Clinicopathological characteristics and prognosis in patients with monoclonal gammopathy and renal damage in central China: a multicenter retrospective cohort study.

Renal involvement is common in monoclonal gammopathy (MG); however, the same patient may have both MG and non-paraprotein-associated renal damage. Accordingly, distinguishing the cause of renal damage is necessary because of the different clinical characteristics and associated treatments. In this multicenter retrospective cohort study, we described the clinicopathological characteristics and prognosis of 703 patients with MG and renal damage in central China. Patients were classified as having MG of renal significance (MGRS), MG of undetermined significance (MGUS), or hematological malignancy. 260 (36.98%), 259 (36.84%), and 184 (26.17%) had MGRS, MGUS, and hematological malignancies, respectively. Amyloidosis was the leading pattern of MGRS (74.23%), followed by thrombotic microangiopathy (8.85%) and monoclonal immunoglobulin deposition disease (8.46%). Membranous nephropathy was the leading diagnosis of MGUS (39.38%). Renal pathological findings of patients with hematological malignancies included paraprotein-associated lesions (84.78%) and non-paraprotein-associated lesions (15.22%). The presence of nephrotic syndrome and an abnormal free light chain (FLC) ratio were independently associated with MGRS. The overall survival was better in patients with MGUS than in those with MGRS or hematological malignancies.

Serum free light chains among twin siblings: is the kappa/lambda ratio genetically determined?

BACKGROUND: Serum kappa, lambda, the K/λ light chain concentrations are used for screening, diagnosis, and monitoring of patients with multiple myeloma and other plasma cell disorders. Biological variation studies conducted on healthy subjects showed that free light chains have a low within and high between-individual variation. We determined if this variation were genetically linked. METHODS: We obtained a single serum sample from 16 pairs of identical twins, 8 neonate twins, and 19 presumed directly-related siblings children, measured Κ and λ light chains and computed the Κ/λ ratio. RESULTS: As expected, Κ/λ results from each twin neonate were near identical (reflecting maternal/placental transfer). For older children and adult twins, the Κ/λ ratio form a cluster of results that were a subset of the reference range. There was one outlier, a female with a high, different from her twin sister. She likely had a monoclonal gammopathy (no followup was possible). Excluding this pair, results from neonate twins (14.4% ±10.3%) and non-neonate twins (18.0 ± 15.3%) were not significantly different. Results between non-twin siblings were more scattered (53.2%±53.4%) and different from neonate and non-neonate twin adult and children. CONCLUSION: We suggest that the Κ/λ free light chains may be genetically linked.

Single monoclonal spike characterized as double monoclonal gammopathy in a patient with multiple myeloma: A rare finding.

Multiple myeloma (MM) is associated with the secretion of a unique monoclonal protein (M-protein) due to overproduction of immunoglobulin (Ig) by a clone of abnormally proliferating plasma cells. However, in 4% of the cases more than one M-protein can be found. This category of gammopathies is called "double monoclonal gammopathies." Here, we present a rare case of MM with double monoclonal gammopathy, where the presence of both M-proteins was observed in the single sharp peak on capillary zone electrophoresis (CZE). Further the interference of Hook effect is also discussed. Double monoclonal gammopathies need to be identified to increase diagnostic accuracy and reliability, and to get a better understanding of the disease pathogenesis and progression.

Establishing Monoclonal Gammopathy of Undetermined Significance as an Independent Pre-Disease State of Multiple Myeloma Using Raman Spectroscopy, Dynamical Network Biomarker Theory, and Energy Landscape Analysis.

Multiple myeloma (MM) is a cancer of plasma cells. Normal (NL) cells are considered to pass through a precancerous state, such as monoclonal gammopathy of undetermined significance (MGUS), before transitioning to MM. In the present study, we acquired Raman spectra at three stages-834 NL, 711 MGUS, and 970 MM spectra-and applied the dynamical network biomarker (DNB) theory to these spectra. The DNB analysis identified MGUS as the unstable pre-disease state of MM and extracted Raman shifts at 1149 and 1527-1530 cm-1 as DNB variables. The distribution of DNB scores for each patient showed a significant difference between the mean values for MGUS and MM patients. Furthermore, an energy landscape (EL) analysis showed that the NL and MM stages were likely to become stable states. Raman spectroscopy, the DNB theory, and, complementarily, the EL analysis will be applicable to the identification of the pre-disease state in clinical samples.

Reporting Practices of Serum Protein Electrophoresis in Pakistan - a Multicenter Survey.

BACKGROUND: Serum Protein Electrophoresis (SPE) is crucial for the diagnosis and follow-up of monoclonal gammopathy (MG), as it helps to separate and identify these paraproteins. Currently, Pakistan lacks standardized guidelines for SPE reporting and analytical performance. This survey aims to analyze reporting variations from Consultant Chemical Pathologists in Pakistani laboratories. METHODS: This cross-sectional survey was conducted by the section of Chemical Pathology, Department of Pathology and Laboratory Medicine, at Aga Khan University Hospital, Karachi. A previously validated and published tool was used with some modifications to assess analytical techniques, reporting patterns, and interpretations provided with SPE by different laboratories. Frequency and percentages were calculated for each response and descriptive results were also evaluated. Differences between laboratories were also assessed qualitatively. RESULTS: Out of the eight laboratories contacted, seven participated in the survey, yielding a response rate of 87.5%. Immunofixation Electrophoresis (IFE) was used by all labs for serum immunotyping. All labs reported a new small abnormal band in patients with no known monoclonal gammopathy or with a known M-protein. Variations were found in terminologies used to label paraprotein, terminologies used to report normal and pathological SPE patterns, electrophoretic technique, methods for quantifying paraprotein in the gamma region on SPE and for albumin quantification. Similarly, the number of decimal places reported, reporting of multiple monoclonal proteins and small paraprotein in the beta region or monoclonal proteins less than 1 g/L, approach for screening, number of fractions reported in gamma region and reporting of interferences were also not standardized and var-iations were noticed. CONCLUSIONS: Our survey highlighted variations in practices of SPE reporting. These differences in laboratory practices could result in inconsistent test results, which could adversely affect patient care.

Laboratory reflex testing strategy for the early identification of primary care patients with multiple myeloma.

OBJECTIVES: Our objective was to shorten the screen for multiple myeloma (MM), through reflex testing. DESIGN AND METHODS: The clinical laboratory in the public University Hospital of San Juan (Alicante, Spain), serves 234,551 inhabitants. Through an intervention agreed with general practitioners, the Laboratory Information System (LIS) automatically registered serum immunoglobulins (Ig) when serum total proteins (STP) > 80 g/L for the first time in primary care patients. When concomitantly one Ig presented a value above and one below its reference interval, the LIS automatically registered a serum protein electrophoresis (SPEP). When a monoclonal peak in SPEP, immunofixation electrophoresis (IFE) for the typification of monoclonal bands (MB) was performed. If MB were present, a comment in the report explained the intervention. The number of additionally registered Ig, SPEP, IFE, and new diagnosis of MM were counted. The number of days elapsed from the report of elevated STP result to the final MM diagnosis was also counted as median and interquartile range (IQR), and compared to a pre intervention period. RESULTS: 2071 cases of hyperproteinemia were identified, and had 91 a monoclonal peak, confirmed by IFE. In 35 patients it was a new finding, and 9 were diagnosed with MM, 3 Waldestrom macroglobulinemia, 2 lymphoplasmacytic lymphoma and 21 monoclonal gammopathy of undetermined significance. The number of days elapsed from hyperproteinemia to diagnosis was lower in the intervention period (21.5 vs 119.4) (P < 0.01). As our results show, in addition to shortening the time to diagnosis, an increased rate of detection of plasma cell disorders was observed when using our algorithm. CONCLUSIONS: The above laboratory interventions agreed with clinicians, making use of laboratory technology resulted in early identification of MM.

Defect in Automated Antigen Excess Detection Discovered after Reviewing Serum Free Light Chain Results in Context with Clinical Findings.

Serum κ and λ free light chains can be markedly elevated in monoclonal gammopathies; consequently, serum free light chain (sFLC) immunoassays are susceptible to inaccuracies caused by antigen excess. As a result, diagnostics manufacturers have attempted to automate antigen excess detection. A 75-year-old African-American woman had laboratory findings consistent with severe anemia, acute kidney injury, and moderate hypercalcemia. Serum and urine protein electrophoresis and sFLC testing were ordered. The sFLC results initially showed mildly elevated free λ light chains and normal free κ. The pathologist noted that sFLC results were discrepant with the bone marrow biopsy, electrophoresis, and immunofixation results. After manual dilution of the serum, repeat sFLC testing revealed significantly higher λ sFLC results. Antigen excess causing falsely low sFLC quantitation may not be detected by immunoassay instruments as intended. Correlation with clinical history, serum and urine protein electrophoresis results, and other laboratory findings is essential when interpreting sFLC results.

The Role of Bone Marrow Biopsy Evaluation in the Workup for Monoclonal Gammopathy of Renal Significance: A Diagnosis of Exclusion.

CONTEXT.­: Monoclonal gammopathy of renal significance (MGRS) is a relatively new concept for patients with renal monoclonal protein deposition (RMPD) (except monoclonal cast nephropathy) and has been used as a reason for nephrologists to obtain a bone marrow biopsy (BMB). It takes a team of pathologists and clinicians to determine when RMPD at our institution can be defined as MGRS. OBJECTIVE.­: To identify the proportion of various subtypes of tentative MGRS diagnosed by renal biopsy that can be confirmed as final MGRS after BMB. DESIGN.­: One hundred thirty kidney biopsies with variants of RMPD were identified during the past 10 years. Biopsy cases with known myeloma, B-cell lymphoma, or monoclonal cast nephropathy were separated as a heavy-burden group. The remaining biopsies with RMPD were considered tentative MGRS. Their BMB and clinical indices were further analyzed to determine the final percentage of MGRS diagnoses. RESULTS.­: Among the 130 renal paraprotein deposition cases, 44 (33.8%) were categorized as the heavy-burden group. In the remaining 86 cases, 33 (38.4%) with subsequent identification of myeloma (>10% of monoclonal plasma cells) or lymphoma in BMB were further considered as heavy-burden cases. Eighteen cases (18 of 86; 20.9%) did not receive follow-up BMB; thus, no further analysis was performed. BMBs diagnosed as either nonmalignant (no plasma cells; 8 of 86 cases; 9.3%) or premalignant (<10% plasma cells; 27 of 86 cases; 31.4%) were confirmed to be final MGRS (35 of 86; 40.7%). CONCLUSIONS.­: The data indicate that BMB is an important element in the confirmation of MGRS.

A review of clinical guidelines, laboratory recommendations and external quality assurance programs for monoclonal gammopathy testing.

Monoclonal gammopathy (MG) is a spectrum of diseases ranging from the benign asymptomatic monoclonal gammopathy of undetermined significance to the malignant multiple myeloma. Clinical guidelines and laboratory recommendations have been developed to inform best practices in the diagnosis, monitoring, and management of MG. In this review, the pathophysiology, relevant laboratory testing recommended in clinical practice guidelines and laboratory recommendations related to MG testing and reporting are examined. The clinical guidelines recommend serum protein electrophoresis, serum immunofixation and serum free light chain measurement as initial screening. The laboratory recommendations omit serum immunofixation as it offers limited additional diagnostic value. The laboratory recommendations offer guidance on reporting findings beyond monoclonal protein, which was not required by the clinical guidelines. The clinical guidelines suggested monitoring total IgA concentration by turbidimetry or nephelometry method if the monoclonal protein migrates in the non-gamma region, whereas the laboratory recommendations make allowance for involved IgM and IgG. Additionally, several external quality assurance programs for MG protein electrophoresis and free light chain testing are also appraised. The external quality assurance programs show varied assessment criteria for protein electrophoresis reporting and unit of measurement. There is also significant disparity in reported monoclonal protein concentrations with wide inter-method analytical variation noted for both monoclonal protein quantification and serum free light chain measurement, however this variation appears smaller when the same method was used. Greater harmonization among laboratory recommendations and reporting format may improve clinical interpretation of MG testing.

Oligoclonal gammopathy: An analysis of 253 cases.

BACKGROUND: Oligoclonal gammopathy (OG) is a rare disorder of the lymphoid system that is characterized by the presence of at least 2 distinct monoclonal proteins in a patient's serum or urine. The biological and clinical characteristics of this disease are as yet poorly understood. OBJECTIVES: The study aimed to assess whether there are significant differences between patients with OG regarding the developmental history (i.e., OG diagnosed at the first presentation compared to OG that has developed in patients with an original monoclonal gammopathy) and the number of monoclonal proteins (2 compared to 3). Moreover, we attempted to determine when secondary oligoclonality develops following the original diagnosis of monoclonal gammopathy. MATERIAL AND METHODS: Patients were analyzed with regard to their age at diagnosis, sex, serum monoclonal proteins, and underlying hematological disorders. Multiple myeloma (MM) patients were additionally evaluated for their Durie-Salmon stage and cytogenetic alterations. RESULTS: Patients with triclonal gammopathy (TG: n = 29) did not differ significantly from patients with biclonal gammopathy (BG: n = 223) (p = 0.81) in terms of age at diagnosis and the dominant diagnosis (MM was the most common diagnosis (65.0% and 64.7%, respectively)). In both cohorts, myeloma patients were mainly classified to the Durie-Salmon stage III. In the TG cohort, there was a higher proportion of males (69.0%) than among patients with BG (52.5%). Oligoclonality developed at various times after diagnosis (up to 80 months in the investigated cohort). However, the occurrence of new cases was higher during the initial 30-month period following the diagnosis of monoclonal gammopathy. CONCLUSIONS: There are only small differences between patients with primary compared to secondary OG, between BG and TG, and most patients have a combination of IgGκ+IgGλ. Oligoclonality could develop at any time after the diagnosis of monoclonal gammopathy, but it happens more frequently during the first 30 months, with advanced myeloma being the most prevalent underlying disorder.

Immunophenotypic assessment of clonal plasma cells and B-cells in bone marrow and blood in the diagnostic classification of early stage monoclonal gammopathies: an iSTOPMM study.

Monoclonal gammopathy of undetermined significance (MGUS) is the earliest discernible stage of multiple myeloma (MM) and Waldenström's macroglobulinemia (WM). Early diagnosis of MG may be compromised by the low-level infiltration, undetectable to low-sensitive methodologies. Here, we investigated the prevalence and immunophenotypic profile of clonal (c) plasma cells (PC) and/or cB-lymphocytes in bone marrow (BM) and blood of subjects with a serum M-component from the iSTOPMM program, using high-sensitive next-generation flow cytometry (NGF), and its utility in the diagnostic classification of early-stage MG. We studied 164 paired BM and blood samples from 82 subjects, focusing the analysis on: 55 MGUS, 12 smoldering MM (SMM) and 8 smoldering WM (SWM). cPC were detected in 84% of the BM samples and cB-lymphocytes in 45%, coexisting in 39% of cases. In 29% of patients, the phenotypic features of cPC and/or cB-lymphocytes allowed a more accurate disease classification, including: 19/55 (35%) MGUS, 1/12 (8%) SMM and 2/8 (25%) SWM. Blood samples were informative in 49% of the BM-positive cases. We demonstrated the utility of NGF for a more accurate diagnostic classification of early-stage MG.

Waldenström's Macroglobulinemia and Cryoglobulinemic Glomerulonephritis: An Unusual Case of Monoclonal Gammopathy of Renal Significance.

Cryoglobulins are immunoglobulins that precipitate at temperatures below 37 °C and dissolve upon reheating. They can induce small-vessel vasculitis with renal involvement. Cryoglobulinemic glomerulonephritis is a rare manifestation that occurs in patients with monoclonal gammopathy, specifically Waldenström's macroglobulinemia. We present the case of a 52-year-old patient with a history of cutaneous vasculitis and hypothyroidism, who presented with generalized edema, moderate anemia, hypercholesterolemia, nephrotic range proteinuria of 12.69 g/day, microhematuria, arterial hypertension, and hypocomplementemia via the classical pathway, without acute kidney injury and with negative serological studies and positive cryoglobulins in the second determination. Serum and urine protein electrophoresis and immunofixation studies showed a monoclonal band of IgM and kappa light chain. Renal biopsy was consistent with cryoglobulinemic glomerulonephritis. In the context of dysproteinemia and cryoglobulinemic glomerulonephritis, bone-marrow aspiration and biopsy were performed, leading to the diagnosis of Waldenström's macroglobulinemia. Monoclonal gammopathies have been described in association with type I cryoglobulinemias. This described association is uncommon, which is why we present this case, along with a review of the literature.

Improved Screening of Monoclonal Gammopathy Patients by MALDI-TOF Mass Spectrometry.

Monoclonal gammopathies are a group of blood diseases characterized by presence of abnormal immunoglobulins in peripheral blood and/or urine of patients. Multiple myeloma and plasma cell leukemia are monoclonal gammopathies with unclear etiology, caused by malignant transformation of bone marrow plasma cells. Mass spectrometry with matrix-assisted laser desorption/ionization and time-of-flight detection is commonly used for investigation of the peptidome and small proteome of blood plasma with high accuracy, robustness, and cost-effectivity. In addition, mass spectrometry coupled with advanced statistics can be used for molecular profiling, classification, and diagnosis of liquid biopsies and tissue specimens in various malignancies. Despite the fact there have been fully optimized protocols for mass spectrometry of normal blood plasma available for decades, in monoclonal gammopathy patients, the massive alterations of biophysical and biochemical parameters of peripheral blood plasma often limit the mass spectrometry measurements. In this paper, we present a new two-step extraction protocol and demonstrated the enhanced resolution and intensity (>50×) of mass spectra obtained from extracts of peripheral blood plasma from monoclonal gammopathy patients. When coupled with advanced statistics and machine learning, the mass spectra profiles enabled the direct identification, classification, and discrimination of multiple myeloma and plasma cell leukemia patients with high accuracy and precision. A model based on PLS-DA achieved the best performance with 71.5% accuracy (95% confidence interval, CI = 57.1-83.3%) when the 10× repeated 5-fold CV was performed. In summary, the two-step extraction protocol improved the analysis of monoclonal gammopathy peripheral blood plasma samples by mass spectrometry and provided a tool for addressing the complex molecular etiology of monoclonal gammopathies.

Post-Transplant Monoclonal Gammopathy of Renal Significance: A Case Report.

The term monoclonal gammopathy of renal significance has been used to classify the presence of a monoclonal gammopathy or lymphoproliferative disorders that do not meet hematological criteria for myeloma but instead cause kidney damage. Mostly, post-transplant monoclonal gammopathy of renal significance occurs due to recurrent disease. In contrast, the incidence of de novo post-transplant monoclonal gammopathy of renal significance has not been established, as it is considered a rare disease, presenting a unique challenge in terms of diagnosis, management, and potential impact on graft survival. Here, we report a case of de novo monoclonal gammopathy of renal significance diagnosed after kidney transplantation and its complexity due to a concomitant chronic active antibody-mediated rejection.

[Classification and Management of MGRS Related Diseases].

Monoclonal Gammopathies of Renal Significance (MGRS) are a complex group of disorders characterized by the production of aberrant monoclonal proteins that interact with kidney structures, causing tissue damage. Unlike neoplastic forms, kidney damage in MGRS does not correlate with clone mass or circulating monoclonal protein levels, conferring unique pre-neoplastic or non-neoplastic properties to the responsible clones. This manuscript explores the heterogeneity of monoclonal proteins involved, varying from full immunoglobulins to free light chains (FLC), and how they result in a spectrum of kidney lesions with differing prognoses. We also elaborate on diagnostic challenges, emphasizing the indispensable role of kidney biopsy, including advanced techniques like laser microdissection and mass spectrometry (LMD/MS) for deposit characterization, particularly in ambiguous or complex cases. Clinical management and treatment considerations, including the necessity for clone identification, are also discussed.

Paraproteinemic Neuropathies.

OBJECTIVE: Coexistence of polyneuropathy and gammopathy is a common but potentially challenging situation in clinical practice. This article reviews the clinical, electrophysiologic, and hematologic phenotypes of the paraproteinemic neuropathies and the diagnostic and treatment strategies for each. LATEST DEVELOPMENTS: Advances in our understanding of the underlying pathophysiology of various paraproteinemic neuropathies and their corresponding phenotypes have identified potential new therapeutic targets. Therapeutic strategies to diminish anti-myelin-associated glycoprotein (MAG) IgM antibodies have shown partial and inconsistent efficacy; however, antigen-specific immune therapy is being investigated as a novel treatment to remove the presumably pathogenic anti-MAG antibody. Advances in genetic and cell signaling studies have resulted in the approval of Bruton tyrosine kinase inhibitors for Waldenström macroglobulinemia. Monoclonal antibodies are being investigated for the treatment of light chain amyloidosis. ESSENTIAL POINTS: Early recognition and treatment of underlying plasma cell disorders improves clinical outcomes in patients with paraproteinemic neuropathy. Despite significant progress, our knowledge regarding underlying mechanisms for paraproteinemic neuropathy is still limited. Clinicians' awareness of clinical phenotypes, electrophysiologic hallmarks, and hematologic findings of the different paraproteinemic neuropathies is crucial to promptly identify and treat patients and to avert misdiagnosis. Multidisciplinary collaboration among specialists, including neurologists and hematologists, is paramount for the optimal treatment of these patients with overlapping conditions.

Quantification of Free Immunoglobulin Light Chains in Urine.

BACKGROUND: The serum-free immunoglobulin light chain assay has been recommended as a screening test for monoclonal gammopathy. We evaluated the usefulness of urine free immunoglobulin light concentration for selection of specimens for immunofixation electrophoresis. METHODS: Using kits from The Binding Site for Freelite ®, we validated examination of urine for measuring free κ and λ light chains. The results of urine free light chain concentrations were evaluated to ascertain if the results could be used to reduce the number of specimens requiring urine protein immunofixation electrophoresis. RESULTS: In the 515 specimens examined, there was no evidence of monoclonal gammopathy or history of monoclonal gammopathy in 331. Monoclonal κ or λ light chains were detectable in 42 and 30 specimens, respectively. There was history of κ or λ chain associated monoclonal gammopathy in 62 and 50 patients, respectively. In the 38 monoclonal κ positive urine specimens, with light chain data, κ/λ ratio was >5.83 in all specimens. In 27 specimens positive for monoclonal λ light chains, with light chain data, the urine λ/κ ratio was > 0.17 in 24 of 27 specimens and > 0.041 in all specimens. In patients without monoclonal gammopathy all specimens had a κ/λ ratio of >5.83 or λ/κ ratio >0.17. CONCLUSIONS: The Freelite ® assay from The Binding Site is suitable for quantification of free light chains in urine. In patients with known history of monoclonal gammopathy, urine immunofixation electrophoresis may be omitted in specimens with κ/λ ratio of <5.83 for κ associated lesions and λ/κ ratio of <0.041 for λ associated lesions. However, the results do not support using this test for first-time urine testing for monoclonal light chains as it is not predictive of positive result, nor does it exclude a monoclonal light chain in urine.

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)