From MGUS to multiple myeloma: Unraveling the unknown of precursor states.

In the 1960s, through laboratory-based investigations of peripheral blood partnered with detailed clinical annotations, Dr. Waldenström described a condition he called "benign monoclonal gammopathy". These patients were asymptomatic with a detectable monoclonal protein, and did not meet imaging and laboratory criteria for multiple myeloma. In 1978, through observational retrospective review of medical records, Dr. Kyle observed that not all cases of monoclonal gammopathy were benign. He introduced the term monoclonal gammopathy of undetermined significance (MGUS) to describe a condition that may potentially progress to multiple myeloma (MM), highlighting clinical inability in predicting which patients might progress. In 1980, Drs. Kyle and Greipp described 6 cases which did not fit the definitions of MGUS or MM, and they remained asymptomatic after at least 5 years of follow-up; they were proposed to have smoldering multiple myeloma (SMM). Over time, SMM was defined by arbitrary numerical values (≥10 % plasma cells in the bone marrow and serum M-protein concentration ≥ 3 g/dL). Numerous clinical scores have been developed to define high-risk groups for progression to MM. Current statistical models for progression provide only average risk scores, offering limited clinical utility since the risk of progression at an individual level remains unknown. Physician-scientists are focusing on emerging technologies, such as whole genome sequencing, tumor microenvironment analysis, and single-cell RNA sequencing, to understand precursor states at a molecular level. The overarching goal of these technologies is to better characterize monoclonal gammopathy and other myeloma precursor states. This will enable clinicians to provide more precise, individualized risk assessments and ultimately improve patient outcomes. This review outlines the history of MM precursor states, current definitions, challenges in risk stratification models, and the role of emerging technologies in enhancing predictions and outcomes.

Successful Treatment of Monoclonal Immunotactoid Glomerulopathy Associated with Chronic Lymphocytic Leukemia Using Ibrutinib.

A 71-year-old woman developed nephrotic syndrome during 10-year follow-up for chronic lymphocytic leukemia. A renal biopsy sample analysis revealed IgG1-lambda-positive monoclonal immunotactoid glomerulopathy (mITG). The patient was treated with ibrutinib, a Bruton tyrosine kinase inhibitor, and complete renal remission was achieved after 24 months. ITG is a rare disease that is characterized by glomerular deposition. In particular, mITG, which presents immune deposits that exhibit light-chain restriction, is often associated with hematologic disorders. Most patients with mITG receive immunosuppressive therapy and/or chemotherapy; however, to our knowledge, there have been no reports of treatment with ibrutinib.

Case Report: Application of 18F-FDG PET/CT in identifying plasmacytoma in monoclonal gammopathy associated peripheral neuropathy.

Peripheral neuropathy is a prevalent complication in plasma cell disorders, posing significant diagnostic and therapeutic challenges. This study presents three cases initially diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP). Despite initial symptom regression post-immunomodulatory treatment, the patients exhibited progressive neurological deficits. Advanced laboratory evaluation confirmed monoclonal protein presence, yet traditional diagnostic methods, including bone marrow biopsy and flow cytometry, yielded normal results. Utilizing 18F-FDG PET/CT, we identified multiple hypermetabolic vertebral lesions, which upon biopsy, confirmed the diagnosis of plasmacytoma. Our findings underscore the utility of PET/CT as a reliable diagnostic tool for monoclonal gammopathy associated neuropathy, advocating for its consideration in cases with equivocal diagnosis. When the diagnosis is in doubt, biopsy of a lesion may facilitate early and accurate diagnosis, potentially influencing treatment strategies and patient outcomes.

Daratumumab-based treatment of monoclonal gammopathy-associated angioedema due to acquired C1-inhibitor deficiency.

Daratumumab-based treatment could control severe, treatment-refractory, life-threatening angioedema due to acquired C1-inhibitor deficiency associated with monoclonal gammopathy.

Psychological Impact in Individuals with Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma.

In our study of 246 newly diagnosed individuals with MGUS or SMM (115 MGUS, 131 SMM), we found that 19% reported anxiety, with no significant difference between the MGUS and SMM groups (22% vs. 17%). Those with a history of psychiatric disorders or belonging to certain racial groups were more likely to experience anxiety. Initial coping responses included religious coping, denial, frustration, irritability, and seeking social support. Given anxiety's detrimental effects, our findings emphasize the importance of incorporating psychosocial assessments to optimize care for MGUS and SMM patients.

Monoclonal Gammopathy of Renal Significance With Preexisting Connective Tissue Disease: A Case Report.

Monoclonal gammopathy of renal significance (MGRS) has lately drawn the interest of physicians and pathologists due to the ability of these monoclonal proteins to cause end-organ damage. The early detection of this monoclonal protein along with hematological studies and renal biopsy are essential to establish the associated nephropathological diagnosis. We herein describe the case of a patient with MGRS and the diagnostic entity involved. She responded well to the treatment as co-managed by a multidisciplinary team of nephrologists, hematologists, and renal pathologists.

A rare case of acquired von Willebrand syndrome type 2B: diagnosis, treatment, and underlying pathophysiology.

Background: Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that usually mimics type 1 or 2A von Willebrand disease (VWD). Key Clinical Question: Can AVWS mimic the phenotype of type 2B VWD? Clinical Approach: A 64-year-old male patient presented with thrombocytopenia, normal routine hemostasis results, and normal VWF antigen and factor VIII levels but reduced von Willebrand factor (VWF) activity (31 IU/dL). The ristocetin-induced platelet aggregation test showed paradoxical aggregation at low doses of ristocetin, suggesting type 2B VWD, but no deleterious sequence variation was found in either the VWF or GP1BA genes, compatible with AVWS. Serum protein electrophoresis revealed a monoclonal immunoglobulin G antibody. Conclusion: This AVWS with a 2B phenotype VWD was probably related to a monoclonal immunoglobulin G antibody causing a VWF conformational change, resulting in increased affinity to platelet glycoprotein-Ib. In the event of surgery or bleeding, treatment with vonicog alfa seems to be the best option for this patient.

3D osteocyte lacunar morphometry of human bone biopsies with high resolution microCT: From monoclonal gammopathy to newly diagnosed multiple myeloma.

Osteocytes are mechanosensitive, bone-embedded cells which are connected via dendrites in a lacuno-canalicular network and regulate bone resorption and formation balance. Alterations in osteocyte lacunar volume, shape and density have been identified in conditions of aging, osteoporosis and osteolytic bone metastasis, indicating patterns of impaired bone remodeling, osteolysis and disease progression. Osteolytic bone disease is a hallmark of the hematologic malignancy multiple myeloma (MM), in which monoclonal plasma cells in the bone marrow disrupt the bone homeostasis and induce excessive resorption at local and distant sites. Qualitative and quantitative changes in the 3D osteocyte lacunar morphometry have not yet been evaluated in MM, nor in the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). In this study, we characterized the osteocyte lacunar morphology in trabecular bone of the iliac crest at the ultrastructural level using high resolution microCT in human bone biopsy samples of three MGUS, two SMM and six newly diagnosed MM. In MGUS, SMM and MM we found a trend for lower lacunar density and a shift towards larger lacunae with disease progression (higher 50 % cutoff of the lacunar volume cumulative distribution) in the small osteocyte lacunae 20-900 µm3 range compared to control samples. In the larger lacunae 900-3000 µm3 range, we detected significantly higher lacunar density and microporosity in the MM group compared to the MGUS/SMM group. Regarding the shape distribution, the MGUS/SMM group showed a trend for flatter, more elongated and anisotropic osteocyte lacunae compared to the control group. Altogether, our findings suggest that osteocytes in human MM bone disease undergo changes in their lacunae density, volume and shape, which could be an indicator for osteolysis and disease progression. Future studies are needed to understand whether alterations of the lacunae architecture affect the mechanoresponsiveness of osteocytes, and ultimately bone adaptation and fracture resistance in MM and its precursors conditions.

FCGR3A F158V alleles frequency differs in multiple myeloma patients from healthy population.

FCGR3A presents a single nucleotide polymorphism at location 158 (V/F), which affects its binding to the fragment crystallizable (Fc) of antibodies (Abs). FcγRIIIa-158 V allotype has the highest affinity and is associated with a better clinical response to IgG1 monoclonal Abs (mAb) treatment. We compared the allele frequency of FCGR3A-F158V polymorphism in cohorts of patients with B-cell lymphoproliferative disorders, including multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), non-Hodgkin lymphoma (NHL), and B-cell chronic leukemia (B-CLL). FCGR3A-158F homozygous were enriched and tended to be in MM and MGUS patients, respectively; but neither in B-CLL nor in NHL patients. We identified a significantly lower concentration of CD8 T-cells and resting memory CD4 T-cells in MM patients bone marrow with the F/F genotype, associated with an increase in the macrophage percentage. In contrast, natural killer cells increased in V/V homozygous patients. This suggests a deregulation of the immune microenvironment in FCGR3A-F/F homozygous patients. However, we did not observe difference in response following treatment combining chemotherapy associated or not with daratumumab, an IgG1 mAb direct against CD38. Our findings suggest that FCGR3A F158V polymorphism can regulate the immune environment and affect the development of tumor plasma cells.

Acute Abdominal Pain as the Initial Presentation of an Acquired C1 Inhibitor Deficiency.

Introduction: Acquired angioedema (AAE), a rare cause of adult-onset non-urticarial mucocutaneous angioedema, can present as acute abdomen, a frequent complaint in the emergency room (ER), often leading to unnecessary and potentially harmful procedures. Case Presentation: We report a 47-year-old hypertense male, controlled with an angiotensin converting enzyme inhibitor (ACEI), who presented in the ER with progressively worsening abdominal pain, nausea, and vomiting, and a radiologic workup revealing small intestine thickening, initially diagnosed with ACEI-induced angioedema. However, further investigation revealed low serum levels of C4, C1q, and C1 inhibitors, with an abnormal function of the latter, favoring the diagnosis of AAE instead. The frequent association of this condition with lymphoproliferative disorders encouraged further studies, which unveiled a monoclonal gammopathy IgM/Kappa, representing an increased risk of Waldenström macroglobulinemia, non-Hodgkin lymphoma, and multiple myeloma. Discussion: AAE should be regarded as an important differential diagnosis in patients presenting with acute abdomen in the ER, especially when more common causes are excluded. A correct and early diagnosis may represent a chance for a better prognosis of underlying diseases.

Introdução: O angioedema adquirido (AA), causa rara de angioedema mucocutâneo não urticariforme de início tardio, pode ter como apresentação inicial abdómen agudo, motivo frequente de admissão no serviço de urgência (SU), promovendo frequentemente procedimentos desnecessários e potencialmente prejudiciais. Apresentação do caso: Um homem de 47 anos, hipertenso e controlado com um inibidor da enzima conversora de angiotensina (IECA), recorreu ao SU por um quadro de dor abdominal com agravamento progressivo, náuseas e vómitos. A investigação radiológica inicial revelou espessamento do intestino delgado, culminando num diagnóstico preliminar de angioedema induzido por IECA. No entanto, uma investigação mais aprofundada em regime ambulatório revelou níveis séricos reduzidos de C4, C1q e de inibidor de C1, com função anormal deste último, favorecendo o diagnóstico de AA. A associação frequente desta condição com distúrbios linfoproliferativos incentivou investigação adicional, que revelou uma gamopatia monoclonal IgM/Kappa, representando um risco aumentado de macroglobulinemia de Waldenström, linfoma não-Hodgkin e mieloma múltiplo. Discussão: O AA deve ser considerado um diagnóstico diferencial de abdómen agudo, principalmente após exclusão de causas mais frequentes. Um diagnóstico precoce pode contribuir para um melhor prognóstico da patologia subjacente.

Unmasking the Veiled Intruder: A Complicated Case of Eosinophilic Fasciitis.

Eosinophilic fasciitis (EF) is a rare inflammatory disease characterized by skin and fascial thickening. Unlike systemic sclerosis, EF lacks internal organ involvement and specific autoantibodies, with peripheral eosinophilia as a hallmark feature. Patients may exhibit joint pain and contractures due to fibrosis. We present a case of a patient who presented with skin thickening involving her upper and lower extremities and was ultimately diagnosed with EF based on a skin biopsy. This case underscores the importance of recognizing the unique clinical and histological features of EF.

Light chain deposition disease: pathogenesis, clinical characteristics and treatment strategies.

Light chain deposition disease (LCDD) is a rare hematologic disorder characterized by the deposition of non-amyloid monoclonal light chains in several organs. Together with renal impairment is being the primary morbidity associated with this disease. Due to its rarity, randomized clinical trials lack to explore treatment strategies and there are no approved or universally accepted standard of care treatment options. We aimed to provide a systematic summary of histological and clinical aspects of LCDD and treatment options of available literature therapies strategies. Currently, drugs used to treat multiple myeloma are recommended when LCDD patients also presented multiple myeloma. Anyway, in patients with LCDD that is not associated to multiple myeloma, haematopoietic stem cell transplantation (ASCT) and chemotherapy with thalidomide, dexamethasone, bortezomib are also recommended. In eligible patients, bortezomib-based chemotherapy followed by ASCT appears to be an effective treatment option with durable hematologic remission and organ responses. Although it appears that the patients undergoing ASCT seem to achieve deeper and durable hematologic remissions and organ responses, no statistically significant superiority can be demonstrated over non-transplant or standard chemotherapy-based approaches. As retrieved by our review, bortezomib-based therapy appears to be favorable strategy as long as no dose modification is required for renal impairment, and early hematologic responses as a recovery of renal function. Encouraging data were also demonstrated by treatment lenalidomide or melpalan based. Moreover, new myeloma treatment strategies, as monoclonal antibody Daratumumab, seem to be effective in LCDD. Instead, renal allograft is not recommended, due to high incidence of relapse.

Schnitzler-Like Syndrome Presenting With IgG Kappa Monoclonal Gammopathy: A Case Report and Review of Diagnostic and Therapeutic Challenges.

Schnitzler syndrome (SS) is a rare autoinflammatory disorder characterized by a constellation of symptoms that include chronic urticarial rash, recurrent fever, arthralgias/arthritis, and monoclonal gammopathy, typically involving immunoglobulin M (IgM). However, cases with overlapping clinical features but lacking specific criteria fall under the umbrella of Schnitzler-like syndromes. This case report describes a 40-year-old male with Schnitzer-like syndrome and underscores the diagnostic complexities and therapeutic challenges of Schnitzer-like syndrome with IgG kappa monoclonal gammopathy, highlighting the need for a comprehensive diagnostic approach and targeted therapy.

Monoclonal gammopathy of renal significance from the perspective of nephrologists.

Kidney disease is a frequent complication of multiple myeloma and other malignancies associated with monoclonal gammopathies. Additionally, dysproteinemia-related kidney disease can occur independently of overt multiple myeloma or hematologic malignancies. Monoclonal gammopathy of renal significance (MGRS) is a spectrum of disorders in which a monoclonal immunoglobulin produced by a benign or premalignant B-cell or plasma cell clone causes kidney damage. MGRS-associated renal disease manifests in various forms, including immunoglobulin-associated amyloidosis, monoclonal immunoglobulin deposition diseases (light chain, heavy chain, and combined light and heavy chain deposition diseases), proliferative glomerulonephritis with monoclonal immunoglobulin deposits, C3 glomerulopathy with monoclonal gammopathy, and light chain proximal tubulopathy. Although MGRS is a nonmalignant or premalignant hematologic condition, it has significant renal implications that often lead to progressive kidney damage and, eventually, end-stage kidney disease. This review discusses the epidemiology, pathogenesis, and management of MGRS and focuses on the perspective of nephrologists.

Kidney thrombotic microangiopathy with concurrent monoclonal gammopathy.

BACKGROUND: The concurrence of monoclonal gammopathy and TMA was suggested in a few studies. However, the complement activation was not fully studied in previous cases. In this study, we aimed to determine the complement activation in these group of patients and the association with clinical, laboratory and pathological features. METHODS: Between 2007 to 2020, 20 patients with biopsy-proven renal TMA patients and monoclonal gammopathy in Peking University First Hospital were included in the study. Complement activation was tested by enzyme-linked immunosorbent assay. Associations with clinical features, pathological data, and laboratory findings were further investigated. RESULTS: Among renal TMA patients beyond 50 years of age, the prevalence of monoclonal gammopathy was 16.51% (18/109) which is almost 4-fold greater than the expected rate in population (4.2%). Eleven patients had acute kidney injury, and two patients required dialysis. Hematological diagnosis was consistent with monoclonal gammopathy of undetermined significance (n = 10), unconfirmed MGUS (n = 3), POEMS syndromes (n = 4), Castleman's disease (n = 2), and chronic lymphocytic leukemia (n = 1). A majority of patients (84.2%) showed the activation of complement classical pathway. 15% (3/20) of patients received conservative therapy, 5% one patient received steroid only, 30% (6/20) received with immunosuppression, and 50% (10/20) received with clone-targeted chemotherapy. During 56 months Of median follow-up, ESRD developed in 2 patients, and 5 patients died mainly because of hematological progression. CONCLUSION: This study found the dysregulation of complement activation, especially the classical pathway, involved in the pathogenesis of biopsy-proven renal TMA and monoclonal gammopathy.

Exploring health disparities in diagnosing multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a plasma cell neoplasm, which accounts for 1-2% of cancers and approximately 17% of hematological malignancies in the United States each year. Fifty percent of patients with symptomatic MM have three or more primary care visits before being referred to a specialist, which is greater than any other cancer. A delay in the diagnosis of multiple myeloma has been shown to negatively impact the clinical course of the disease; patients with longer diagnostic intervals have been shown to experience shorter disease-free survival and higher rates of treatment-related complications. RESEARCH DESIGN AND METHODS: We performed a retrospective analysis of patients diagnosed with MM in our institution, to determine the time from the first detectable lab abnormality to the diagnosis of MM. RESULTS: We included 92 patients in this study. Fifty-two percent of patients had isolated anemia at the time of diagnosis. Twenty-nine percent of patients had a delay in diagnosis of ≥1 year, while 18% had a delay of ≥3 years. Nine patients in our cohort had anemia and an elevated serum total protein (31%). This group had the longest time to diagnosis with a median of 38 months. CONCLUSIONS: Our results did not show any difference in time to diagnosis by race, ethnicity, gender, or socioeconomic status.

Rapidly Progressive Glomerulonephritis Secondary to Immunoglobulin M-associated Monoclonal Gammopathy of Renal Significance: A Report of a Rare Case.

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition characterized by monoclonal paraprotein production, with IgM and non-IgM variants. While IgM MGUS is often associated with lymphoid neoplasms, non-IgM MGUS can progress to multiple myeloma. Comorbidities include bone mineral density loss and renal complications, such as monoclonal gammopathy of renal significance (MGRS) and peripheral neuropathy. Cardiovascular risks are also elevated. Despite its significance, MGUS often goes undiagnosed due to its asymptomatic nature and overlap with age-related comorbidities. We present a case of IgM MGRS manifesting as rapidly progressive glomerulonephritis, highlighting the diagnostic challenges and clinical implications of MGUS-associated complications.