Monoclonal Gammopathy Research Articles

Autoantibodies Against Dihydrolipoamide S-Acetyltransferase Are Not Associated With Immune-Mediated Neuropathies.

Dihydrolipoamide S-acetyltransferase (DLAT), the E2 component of the mitochondrial pyruvate dehydrogenase complex (PDC-E2), has recently been suggested to be a biomarker of chronic inflammatory demyelinating polyneuropathy (CIDP). It was particularly associated with sensory variants of CIDP. Antimitochondrial antibodies are important for the diagnosis of primary biliary cholangitis, but insofar, only 2 studies have reported an association with CIDP. Here, we aimed to validate these observations in a cohort of French patients with immune-mediated neuropathy. The positivity against PDC-E2/DLAT was examined using ELISA and confirmed using commercially available immuno-DOT and by indirect immunofluorescence on stomach, kidney, and liver sections. None of the 20 healthy controls, 31 patients with Guillain-Barré syndrome, 102 patients with CIDP (including 24 patients with sensory CIDP), 26 patients with monoclonal gammopathy, 23 patients with Charcot-Marie-Tooth disease, or 20 patients with autoimmune nodopathy showed IgG against PDC-E2/DLAT. PDC-E2/DLAT is accurately a target antigen in immune-mediated neuropathies.

The Role of Complement Activation in IgM M-Protein-Associated Neuropathies.

Polyneuropathy associated with an immunoglobulin M (IgM) monoclonal gammopathy is characterized by slowly progressive, predominantly distal sensorimotor deficits, sensory ataxia, and electrophysiologic features of demyelination. IgM antibodies against myelin-associated glycoprotein (MAG) are present in serum from most patients. Nerve damage most likely results from the concerted action of binding of anti-MAG antibodies to nerves, followed by complement activation. The interaction of anti-MAG antibodies with complement activation and their relation to clinical characteristics have not been studied in detail. We studied the correlation among anti-MAG antibody titers, complement activation, and IgM-associated polyneuropathy disease severity. We used serum samples from 101 patients with IgM-associated polyneuropathy to assess IgM anti-MAG titers by ELISA and antibody-mediated complement deposition using both an ELISA-based system and a cell-based system of primate peripheral nerve slides. We studied correlations of complement activation with anti-MAG ELISA titers and clinical characteristics. IgM anti-MAG titers varied from negative to strongly positive. Complement deposition in the ELISA-based system correlated significantly with anti-MAG antibody titer (Spearman rho 0.80; p < 0.0001) despite large variability between serum samples with comparable anti-MAG titers. This variability was even larger in the cell-based assay, which also showed complement deposition in IgM anti-MAG negative patients, indicating the presence of autoantibodies directed against epitopes other than MAG in a subset of patients with IgM-associated polyneuropathy. Clinical characteristics did not correlate with anti-MAG titers or complement activation. Anti-MAG antibody titers correlate with the level of complement activation in both ELISA and cell-based systems. However, clinical characteristics of IgM-associated polyneuropathy do not or only weakly correlate with titers or the level of complement deposition. The lack of clear correlations between complement activation and clinical characteristics does, at this stage, not support the use of complement inhibitors in the treatment of IgM-associated polyneuropathy.

Прогностическое значение экспрессии галектина-1 опухолевыми плазматическими клетками и концентрации некоторых сывороточных цитокинов (IL-2, IL-6, TNF) у пациентов с моноклональной гаммапатией неопределенного значения и множественной миеломой

AIM. To study the prognostic value of the galectin-1 expression by bone marrow (BM) tumor plasma cells (PCs) and the concentration of serum cytokines (interleukins [IL-2, IL-6] and tumor necrosis factor [TNF]) in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (ММ). MATERIALS &amp; METHODS. The trial enrolled 129 patients: 77 patients with newly diagnosed MM (median age 64 years) and 52 patients with MGUS (median age 62.5 years) followed-up at the Republican Scientific and Practical Center for Radiation Medicine and Human Ecology from 2018 to 2023. All patients underwent general clinical examination as well as BM aspirate cytology with myelogram and iliac BM core biopsy with immunohistochemical (IHC) analysis of BM biopsy. RESULTS. In the BM biopsy, the IHC analysis revealed a significant increase of galectin-1 expression (measured by expressing tumor PC count) in MM vs. MGUS patients (p &lt; 0.001). Galectin-1 expression defined as expressing tumor PC count was significantly higher in patients with progressing MGUS compared to progression-free MM patients (p &lt; 0.001). The median galectin-1 expression level was 8.5 % (Q25 0.2 %; Q75 15.7 %) in progression-free MGUS patients and 37.4 % (Q25 24.7 %; Q75 64.0 %) in progressing MGUS patients. Among MM patients, no significant differences were identified either in those with and without tumor progression. The IHC analysis of BM core biopsies in MM patients showed that high galectin-1 expression level is associated with pronounced vasculature but not with fibrotic changes, it also identified an increase in serum concentrations of IL-2 and TNF as well as a direct correlation with β2-microglobulin level. With MGUS progression into ММ, there was a direct correlation between galectin-1 expression level and serum M-protein. An increase of IL-2 concentration was registered only when MGUS progressed into ММ. CONCLUSION. The results of this study indicate the evidence of a high level of galectin-1 expression by tumor PCs in MM. In MGUS, an increase of galectin-1 expression by clonal BM PCs was associated with the disease progression. Galectin-1 expression by clonal BM PCs can well be clinically used as a marker for MGUS progression into MM.

Hypergammaglobulinemia in Hidradenitis Suppurativa Patients: A New Emerging Association.

Hypergammaglobulinemia is a sign of B cell and plasma cell hyperactivity marked by elevated levels of gamma globulins, proteins within the gamma fraction of serum electrophoresis, linked to diseases like acute hepatitis, Hodgkin's lymphoma, autoimmune conditions, and neoplasms. Monoclonal gammopathy of undetermined significance (MGUS) is found in 3.2% of individuals over 50 and 5.3% over 70 due to immunosenescence, the gradual immune decline influenced by chronic infections, malnutrition, hormonal dysregulation, and smoking. This retrospective, single-center observational study explored the association between hypergammaglobulinemia and Hidradenitis Suppurativa (HS) based on sex, age, disease severity (IHS4 score), and Adalimumab treatment. Sixty patients (54% women, 46% men, average age 47) were observed over 12 months. Hypergammaglobulinemia was found in 68% of patients, with the highest prevalence in the 15-29 age group (80%). It was also associated with increased disease severity, particularly in younger patients, who showed a reduced clinical response to Adalimumab (average HiSCR difference of 25%). While common inflammation markers like CRP and ESR remain essential for HS management, this study highlighted that hypergammaglobulinemia is more prevalent in younger patients with severe forms of HS. Unlike older patients, where immunosenescence can lead to more normal gamma globulin levels, younger patients demonstrated a strong link between chronic inflammation and disease. The findings suggest further investigation is needed to determine whether hypergammaglobulinemia is merely a marker or contributes to HS pathogenesis. If validated, hypergammaglobulinemia could be used to monitor disease progression and customize treatments. In conclusion, integrating immunological assessments into HS management could improve patient outcomes, particularly in younger demographics. With larger studies, hypergammaglobulinemia might be considered a predictive factor for HS, especially for severe or treatment-resistant cases.

Prevalence of monoclonal gammopathy of undetermined significance in Shenzhen, China

ABSTRACT Background Data on the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in China are very limited. Our aim was to determine the prevalence and clinical characteristics of MGUS in a large Chinese population. Methods This study included 49,220 healthy people who received serum immunofixation electrophoresis (sIFE) and serum protein electrophoresis (SPE) tests. Serum free light chain ratio, immunoglobulin quantification, and other clinically correlates of MGUS were performed for all patients with M-protein. Results A total of 576 MGUS patients were identified by sIFE, with a median age of 58 years and an overall prevalence of 1.17% (95% CI, 1.08–1.27). Among those aged 50 years and older, the prevalence of MGUS was 2.26% (95% CI, 2.04–2.50). The prevalence of MGUS was significantly higher in males than in females (P < 0.05). The median concentration of M-protein was 3.1 g/L, ranging from 0.5 g/L to 25.1 g/L. The M-protein type was IgG in 55.4% of MGUS patients, followed by IgA (31.1%), IgM (9.5%), IgD (0.5%), biclonal (2.3%), and light chain (1.2%). Abnormalities in SPE, FLC ratios, and immunoglobulin levels were observed in 78.3%, 31.1%, and 38.4% of MGUS patients, respectively. Conclusions The prevalence of MGUS is substantially lower in southern China than in whites and blacks.

Treatment results and clinical outcomes in patients with Monoclonal Gammopathy of Renal Significance

Treatment results and clinical outcomes in patients with Monoclonal Gammopathy of Renal Significance

Monoclonal gammopathy of undetermined significance and the risk of thrombotic events: Results from iStopMM, a prospective population-based screening study.

Monoclonal gammopathy of undetermined significance (MGUS) is the asymptomatic precursor of multiple myeloma and related diseases but has also been associated with thrombosis. Prior studies have not been based on screened cohorts leading to bias. We assessed the risk of thrombosis in a cohort of 75 422 individuals over 40 years old who were screened for MGUS in Iceland. We also evaluated the association of M protein concentration with thrombotic risk. A total of 3668 participants had MGUS. After a median follow-up of ~3.7 years, 124 venous and 252 arterial thrombotic events (10.3 and 21.0 per 1000 person years respectively) were observed in the MGUS group, compared to 1509 and 3471 in the non-MGUS group (6.0 and 13.8 per 1000 person years respectively). After adjusting for multiple confounders, MGUS was associated with an increased risk of venous thrombosis (hazard ratio [HR] = 1.43; 95% confidence interval [CI]: 1.19-1.73) but not arterial thrombosis (HR = 0.96; 95% CI: 0.87-1.13). M protein concentration was not associated with venous (p = 0.72) or arterial (p = 0.95) thrombosis. The findings show, in a screened cohort, that MGUS is associated with venous, but not arterial, thrombosis. Furthermore, they suggest that there is a subset of individuals with MGUS with subclinical monoclonal gammopathy of thrombotic significance.

Diagnostic and Therapeutic Aspects of Monoclonal Gammopathies of Renal Significance (MGRS): An Update.

Monoclonal gammopathy of renal significance (MGRS) refers to a group of renal disorders caused by a monoclonal immunoglobulin (MIg), secreted by a non-malignant B-cell clone. Unlike overt multiple myeloma or B-cell proliferation, MGRS does not meet those diagnostic criteria. However, it is associated with significant morbidity, due to severe renal, and sometimes systemic, lesions induced by the MIg. Early recognition is crucial, as chemotherapy to suppress MIg secretion often improves outcomes. The spectrum of renal diseases in MGRS is broad, including both well-known conditions like AL amyloidosis and newly described lesions. Kidney biopsy is essential to determine the specific lesion associated with MGRS and assess its severity. Diagnosis involves integrating morphologic alterations using techniques such as light microscopy, immunofluorescence (IF), electron microscopy, and, in some cases, IF staining for Ig isotypes, immunoelectron microscopy, and proteomic analysis. Additionally, a complete hematologic evaluation, including serum and urine protein electrophoresis, immunofixation, and a serum-free light-chain assay, is necessary.

Effect of adipose tissue on the development of multiple myeloma.

Multiple myeloma(MM), also referred to as Kahler's disease, is a cancer characterized by the uncontrolled growth of abnormal plasma cells and is associated with alterations in the bone tissue microenvironment. Bone marrow adipose tissue (BMAT), which comprises approximately ten percent of total body fat, can influence the progression, survival, and drug resistance of MM cells through paracrine, hormonal, and metabolic pathways. Obesity can lead to an increase in BMAT mass, which not only disrupts bone metabolism but also reduces bone density, potentially progressing from monoclonal gammopathy of undetermined significance, a benign condition, to MM. A range of factors, including impaired fatty acid metabolism, increased production of adipokines that support myeloma, and heightened expression of oncogenic microRNAs in multiple myeloma, contribute to the progression of this incurable blood cancer. To better understand the relationship between excess adipose tissue accumulation and the risk of developing multiple myeloma, a comprehensive review of published data was conducted.

Very Late Recurrence of Dense Deposit Disease after Kidney Transplantation

A woman in her 40s with kidney failure secondary to biopsy-proven dense deposit disease (DDD) with positive C3 nephritic factor (C3Nef) and no complement gene defect received a kidney transplant from a deceased donor. Eighteen years after transplantation, laboratory workup revealed new-onset microscopic hematuria, with 547 red blood cells/μL (normal &lt;25), and proteinuria, with a urine protein-to-creatinine ratio of 1.0 g/g creatinine (normal &lt;0.150), increasing to 7.5 g/g within a few months. Glomerular filtration rate, estimated from the CKD-EPI equation, was normal (88 mL/min/1.73m2). Serum C3 level was very low (0.09 g/L, N 0.90 -1.80), while serum C4 level was normal. Screening for monoclonal gammopathy, BK viremia and circulating donor-specific antibodies, was negative.

Strain echocardiography predictors in patients with concomitant cardiac amyloidosis and aortic stenosis: a cross-sectional study

BackgroundConcomitant cardiac amyloidosis (CA) and aortic stenosis (AS) may be mistaken for isolated AS, potentially impacting the treatment strategy and patient’s prognosis. Therefore, it is crucial to distinguish between these conditions, as failure to promptly diagnose CA may lead to considerable complications. The aim of this study is to investigate the diagnostic value of strain predictors in patients with concomitant CA and AS compared to isolated AS.MethodsForty-two patients with severe AS suspected of concomitant CA based on a comprehensive clinical evaluation were selected to undergo 99mTc-DPD scintigraphy. Those showing Perugini grade 2 or 3 tracer uptakes without evidence of monoclonal gammopathy were diagnosed with CA and underwent speckle-tracking echocardiography. Furthermore, strain analysis was performed to evaluate myocardial deformation, with a focus on detecting apical sparing and reduction in bull’s eye mapping, resulting in the characteristic “cherry on top” sign.ResultsEight patients were diagnosed with CA, representing 19.0% of those suspected of concomitant CA and 7.8% of the overall cohort with severe AS. AF arrhythmia was significantly more frequent in these patients compared to those with isolated AS. Echocardiography findings revealed that E/E’ ratio and RALS were significantly higher in patients with concomitant CA, while GLS and mean basal LS were significantly lower in this group. The “cherry on top” sign was detected in 19 patients (45.2%), present in 100% of those with concomitant CA and AS, versus 32.4% in isolated AS cases (P = 0.04). This sign demonstrated a sensitivity of 100% and a specificity of 67.6% for predicting concomitant CA and AS.ConclusionsIn conclusion, the “cherry on top” sign was significantly more prevalent in patients with concomitant CA and AS, compared to those with isolated AS, demonstrating a sensitivity of 100% and a specificity of 67.6% for predicting concomitant CA. Moreover, RALS and E/E’ ratios were significantly higher in patients with concomitant CA, whereas GLS and mean basal LS were significantly lower in this group.

Approaching Hypercalcemia in Monoclonal Gammopathy of Undetermined Significance: Insights from the iStopMM study.

Hypercalcemia in monoclonal gammopathy of undetermined significance (MGUS) presents a clinical challenge since it may indicate progression to multiple myeloma (MM) but could also be due to a multitude of unrelated disorders. To inform the approach to this clinical challenge, we conducted a nested cohort study within the iStopMM screening study. Of the 75,422 Icelanders aged 40 years and above who underwent screening for MGUS, we included 2,546 with MGUS who were in active follow-up, including regular serum calcium measurements. In total, 191 individuals (7.5%) had hypercalcemia detected at least once, of whom 93 had persistent hypercalcemia (48.7%). MM was found in 3 participants with persistent hypercalcemia (3.2%); all had concurrent bone disease and other end-organ damage. The most common causes of hypercalcemia were primary hyperparathyroidism (56.0%) and malignancies other than MM (16.0%). In this first comprehensive study on hypercalcemia in MGUS, we observed that hypercalcemia rarely indicated MGUS progression and never in the absence of other symptoms of MM. More than half of hypercalcemia cases were transient and the underlying causes were similar to those in the general population. We conclude that hypercalcemia in MGUS should be approached in the same way as in those without MGUS.

The significance of free light-chain ratio in light-chain monoclonal gammopathy of undetermined significance: a flow cytometry sub-study of the iStopMM screening study

Light-chain (LC) monoclonal gammopathy of undetermined significance (MGUS) is a precursor of multiple myeloma (MM) and related conditions. LC-MGUS is characterized by free light-chain (FLC) levels outside defined reference intervals, indirectly indicating underlying plasma cell (PC) monoclonality. Next-generation flow cytometry (NGF) was used to evaluate clonal PC presence in bone marrow (BM) samples from individuals with LC-MGUS in the iStopMM study, aiming to assess the predictive value of the FLC ratio for clonal PC presence and its prognostic implications. BM samples from 61 individuals with LC monoclonal gammopathy were analyzed. Clonal plasma cells were detected in 53.6% of LC-MGUS samples (n = 28) and in all samples from individuals with more advanced conditions (n = 33). The FLC ratio was predictive of clonal PC presence for kappa-involved FLC ratios (p < 0.05; n = 42), with an optimal cutoff of 3.15 (96.7% sensitivity, 91.7% specificity). Of 195 individuals with kappa-involved LC-MGUS in follow-up within the iStopMM study, none with FLC ratios >1.65 to 3.15 progressed to MM (n = 124), whereas 4/71 (5.6%) with FLC ratios >3.15 progressed over median follow-up of 55 months. These findings support using a kappa-involved FLC ratio cutoff of >3.15 to more accurately identify individuals at increased risk of developing symptomatic PC disorders.

Monoclonal gammopathy is present in one fourth of patients undergoing renal biopsy but is pathogenic only in half of them.

About 4-7% of renal biopsies show a monoclonal gammopathy-related nephropathy, such as AL amyloidosis, cast nephropathy, or light chain deposition disease. Both a high prevalence and a causal role of monoclonal gammopathy have been observed in patients with C3 glomerulopathy or thrombotic microangiopathy, although a definitive causative role cannot be established in most cases (potentially monoclonal gammopathy-related nephropathies). A coexisting monoclonal gammopathy has been identified in many cases of nephropathy without a defined causative role (monoclonal gammopathy-unrelated nephropathies). The aim of this study was to investigate the prevalence and distribution of monoclonal gammopathy in patients who underwent arenal biopsy and assess its possible causal role in nephropathies not ordinarily related to monoclonal gammopathy. In our single-center retrospective observational study, we considered patients who underwent native kidney biopsy from 2009 to 2023 at the Nephrology Unit, Careggi University Hospital, Florence (Italy)and for whom a complete monoclonal gammopathy workup (serum electrophoresis, serum and urinary immunofixation, serum free light chains) was available. Overall, 827 patients were included: 208 (25%) had a monoclonal gammopathy: in104 cases the monoclonal gammopathywasunrelated tothekidney disease; 87 subjects showed renal pathology related to monoclonal gammopathy (monoclonal gammopathy-related nephropathies). Patients with thrombotic microangiopathy and C3 glomerulopathy (potentially monoclonal gammopathy-related nephropathies) exhibited a prevalence of monoclonal gammopathy > 30%. In a subgroup of diagnoses (e.g. tubulointerstitial nephritis, membranoproliferative glomerulonephritis) a possible causal and/or prognostic role of a concomitant monoclonal gammopathy may be hypothesized. In our cohort, one fourth of patients undergoing arenal biopsy had a monoclonal gammopathy, although in half of them the monoclonal gammopathy did not have a causative rolein the kidney disease.Hence, it is impossible to conclude that a monoclonal gammopathy in the context of renal disease equates to a causal association without performing a renal biopsy because of the high frequency of monoclonal gammopathy in patients undergoing a kidney biopsy.

Monoclonal Gammopathy-Associated Neuropathy.

Peripheral neuropathy (PN) is more commonly seen in individuals with monoclonal gammopathies, especially in patients with an IgM monoclonal gammopathy or Waldenström macroglobulinemia. There are multiple potential ways that the paraprotein may result in peripheral neuropathy. The diagnosis and management of monoclonal gammopathy-associated PN are challenging and necessitate a concerted effort between the hematologist/oncologist and the neurologist. This review describes the most common PN syndromes associated with monoclonal gammopathy, such as anti-myelin-associated glycoprotein neuropathy, light chain amyloidosis, cryoglobulinemia, POEMS, CANOMAD, and others. We also review the therapies used to treat these conditions.

Epidemiological and clinicopathological characteristics of vascular-limited renal AL amyloidosis.

Kidney involvement, along with cardiac disease, is the most frequent manifestation of systemic AL amyloidosis usually resulting in nephrotic-range proteinuria. Rarely, deposits predominantly or exclusively affect the intrarenal arterioles or arteries, these vascular-limited forms following a distinct clinical course, but very little is known about these forms. Our work plan at better characterizing renal vascular limited AL amyloidosis. By mining French Paris hospital database, we found that this unusual phenotype accounts for approximatively 9% of renal AL amyloidosis cases. We retrospectively studied 35 patients with the renal vascular-limited variant of AL amyloidosis on kidney biopsy. All showed predominant or only (n=21) intra-renal vascular deposits, of lambda isotype in 63%. At diagnosis, median urine protein/creatinine ratio was 0.5g/g, with serum creatinine of 167 (127-213) µmol/L and estimated glomerular filtration (eGFR) rate of 36.2 (24.3-49.6) ml/min/1,73 m2. Cardiac involvement was present in 67% of cases. A serum and/or urine monoclonal gammopathy was identified in all but one patient and 31 (88%) had an abnormal FLC ratio. Among 28 treated patients, hematological and renal response rates were 75% (including deep hematological response in 43%) and 18%, respectively. Median time from diagnosis to renal event, defined be a composite criterion composed of end-stage renal disease or>40% decrease in eGFR, was 56 months. Median overall survival (OS) was 59 months, significantly longer in patients who achieved a deep hematological response (178vs 20 months, p=0.002). renal vascular limited AL amyloidosis is a probably underdiagnosed disease with markedly reduced eGFR, low-grade proteinuria and severe overall prognosis. Rapid achievement of a deep hematological response is required to preserve long-term renal and patient outcomes.

Clinicopathological characteristics of light chain proximal tubulopathy: a multicentre case series

AimsLight chain proximal tubulopathy (LCPT) is a rare complication of paraprotein-related diseases. We report a case series to present the clinicopathological characteristics and outcomes of LCPT.MethodsA multicentre retrospective case series...

Pathological Fracture of Multiple Myeloma with CRAB Criteria: A Case Report

Multiple myeloma (MM) is a malignancy of plasma cells, often preceded by an asymptomatic condition known as the precursor state of monoclonal gammopathy of undetermined significance (MGUS). The diagnosis of multiple myeloma is typically confirmed using the CRAB criteria, which include hypercalcemia, renal impairment characterized by elevated serum urea and creatinine levels, anemia, and bone abnormalities. We report a rare case of multiple myeloma in a 63-year-old male patient who presented with pain in his left hand following a fall against a wall. Clinical and radiological examinations revealed findings consistent with multiple myeloma, with a differential diagnosis including metabolic bone disease and metastatic bone disease

Role of Imaging in Multiple Myeloma: A Potential Opportunity for Quantitative Imaging and Radiomics?

Multiple myeloma (MM) is the second most prevalent hematologic malignancy, particularly affecting the elderly. The disease often begins with a premalignant phase known as monoclonal gammopathy of undetermined significance (MGUS), solitary plasmacytoma (SP) and smoldering multiple myeloma (SMM). Multiple imaging modalities are employed throughout the disease continuum to assess bone lesions, prevent complications, detect intra- and extramedullary disease, and evaluate the risk of neurological complications. The implementation of advanced imaging analysis techniques, including artificial intelligence (AI) and radiomics, holds great promise for enhancing our understanding of MM. The integration of advanced image analysis techniques which extract features from magnetic resonance imaging (MRI), computed tomography (CT), or positron emission tomography (PET) images has the potential to enhance the diagnostic accuracy for MM. This innovative approach may lead to the identification of imaging biomarkers that can predict disease prognosis and treatment outcomes. Further research and standardized evaluations are needed to define the role of radiomics in everyday clinical practice for patients with MM.

Renal manifestations of MGUS.

Kidney disease is a common complication of monoclonal immunoglobulin (MIg)-secreting B-cell disorders and predominantly occurs in patients who do not meet the criteria for an overt hematological disease. To distinguish this situation from monoclonal gammopathy of undetermined significance, which lacks organ damage, the term monoclonal gammopathy of renal significance (MGRS) was introduced to depict the association of a small, otherwise indolent B-cell clone, with renal disease induced by the secreted MIg. The spectrum of renal disorders in MGRS is wide, encompassing both tubular and glomerular disorders, classified according to the composition of deposits and their ultrastructural pattern of organization. Renal lesions, independent of the tumor burden, are mostly governed by the molecular characteristics of the MIg variable domain and involve either direct (deposition or precipitation) or indirect (autoantibody activity, complement activation) mechanisms. The diagnosis, often suggested by careful analysis of renal and extrarenal symptoms, almost always requires histological confirmation by a kidney biopsy with light, immunofluorescence, and electron microscopy studies. Most patients do not have a known monoclonal gammopathy at presentation. Hematologic investigations should include serum and urine protein electrophoresis and immunofixation, serum-free light chain measurements, and bone marrow studies with flow cytometry and cytogenetics to determine the nature of the pathogenic clone (most commonly plasmocytic). Early diagnosis before the development of severe chronic kidney disease and rapid achievement of deep hematological response through clone-targeted chemotherapy (currently based on proteasome inhibitor and monoclonal anti-CD38 antibody-based combinations for plasma cell clones) are the main factors influencing long-term renal and patient outcomes.