IgG Lambda Research Articles

NCMP-12. AN ATYPICAL CASE OF POEMS WITH MACROFOCAL MYELOMA

Abstract Polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes (POEMS) syndrome is a rare paraneoplastic syndrome secondary to an underlying plasma cell dyscrasia. Symptoms of peripheral neuropathy dominate the clinical picture and is postulated to be related to serum vascular endothelial growth factor (VEGF) mediated altered permeability of the blood nerve barrier. The classic presentation includes a solitary osteosclerotic plasmacytoma and an elevation of VEGF. In this case, we present a patient with neither of these features who met diagnostic criteria for POEMS though had predominantly osteolytic lesions and was diagnosed with macrofocal myeloma, a unique subset of multiple myeloma. Our patient is a young male who presented with progressive leg numbness/weakness and was found to have marked ankle weakness, diffuse areflexia and unilateral gynecomastia on examination. EMG showed a motor predominant demyelinating polyneuropathy. Labs showed a serum IgG lambda M protein, low estradiol and low testosterone. He had a normal serum VEGF level though the lab was drawn after treatment initiation. Bone biopsy of a dominant osteolytic lesion was consistent with a plasma cell neoplasm (light chain restricted). Of note, he had mild cauda equina nerve root and ventral conus enhancement initially concerning for leptomeningeal involvement however, two lumbar punctures were negative for malignant cells. Spinal enhancement has been reported in POEMS. The patient underwent chemotherapy, radiation therapy and autologous stem cell transplantation. We present a patient diagnosed with MFMM, a rare subset of multiple myeloma, comprising only 3% of all cases, along with POEMS, a rare paraneoplastic syndrome. Interestingly, as osteolytic lesions can be seen in POEMS alone though not predominantly so, it is possible the patient could have atypical POEMS without underlying multiple myeloma. POEMS may remain under-recognized when presentations or setting are atypical.

Monoclonal gammapathies: Epidemiological, immunochemical and etiological analysis of a series of 50 cases

During the period from September 2022 to January 2023, 50 cases of monoclonal gammopathy (GM) were collected at the Avicenne military hospital in Marrakech. The average age of the patients was 62 years. Thirty patients were male and 20 were female. The etiological diagnosis could be established for the 50 observations: 5 were classified as GM of undetermined significance (GMSI), 42 were classified as myeloma, two case of Waldenström's disease and one case of AL amyloidosis. The clinical symptomatology was dominated by bone pain in 78% of patients with a deterioration in general condition in 43%. The most frequently found biological abnormalities were anemia in 62% of patients, renal failure in 48% of patients and 19% had hypercalcemia. A monoclonal peak was found in the electrophoreses of 45 patients (90%), of whom 6 migrated to the beta zone and 39 migrated to the gamma zone. The IgG Kappa isotype was the most frequent with a rate of 56%, followed by IgG Lambda (27%), IgA Kappa (8%), IgA Lambda (3%), IgM Lambda (3%) and lambda free light chains (3%).

Co-existence of Myelodysplastic Disorders and Plasma Cell Neoplasms: Case Series

Abstract Introduction/Objective The development of myelodysplastic syndrome (MDS) in patients with plasma cell neoplasm (PCN) receiving treatment is well reported. However, co-occurrence of both, without any chemotherapy history, is sparsely documented in the literature. We aim to highlight the possible association between both. Methods/Case Report Database search was done using Epic Slicer-Dicer for cases with biopsy proven co-existing MDS and PCN (from 2010-2022). The patients’ charts were reviewed to collect and analyze the clinical features. Results (if a Case Study enter NA) We identified 3 patients, all in their seventies on presentation: First patient: man, presented with unexplained chronic anemia. Serum protein electrophoresis (SPEP) showed elevated levels of monoclonal IgG kappa (4.2 g/dl). Evaluation of the BM biopsy revealed MDS with low blasts (WHO-5) with IgG plasma cell myeloma (56% Kappa-restricted plasma cells). Chromosome analysis revealed normal karyotype. Molecular studies were not done. Second patient: man, with Rheumatoid Arthritis and anemia. SPEP revealed biclonal IgG lambda (2.0 g/dl). BM biopsy indicated 5-8% lambda-restricted plasma cell proliferation. Anemia was managed with darbopoetin, but without improvement. The patient did not get chemotherapy. Follow-up BM biopsy was done, showing MDS with low blasts and ringed sideroblasts (WHO-5) alongside the PCN. FISH showed two abnormal IGH rearrangement populations. Chromosome analysis revealed normal karyotype. Molecular studies were not done. Third patient: woman, with pancytopenia. SPEP indicated monoclonal protein IgG lambda (1.8 g/dl). BM biopsy revealed 10% lambda-restricted plasma cell proliferation, coexisting with MDS with increased blasts grade 2 (WHO-5). Molecular studies showed: 2-FLT3 L601_K602insNFREYEYDL and ASXL1 E635fs*15. Chromosome analysis revealed normal karyotype. No in common clinical findings found during chart reviewing the cases. Conclusion Further investigating the underlying pathology, bone marrow microenvironment, and molecular and cytogenetics abnormalities in a larger number of patients with co-existing MDS and PCN is important. Also, if there was an association, it is important to study the sequence of occurrence between them.

7246 Cardiac Paraganglioma: A Rare Entity

Abstract Disclosure: L. Javed: None. L. Jonea: None. Cardiac paragangliomas are an exceptionally uncommon subset of neuroendocrine neoplasms. We present a case of a patient presenting with this condition. 70-year-old woman with pertinent past medical history of chronic veinous insufficiency complicated by recurrent abscesses of her right leg since venaseal procedure. The patient had positive IgG lambda on immunofixation that raised concerns for MGUS. Therefore, a F-18 FDG PET-CT scan was performed for further evaluation. PET-CT revealed a hypermetabolic mass in the upper inner right thigh and the right atrium (SUV 17.6) raising concern for septic thrombi. She was admitted in the hospital for initiation of antibiotic therapy. Transesophageal echocardiogram (TEE) revealed a 4.5 cm x 4.0 cm mass in the right atrioventricular (AV) groove region, extending over the root of the main pulmonary artery. Following discharge, despite completing six weeks of IV antibiotic therapy a CT scan on a subsequent clinic visit revealed the same mass as seen on TEE. CT imaging raised suspicion of neuroendocrine tumor. This led to referral to the endocrinology department. Laboratory results showed elevated normetanephrine and dopamine levels increasing likelihood of paraganglioma. Lab Results: 24 hr urine normetaneprhine :7197(N ≤ 376 mcg), 24 hr urinary dopamine :879 (N ≤400 mcg), 24 urinary metanephrine: 84 (N ≤96 mcg) & 24 hr urinary epinephrine <3 (N ≤20 mcg). Her home systolic blood pressure readings varied between 120’s & 170’s. She was initiated on Prazosin 1 mg daily in addition to the existing antihypertensive medications of nebivilol, amlodipine & furosemide. Few months later, this patient successfully underwent cardiac mass resection. Histologic findings of the resected mass were consistent with paraganglioma. Post-surgery, anti-hypertensive medications were discontinued, and blood pressure normalized to systolic readings in the 90s to 120s and diastolic readings in the 60s to 80s. Repeat biochemical tests indicated a normalization of normetanephrine & dopamine levels, validating the success of the resection. This case features an extremely rare entity cardiac paraganglioma that had an atypical clinical manifestation of being asymptomatic. Timely diagnosis and appropriate management are crucial for patient outcomes. Surgical intervention, although fundamental, bears significant risks, necessitating meticulous preoperative management to mitigate potential complications. The medical approach focuses on averting perioperative complications such as hypertensive crisis, cardiac arrhythmias and myocardial infarction. This is achieved by administering alpha and beta adrenoceptor blockers for a minimum of two weeks before the scheduled surgery. Regular follow up is also essential due to the unpredictable malignant potential of these tumors. Presentation: 6/3/2024

B-342 Teclistamab interference in serum protein electrophoresis and serum immunofixation electrophoresis in patients with recurrent or relapsed multiple myeloma

Abstract Background Serum protein electrophoresis (SPEP) and serum immunofixation electrophoresis (IFE) analyses are mainstays in the initial diagnosis, risk stratification, and evaluating treatment response in patients with multiple myeloma (MM) in accordance with the International Myeloma Working Group criteria. Published reports have demonstrated that therapeutic monoclonal antibodies (mAbs) used to treat MM (e.g. anti-CD38 IgG-kappa) are detectable by SPEP and IFE, which may interfere with accurate evaluation of complete response. Recently, Teclistamab (Tecvayli®; Janssen Biotech, Horsham Township, PA), a humanized bispecific IgG-lambda mAb targeting B-cell maturation antigen (BCMA) and CD3 on T cells was approved for treating patients with penta-refractory MM. In contrast with other IgG-kappa therapeutic mAbs, the degree to which Teclistamab may interfere with detection and quantification of monoclonal proteins is unknown. Therefore, we sought to assess the interference of Teclistamab therapy on routine SPEP and IFE analysis. Methods Patients treated with Teclistamab were identified by retrospective review of electronic medical records. Teclistamab (90 mg/mL) was spiked into a remnant patient sample with IgG lambda MM at a final concentration of 10 μg/mL, which corresponds to ½Cmax values in patients infused with Teclistamab. SPEP and IFE were performed using the Helena SPIFE Touch instrument. Computer-assisted densitometry was used to quantify monoclonal proteins in the gamma region of SPEP gels. Results In several patients with refractory MM treated with Teclistamab, IFE analysis revealed IgG lambda or lambda light chain monoclonal proteins, which were inconsistent with previously-identified monoclonal proteins (e.g. IgG kappa). In one patient diagnosed with IgG lambda MM, spiking 10 μg/mL Teclistamab increased M-spike abundance by approximately 0.15 g/dL when quantified by SPEP. Conclusions In patients with relapsed or refractory MM, treatment with Teclistamab may confound accurate clinical assessment of complete response by SPEP and IFE methods. Increased awareness of this preanalytical interference is necessary to guide clinical decision making.

Detecting M-Protein via Mass Spectrometry and Affinity Beads: Enrichment With Mixed Kappa-Lambda Beads Enables Prompt Application in Clinical Laboratories.

Detecting monoclonal protein (M-protein), a hallmark of plasma cell disorders, traditionally relies on methods such as protein electrophoresis, immune-electrophoresis, and immunofixation electrophoresis (IFE). Mass spectrometry (MS)-based methods, such as matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) and electrospray ionization-quadrupole time-of-flight (ESI-qTOF) MS, have emerged as sensitive methods. We explored the M-protein-detection efficacies of different MS techniques. To isolate immunoglobulin and light chain proteins, six types of beads (IgG, IgA, IgM, kappa, lambda, and mixed kappa and lambda) were used to prepare samples along with CaptureSelect nanobody affinity beads (NBs). After purification, both MALDI-TOF MS and liquid chromatography coupled with Synapt G2 ESI-qTOF high-resolution MS analysis were performed. We purified 25 normal and 25 abnormal IFE samples using NBs and MALDI-TOF MS (NB-MALDI-TOF). Abnormal samples showed monoclonal peaks, whereas normal samples showed polyclonal peaks. The IgG and mixed kappa and lambda beads showed monoclonal peaks following the use of daratumumab (an IgG/kappa type of monoclonal antibody) with both MALDI-TOF and ESI-qTOF MS analysis. The limits of detection for MALDI-TOF MS and ESI-qTOF MS were established as 0.1 g/dL and 0.025 g/dL, respectively. NB-MALDI-TOF and IFE exhibited comparable sensitivity and specificity (92% and 92%, respectively). NBs for M-protein detection, particularly with mixed kappa-lambda beads, identified monoclonal peaks with both MALDI-TOF and ESI-qTOF analyses. Qualitative analysis using MALDI-TOF yielded results comparable with that of IFE. NB-MALDI-TOF might be used as an alternative method to replace conventional tests (such as IFE) to detect M-protein with high sensitivity.

Belimumab Is an IgG Lambda Therapeutic Monoclonal Antibody with the Potential to Cause Misdiagnosis of a Monoclonal Gammopathy.

Belimumab Is an IgG Lambda Therapeutic Monoclonal Antibody with the Potential to Cause Misdiagnosis of a Monoclonal Gammopathy.

IgG4-Related Disease and Monoclonal Gammopathy: Case Report

Background: IgG4-related disease (IgG4-RD) is a progressive, chronic, atypical presenting clinical entity characterized by an elevated serum IgG4 level, leading to an immune-mediated fibroinflammatory condition affecting various organs.Case Summary: We present the case of a patient with clinical manifestations compatible with chronic pancreatitis due to the time of evolution. Physical examination revealed submaxillary, axillary, and inguinal lymphadenopathy and pain on abdominal palpation. Laboratory tests showed eosinophilia and a hepatocellular pattern in the liver profile. Immunofixation showed a monoclonal IgG lambda band with IgG4 values of 1183 mg/dl. To confirm the diagnosis of autoimmune chronic pancreatitis associated with IgG4-related sclerosing cholangitis, imaging tests were performed, which showed intrahepatic and extrahepatic cholestasis associated with pancreatic parenchymal alterations compatible with this entity. Subsequently, upon initiating glucocorticoid therapy, the patient evolved favorably. Conclusion: ER-IgG4 is a rare condition that causes inflammation and scarring in various organs. It is hard to diagnose and often mistaken for other diseases. The pancreas and biliary tract are frequently affected.

IgG4-Related Disease and Monoclonal Gammopathy: Case Report

Background: IgG4-related disease (IgG4-RD) is a progressive, chronic, atypical presenting clinical entity characterized by an elevated serum IgG4 level, leading to an immune-mediated fibroinflammatory condition affecting various organs. Case Summary: We present the case of a patient with clinical manifestations compatible with chronic pancreatitis due to the time of evolution. Physical examination revealed submaxillary, axillary, and inguinal lymphadenopathy and pain on abdominal palpation. Laboratory tests showed eosinophilia and a hepatocellular pattern in the liver profile. Immunofixation showed a monoclonal IgG lambda band with IgG4 values of 1183 mg/dl. To confirm the diagnosis of autoimmune chronic pancreatitis associated with IgG4-related sclerosing cholangitis, imaging tests were performed, which showed intrahepatic and extrahepatic cholestasis associated with pancreatic parenchymal alterations compatible with this entity. Subsequently, upon initiating glucocorticoid therapy, the patient evolved favorably. Conclusion: ER-IgG4 is a rare condition that causes inflammation and scarring in various organs. It is hard to diagnose and often mistaken for other diseases. The pancreas and biliary tract are frequently affected.

Prevalence of the t(11; 14)(q13; q32) immunoglobulin H/CCND1 in Mexican mestizos with multiple myeloma: A single institution experience

Abstract: BACKGROUND: Multiple myeloma (MM) is a hematologic malignancy resulting from clonal proliferation of plasma cells in which significant heterogeneity has been demonstrated, both cytogenetically and molecularly. Translocation (11;14)(q13;q32), involving the CCND1 gene, has been described as the most common one, its estimated prevalence being around 15%–24%. OBJECTIVE: The objective of the study was to report the prevalence of t(11;14) in Mexican individuals with MM in a single institution. MATERIALS AND METHODS: A descriptive cross-sectional study in 26 patients with MM undergoing a fluorescence in situ hybridization study with fluorescent probes for the detection of t(11;14) employing a fluorescence microscope and studying 200 interphase nuclei, referred to Laboratorios Ruiz and Synlab, Puebla, México from 2017 to 2021. RESULTS: The t(11;14) was found in 5 (19%) of the cases. Data on the clinical evolution of the patients was not available. In the 26 subjects, serum immunofixation was performed to identify the type of monoclonal gammopathy (MG), 13 (50%) were compatible with MG immunoglobulin (Ig) G-Lambda, 8 (30.7%) with IgG-Kappa, 4 (15.3%) with IgA-Lambda, and 1 (4%) with IgA-Kappa. Of the five individuals positive for t(11;14), four were IgG Lambda and one IgG Kappa. CONCLUSION: The presence of t(11;14) in our cohort is similar to that reported in other populations. The clinical implications of the t(11;14) translocation in MM have been observed in various populations, but further studies are needed to comprehensively assess its relationship to the clinical course of the disease.

Observations from Mass-Fix: Prevalence and Characteristics of Therapeutic Monoclonal Antibodies (t-mabs) Detected by Isotyping of Monoclonal Immunoglobulins via MALDI-TOF Mass Spectrometry

Abstract Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (“Mass-Fix”) has replaced serum immunofixation at our institution for detection of monoclonal immunoglobulins. One advantage of Mass-Fix is the ability to differentiate pathogenic endogenous monoclonal antibodies from therapeutic monoclonal antibodies (t-mabs), which are often the first-line treatment for multiple myeloma, by reviewing the light chain signature mass. The objective of this study was to describe the distribution of t-mabs and other key characteristics of clinical serum samples analyzed by Mass-Fix in 2022. Comprehensive results for each sample were extracted retrospectively from the laboratory information system. Of 66,710 total analyzed, 30,701 (46%) samples were reported as “positive” (i.e., contains a monoclonal protein), given the tertiary nature of our institution and reference laboratory services. The positive samples were further subdivided by t-mab (detected by Mass-Fix), with a total of 7,769 (25.3%) t-mabs reported. The top five IgG kappa t-mabs reported include daratumumab (n=6,537), elotuzumab or REGN5458/5459 (n=499), isatuximab (n=348), and rituximab (n=102). Rare observations included monoclonal proteins consistent with tixagevimab/ cilgavimab, for COVID-19 infection (n=7), obinutuzumab, an anti-CD20 t-mab for multiple sclerosis (n=1) and evolocumab, an IgG lambda anti-PCSK9 inhibitor (n=6). Of the 7,769 samples, the t-mab was the only reported clone in 47.7% of cases and was found along with the original disease-associated clone in remaining cases. When the original disease clone was present, it was an IgG kappa isotype 31% of the time and could have confounded the definition of complete therapy response for patients. 69% were non-IgG kappa original clones. Mass-Fix test orders have a multiple-choice prompt to provide any current therapy to aid in the patient’s result interpretation. For those samples where a t-mab was reported, the answer to this question regarding administered therapy was often discrepant from the report: only 38.5% of daratumumab-positive samples had an affirmation of daratumumab administration. The remaining 61.5% of daratumumab-positive samples reported an assortment of therapies, including bone marrow transplant, other t-mabs, no active therapy, or the field was left blank, highlighting poor compliance. Additionally, 154/36,009 samples where the provider affirmed daratumumab administration were reported as negative (i.e., no monoclonal protein observed on Mass-Fix). Often, the send-out laboratory does not have medical record access where treatment information is detailed. In conclusion, we reported the presence of a t-mab in 11.6% of all samples tested with Mass-Fix, suggesting that t-mabs have entered the clinical practice to stay, and accurately determining their presence in the challenging environment of poor compliance to prompt questions and evolving treatment regimens is something that cannot be ignored by clinical laboratories. Mass-Fix allows detection of a t-mab in the same routine run as other testing, without need of a second immunofixation to rule out the IgG kappa finding is not a t-mab.

Multicenter Descriptive Study of Monoclonal Gammopathy of Undetermined Significance in Patients with Heart Failure

Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is the presence of a monoclonal immunoglobulin without concurrent lymphoproliferative disease. It is found in about 5% of people aged 50 and older in the general population. Prevalence rates of MGUS increase with age, especially in men and individuals of Black ethnicity compared to women and White individuals, respectively. The diagnostic criteria for MGUS includes a serum M-protein level <3 g/dL, <10% clonal plasma cells in the bone marrow, and the absence of a myeloma-defining event. Though historically considered benign, emerging evidence suggests that MGUS patients, even without lymphoproliferative disorders, face increased risks of various diseases like bone diseases, recurrent infections, autoimmune disorders, peripheral neuropathy, renal complications, and cardiovascular disease (CVD). This study aims to investigate the prevalence and characteristics of individuals with both MGUS and heart failure (HF) and examine potential racial disparities between Black patients and non-Black patients with MGUS and HF. Methods: This is a retrospective multicenter study that includes patients diagnosed with both MGUS and New York Heart Association grade II or higher HF from January 2010 to January 2023. Patients with potential confounding conditions of MGUS were excluded, such as non-MGUS plasma cell dyscrasias, hematologic malignancies, autoimmune/inflammatory disorders, and viral illnesses. Laboratory data was recorded at the time of MGUS diagnosis, and HF data was derived from imaging studies performed closest to the time of MGUS diagnosis or at the initial diagnosis of HF if it was diagnosed after MGUS. Findings were summarized using descriptive statistics. Results: We analyzed a total of 128 patients with MGUS and HF, excluding 24 patients with potential MGUS confounders. Among the remaining 104 patients, 41 (39.4%) were female, and 63 (60.6%) were male. The cohort consisted of 80 (76.9%) Black patients and 24 patients of non-Black ethnicity. For the overall cohort, the mean age at MGUS diagnosis was 72, and the mean time from HF diagnosis to MGUS diagnosis was 22.5 months with a median of 9.1 months. In 24% of patients, HF and MGUS were diagnosed within less than 1 month of each other. The predominant monoclonal proteins observed were IgG Kappa, IgG Lambda, and IgA Kappa, found in 54 (51.9%), 30 (28.8%), and 13 (12.5%) patients, respectively. The average M spike was 0.7 +/- 0.6 (SD, standard deviation), and the average free light chain ratio was 2.3 +/- 2.3 (SD). The most common type of HF diagnosed was heart failure with reduced ejection fraction (HFrEF, EF <40%), occurring in 63.5% of the cohort. The etiology of HF in the cohort was attributed to ischemic cardiomyopathy in 43.3%, non-ischemic cardiomyopathy in 51%, and a combination of both in 5.7%. Table 1 presents the MGUS variables for the overall cohort and stratification by race. Table 2 displays the characteristics of study subjects based on the type of HF, including HFrEF, mid-range ejection fraction (HFmrEF, EF 40-49%), and preserved ejection fraction (HFpEF, EF >50%). Conclusion: This study did not find a significant association between MGUS variables and HF, likely due to the limited sample size. However, a larger study by Schwartz et al. using a Danish nationwide database with over 8,000 participants suggested that MGUS patients had a higher risk of incident CVD, even after adjusting for other comorbidities. They also noted a higher prevalence of CVD risk factors in patients with MGUS. These findings indicate a possible link between MGUS and CVD, though the true nature of this association remains uncertain - whether it's causal or coincidental. An interesting observation from our study is that MGUS is often incidentally detected in patients already diagnosed with HF. This suggests that physicians may come across MGUS while investigating the underlying causes of HF, raising the possibility of shared underlying factors or pathological processes between both conditions. Considering our findings, it's essential to recognize that MGUS patients may have a higher mortality risk independent of developing plasma cell disorders. Large-scale studies are needed to better understand the association between MGUS and CVD, potentially influencing monitoring and follow-up strategies for MGUS patients, especially concerning potential cardiovascular implications.

Characteristics and Outcomes of Adolescent, Young Adults, and Adults 40-50 Years Old with Multiple Myeloma: A Single Center Experience

Background Multiple myeloma (MM) is a malignant tumor with abnormal proliferation of plasma cells. Adolescent and Young Adult (AYA) patients are defined as patients between 15-39 years of age. Multiple myeloma is uncommon in non-elderly populations. Its prevalence is only 2% in AYA age group and only 10% in patients 40-50 years old. The feature of MM is not well known or understood in those two age groups. In this retrospective study we describe the clinical characteristics, cytogenetics, prognostic markers, treatments given and outcomes of MM in AYA and 40-50 years old patients. Methods We retrospectively analyzed data from the clinical database of our single tertiary hematology center, The National Center for Cancer Care and Research, Doha, Qatar. This center serves a country's population of about 2,8 million people. All patients diagnosed with MM between the age 50 or less during the period of January 2007 to December 2022 were included. Results Seventy-four patients were diagnosed at our centre with MM before the age of 50 years, total of all MM cases 222 (33%) Males was predominant 55/74 (74.3 %) with a median age of 41 years (range, 15-49). Most of the patients were from Asian 55%. At diagnosis patients had a median hemoglobin of 10.2 g/dl, creatinine 294 umol/L, total protein 90 gm/L, albumin 34.75 gm/L, calcium 2.7 mmol/L, LDH 255 U/L, IgG 2289.75 mg/dl, IgA 424.15 mg/dl, IgM 34.2 mg/dl, FLC-Kappa 1993 mg/L and FLC-Lambda 1177 mg/L. Median of bone marrow filtration by plasma cell was 51 %. Most of the patients presented at advance stages with 44 patient (59%) presented as IIIA Durie Salmon or stage III and IV by ISS 70 %. IgG Kappa most frequent type of MM 18 patients (24%), followed by Free light chain kappa (23%), IgG Lambda (18%) and others including two cases of plasmacytoma (Most recurrent cytogenetics were diploid cytogenetics in 42 patients (57%), while 7 patients (9%) had complex cytogenetics. Twenty-eight patients had spinal cord compression at single or multiple levels ( thoracic were most common site 20%) while 3 patients had pathological fractures. Bortezomib based regimen is most one used to treat our patients. Daratumumab- Velcade, Revlimid, and dexamethasone (D-VRD) was used for 35 patients (74%) and Velcade,Cyclophosphamide and Dexamethasone VCD in 20 patients (27%). The first response to treatment showed completed remission (CR) in 35 patients, very good partial remission in 10 patients, partial response in 9 patients, four patients either refractory or primary refractory disease and one patient with stable disease. Thirty -five patients (48%) underwent their first autologous bone marrow transplant ASCT. A total of 8 patients underwent second ASCT and one patient underwent third ASCT. After a median duration of follow up of 6.25 years and 72 % of the patients were still alive. We compared the characteristics and outcome for the AYA group (18-39) with patient age group 40 to 49 years. Although there was no statistical significance difference between the two groups regarding overall survival (p=0.21) , the older group had more cases of spinal cord compressions and more cases of refractory disease. Patient characteristics are described in Table 1. Conclusion One third of MM patients in our center are younger than 50 years. These patients tend to present with advanced stage and serious manifestation such as spinal cord compression. IgG kappa and free light chain are the most common myeloma type in this cohort. D-VRD is the most used protocol with a good response rate. Patient characteristics and treatment outcomes are the same for AYA patients compared with patients 40-49 years old (p=0.21). Patients who received first transplant had better OS compare the those who didn't (p0.01)

Albumin: Globulin Reversal As a Screening Tool for Monoclonal Gammopathy (Targeted Screening) in Hospitalized Setting

A Introduction: There is an unmet need to discover novel targeted screening guidelines for Qmonoclonal gammopathy of undetermined clinical significance (MGUS) in the Indian scenario which can help in early detection and diagnosis. Liver function tests (LFTs) are routinely performed in hospital settings for a variety of indications, with many having albumin-globulin (A:G) ratio reversals. We have designed this study to gauge the prevalence of MGUS in individuals above the age of 50 years with A: G ratio reversal in hospitalized settings. The objectives of the study were to measure the incidence of A: G ratio reversal in total LFT samples run in the hospital for various indications and to determine whether targeted screening of unexplained A: G ratio reversal in hospitalized patients is a fruitful strategy. Materials and Methods: This is a single-center, prospective observational study carried out from 01 May 2022 to 30 May 2023 at tertiary care center in Western India. All the LFTs of the admitted patients over the study period to the medical wards were included in the study. Patients with A:G reversal were subjected to detailed clinical examination and investigations to rule out non-myelomatous causes for the reversal of the ratio. Samples with unexplained A:G ratio reversal and unresolving A:G reversal despite of three months of observation were subjected to Serum Protein Electrophoresis (SPEP). Data was analysed using JMP ver. 16.0.0. Results: A total of 5148 LFTs were screened during the study period, of which 300 (5.82%) had A:G reversal. The median age of the study population with A:G reversal was 59 years (IQR - 14.3) with a male preponderance (59%). Etiologically amongst patients with A:G reversal 54% had infection, 15% had inflammation, 13% suffer from Chronic Liver Disease and 9% have Chronic Kidney Disease. Only 9% of patients (n-27) had no evident secondary causes, and of these 11% (n-3) have an M-spike on SPEP. Of all patients with A:G reversal, 1.1% have evidence of MGUS, all being IgG Lambda variants and none having any features of smoldering or multiple myeloma based on IMWG guidelines. Conclusion: G reversal compounded with good clinical history and examination can be an effective tool for targeted screening of MGUS. A majority of A:G reversals in hospital settings are due to secondary causes, requiring deliberate effort for exclusion.

Abstract 11919: Cardiac Conundrum: A Novel Case of Isolated Cardiac Scleromyxedema

Case Presentation: A 41-year-old woman with history of diabetes, inferior STEMI with RCA PCI, and HFmrEF was transferred to our hospital with worsening cardiogenic shock on ionotropic support. She was admitted to an outside facility one month prior with worsening dyspnea on exertion, peripheral edema, paroxysmal nocturnal dyspnea, pre-syncope, and weakness. TTE demonstrated LVEF of 30-35% (40-45% previously) with severe inferior and posterior wall hypokinesis. Cardiac MRI revealed LVEF of 23%, prior RCA infarct, full-thickness late gadolinium enhancement in the left ventricular basilar wall, global abnormal parametric mapping parameters of both native T1, T2 and ECV, and severe biventricular dysfunction concerning for infiltrative cardiomyopathy. Left heart catheterization revealed nonobstructive CAD. Right heart catheterization showed severely elevated right sided filling pressures and endomyocardial biopsy revealed frequent deposits of interstitial mucin (Figure 1), later confirmed by electron microscopy; a Congo red stain was negative for amyloid deposition. Additional work up included serum protein electrophoresis, which was negative for monoclonal proteins. She had no dermatologic disease. A diagnosis of isolated cardiac scleromyxedema was made. Discussion: Scleromyxedema is a rare mucinous disorder typically characterized by cutaneous mucin deposits and fibroblastic proliferation. It is commonly associated with monoclonal gammopathies, specifically IgG lambda; however, there are rare cases without paraproteinemia. Systemic mucinous infiltration has been reported and cardiac involvement specifically has been described in up to 20% of patients, although it has never been reported without cutaneous manifestations or monoclonal gammopathy as demonstrated with our patient. The patient received IVIg treatment, however required two additional hospitalizations over the next four months for decompensated heart failure.

Proliferative glomerulonephritis with monoclonal IgG Lambda deposits caused by plasmablastic lymphoma: a case report

IntroductionAs a very rare form of B-cell lymphoma, plasmablastic lymphoma (PBL) typically occurs in patients with underlying immunosuppression, including human immunodeficiency virus (HIV), organ transplantation, and autoimmune diseases. For HIV-positive patients, PBL normally originates in the gastrointestinal tract, especially from the oral cavity in most cases. It is extremely rare to find abdominal cavity involvement in PBL, and there has been no previously reported instance of proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) attributed to monoclonal IgG (MIgG) lambda secreted by PBL.Case presentationWe report the case of an HIV-negative female with nephrotic syndrome, renal insufficiency, and multiple swollen lymph nodes. Ascitic fluid cytology revealed a high level of plasmablast-like lymphocytes with the restriction of lambda light chains. Besides, the renal biopsy revealed PGNMID, which could presumably be secondary to MIgG-lambda-secreting by PBL. MIgG-lambda-restricted expression was discovered earlier in the kidney tissue than in the blood.ConclusionThe diagnostic landscape for PBL is notoriously intricate, necessitating a multifaceted and nuanced approach to mitigate the risks of erroneous identification.

B-179 Development of a Reflex Mass Spectrometric Workflow for Confirmation of IgE and IgD Specificity Paraproteins Utilising the EXENT® Platform

Abstract Background The EXENT® (GAM) assay is a MALDI-TOF (Matrix Assisted Laser Desorption Ionisation Time of Flight) mass spectrometry-based solution which utilises IgG, IgA, IgM, total kappa and total lambda specific paramagnetic beads, which could be used in the investigation of monoclonal proteins in multiple myeloma and other plasma cell disorders (in development by The Binding Site (TBS), part of Thermo Fisher Scientific). Rare cases of IgD and IgE myelomas will be partially typed with the current iteration of the EXENT (GAM) assay. We present here a workflow to confirm the heavy chain specificity of such paraproteins as IgD or IgE using reflex LC-MS analysis of EXENT eluates. Methods Samples known to contain IgD (2) or IgE (3) paraproteins were provided from either routine workload at the immunology laboratory at Birmingham Heartlands Hospital, UK or an internal library of historical myeloma samples. Capillary zone electrophoresis (CZE) and immunofixation (IFE) were performed on Capillarys2™ and Hydrasys2 Scan™ platforms, respectively (Sebia, France). Serum free light chain (sFLC) measurement was performed using Freelite® reagents (The Binding Site, UK) on a Cobas c501 turbidimeter (Roche, Switzerland). Samples were prepared via EXENT (GAM) assay, by separately incubating diluted serum with antisera specific for IgG, IgA, IgM, total kappa and total lambda conjugated to paramagnetic beads. After washes, purified immunoglobulins were treated to reduce and elute the light chain component. Samples were mixed with matrix, spotted onto a MALDI target plate and acquired by MALDI-TOF MS. Once light-chain specificity of the suspected IgD or IgE paraprotein was determined, repeat immuno-precipitation with the same light-chain bead was carried out. Eluted samples were neutralised, transferred to fresh tubes, reduced, alkylated and digested with trypsin for 3 h. After acidification digested samples were analysed by C18 reverse phase UPLC on a BioAccord LC-MS system (Waters, UK). Data was then screened against a database of known immunoglobulin heavy chain peptides to assess the presence of heavy chain peptides specific for each immunoglobulin isotype. Results In each sample tested, the EXENT solution identified at least one monoclonal light chain that was only seen in the total kappa or total lambda immunoprecipitations with no corresponding monoclonal peak(s) at the same mass(es) in the IgG, IgA or IgM specificities. This finding would be consistent with the presence of clonal plasma cells producing either monoclonal free light chains only, or IgD and IgE paraproteins. Subsequent LC-MS and LC-MSe (tandem MS) analysis of reduced, alkylated and tryptically digested eluates corresponding to these suspected IgD and IgE samples produced high quality peptide sequencing data. The data identified multiple IgD or IgE specific peptides in each sample and showed between 40% and 66% sequence coverage for IgD or IgE heavy-chain constant regions. Thus, confirming the presence of IgD or IgE in these samples which had been partially typed by the EXENT solution. Conclusion This data demonstrates that the EXENT (GAM) assay could potentially aid in detection of IgD and IgE paraproteins when combined with LC-MS proteomic techniques, as it allows efficient and facile confirmation of these rare heavy chain isotypes.

Recurrent atypical antiglomerular basement membrane nephritis in the kidney transplant

Atypical antiglomerular basement membrane (anti-GBM) nephritis can be defined as linear GBM staining for monotypic or polytypic immunoglobulin (Ig) by immunofluorescence (IF) without a diffuse crescentic pattern. We describe the clinicopathologic features of 6 patients (18 biopsies) in this first series of recurrent atypical anti-GBM nephritis after kidney transplantation. Recurrent glomerulonephritis occurred at a mean of 3.8 months posttransplant (range 1-7 months). Three index biopsies were for clinical indication, and 3 were protocol biopsies. Glomerular histologic changes were mild, with 2 showing segmental endocapillary hypercellularity, 1 focal glomerular microangiopathy, and the others no significant glomerular histologic changes. All 6 allografts showed monotypic linear glomerular Ig staining by IF: IgG kappa (n = 2), IgG lambda, IgA kappa, IgA lambda, and IgM lambda. Follow-up biopsies were available for 5 patients and showed similar histologic and IF findings without evidence of significant progression. No patients had detectable serum anti-GBM antibody or monoclonal proteins. The mean serum creatinine level on follow-up (24-62 months posttransplant) was 1.8 (range 0.93-2.77) mg/dL; no grafts were lost to recurrent disease. This series demonstrates that monotypic atypical anti-GBM recurs in the allograft and supports the idea that this disease is due to a circulating monoclonal protein.

An unusual cause of portal hypertension.

A 66-year-old male with a medical history of coronary artery disease presented with nonspecific symptoms of anorexia, lethargy and an increase in abdominal girth. He was diagnosed 3 months ago with chronic liver disease of undetermined aetiology. He did not smoke and was a social drinker till 4 months ago. He was taking tests showed progressive cholestatic liver enzymes (total bilirubin 1,09 mg/dL, AST 130 U/L, ALT 129 U/L, GGT 517 U/L and ALP 641 U/L) and a severe hypoalbuminemia. Laboratory workup made a metabolic, autoimmune, and viral aetiology of the suspected cirrhosis less probable. Urinalysis showed a rapidly progressive proteinuria in the nephrotic range accompanied by the presence of serum spike of monoclonal lambda light Furosemide, Aldactone, Pantoprazole, Acetylcysteine and Atorvastatin. He had no personal or familial history of liver diseases. Physical examination revealed a tender but distended abdomen and large ascites was present. The laboratory chain protein on electrophoresis with immunofixation. Doppler echocardiography revealed a hypertrophic cardiomyopathy based on diffuse left and right ventricular hypertrophy with relative apical sparing. A diagnostic paracentesis was undertaken and the results were consistent with portal hypertension (SAAG 1,6 g/ dL). Considering the concomitant presence of hypertrophic cardiomyopathy, nephrotic syndrome and a presentation of portal hypertension of undetermined aetiology in presence of a monoclonal IgG lambda light chain spike, a transjugular liver biopsy (figure 1 and 2) was performed with HVPG measurement consistent with significant portal hypertension (15 mmHg).

Evolution of monoclonal gammopathy of undetermined significance in patients treated with JAK inhibitors for rheumatic diseases: data from the MAJIK-SFR registry.

Monoclonal gammopathy of undetermined significance (MGUS) is common, but there are scarce data regarding the effect of DMARDs on this premalignant condition. We aimed to evaluate the impact of JAK inhibitors (JAKis) on MGUS when initiated for an active rheumatic disease. Patients with monoclonal abnormality prior to JAKi initiation for an active rheumatic disease were identified through the MAJIK-SFR Registry, a French multicentre prospective study. Clinical and biological data were collected using a standardized case report form. Twenty patients were identified with a mean age of 65 years and a diagnosis of RA (n = 15), PsA (n = 3), and axial SpA (n = 2). The JAKi prescribed was baricitinib (n = 9), tofacitinib (n = 6) or upadacitinib (n = 5), with a mean duration of 15.5 months. Seventeen patients had individualized serum monoclonal protein (IgG kappa n = 9; IgG lambda n = 4; IgM kappa n = 3; IgA lambda n = 1) ranging from 0.16 to 2.3 g/dl, and three patients did not have an initial measurable spike but they had a positive serum immunofixation. With a follow-up of 4-28 months, the serum monoclonal protein level decreased in 8 of 17 patients (47%), remained stable in 8 patients (47%) and increased in 1 patient (6%). The maximal decrease observed was an initial IgG kappa of 2.3 g/dl, decreasing to 0.2 g/dl at month 14. This study provides reassuring and promising data on MGUS evolution in patients treated with JAKis for rheumatic diseases, which may guide the choice of treatment in patients with both conditions.