifestations, prognosis, treatment, and pathogenesis of monoclonal Ig crystalline nephropathies.