A case of paraprotein-negative POEMS syndrome: Case report and literature review.

RATIONALE: POEMS syndrome is a rare monoclonal plasma cell disease. The diagnosis of POEMS requires polyradiculoneuropathy and monoclonal plasma proliferating as 2 mandatory criteria, at least 1 of the major criteria (Castleman disease, elevated vascular endothelial growth factor level, and sclerotic bone lesion), and at least 1 of the minor criteria (organomegaly, extravascular volume overload, endocrinopathy, skin changes, papilledema, and thrombocytosis/polycythemia). This multisystem disorder is of high heterogeneity, and few variants of POEMS with no evidence of monoclonal gammopathy have been described, which further complicates the diagnosis in clinical practice. Now, we report a case of paraprotein-negative POEMS syndrome. PATIENTS CONCERNS: A 45-year-old woman complained of lower extremity edema, shortness of breath, abdominal distension, and lymphadenopathy for few years. Finally, she was diagnosed with paraprotein-negative POEMS syndrome. With the lenalidomide-based regimen, the symptoms were all relieved. DIAGNOSIS: Paraprotein-negative POEMS syndrome. INTERVENTION: Lenalidomide-based regimen and some supportive therapy. OUTCOME: All symptoms were relieved after 1 year of treatment. LESSONS: Physicians should pay more attention to the POEMS syndrome, especially the POEMS syndrome variants, which are absence of paraprotein; probably, these variants are just "on the way" to classic POEMS syndrome antiplasma cell therapy, which remains the treatment of choice.

Spurious dyslipidemia due to paraprotein in a patient with Waldenström macroglobulinemia.

INTRODUCTION: Serum lipid profiles play a crucial role in diagnosing and evaluating cardiovascular diseases. However, the presence of paraprotein can lead to inaccurate dyslipidemia results on automated analyzers. CASE REPORT: A 65-year-old woman whose combined concentrations of HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C) consistently surpassed her total serum cholesterol levels over a period of three months presented with unusual lipid component detection. Further analysis revealed the presence of a monoclonal paraprotein, identified as an IgMλ band, with a concentration of 28.0 g/L. The patient was subsequently diagnosed with Waldenström macroglobulinemia. The use of abnormal reaction kinetic curves and the ß quantification method, along with an alternative method that did not suffer from interference, revealed that the monoclonal paraprotein interfered with the measurements of HDL-C, LDL-C, apolipoprotein A-I (apoA-I), and apolipoprotein B (apoB) when using the Roche detection system. This interference led to spurious elevated HDL-C concentrations and falsely decreased apoA-I and apoB concentrations, while the LDL-C results were minimally affected. Although diluting the sample normalized the HDL-C and LDL-C measurements, the interference with the apoA-I and apoB assays persisted. No other common biochemical tests were interfered with this paraprotein. CONCLUSION: Caution is advised when using a homogenous method for direct measurement of HDL-C and LDL-C in patients with monoclonal paraprotein. Techniques to recognize and eliminate this interference are available. However, immunoturbidimetric detection of apoA-I and apoB levels is also susceptible to this interference, which is not readily removable.

Discrepant serum creatinine concentrations caused by paraprotein interference preceding diagnosis of monoclonal gammopathy of undetermined significance.

We report a man in his 70s who presented with discrepant serum creatinine concentrations in different hospitals at the same time. Further examinations of these discrepancies revealed turbidity of the serum sample and, thus, a reagent reaction and false hypercreatinine caused by paraprotein interference were suspected. Serum protein electrophoresis revealed a small amount of monoclonal γ globulin (2.9 g/L), which may have been involved in paraprotein interference. Monoclonal λ-type IgG was detected in the serum, resulting in a diagnosis of monoclonal gammopathy of undetermined significance. Previous studies indicated paraprotein interference in serum containing monoclonal IgM or a large amount of IgG (> 25 g/L). Although this case of paraprotein interference induced by a small amount of IgG is rare, a discrepancy in creatinine results may be an indicator leading to the diagnosis of plasma cell proliferative diseases.

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.

Paraproteins and electrolyte assays: exclusion effect and effect of paraprotein elimination.

Paraproteins are a potential source of error for electrolyte analyses. The exclusion effect itself causes a discrepancy between direct and indirect ion selective electrode assays (dISE and iISE, respectively). We tested the applicability of different pretreatment methods and the difference of dISE and iISE with paraprotein-rich samples. We analysed chloride (Cl-), potassium (K+), and sodium (Na+) on 46 samples with paraproteins up to 73 g/L. We compared pretreatment methods of preheating, precipitation, and filtration to the native sample. All induced a statistically significant difference (p-value <0.05). Clinically significant difference was induced by precipitation for all analytes, and filtration for Cl- and Na+, but for none by preheating. The difference in electrolyte measurements with either dISE or iISE on native samples was explained by total protein concentration (TP). There was a statistically significant difference in all electrolyte measurements. On average, there was a clinically significant difference in Na + but not in Cl- and K + measurements. Paraprotein concentration (PP) or heavy chain class did not induce a statistically significant effect. The regression analysis and comparison to the theoretical exclusion effect supported the conclusion that TP is the only explanatory factor in the difference between dISE and iISE. We conclude that preheating is a suitable pretreatment method for all the studied analytes. Precipitation is not valid for any of them, and filtration can be considered only for K+. Because the difference between dISE and iISE was explained by the exclusion effect caused by TP, dISE is the more suitable method to analyse paraprotein-rich samples.

[Detection of paraprotein in plasma cell tumors].

Paraprotein is a laboratory biomarker of plasma cell tumors and other lymphoproliferative diseases. Its determination is necessary for diagnosing, monitoring and assessment of therapy effectiveness. The lecture presents the main methods of qualitative and quantative analysis of monoclonal proteins: gel electrophoresis, capillary electrophoresis, immunofixation and nephelometry features, possibilities and limitations are reviewed. The main sources of errors and artifacts during these studies are considered. Also the difficulties in the diagnosis and interpretation of the results of serum and urine tests are highlighted.

Bortezomib plus dexamethasone as first-line therapy for patients with POEMS syndrome.

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare plasma cell dyscrasia without standard front-line treatment. Merely, few studies have reported the responses and outcomes of bortezomib plus dexamethasone (BDex) in POEMS syndrome. In this study, a total of 69 patients (40 males) treated with front-line BDex were included. The median age at diagnosis was 50 years (range, 30-78 years). After a median of 9 cycles BDex (range 1-9), fifty-two (88.1%), thirty-two (46.4%), and forty-seven (71.2%) patients achieved the best neurologic response, hematological complete response, and serum vascular endothelial growth factor (VEGF) response, respectively. The extravascular overload, pulmonary hypertension, and renal impairment also substantially improved. No treatment-related death occurred. Two patients developed grade-1 bortezomib-induced peripheral neuropathy and were reversible after drug withdrawal. After a median follow-up of 22.5 months, the estimated 2-year overall survival and time to next treatment were 95.7% and 65.6%, respectively. In conclusion, the combination of bortezomib and dexamethasone is effective, with a high response rate and safety profile for patients with newly diagnosed POEMS syndrome.

Not the usual suspect: Polymeric IgA paraprotein causes false positive results in kinetic interaction of microparticles in solution (KIMS) immunoassays.

Immunoassays are commonly used by the clinical laboratory, but paraproteins can occasionally produce erroneous results. In this study, we investigated the cause of apparent false positive results for multiple Kinetic Interaction of Microparticles in Solution (KIMS) immunoassays. Patient controls and samples containing the interference were analyzed using automated chemistry platforms, gel electrophoresis, immunofixation, affinity chromatography, and size exclusion chromatography. Our results show that IgA paraprotein caused false positive results for the KIMS measurement of three therapeutic drugs. To our knowledge, this is the first report of IgA paraprotein-causing immunoassay interference. The clinical implications of this interference are discussed.

MASS-FIX for the detection of monoclonal proteins and light chain N-glycosylation in routine clinical practice: a cross-sectional study of 6315 patients.

Immunoenrichment-based matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), termed MASS-FIX, offers several advantages over immunofixation for the detection and isotyping of serum monoclonal protein, including superior sensitivity and specificity, the ability to differentiate therapeutic monoclonal antibodies, and the rapid identification of light chain (LC) N-glycosylation. We identified 6315 patients with MASS-FIX performed at our institution since 2018. Of these, 4118 patients (65%) with a wide array of plasma cell disorders (PCD), including rare monoclonal gammopathies of clinical significance, had a positive MASS-FIX. Two-hundred twenty-one (5%) of the MASS-FIX positive patients had evidence of LC N-glycosylation, which was more commonly identified in IgM heavy chain isotype, kappa LC isotype, and in diagnoses of immunoglobulin light chain (AL) amyloidosis and cold agglutinin disease (CAD) compared to other PCD. This cross-sectional study describes the largest cohort of patients to undergo MASS-FIX in routine clinical practice. Our findings demonstrate the widespread utility of this assay, and confirm that LC N-glycosylation should prompt suspicion for AL amyloidosis and CAD in the appropriate clinical context.

Calculated globulin as a screening tool for hypogammaglobulinaemia or paraproteins in hospitalized patients.

BACKGROUND: Calculated globulin fraction is derived from the liver function tests by subtracting albumin from the total protein. Since immunoglobulins comprise the largest component of the serum globulin concentration, increased or decreased calculated globulins and may identify patients with hypogammaglobulinaemia or hypergammaglobulinaemia, respectively. METHODS: A retrospective study of laboratory data over 2.5 years from inpatients at three tertiary hospitals was performed. Patients with paired calculated globulins and immunoglobulin results were identified and clinical details reviewed. The results of serum electrophoresis testing were also assessed where available. RESULTS: A total of 4035 patients had paired laboratory data available. A calculated globulin ≤20 g/L (<2nd percentile) had a low sensitivity (5.8%) but good positive predictive value (82.5%) for hypogammaglobulinaemia (IgG ≤5.7 g/L), with a positive predictive value of 37.5% for severe hypogammaglobulinaemia (IgG ≤3 g/L). Paraproteins were identified in 123/291 (42.3%) of patients with increased calculated globulins (≥42 g/L) who also had a serum electrophoresis performed. Significantly elevated calculated globulin ≥50 g/L (>4th percentile) were seen in patients with either liver disease (37%), haematological malignancy (36%), autoimmune disease (13%) or infections (9%). CONCLUSIONS: Calculated globulin is an inexpensive and easily available test that assists in the identification of hypogammaglobulinaemia or hypergammaglobulinaemia which may prompt further investigation and reduce diagnostic delays.

6q deletion in Waldenström macroglobulinaemia negatively affects time to transformation and survival.

Deletion of the long arm of chromosome 6 (del6q) is the most frequent cytogenetic abnormality in Waldenström macroglobulinaemia (WM), occurring in approximately 50% of patients. Its effect on patient outcome has not been completely established. We used fluorescence in situ hybridisation to analyse the prevalence of del6q in selected CD19+ bone marrow cells of 225 patients with newly diagnosed immunoglobulin M (IgM) monoclonal gammopathies. Del6q was identified in one of 27 (4%) cases of IgM-monoclonal gammopathy of undetermined significance, nine of 105 (9%) of asymptomatic WM (aWM), and 28/93 (30%) of symptomatic WM (sWM), and was associated with adverse prognostic features and higher International Prognostic Scoring System for WM (IPSSWM) score. Asymptomatic patients with del6q ultimately required therapy more often and had a shorter time to transformation (TT) to symptomatic disease (median TT, 30 months vs. 199 months, respectively, P < 0·001). When treatment was required, 6q-deleted patients had shorter progression-free survival (median 20 vs. 47 months, P < 0·001). The presence of del6q translated into shorter overall survival (OS), irrespective of the initial diagnosis, with a median OS of 90 compared with 131 months in non-del6q patients (P = 0·01). In summary, our study shows that del6q in IgM gammopathy is associated with symptomatic disease, need for treatment and poorer clinical outcomes.

Paraprotein associated syndrome treated successfully with chemotherapy.

We report a 50-year-old Caucasian woman who presented with recurrent erythema nodosum, leg swelling, malaise, weight loss and abdominal pain associated with an IgM lambda paraprotein. She was treated with six courses of an anti-CD20 monoclonal antibody and bendamustine chemotherapy over 6 months with a good clinical response.