Monoclonal Protein Research Articles

Monoclonal Gammopathy of Undetermined Significance in General Practice

Background: In addition to progression to lymphoproliferative diseases, patients with monoclonal gammopathy of undetermined significance (MGUS) appear to suffer from other types of comorbidities although the extent to which MGUS contributes to these comorbidities is unclear. The aim of this study is to evaluate the presence of patients with MGUS who attend general practice (GP) in our healthcare area, as well as to describe the comorbidities and abnormal blood test results associated with these patients.Methods: A retrospective study was carried out, where demographic data, comorbidities, and results of some analytical parameters were collected from 1201 patients who visited their general practice physician: 201 patients with a monoclonal protein detected, and 1000 patients without presence of monoclonal protein.Main findings: Out of the 6307 proteinograms performed on patients from GP, 201 presented an M-protein (3.2%). The presence of MGUS increased with age and was significantly higher in men than in women (55.7% vs 44.3%, p<0.05). We found that the most frequently associated comorbidities with MGUS are renal and cardiovascular diseases, osteoporosis and bone lesions, anemia, and hyperlipidemia. There was a significant association between MGUS and the following blood parameters: hemoglobin, leukocytes, neutrophils, monocytes, proteins, albumin, globulin and creatinine; as well as for the indices neutrophil-to-lymphocyte, monocyte-to-lymphocyte and albumin-to-globulin ratio.Principal conclusions: We conclude that MGUS is a common premalignant plasma cell disorder in general practice patients, the prevalence of which increases with age. Likewise, a series of blood parameters and comorbidities associated with MGUS that support the need to implement a program for early detection and monitoring of MGUS was described.Key words: MGUS, paraprotein, general practice, comorbidities

AMYLOID CARDIOMYOPATHY: DIAGNOSIS AND TREATMENT

The review presents current data on heart disease in systemic amyloidosis. The article discusses variants of amyloi-dosis with common heart disease: AL-, ATTRwt- and ATTRv amyloidoses. Clinical signs of amyloid cardiomyopathy and extracardiac manifestations that allow one to suggest amyloidosis are described. Methods for diagnosing amyloid cardiomyopathy are presented. Echocardiographic diagnostic characters include increased thickness of the left ventricular wall, atrioventricular valve, right ventricular wall, thickening of the interatrial septum, and also diastolic dysfunction, and decreased global longi-tudinal strain with relative preservation of apical longitudinal strain. Magnetic resonance imaging reveals signs specific for amyloidosis: increased extracellular volume and diffuse suben-docardial or transmural delayed enhancement after gadolinium administration. Scintigraphy using technetium-99m labeled compounds can confirm the diagnosis of ATTR cardiomyopathy. The diag-nosis of ATTR cardiomyopathy is only possible in combination with blood and urine tests to exclude the presence of a monoclonal protein. Screening for monoclonal protein includes three laboratory tests: determination of free light chains in blood serum, electrophoresis of serum protein and urine protein with immunofixation. Indications for myocardial biopsy and the role of extracardiac tissue biopsy are discussed. Endomyocardial biopsy should be performed: a) in case of strong clinical suggestion of cardiac amyloidosis in a patient with monoclonal pro-tein; b) in case of strong clinical suggestion of cardiac amyloidosis, despite negative or equivocal scintigraphy result; c) if cardiac scintigraphy is not available. The possibilities of pathogenetic therapy for ATTR- and AL amyloidosis, aimed at stopping or slowing amyloid deposi-tion in the heart, and symptomatic treatment are discussed.

Prognostic significance of serum monoclonal proteins based on immunofixation electrophoresis in B-cell non-Hodgkin lymphoma.

The presence of serum monoclonal components has been associated with poor outcomes in various hematological malignancies. The current study focused on exploring its prognostic role in B-cell non-Hodgkin lymphoma. Our study represented 314 patients with information on serum immunofixation electrophoresis at diagnosis that were available with B-cell non-Hodgkin lymphoma. IFE was positive in 61 patients (19%). Baseline features were comparable between pairs of groups, poor ECOG PS, B symptoms, advanced stage, and high-risk IPI score were significantly more frequent in the + IFE group. Shorter PFS and OS of B-NHL patients were observed in patients who presented at diagnosis with a + IFE, and IFE was the independent predictor of PFS and OS in multivariate analysis. Moreover, integrating IFE into the IPI-M1, IPI-M2, and IPI-M3 models improved the area under the curve for more accurate survival prediction and prognosis. Serum monoclonal proteins are significant prognostic indicators for newly diagnosed B-cell non-Hodgkin lymphoma that can early identify patients with poor prognosis and guide clinical treatment decisions.

Frequency of Cysts by Immunofluorescence Assay in Human Brain Tissue of Suicide, Traffic Accident and Homicide Decedents

BACKGROUND: Several studies link toxoplasmosis with neuropsychiatric disorders. There are no previous reports of the frequency of the presence of parasite tissue cysts in autopsy cases from violent death or how is the distribution of frequency according to brain regions related with behavior (amygdala or hippocampus). The immune fluorescent antibody technique (IFAT) detects specific target antigens that allow the observation of bradyzoites within tissue cysts. We describe the frequency of tissue cysts using the IFAT detection in human brain tissue samples from immunocompetent persons deceased by suicide, traffic accidents and homicide. METHODS: 21 brains from the National Institute of Legal Medicine and Forensic Sciences chapter “Eje Cafetero” (including cities of Armenia, Pereira, and Manizales) of violently deceased (which includes suicide, traffic accidents and homicide) persons were obtained, subsequently sections of the amygdala and hippocampus areas were processed in paraffin and thick sections were cut from paraffin blocks and mounted on slides by means of the IFAT, by using specific monoclonal anti BAG1 protein of the bradyzoite. Serum samples from the decedents were also examined for the presence of IgG and IgM antibodies to establish the existence of a previous infection. Data such as age, gender, sociodemographic data, and type of death were also obtained. Evaluation of the differences in the percentage of positivity according to the cause of death were assayed by using the Fisher exact test. RESULTS: Two decedents (9.5%) were female and 19 (90.4%) were male. The age ranged from 14 to 65 years; most completed or were in high school level of education. By city, 9 were from Armenia (42.8%%) and 12 from Manizales (57.1%). By type of death, 11 samples (52.3%) were victims of homicide, 9 samples (42.8%) were suicide, and one sample (4.7%) was a traffic accident. We identified tissue cysts containing the bradyzoites in two cases in amygdala (9.5%), in amygdala and hippocampus in tree (14.2%), and one case only in hippocampus (4.7%). In total we have six of 23 (26%) were positive for cysts in the brain. No statistically significant differences were found between groups in the percent of positivity. After counting we found a mean 1,3 ± 0,4 cysts by 20 microscopy fields of positive brain tissue examined. We found one of 21 positives for IgG antibodies in blood (47%). Within six cases with positive by IFAT in brain tissue five were also positive in antibodies (83%) only one case was negative for antibodies. CONCLUSION: The presence of bradyzoite was demonstrated in brain tissue samples from immunocompetent patients who suffered a violent death in the cities of Armenia and Manizales, Colombia. The results suggest that the bradyzoite after infection is permanently localized in brain tissue. A higher prevalence of bradyzoite parasites is observed in amygdala samples, an important region for behavior control.

Identification and management of gastrointestinal manifestations of hereditary transthyretin amyloidosis: Recommendations from an Italian group of experts

Gastrointestinal manifestations are common across all hereditary transthyretin amyloidosis (ATTRv) genotypes. However, they are poorly specific, and their recognition as part of ATTRv is difficult, resulting in misdiagnosis with more common conditions. Moreover, delays in diagnosis occur because of fragmented knowledge, a shortage of centers of excellence and specialists dedicated to ATTRv management, and the scarce involvement of gastroenterologists in multidisciplinary teams. A group of Italian gastroenterologists with experience in the management of ATTRv took part in a project aimed at assessing the awareness of ATTRv among the community of Italian gastroenterologists through an online survey and providing education about practical aspects of ATTRv management. Survey results reported low participation, and very few patients with ATTRv were cared for by gastroenterologists. This highlights the need for greater attention to rare diseases in gastroenterology and emphasizes increasing awareness of ATTRv and diagnostic suspicion. Based on the experts' recommendations, a diagnosis of ATTRv should be suspected when at least one of the 'red flags' is detected. Subsequently, it is suggested to promptly ask for genetic testing and exclude a serum and urinary monoclonal protein, even before the detection of amyloid in biopsy samples, particularly in non-endemic areas.

Cytogenetics of Multiple Myeloma

Multiple myeloma is a type of cancer that affects the plasma cells in the bone marrow. In this abstract, we discuss the cytogenetic abnormalities in multiple myeloma patients and their correlation with age and gender. We also describe the techniques used for cytogenetic analysis in the Indian population. Our study included 70 patients with multiple myeloma, and cytogenetic analysis was performed using conventional karyotyping and Fluorescence In-situ Hybridization (FISH) techniques. We observed a higher incidence of cytogenetic abnormalities in patients above 60 years of age, with male predominance. FISH analysis showed a higher detection rate of cytogenetic abnormalities compared to conventional karyotyping. FISH also provided additional information on the extent and complexity of the chromosomal aberrations. It is a cytogenetic technique that uses fluorescently labelled probes to detect genetic abnormalities in the chromosomes of cells obtained from bone marrow. This analysis can provide valuable information about the type and stage of the disease, Translocations t(4;14),t(14;16), t(6;14), and t(14;20) were associated with anaemia, t(4;14) was associated with a higher serum monoclonal protein and plasma cell proliferation. Monosomy 13 is associated with a short survival rate with transition monoclonal gammopathy. In conclusion, our study confirms the age and male predominance in multiple myeloma and highlights the importance of cytogenetic analysis in the diagnosis and prognosis of the disease. By studying the chromosomal abnormalities in MM, we can gain insights into the underlying causes of the disease. In this study, we will discuss the cytogenetics of MM and explore how it can help understand the genetics of cancer. The study highlights the chromosomal abnormalities associated with MM and its implications for diagnosis and prognosis.

Clinical specificity of two assays for immunoglobulin kappa and lambda free light chains.

Free light chain (FLC) assays and the ratio of κ/λ are recommended for diagnosis, prognosis and monitoring of plasma cell dyscrasias (PCD). Limited data exists on FLC clinical specificity in patients diagnosed with other conditions. We assessed the κ, λ, and κ/λ FLC ratio using the FreeLite assay and the Sebia FLC ELISA assay in 176 patients with clinical presentations of fatigue, anemia, polyclonal hypergammaglobulinemia, joint disorders, kidney disease and non PCD-cancers with no monoclonal protein observed on serum protein electrophoresis or MASS-FIX immunoglobulin isotyping. Manufacturer defined reference intervals (RI) and glomerular filtration rate (GFR) specific RI (renal RI) were utilized. For the κ/λ ratio, 68.7 % (121/176) of specimens on the FreeLite and 87.5 % (154/176) of specimens on the Sebia assay were within RI. For κ, 68.2 % (120/176) and 72.2 % (127/176) of results were outside RI for FreeLite and Sebia respectively. For λ, 37.5 % (66/176) and 84.1 % (148/176) of FreeLite and Sebia results were outside RI. With FreeLite and Sebia, patients with kidney disease (n=25) had the highest κ/λ ratios. 44 patients (25.0 %) had GFR <60 mL/min/BSA. When renal RI were applied, 13.6 % had a FLCr outside the renal RI with FreeLite, and 4.5 % with Sebia. In a cohort of patients with signs and symptoms suggestive of PCDs, but ultimately diagnosed with other conditions, Sebia FLC had improved clinical specificity relative to FreeLite, if one was using an abnormal κ/λ ratio as a surrogate for monoclonality.

Monoclonal Gammopathy of Undetermined Cardiovascular Significance; Current Evidence and Novel Insights.

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition characterized by the presence of low levels of a monoclonal protein in the serum and a low percentage of clonal plasma cells in the bone marrow. MGUS may progress to multiple myeloma or other plasma cell disorders at a rate of 1% annually. However, MGUS may also have adverse effects on the cardiovascular system independent of its malignant potential. Emerging data have shown that MGUS is associated with cardiovascular disease. The mechanisms underlying this association are not fully understood but may involve genetic abnormalities, vascular calcification, cryoglobulinemia, cold agglutinin disease, autoantibodies and the direct or indirect effects of the monoclonal protein on the vascular endothelium. Herein, we review current evidence in this field and we suggest that patients with MGUS may benefit from regular cardiovascular risk assessment to prevent severe cardiovascular complications, in parallel with close hematological follow-up to monitor potential disease progression.

Sindrome de Poems

Poems syndrome :s a rare multisistemic disorder. It manifestations are Polynueropathy, Organomegaly, Endocrinopathy,and / 01Edema. Monoclonal protein and changes in the Skin. (P.O.E.M.S.)Though some bibliography make no difference with osteoesclerotic mieloma it is considered a real syndrome.The polynueropathy is customarily severe. Although high levels of inrnullo- globulins has been found in the poems, it has not been isolatcd a specific antibody that explain the polynueropathy even though it is strongly suspected.The organomegaly, endocrinopathy, changes in the skin and other systems and involved organs could be in relationship toproducts secreted by plasmatic celis. Wc review the physiopathology and bibliography of the Poems, especially its neurological expression its nosologic location different from osteosclerotic myeloma and a possible relationship to the Herpes Virus S.It was crossed in Medline the terms P.O.E.M.S. and syndrome and were obtained 271 abstracts that were all examined and finallyselected the bibliography considerate meaningful for the objectives. It is presented briefly a case.P.O.E.M.S. is a syndrome that is associated to multiple plasma eclI dyscracia, included the osteoesclerotic myeloma.Prognosis and the treatment vary with the underlying diseasc. As physiopathology of this syndrome is insinuated the action of the interleukines 1- (IL-1 beta) and 6 (IL-6), the vascular growth endothelial factor (VGEF), the tunioral necrosis factor alpha (TNF-alpha) and antibodies anti- nerve. The P.O.E.M.S. is a syndrome with own Palabras claves: Síndrome de POEMS aso- identity. ciado con mieloma múltiple.The Herpes Virus 8 may plays a key rol Material y Métodos to uncover the Poems physiopathology.

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.

Myelomatous Ascitis, a Rare Presenting Symptom of Multiple Myeloma

Abstract Introduction/Objective In 2022, plasma cell neoplasms accounted for approximately 1.8% of all new cancers in the United States with an estimated 34,470 new cases of multiple myeloma. Diagnosis is often straight forward in ~80% of cases by performing serum protein electrophoresis (SPEP), serum immunofixation (SIFE), and/or urine immunofixation (UIFE) with M-spike quantification. The diagnostic challange is in the remainder of asymptomatic myeloma cases (~20%) which are found incidentally. Specialized laboratory technicians are often the first step in identifying plasma cells in body fluids and/or peripheral blood smears. These incidental findings on routine labs, paired with the keen eye of a specialist, are one of the first steps in early detection of multiple myeloma. Methods/Case Report A 62 year-old male, originally from Cambodia, presented to an outside hospital emergency department with abdominal distention and pain. His past medical history was significant for dialysis-dependent end- stage renal disease and insulin-dependent diabetes mellitus type 2. Abdominal CT showed ascites with no other diagnostic findings. Cardiac, renal and hepatic etiologies of ascites were ruled out. Body fluid analysis of the ascites in the Clinical Pathology laboratory revealed numerous plasma cells. Cytologic examination, after consultation with Clinical Pathology, also revealed numerous plasma cells. Subsequent SPEP and SIFE disclosed an IgA lambda monoclonal protein. A diagnosis of multiple myeloma was confirmed by bone marrow biopsy with FISH studies. Results showed several high-risk abnormalities including translocations of 4::14, 14::16, and 14::20, denoting a “triple hit” multiple myeloma. Results (if a Case Study enter NA) NA Conclusion Plasmacytosis in ascites is an extremely rare initial presentation for multiple myeloma. With only a few cases reported in the literature, many technicians and pathologists might easily overlook plasma cells on routine cytology, especially with normal imaging and no previous diagnosis of myeloma. In this case, flagged peritoneal fluid by a skilled medical laboratory technician was key to making a diagnosis. Without any signs of a plasmacytoma or lytic bone lesions on imaging, a normal CBC with non-specific labs, and an unsuspecting surgical pathology report, multiple myeloma was not on the differential. Fast interdepartmental consultation, communication, and teamwork between surgical pathology and clinical pathology, lead to a rapid diagnosis and prompt treatment of this patient.

Focal Plasmacytoid and Fibrotic Hepatic Lesion In An Autopsy Examination Of A Patient With Multiple Myeloma

Abstract Introduction/Objective Multiple Myeloma (MM) is a plasma cell neoplasm mainly affecting the bone marrow. Common sites of extramedullary dissemination are skin, liver, kidneys, and the central nervous system. Though diffuse plasma cell infiltration of the liver has been described in autopsy literature in about 50% of patients with multiple myeloma, it is usually not associated with focal infiltration. Rare cases of plasma cell infiltration leading to non-obstructive cholestasis and acute hepatic failure have been described. Methods/Case Report We hereby present a case of 54-year-old decedent male with past medical history of obesity, hypertension, and diabetes mellitus who presented to the emergency department with complains of productive cough, dyspnea, vomiting and back discomfort. Labs showed leukocytosis, thrombocytopenia and hypercalcemia. Additionally, there was an increase in lactate and serum monoclonal protein levels and derangements in renal and liver function tests. Skeletal bone survey showed a 1.4 cm well-circumscribed lucent lesion within the distal third of the left clavicle and in the calvarium which raised concern for multiple myeloma and tumor lysis syndrome. During the hospital course, the patient’s overall clinical condition declined rapidly, and he passed away on the third day of admission. During the autopsy examination, the patient’s bone marrow revealed diffuse infiltration of plasma cells confirming multiple myeloma. In addition, the histopathological examination of the liver revealed focal plasmacytoid fibrosis, moderate periportal inflammation with plasma cell infiltration and microsteatosis. Immunohistochemical stains with CD138, MUM-1, ISH kappa and lambda and trichrome highlighted the focal plasma cell infiltration and fibrosis in the liver, respectively. Results (if a Case Study enter NA) NA Conclusion Our case shows the importance of utilizing histopathological and immunohistochemical examination in confirming the diagnosis of multiple myeloma, specifically in the autopsy cases where there is no previous diagnosis of multiple myeloma. In addition, it highlights the awareness of rare focal plasmacytoid fibrosis and infiltration as an extramedullary presentation of multiple myeloma.

Assessing a New Paradigm in Defining High Risk Precursor Disease State for Patients with Plasma Cell Dyscrasia: Fluctuating Monoclonal Protein

Multiple Myeloma (MM) is a malignancy originating from mature plasma cells in the bone marrow, typically preceded by clinically asymptomatic precursor conditions. Early identification of the risk of progression from these precursor states, like Monoclonal Gammopathy of Undetermined Significance (MGUS) or Smoldering Myeloma, to full-blown MM is critical for improving patient outcomes. The current risk models for MM rely on limited clinical and laboratory parameters, unable to fully encompass the complex nature of the disease continuum. To overcome these challenges, developing and validating a more comprehensive risk model is imperative, incorporating a wider array of clinical, genetic, and immune-related factors. This approach will enhance predictive accuracy and clinical applicability significantly. Notably, changes in serum monoclonal protein spike (M-spike) levels can reflect dynamic fluctuations in the net clonal mass, representing the ongoing battle between the plasma cell clone and the anti-myeloma immune response within patients. However, the impact of this highly dynamic state on the risk of progression to MM remains largely unexplored. Our study aims to bridge this knowledge gap by investigating the association between the dynamic M-spike pattern and the risk of progression from a precursor clone to MM, offering valuable insights into a potential novel prognostic marker for disease advancement. Methods: This study aimed to redefine high-risk precursor states in patients with plasma cell dyscrasias, focusing on positive serum electrophoresis (SPEP) results recorded between January 2011 and January 2021. We categorized precursor states as patients with positive SPEP, excluding those who had received active multiple myeloma (MM) treatment within 90 days of their first positive SPEP, showed M-spike values exceeding 3g/l, or displayed evident signs of disease progression. To assess M-spike patterns, we classified them as stable or fluctuating, using a 20% difference criterion to differentiate between the two (i.e., fluctuations less than 20% from baseline were labeled as stable). The time-to-treatment (TTT) was calculated from the first positive SPEP to the initiation of treatment, with death considered a competing risk. Results: The study included 565 patients, among whom 372 showed a stable M-spike pattern, while 193 exhibited a fluctuating pattern. The racial composition of the study population was predominantly white (75.58%), followed by black (21.77%) and other races (2.65%). The distribution of races was virtually identical in both the fluctuation and stable groups (p=0.977). The fluctuation group had a slightly lower proportion of females (49.7%) than the stable group (53.2%), but this difference was not statistically significant (p=0.432). Univariate analysis revealed that patients in the fluctuating group had a significantly higher odds ratio (OR) of requiring treatment (OR: 4.5, 95% CI: 1.37 - 14.18, p = 0.013) than those in the stable group. Interestingly, the prevalence of autoimmune conditions differed significantly between the groups. While 11.86% of the whole group had an autoimmune disorder, the proportion was lower in the fluctuation group (9.8%) than in the stable group (16.7%) (p=0.028).Confirming these findings, the multivariate time-to-event analysis further demonstrated that patients with fluctuating M-spike patterns had a greater likelihood of needing therapy (Hazard Ratio: 3.73, 95% CI: 1.19 - 11.66, p = 0.024) compared to those with stable patterns. Conclusion: Our study introduces a novel approach to defining high-risk precursor states in patients with plasma cell dyscrasias, emphasizing the significance of undulating monoclonal protein patterns. The dynamic nature of these fluctuations, representing the delicate interplay between pro-growth myeloma clones and anti-tumor immunity, emerges as a strong predictor of progression to MM. Further investigation and validation of these findings in more extensive studies hold promise for advancing personalized risk assessment and the development of targeted therapeutic strategies to prevent or delay the onset of multiple myeloma.

Outcomes Associated with Clone-Directed Therapies for Monoclonal Gammopathy of Renal Significance

Background: Monoclonal Gammopathy of Renal Significance (MGRS) is a category of diseases not meeting criteria for cancer, in which a clonal population of B-lymphoid or plasma cells produces a nephrotoxic protein leading to kidney injury. Informal consensus has arisen that therapy targeting the causal clone is most likely to be efficacious, and the primary goal of therapy is to prolong renal survival. Light chain (AL) amyloidosis has been extensively studied, yet there is a paucity of data describing outcomes associated with clone-directed therapy for the various subtypes of non-AL MGRS. Methods: This was a retrospective analysis of patients treated at two National Cancer Institute (NCI)-designated cancer centers in the United States. Medical records of adult patients seen between January 2010 and March 2023 were screened for MGRS. Patients were eligible if they had renal biopsy-confirmed histopathologic findings compatible with MGRS. AL amyloidosis was excluded. The primary outcome was renal survival, defined as time from diagnosis of MGRS to requiring renal replacement therapy (RRT) or renal transplant, with patients censored at last follow up or death. Baseline characteristics were described, including 24-hour proteinuria, estimated glomerular filtration rate (eGFR), whether a clonal population of B cells or plasma cells could be identified on histopathologic examination of marrow or lymph node biopsy, concentration of monoclonal protein, and involved serum free light chain concentration. Initial therapy was reported, although differences in outcomes across therapeutic strategies were not compared. Baseline clinical characteristics between patients who required RRT and those who did not were compared. Baseline clinical variables and time to RRT were compared across the two most common MGRS subtypes in the cohort: proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and light chain deposition disease (LCDD). Continuous variables were compared across subgroups using Wilcoxon rank-sum test. Time-to-event outcomes were analyzed according to the Kaplan-Meier method. All analyses were conducted using R version 3.6.1. Results: In total, 65 patients were included, 23 (35%) of whom ultimately required RRT or transplant. Four patients died, all after RRT. Median baseline proteinuria was 2802 mg/24h (IQR 972.5 - 4492.0) and median eGFR was 33.0 mL/min (IQR 23 - 53) for the entire cohort. In all cases proteinuria was mostly albumin. Median baseline involved light chain concentration was 8.3 mg/dL (IQR 3.1 - 26.4). A majority of patients (n=33, 51%) had no identifiable serum monoclonal protein. The two most common MGRS subtypes were PGNMID (n = 26) followed by LCDD (n = 21). Clonal populations thought to be causing MGRS were identified in 41/64 patients (64%), including 37 (58%) with plasma cell clones, 1 (2%) with a lymphoplasmacytic lymphoma clone, and 3 (4.7%) with other B-cell clones. Clones were not identified in 23 (36%). The most common chemotherapy agents included bortezomib (n=42, 64%) and rituximab (n=14, 22%). Compared to patients not requiring RRT, patients requiring RRT had higher baseline proteinuria (median 3531 vs. 1980 mg/24h, p&amp;lt;0.001) and lower eGFR (median 16 v. 44 mL/min, p&amp;lt;0.001); differences in serum free light chain concentrations were not significant ( Figure 1). A clonal population thought to be causing MGRS was identified on bone marrow biopsy in a majority of LCDD patients (n = 20, 95%), while clones were infrequently found in PGNMID (n = 6, 23%). The vast majority (n=20, 95%) of patients with LCDD received bortezomib-based therapy. Initial therapy in patients with PGNMID was more evenly divided: 9 (35%) received bortezomib-based therapy, 10 (38%) received rituximab-based therapy, and 6 (23%) received other regimens. Despite differences in therapeutic approach, patients with LCDD and in patients with PGNMID had similar risk of RRT (cumulative risk 35% v. 43%, p=0.54; HR 0.83 (95% CI 0.52-1.33); p =0.44) ( Figure 2). Conclusion: Patients with MGRS remain at high risk of requiring RRT even with clone-directed therapy. Despite differences in pathogenic clones and therapeutic strategies, outcomes of patients with PGNMID and LCDD are similar. Because the severity of baseline renal function across MGRS histologies predicts renal survival, early diagnosis and treatment is likely critical to improving renal outcomes.

Prevalence of MGUS in Rural Indian Population: Results of Simple (IMAGe-002A) Study

Introduction: The incidence of monoclonal gammopathies is rising across the globe. Although the prevalence of monoclonal gammopathy of undetermined significance (MGUS) has been evaluated in two hospital-based studies in India, no data exists on its prevalence in community-based settings amongst the rural Indian population. Objectives: To determine the prevalence of MGUS in a rural Indian population in a community-based setting. Methods: A cross-sectional study was conducted in an agrarian village in India covering a perimeter of 24.76Km and 4588.3 hectares with an 89.2% population coverage for adults more than 45y spending 12096 man-hours as part of SIMPLe ( Screening Intervention for Myeloma and Prevention of Lifestyl e diseases) study under the aegis of Indian Myeloma Academic Group e (IMAGe) registered vide CTRI/2023/03/051220. For the complete study population, demographic details, medical history, and blood samples were collected after a thorough medical examination. Hemogram, biochemistry (Liver and renal function tests), and serum protein electrophoresis (SPEP) were universally performed in all individuals. Serum immunofixation electrophoresis (SIFE) was performed for those with abnormal SPEP graphs (those with M spike and those with abnormal bulges in beta-2 or gamma region suspicious of MGUS). Patients with monoclonal protein on SPEP or SIFE were further assessed for any features of smoldering/ multiple myeloma. The data was analyzed using JMP ver. 16.0.0. Results: The prevalence of MGUS in the study population was 1.75%. The mean age of individuals with MGUS was 63.4±5.2y with male preponderance (60%). The mean Hb was 12.39±1.8g/dL with none of the patients having any renal dysfunction. None of the patients fit into the criteria for smoldering or multiple myeloma using IMWG criteria. Among those with MGUS, the distribution of Heavy and light chains was IgG - 83.33%, IgA - 16.67% with none having IgM/ IgD paraprotein, Kappa - 50%, and Lambda - 50%. Two individuals only had light chain MGUS. Conclusion: Our study provides a comprehensive description of the prevalence of MGUS in a rural community setting in India. The background prevalence is much less compared to the Western (both USA ~3% and European~5%) population.

Clinical Characteristics of Long-Term Survivors Treated with BCMA CAR T Cell

Introduction Anti-BCMA(B-cell maturation antigen) CAR-T therapy, a novel and efficacious method for treating relapsed/refractory multiple myeloma (RRMM), has been approved and applied in clinics. Here, we report the survival analysis and clinical characteristics associated with long-term survivors (complete response at 18 months) after CAR-T cell therapy. Methods Between 1 January 2018 and 1 February 2023, 22 consecutive patients with relapsed/refractory MM were enrolled in a clinical trial of BCMA CAR T cells (registered at www.clinicaltrials.gov as #NCT04500431). This study was approved by the Tongji Hospital of Tongji University Ethics Committee, and written informed consent was provided by each patient. They all were treated with a single infusion of CAR-T cells. FC chemotherapy regimen was administered before transfusion. The median number of CAR-T cells transfused was 5.0 (range 4.0-6.6) ×10 6/kg. Long-term efficacy and related clinical characteristics were evaluated. Results In the 22 patients treated, the overall response rate was 77% (17 of 22). With a median follow-up of 24 months (range, 4-52), the median PFS were 17 months. The adverse events within 30 days after infusion were well tolerated. Toxic hematologic effects were the most common grade ≥3 events, including neutropenia (68%), anemia (54%), and thrombocytopenia (36%).Only 1 patient experienced grade 1 neurologic toxicity.No patients experienced severe infection within 30 days after infusion. Detailed patient baseline characteristics are described in Tables 1. During follow-up after CAR T-cell therapy, the complete response rate was 36.3%(8/22), 40.9(9/22) and 27.2(6/22) at 12 months, 18 months and 24 months, respectively. At 18 months, the patients achieved the highest complete response rate. Baseline characteristics, such as age, sex, isotype, ECOG, high-risk cytogenetics, prior lines of therapy, percentage of plasma blasts in bone marrow, serum monoclonal protein and extramedullary disease in the 9 complete response patients at 18 months were similar to other progressive disease 13 patients. However, the significant differences of International Staging system stage(p=0.034) and Durie-Salm staging system(p=0.002) at baseline were observed between the 9 complete response patients and 13 progressive disease patients at 18 months(Table 1). The International Staging system stage(area under curve 0.80) and Durie-Salm staging system(area under curve 0.86) predicted the outcome of patients at 18 months well. Durie-Salmon Staging system was published in 1975, which used commonly available clinical parameters including calcium, hemoglobin, bone lesions, creatinine level and serum or urine monoclonal protein. The ISS staging system was proposed in 2005 based on baseline serum levels of beta2-microglobulin (β2M) and albumin. And there was no statistically significant difference in the baseline serum levels of beta2-microglobulin, albumin, calcium, bone lesions and creatinine level between the 9 complete response patients and 13 progressive disease patients at 18 months. As figure 1 illustrates, the hemoglobin of 9 complete response patients was higher than that of 13 progressive disease patients with statistical significance at 9 time-points: PreFC(117.6±20.7 vs 94.6±23.6 , p = 0.028), D -4(113.6±15.9 vs 86.0±25.7 , p = 0.016), D -3(107.8±11.8 vs 84.6±23.0 , p = 0.027), D -2(117.6±20.7 vs 94.6±23.6 , p = 0.0009), D -1(111.0±19.9 vs 81.8±19.0 , p = 0.013), D0(107.1±20.4 vs 83.0±22.8 , p = 0.029), D1(107.7±19.1 vs 84.2±24.3 , p = 0.032), D4(104.1±14.9 vs 82.7±19.9 , p = 0.015), D5(103.4±19.1 vs 82.2±18.3 , p = 0.018). In the univariate Cox regression analysis, the hemoglobin at PreFC(hazard ration (HR) = 0.97; 95% confidence interval (CI): 0.95-1; p = 0.029), D -4(HR=0.96 ;95% CI:0.92-1, p = 0.012), D -3 (HR=0.97 ;95% CI:0.94-1, p = 0.029), D -2(HR=0.93 ;95% CI:0.89-1, p = 0.003), D -1(HR=0.97 ;95% CI:0.95-1, p = 0.047), D0(HR=0.97 ;95% CI:0.94-1, p = 0.038), D1(HR=0.97 ;95% CI:0.94-1, p = 0.044), D4(HR=0.95 ;95% CI:0.92-1, p = 0.01) and D5(HR=0.97 ;95% CI:0.94-1, p = 0.027) were relative factors of prognosis. Conclusions These long-term follow-up data in patients after BCMA CAR -T therapy suggest that baseline ISS ,DS staging and hemoglobin at 9 time-points display opposing association with long-term progression-free survival.

Outcomes of Patients with Relapsed/Refractory Lymphoplasmacytic Lymphoma Treated with Venetoclax: A Multicenter Retrospective Analysis

Outcomes of Patients with Relapsed/Refractory Lymphoplasmacytic Lymphoma Treated with Venetoclax: A Multicenter Retrospective Analysis

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 &amp;lt;3 g/dL, &amp;lt;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 &amp;lt;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 &amp;gt;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.

Prevalence of Exclusion Criteria in Multiple Myeloma Randomized Controlled Trials: A Systematic Review

Introduction: Patients with the most aggressive, hardest-to-treat, and rarer forms of multiple myeloma (MM), such as patients with severe renal impairment, central nervous system (CNS) disease, extramedullary disease, and plasma cell leukemia, have the greatest need of novel therapeutic approaches. Strict eligibility criteria for randomized controlled trials (RCTs) both deny access to clinical trials to these patients in greatest need, and also limit generalizability of trial results. We thus systematically assessed newly diagnosed MM RCT's from 2006 to 2023 to ascertain the prevalence of restrictive eligibility criteria, and their trends over time. Methods: We searched MEDLINE/PubMed, Embase, and the Cochrane Registry of Controlled Trials to measure the prevalence of restrictive inclusion criteria MM RCTs. We included all published newly-diagnosed MM RCTs from 2006-2023. Restrictive eligibility criteria evaluated included 1) age exclusions, 2) projected life expectancy requirements, 3) performance status 4) requiring thresholds of “secretory disease”, 5) CNS disease, 6) plasma cell leukemia, 7) hepatic and/or 8) renal function requirements, 9) hematological thresholds, 10) prior malignancy, 11) history of neuropathy, and 12) exclusion of extramedullary disease. We searched manuscripts, clinicaltrials.gov listings, and individual protocols whenever publicly available to ascertain these criteria. We ascertained what proportion of trials had each of these twelve restrictive criteria and assessed trends over time. A logistical regression was used to compare these variables over time. Results: 85 RCTs were included (Table 1). Exclusion criteria included: age in 43 (51%); projected life expectancy in 20 (24%); performance status in 74 (87%); thresholds of “secretory or measurable” disease in 47 (55%), , hepatic function in 64 (79%), renal function in 63 (74%), hematological thresholds in 50 (59%), prior malignancy (various time windows) in 68 (80%), neuropathy in 50 (59%) (various grades), plasma cell leukemia in 16 (18.8%), extramedullary disease in 4 (4.7%) and CNS disease in 9 (10.6%). Trends in exclusion criteria were assessed over time (Figure 1) showing all criteria (other than performance status) have failed to improve from 2006 to 2023, and there has been an increase in exclusionary criteria pertaining to plasma cell leukemia, extramedullary disease, CNS involvement and pre-existing neuropathy. Specific definitions of secretory disease varied with trials that required secretory disease (n=47), with 24 (51%) of these trials requiring a serum monoclonal protein of 1 g/dL or 0.5 if IgA/IgD/IgE/IgM MM, 2 (4.3%) requiring serum monoclonal protein of 2 g/dL regardless of MM subtype, 3 (6.4%) requiring serum monoclonal protein of 0.5 regardless of MM subtype, 11 (23.4%) requiring a serum free light chain of 10 mg/dL, and one (2.1%) requiring a serum free light chain of 5 mg/dL. Conclusion: The majority of MM RCTs have restrictive eligibility criteria that limit enrollment of the sickest MM patients and subsequent external validity of these trials, which perpetuates the status quo where limited data are available to guide the treatment of these challenging MM subtypes. It is very likely our methodology under-estimates the true prevalence of exclusionary criteria, as protocols were not universally available, and a trial was considered as having an exclusionary criteria only if explicitly listed. The presence of these restrictive eligibility criteria has failed to decrease over time.

GI Amyloid: More Than a Heavy Heart

Amyloid transthyretin (ATTR) amyloidosis is caused by the accumulation of insoluble transthyretin (TTR) amyloid fibrils. These proteins can build up in various organ systems such as the musculoskeletal, gastrointestinal, and ocular system. However, there is usually a predilection for the heart and nervous system [1]. ATTR comprises approximately 16% of GI amyloid cases, with the small bowel being the most common area of involvement [2]. Symptoms typically include abdominal pain, nausea and vomiting, unintentional weight loss, diarrhea, and constipation. Given the rarity of the disease, we present a case of biopsy proven ATTR GI amyloidosis to raise awareness and, consequently, aid in early recognition. Our patient is a 48-year-old female with a medical history of substance use disorder who had multiple evaluations for complaints of chest discomfort and gastrointestinal symptoms including nausea, vomiting and diarrhea. Initial evaluation included an echocardiography which found severe left ventricular hypertrophy. Given her significant family history of myocardial infarction, a left cardiac catheterization was completed, however, this revealed normal coronary vasculature. Subsequently, the patient started medical therapy for heart failure with preserved ventricular function pending further testing. Despite medical management, the patient developed worsening symptoms of heart failure warranting repeat echocardiography which showed a significant reduction in ejection fraction. In addition to the patient's worsening cardiac symptoms, she continued to have refractory gastrointestinal symptoms and developed new epigastric pain. Therefore, the patient underwent upper endoscopy with discovery of abnormal peristalsis. After which, a gastric emptying study was done, resulting in a diagnosis of gastroparesis. With the constellation of findings i.e., the pattern of ventricular hypertrophy, lack of hypertensive and coronary artery disease, as well as gastroparesis without a known etiology, there was suspicion for systemic infiltrative disease, which led to further investigation. Gastric, small, and large bowel biopsies confirmed amyloid deposits. The patient also underwent a Tc99m-PYP scan which revealed evidence of cardiac amyloidosis; monoclonal protein analysis test was negative, and a cardiac biopsy showed a profile consistent with amyloid transthyretin type. The patient remained on pharmacologic therapy for gastroparesis and has been referred to cardiac transplantation services for further management.Our case highlights that amyloidosis, including GI amyloidosis, has the potential to go unrecognized due to non-specific signs and symptoms. Clinicians should therefore always have a high index of suspicion as GI involvement in systemic amyloidosis, regardless of protein subtype, is common. This high index of suspicion will allow for the appropriate pathologic examination to be pursued, and ultimately the appropriate management.