Search Results (27)

Introduction: Immunoglobulin M (IgM) paraproteins may interfere with enzymatic creatinine assays, potentially affecting renal function assessment. Reflex IgM testing has been proposed to detect such interference, but its impact on laboratory workflow remains insufficiently characterized. Material and Methods: This retrospective observational study combined two complementary datasets: (1) a clinical cohort of patients evaluated for suspected IgM-related interference over a 7-month period, and (2) a two-month and half representative operational analysis assessing testing volume and turnaround time (TAT) in a high-throughput clinical laboratory. An automated LIS rule triggered IgM testing when creatinine was ≥177 μmol/L. Samples with IgM ≥ 2.5 g/L underwent polyethylene glycol (PEG) precipitation to evaluate potential interference. Test volume and TAT were compared between creatinine-only and reflex workflows. Results: During the 2.5-month operational analysis, 102,849 creatinine measurements were performed, of which 7740 (7.5%) triggered reflex IgM testing, generating 11,091 IgM determinations, 56.5% of which were reflex-driven. During the full seven-month clinical observation period, clinically relevant IgM-related interference was confirmed in 8 patients. Reflex workflows were associated with increased TAT compared with creatinine-only testing. Conclusions: Universal reflex IgM testing improves detection of rare analytical interference but generates substantial workload and increases TAT. During the 2.5-month operational analysis period, only 2 of 7740 reflex-triggered samples (0.026%) resulted in confirmed clinically relevant interference. A selective, risk-based strategy may therefore represent a more efficient and sustainable approach to routine laboratory practice. Full article

There is a growing recognition of bidirectional relationships between immune phenomena in plasma cell disorders, such as multiple myeloma and its precursor malignancies, including autoimmune phenomena that either precede or complicate the development of neoplasms. The development of specific autoimmune disorders is a well-known aspect of B-cell lymphoproliferative diseases. At the same time, the development of plasma cell dyscrasia in patients with autoimmune diseases is well established. This may suggest that some subclones of multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance, originate in the setting of persistent autoimmune activation. Interestingly, monoclonal immunoglobulins, which are key biomarkers for characterizing and monitoring monoclonal gammopathies, have long been overlooked in clinical research because they are thought to have no significant antibody function. It is plausible that unusual clinical consequences may occur when monoclonal myeloma paraproteins bind to endogenous self-antigens. Published clinical data illustrate this possibility well. This review synthesizes published evidence demonstrating that many patients with multiple myeloma and related plasma cell dyscrasias exhibit specific clinical manifestations of antigen–antibody interactions between a monoclonal immunoglobulin produced by proliferating B-cell or plasma-cell clones and autologous antigens, including neural antigens, insulin, complement components, and others. We present pilot data showing antinuclear antibody reactivity in 38% of IgM monoclonal gammopathy sera. Numerous experimental and clinical data support the importance of identifying the target of the monoclonal immunoglobulins in monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and multiple myeloma. This approach not only aids in selecting an appropriate treatment strategy and predicting prognosis but may also guide the development of targeted therapies for managing monoclonal gammopathy cases that present with a paraprotein reactive against a known self-antigen. We propose the term monoclonal autoimmune gammopathies (MAGa) to describe this clinically distinct subset of plasma cell disorders characterized by pathogenic autoantibody activity of the monoclonal immunoglobulin. Full article

Background/Objectives: Kidney injury is a frequent complication of multiple myeloma (MM) and monoclonal gammopathies. Podocyte stress markers, such as urinary nephrin and podocin, have been studied in other renal diseases but their utility in paraprotein-related kidney disease remains unclear. This pilot study investigated the association of urinary nephrin and podocin levels with albuminuria and biopsy-proven podocytopathy in patients with paraprotein-related diseases. Methods: We retrospectively analyzed 75 patients with plasma cell dyscrasias, including MM and MGRS, along with 11 healthy controls. Urinary podocin and nephrin mRNA levels were measured using qPCR, and urinary podocin protein levels were quantified via ELISA. Associations were assessed between these biomarkers and urinary protein-to-creatinine ratio (uPCR), albumin-to-creatinine ratio (uACR), and histologically confirmed podocytopathia. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis. Results: Higher urinary podocin protein levels were significantly associated with lower uACR (p = 0.007) and uPCR (p = 0.026). Neither podocin nor nephrin mRNA showed significant associations with proteinuria metrics. ROC analysis indicated that podocin ELISA (AUC = 0.350) and podocin mRNA (AUC = 0.510) lacked diagnostic accuracy for predicting renal involvement. The presence of urinary tract infection (UTI) was a significant confounder, leading to increased levels of podocin and nephrin mRNA. Conclusions: Urinary podocin shows a trend toward elevation in MM/MGRS patients with histological podocyte injury. The study revealed an unexpected inverse association between urinary podocin and albuminuria, suggesting complex release kinetics or stage mismatches in this population. Given the confounding effect of UTIs, and the pilot nature of this study, further research is required to validate these podocyte proteins as biomarkers in paraprotein-related kidney disease. Full article

Light-chain (AL) amyloidosis is a rare and incurable disease, classified under the category of plasma cell neoplasms and other diseases with paraproteins in the 5th Edition of the World Health Organization classification of lymphoid tumors. This entity shares some similarities with multiple myeloma (MM), remarkably a bone marrow infiltration of clonal plasma cells. Moreover, one out of five newly diagnosed cases of AL amyloidosis (NDAL) also fulfills the current diagnostic criteria for MM. A multidisciplinary therapy approach should be established, in which hematological therapy plays a crucial role. Anti-clonal therapy is the basis of hematological therapy, in addition to supportive therapy and emerging anti-fibrils therapy. In recent years, advances in the anti-clonal therapy for MM have progressively transferred to carefully selected patients with systemic AL amyloidosis, significantly improving outcomes in this rapidly changing field. This review aims to critically analyze the comparative evolution and evidence-based approach of anti-clonal therapy in NDAL vs. MM since the introduction of bortezomib. Participation in clinical trials remains the first option to consider in daily clinical practice. Full article

Background: Hypercalcemia is a common and serious complication of malignancy, often contributing to morbidity and mortality. In patients with paraproteinemia, elevated total calcium with normal ionized calcium, termed pseudohypercalcemia, can complicate diagnosis and lead to inappropriate treatment. While this phenomenon has been described in case reports, its prevalence and clinical impact in routine practice remain poorly defined. Methods: We report a case of pseudohypercalcemia in a patient with IgG κ multiple myeloma and conducted a retrospective review of de-identified data to assess the prevalence and biochemical associations of pseudohypercalcemia in paraproteinemia. Available data included serum protein electrophoresis (SPEP), total calcium, albumin, total protein, creatinine, and parathyroid hormone (PTH). Associations between calcium status, paraprotein levels, and the gamma globulin gap were examined. Results: The index case demonstrated pseudohypercalcemia, with elevated total calcium (13.5 mg/dL) but normal ionized calcium (1.22 mmol/L), in the setting of IgG κ paraproteinemia (4.4 g/dL). In the retrospective cohort of 2537 samples, 986 (39%) had a single monoclonal paraprotein. Gamma globulin gap showed a moderate correlation with paraprotein concentration for IgG (r = 0.56, p < 0.0001) and IgA (r = 0.44, p < 0.0001), but a weaker relationship for IgM (r = 0.49, p < 0.0001). In contrast, total calcium showed no significant correlation with paraprotein concentration in the overall cohort. Among samples with elevated calcium (>10.5 mg/dL), the association between calcium and IgG paraprotein levels remained weak (r = 0.34, p = 0.23), and was similar for IgG κ (r = 0.61, p = 0.12) and IgG λ (r = 0.09, p = 0.87). Hypercalcemia was uncommon, occurring in only ~2% of IgG-positive samples, and rarely at paraprotein levels ≥ 1.5 g/dL. Conclusions: Pseudohypercalcemia in paraproteinemia is uncommon but clinically important, as total calcium may be artifactually elevated due to paraprotein-related assay interference, either from assay precipitation effects or calcium binding by paraproteins. Paraprotein burden correlates with gamma globulin gap but not with true calcium status. Reliance on total calcium alone may lead to diagnostic misclassification; ionized calcium should be measured in patients with monoclonal gammopathies to distinguish true hypercalcemia from analytical interference and avoid unnecessary treatment. Full article

The cause of nephrotic–nephritic syndrome and elevated blood pressure values was investigated by renal biopsy in a 72-year-old Caucasian male with B-cell chronic lymphocytic leukemia (B-CLL) and a low level of IgG/lambda paraprotein. Double-contoured glomerular capillaries, glomerular thrombi, interstitial B-CLL infiltrates, and normal-looking arteries and arterioles were observed histologically. The glomerular capillaries displayed nonspecific entrapment of IgM and C3 and pseudolinear C4d positivity immunohistochemically. With electron microscopy, diffusely effaced foot processes, widened and duplicated glomerular basement membrane (BM), mesangial cell interposition, and thickened, non-fenestrated, and serrated endothelial cells located on subendothelial BM layer(s) were seen. The peritubular capillaries lacked any significant BM multilayering. Chronic glomerular thrombotic microangiopathy (TMA) was diagnosed; the C4d positivity result indicated structural remodeling of glomerular capillary walls. Laboratory features of microangiopathic hemolytic anemia were absent. The functional complement assay found selective classical pathway activation and the consumption of early complement components. The components of the alternative pathway were not consumed. A disease-causing variant in the coding region of the complement C2 gene was screened, with negative results. The kidney function gradually deteriorated to stage 4 chronic kidney disease over a period of six months. Second-line treatment with ibrutinib markedly decreased the leukemic symptoms, stopped the production of paraprotein, and eliminated the nephrotic syndrome; the kidney function improved. The decreased activity of the classical pathway remained unchanged. The culprit of glomerular anomalies seemed to be the paraprotein, which acted as a nephrotoxic mediator and triggered glomerular TMA. A hypothetical pathophysiologic explanation of TMA is presented. The paraneoplastic classical pathway activation of complement did not play any role in the development of glomerular TMA. Full article

Systemic light-chain (AL) amyloidosis is a challenging, complex and heterogeneous disease. AL amyloidosis is classified under the category of plasma cell neoplasms and other diseases with paraproteins in the fifth edition of the World Health Organization classification of lymphoid tumors. Epidemiological information is limited, largely due to its low incidence and the lack of a global network of population-based specific registries. Despite recent advances, AL amyloidosis is still considered an incurable disease. The presence of a precursor disease, particularly monoclonal gammopathy of uncertain significance, is the main consolidated risk factor. Limited knowledge about other risk factors precludes the possibility of establishing preventive measures. A relevant percentage of AL amyloidosis patients fulfill the current diagnostic criteria of multiple myeloma. Incidence should be evaluated in the setting of population-based studies. On the one hand, incidence shows a slightly increasing pattern. On the other hand, survival is progressively increasing. Consequently, prevalence is also rising. Early mortality, commonly associated with advanced heart involvement, remains a serious drawback to improve the outcome. Epidemiology represents the first level of heterogeneity in AL amyloidosis. Both genomic and clinical epidemiological research in systemic AL amyloidosis have a crucial role in the global strategy to combat this multifaceted disease. Full article

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for relapsed or refractory multiple myeloma (RRMM), with high response rates of 80–95%. Serum immunoglobulin changes have been observed throughout conventional multiple myeloma treatment, including after immunomodulatory drugs, proteasome inhibitors, and autologous stem cell transplantation. However, the clinical significance of new abnormal protein bands (APBs) following CAR T-cell therapy is largely unexplored. We retrospectively analyzed consecutive multiple myeloma (MM) patients who received CAR T-cell therapy at the University Hospital Bern between May 2021 and February 2024. Serum paraprotein (M-protein) patterns were assessed using immuno-fixation electrophoresis (IFE) before and after CAR T-cell treatment. Patients were grouped based on serum immunoglobulin changes. Among 46 patients, 9 (19.6%) developed new APBs following CAR T-cell therapy. No significant differences in overall survival (OS) or progression-free survival (PFS) were observed between patients with and without APBs. Immunoglobulin changes occurred in both relapsed and non-relapsed patients, suggesting that the appearance of new APBs does not indicate disease progression. This observation aligns with previous reports of paraprotein changes following conventional MM therapies. This report suggests that new APBs following CAR T-cell therapy are a relatively common finding but do not correlate with inferior clinical outcomes. Our results highlight the need for larger, multi-center studies to further investigate this phenomenon in MM patients undergoing CAR T-cell therapy. Full article

Waldenström Macroglobulinemia (WM) is a rare, indolent B-cell lymphoproliferative disorder characterized by the production of monoclonal IgM paraprotein and infiltration of the bone marrow by lymphoplasmacytic cells. While WM generally exhibits a slow clinical course, it has the potential to progress into more aggressive hematologic malignancies, such as diffuse large B-cell lymphoma. The TP53 gene, often referred to as the “guardian of the genome”, plays a pivotal role in maintaining genomic stability, regulating the cell cycle, and orchestrating apoptosis. Mutations in TP53 undermine these essential processes, resulting in dysregulated cellular proliferation, defective apoptotic mechanisms, and genomic instability—hallmarks of cancer development. Although TP53 mutations have been extensively investigated in several hematologic malignancies, including acute myeloid leukemia, myelodysplastic syndromes, and chronic lymphocytic leukemia, their role in WM remains underexplored. Emerging evidence suggests that TP53 mutations may have a significant impact on the disease progression and therapeutic response in WM. This review examines the current knowledge of TP53 mutations in WM, highlighting their implications for prognosis and therapeutic strategies. A deeper understanding of the role of TP53 in WM could provide critical insights for improving disease management and advancing the development of targeted therapies. Full article

Background/Objectives: Cryofibrinogenemia, characterized by plasma cryoprecipitation of fibrinogen and related proteins, is a rare and often under-recognized entity that can present with significant renal involvement. Methods: we describe a 66-year-old woman with progressive renal failure due to membranoproliferative glomerulonephritis driven by cryofibrinogen deposits. Her clinical course was marked by relapsing–remitting disease with limited response to high-dose corticosteroids but significant improvement following plasma exchange. Over seven years, she underwent three kidney biopsies, revealing progressive histopathological changes, including glomerular cryofibrinogen deposits and evolving chronicity. A detailed review of the literature identified 50 cases of cryofibrinogenemia, highlighting its association with monoclonal gammopathies, malignancies, and autoimmune diseases. Results: our case uniquely underscores the pathogenic interplay between cryofibrinogenemia and a monoclonal IgG-kappa paraprotein, which was found to directly stabilize fibrinogen and drive cryoprecipitation. This novel observation aligns cryofibrinogenemia with monoclonal gammopathy of renal significance, expanding the diagnostic and therapeutic landscape for this entity. Conclusions: this report also highlights the pivotal role of kidney biopsy with electron microscopy in diagnosing cryofibrinogen-associated renal disease, particularly when conventional biomarkers are insufficient. Moreover, our findings emphasize the therapeutic utility of plasmapheresis and the potential need for therapies aimed at eliminating the pathogenetic monoclonal antibody in managing refractory cases. Enhanced awareness and further research into this rare entity are essential for advancing patient care and outcomes. Full article

Monoclonal gammopathy of renal significance (MGRS) refers to a group of renal disorders caused by a monoclonal immunoglobulin (MIg), secreted by a non-malignant B-cell clone. Unlike overt multiple myeloma or B-cell proliferation, MGRS does not meet those diagnostic criteria. However, it is associated with significant morbidity, due to severe renal, and sometimes systemic, lesions induced by the MIg. Early recognition is crucial, as chemotherapy to suppress MIg secretion often improves outcomes. The spectrum of renal diseases in MGRS is broad, including both well-known conditions like AL amyloidosis and newly described lesions. Kidney biopsy is essential to determine the specific lesion associated with MGRS and assess its severity. Diagnosis involves integrating morphologic alterations using techniques such as light microscopy, immunofluorescence (IF), electron microscopy, and, in some cases, IF staining for Ig isotypes, immunoelectron microscopy, and proteomic analysis. Additionally, a complete hematologic evaluation, including serum and urine protein electrophoresis, immunofixation, and a serum-free light-chain assay, is necessary. Full article

Background: Despite extensive research on proteinuria’s impact on chronic kidney disease progression, there is no direct comparison of outcomes in biopsy-diagnosed glomerular disease (GD) patients with nephrotic syndrome (NS) or nephrotic range proteinuria (NRP). Our study addresses this gap, comparing long-term outcomes between NS and NRP. Methods: We conducted a retrospective study on 240 kidney biopsy-proven GD patients, tracked from 2010 to 2015 until end-stage kidney disease (ESKD), death, or the study end in January 2022. Results: The median follow-up was 8.8 years. Diagnoses were predominantly nonproliferative (53%), proliferative (25%) nephropathies, diabetic nephropathy (12%), and paraprotein diseases (10%). NS was observed in 141 (59%) patients, presenting more frequently with arterial hypertension, higher eGFR, increased proteinuria, and dyslipidemia than NRP patients. NRP patients often had proliferative GD and diabetic nephropathy; their renal chronicity score was higher. The ESKD endpoint occurred in 35% NS and 39% NRP patients (p 0.4). The cohort’s mean kidney survival time was 8.2 years. In a multivariate analysis, NS, lower eGFR, a higher renal chronicity score, and diabetic nephropathy were associated with ESKD. A total of 64 patients (27%) died, 73% post-kidney replacement therapy initiation, and mostly from cardiovascular disease (63%). Mortality between proteinuria forms showed no difference. The multivariate analysis found lower eGFR, a higher Charlson comorbidity score, and diabetic nephropathy associated with mortality. Conclusions: Our study found no difference in all-cause mortality between NS and NRP in glomerular diseases. However, an adjusted analysis revealed poorer kidney survival for NS patients, emphasizing the need for personalized management to improve renal prognoses. Full article

Background/Objectives: Transthyretin amyloid (ATTR) cardiomyopathy mimics left ventricular hypertrophy (LVH) and has been identified as a specific cause of heart failure (HF). The aim of this study was to assess the prevalence of ATTR among patients presenting to the Emergency Department (ED) with acute HF (AHF) and LVH and explore their clinical characteristics and outcomes. Methods: Of 127 AHF patients with LVH, 95 completed the diagnostic protocol, which included monoclonal paraprotein testing and technetium-99 m pyrophosphate scintigraphy. Patients were followed for 6 months, and adverse events, including mortality and HF-related hospitalizations, were recorded. Results: ATTR was diagnosed in 8.4% of patients. The mean left ventricular ejection fraction (EF) was 46 ± 7% in ATTR subjects, with 25% classified as HF with reduced EF, 37.5% HF with mildly reduced EF, and 37.5% HF with preserved EF. N-terminal pro b-type natriuretic peptide (NT-proBNP) and high sensitivity troponin T (hs-TnT) were higher in ATTR compared to the non-ATTR group [NT-proBNP: 5863 (6519–12382) pg/mL versus 3586 (1393.5–6322) pg/mL, p = 0.007; hs-TnT: 35.9 (47.9–83.8) pg/mL versus 30.0 (19.4–49.5) pg/mL, p = 0.0006]. During follow-up, twenty-three patients from the cohort died: six in the ATTR and seventeen in the non-ATTR group. The estimated survival rate was significantly lower in ATTR versus non-ATTR patients (log-rank p < 0.0001). Conclusions: In this cohort of AHF patients with LVH presenting to the ED, ATTR cardiomyopathy was detected in 8.4%. Using routinely used cardiac biomarkers and basic echocardiography allows for the raising of suspicion of the disease from the ED setting, potentially facilitating earlier diagnosis in this population. Full article

The purpose of this article is to evaluate the course of paraproteinemic keratopathy (PPK) in patients undergoing systemic therapy for the underlying hematological disease. Baseline and follow-up examinations included hematological work-up, best-corrected visual acuity, slit-lamp biomicroscopy, and in vivo confocal laser scanning microscopy (IVCM). We included 22 patients with bilateral PPK (aged 68 ± 10.4 years, 11 males). Ten patients with multiple myeloma (MM) underwent on-label systemic therapy. During follow-up, we observed a regression of corneal opacities in three patients under slit-lamp examination and under IVCM, while PPK remained unchanged in seven patients. In three patients with monoclonal gammopathy of ocular significance (MGOS), systemic therapy was initiated off-label to reduce the serum paraprotein load before penetrating keratoplasty (PKP). These patients showed no signs of PPK recurrence for up to 24 months after PKP. In one patient without systemic therapy, a recurrence in corneal grafts occurred within 12 months of PKP. In eight patients without systemic therapy, PPK remained stable. In conclusion, systemic therapy for MM patients reduced corneal opacity in 30% of treated patients. Furthermore, systemic therapy performed before PKP in patients without conventional systemic therapy indication (MGOS) likely postpones PPK recurrence in the corneal graft. Full article

The presence of a serum paraprotein (PP) is usually associated with plasma-cell dyscrasias, Waldenstrom Macroglobulinemia/lymphoplasmacytic lymphoma, and cryoglobulinemia. However, PP is also often reported in other high- and low-grade B-cell malignancies. As these reports are sparse and heterogeneous, an overall view on this topic is lacking, Therefore, we carried out a complete literature review to detail the characteristics, and highlight differences and similarities among lymphoma entities associated with PP. In these settings, IgM and IgG are the prevalent PP subtypes, and their serum concentration is often low or even undetectable without immunofixation. The relevance of paraproteinemia and its prevalence, as well as the impact of IgG vs. IgM PP, seems to differ within B-NHL subtypes and CLL. Nonetheless, paraproteinemia is almost always associated with advanced disease, as well as with immunophenotypic, genetic, and clinical features, impacting prognosis. In fact, PP is reported as an independent prognostic marker of poor outcome. All the above call for implementing clinical practice, with the assessment of paraproteinemia, in patients’ work-up. Indeed, more studies are needed to shed light on the biological mechanism causing more aggressive disease. Furthermore, the significance of paraproteinemia, in the era of targeted therapies, should be assessed in prospective trials. Full article