Immune-Pathogenesis of Myeloma.

This research indicates that monoclonal gammopathy of undetermined significance (MGUS) and myeloma may stem from chronic immune activation and inflammation, causing immune dysfunction and spatial immune exclusion. As the conditions progress, a shift toward myeloma involves ongoing immune impairment, affecting both innate and adaptive immunity. Intriguingly, even in advanced myeloma stages, susceptibility to immune effector cells persists. This insight highlights the intricate interplay between immune responses and the development of these conditions, paving the way for potential therapeutic interventions targeting immune modulation in the management of MGUS and myeloma.

Impact of viral hepatitis therapy in multiple myeloma and other monoclonal gammopathies linked to hepatitis B or C viruses.

Subsets of multiple myeloma (MM) and monoclonal gammopathies of undetermined significance (MGUS) present with a monoclonal immunoglobulin specific for hepatitis C virus (HCV), thus are presumably HCV-driven, and antiviral treatment can lead to the disappearance of antigen stimulation and improved control of clonal plasma cells. Here we studied the role of hepatitis B virus (HBV) in the pathogenesis of MGUS and MM in 45 HBV-infected patients with monoclonal gammopathy. We analyzed the specificity of recognition of the monoclonal immunoglobulin of these patients and validated the efficacy of antiviral treatment (AVT). For 18 of 45 (40%) HBV-infected patients, the target of the monoclonal immunoglobulin was identified: the most frequent target was HBV (n=11), followed by other infectious pathogens (n=6) and glucosylsphingosine (n=1). Two patients whose monoclonal immunoglobulin targeted HBV (HBx and HBcAg), implying that their gammopathy was HBV-driven, received AVT and the gammopathy did not progress. AVT efficacy was then investigated in a large cohort of HBV-infected MM patients (n=1367) who received or did not receive anti-HBV treatments and compared to a cohort of HCV-infected MM patients (n=1220). AVT significantly improved patient probability of overall survival (P=0.016 for the HBV-positive cohort, P=0.005 for the HCV-positive cohort). Altogether, MGUS and MM disease can be HBV- or HCV-driven in infected patients, and the study demonstrates the importance of AVT in such patients.

It is worth the weight: obesity and the transition from monoclonal gammopathy of undetermined significance to multiple myeloma.

The overweight/obesity epidemic is a serious public health concern that affects >40% of adults globally and increases the risk of numerous chronic diseases, such as type 2 diabetes, heart disease, and various cancers. Multiple myeloma (MM) is a lymphohematopoietic cancer caused by the uncontrolled clonal expansion of plasma cells. Recent studies have shown that obesity is a risk factor not only for MM but also monoclonal gammopathy of undetermined significance (MGUS), a precursor disease state of MM. Furthermore, obesity may promote the transition from MGUS to MM. Thus, in this review, we summarize the epidemiological evidence regarding the role of obesity in MM and MGUS, discuss the biologic mechanisms that drive these disease processes, and detail the obesity-targeted pharmacologic and lifestyle interventions that may reduce the risk of progression from MGUS to MM.

Monoclonal Gammopathy of Undetermined Significance: A Comprehensive Review.

Monoclonal Gammopathy of Undetermined Significance (MGUS) is an asymptomatic premalignant plasma cell dyscrasia with a predominate rise of the IgG immunoglobulin fraction without end-organ damage, often diagnosed incidentally. Despite its progression into various subsequent forms of hematological malignancies, MGUS remains underdiagnosed. A literature search was conducted using the Medline, Cochrane, Embase, and Google Scholar databases, including articles published until December 2022. Keywords used encompassed "Monoclonal Gammopathy of Undetermined Significance," "Plasma Cell dyscrasia," "Monoclonal gammopathy of renal significance," and "IgM Monoclonal gammopathy of Undetermined Significance," This study aimed to conduct a critical review to update knowledge regarding the pathophysiology, risk factors, clinical features, diagnostic protocols, complications, and current and novel treatments for MGUS. We recommend a multidisciplinary approach to manage MGUS due to the complexity of the illness's etiology, diagnosis, and therapy. This comprehensive review also highlights future prospects, such as developing screening protocols for at-risk populations, prevention of disease progression by early diagnosis through genome-wide association studies, and management using Daratumumab and NSAIDs.

Autoimmunity, Infections, and the Risk of Monoclonal Gammopathy of Undetermined Significance.

Various epidemiological studies, including case reports and -series in addition to larger, population-based studies, have reported an increased prevalence of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma in individuals with a prior history of immune-related conditions. This is believed to support the role of chronic antigen stimulation in the pathogenesis of these conditions. In this short review, we summarize some of the largest population-based studies researching autoimmune diseases, infections, and the subsequent risk of MGUS, and discuss our understanding on its etiology and pathogenesis. Furthermore, we highlight important methodological limitations of previous studies in the field, but almost all studies on MGUS have been based on clinical, possibly biased, cohorts. Finally, we discuss future directions in researching the associations of MGUS and other disorders, including immune-related conditions, where screening studies play an important role.

Smoldering multiple myeloma - Past, present, and future.

Smoldering multiple myeloma (SMM) routinely precedes the development of multiple myeloma. While some patients experience aggressive disease, others have more indolent courses akin to those with monoclonal gammopathy of undetermined significance. Much effort has been made to understand the pathobiological basis of this heterogeneity. Scientific advancements have led to the emergence of various clinical and genomic markers of relevance, translating into evolution of disease definitions over time. More recently, the interest in manipulation of biological pathways has intensified in a bid to stall or halt disease progression. Studies with lenalidomide have exemplified the promise of early intervention, whereas numerous therapeutic approaches remain the subject of ongoing clinical investigation. This review summarizes the historic progress made in defining SMM as a distinct clinicopathologic entity, provides a critical appraisal of the evidence guiding risk assessment, and suggests a pragmatic approach to its modern-day management. Finally, an overview of developments on the horizon is also provided.

Advances in MGUS diagnosis, risk stratification, and management: introducing myeloma-defining genomic events.

In the 1960s, Dr Jan Waldenström argued that patients who had monoclonal proteins without any symptoms or evidence of end-organ damage represented a benign monoclonal gammopathy. In 1978, Dr Robert Kyle introduced the concept of "monoclonal gammopathy of undetermined significance" (MGUS) given that, at diagnosis, it was not possible with available methods (ie, serum protein electrophoresis to define the concentration of M-proteins and microscopy to determine the plasma cell percentage in bone marrow aspirates) to determine which patients would ultimately progress to multiple myeloma. The application of low-input whole-genome sequencing (WGS) technology has circumvented previous problems related to volume of clonal plasma cells and contamination by normal plasma cells and allowed for the interrogation of the WGS landscape of MGUS. As discussed in this chapter, the distribution of genetic events reveals striking differences and the existence of 2 biologically and clinically distinct entities of asymptomatic monoclonal gammopathies. Thus, we already have genomic tools to identify "myeloma-defining genomic events," and consequently, it is reasonable to consider updating our preferred terminologies. When the clinical field is ready to move forward, we should be able to consolidate current terminologies-from current 7 clinical categories: low-risk MGUS, intermediate-risk MGUS, high-risk MGUS, low-risk smoldering myeloma, intermediate-risk smoldering myeloma, high-risk smoldering myeloma, and multiple myeloma-to future 3 genomic-based categories: monoclonal gammopathy, early detection of multiple myeloma (in which myeloma-defining genomic events already have been acquired), and multiple myeloma (patients who are already progressing and clinically defined cases). Ongoing investigations will continue to advance the field.

Progress in the Management of Smoldering Multiple Myeloma.

PURPOSE OF REVIEW: Smoldering multiple myeloma (SMM) is defined as an asymptomatic clonal proliferation of pre-malignant plasma cells and an increased risk of progression to multiple myeloma (MM) relative to monoclonal gammopathy of undetermined significance. Whether patients with SMM should be treated prior to development of symptomatic disease is fiercely debated and is a highly active area of research. RECENT FINDINGS: The ECOG E3A06 study demonstrated that early treatment with lenalidomide significantly reduced the risk of progression to MM compared to observation in patients with high risk SMM. The IMWG recently validated a risk stratification model to include cytogenetics and a personalized risk calculator for individual patients. Beyond this, molecular genomic aberrations and immunological phenomena that promote progression from asymptomatic disease to MM have been recently characterized and may help to more precisely identify patients who are most suitable for early intervention. As highly effective and tolerable therapies for plasma cell disorders evolve, the field is approaching a paradigm shift that involves the adoption of intervention for patients with SMM who are at high risk for progression to symptomatic myeloma in order to prevent morbidity and mortality. This review highlights our current understanding of the biology of patients with SMM, clarifies the rationale for early intervention, and summarizes early results of various treatment strategies for patients with high-risk smoldering myeloma.

Overweight/Obesity and Monoclonal Gammopathy of Undetermined Significance.

BACKGROUND: Obesity and high body mass index (BMI) are associated with increased incidence of multiple myeloma (MM). MM usually evolves from a precursor asymptomatic disease, namely monoclonal gammopathy of undetermined significance (MGUS). MGUS progresses to MM at a 1% annual rate; however, risk factors predisposing to MGUS are not completely understood. We conducted a systematic review to assess the relationship between obesity and high BMI with MGUS prevalence and progression to MM. To our knowledge, this is the first systematic review evaluating the role of obesity in MGUS. PATIENTS AND METHODS: We searched the Medline database and ClinicalTrials.gov for studies investigating BMI and obesity association with MGUS incidence and progression. The algorithm consisted of a predefined combination of the words "obesity," "obese," "body mass index," "overweight," "diet," "nutrition," "food," "dietary," "adiponectin," "monoclonal gammopathy," and "MGUS". RESULTS: Overall, 12 articles were retrieved, including 11 eligible articles and 1 clinical trial. More than 57,068 patients were evaluated in this systematic review. Discrepancies between the identified studies were noted. Multiple studies support the notion that obesity or high BMI are positively linked to MGUS prevalence and transition to MM. In contrast, other studies revealed no such association. Visceral adipose tissue metabolic activity and decreased adiponectin concentrations were identified as biomarkers of MGUS progression to MM. CONCLUSION: Obesity and increased BMI seem to be implicated both in MGUS development and progression to MM. Further studies should be designed to confirm this hypothesis.

Screening for M-proteinemia consisting of monoclonal gammopathy of undetermined significance and multiple myeloma for 30 years among atomic bomb survivors in Hiroshima.

Monoclonal gammopathy (M-proteinemia) is a premalignant plasma cell disorder. The prevalence of M-proteinemia increases with age and is affected by genetic or environmental factors. Atomic bomb (A-bomb) survivors in Hiroshima are in an age range when they are susceptible to M-proteinemia. The prevalence and incidence of M-proteinemia in Hiroshima A-bomb survivors were investigated for 30 years (1989-2018) to examine the influence of radiation exposure. The overall prevalence of M-proteinemia among 38,602 A-bomb survivors was 2.4%. M-proteinemia prevalence at age 70 years and monoclonal gammopathy of undetermined significance (MGUS) incidence were not associated with radiation exposure category. Males had a 2.30-fold higher prevalence and a 2.08-fold higher incidence than females. The risk of incidence for MGUS was 4.32-fold higher in persons aged < 10 years at the time of the A-bombing and 2.56-fold higher in those aged 10-19 years compared with those aged over 30 years. IgG type M-proteinemia was common and the IgM type developed 5-8 years later than other immunoglobulin types. Exposure to radiation was not clearly associated with the prevalence of M-proteinemia or incidence of MGUS in Hiroshima A-bomb survivors. However, males and those aged < 20 years at A-bombing had higher susceptibility to MGUS.

Efficacy of Antiviral Treatment in Hepatitis C Virus (HCV)-Driven Monoclonal Gammopathies Including Myeloma.

Multiple myeloma (MM) remains an incurable plasma cell malignancy. While its origin is enigmatic, an association with infectious pathogens including hepatitis C virus (HCV) has been suggested. Here we report nine patients with monoclonal gammopathy of undetermined significance (MGUS) or MM with previous HCV infection, six of whom received antiviral treatment. We studied the evolution of the gammopathy disease, according to anti-HCV treatment and antigen specificity of purified monoclonal immunoglobulin, determined using the INNO-LIA™ HCV Score assay, dot-blot assays, and a multiplex infectious antigen microarray. The monoclonal immunoglobulin from 6/9 patients reacted against HCV. Four of these patients received antiviral treatment and had a better evolution than untreated patients. Following antiviral treatment, one patient with MM in third relapse achieved complete remission with minimal residual disease negativity. For two patients who did not receive antiviral treatment, disease progressed. For the two patients whose monoclonal immunoglobulin did not react against HCV, antiviral treatment was not effective for MGUS or MM disease. Our results suggest a causal relationship between HCV infection and MGUS and MM progression. When HCV was eliminated, chronic antigen-stimulation disappeared, allowing control of clonal plasma cells. This opens new possibilities of treatment for MGUS and myeloma.

Light Chain Predominant Intact Immunoglobulin Monoclonal Gammopathy Disorders: Shorter Survival in Light Chain Predominant Multiple Myelomas.

BACKGROUND: A proportion of intact immunoglobulin (Ig)-producing multiple myelomas (MMs) was observed to secrete much higher amounts of free light chains (LCs) than usual. OBJECTIVES: To determine the change point between usual and LC-predominant intact Ig-secreting MMs and other monoclonal gammopathic manifestations and the biological significance of the observation. METHODS: We conducted retrospective examination of laboratory findings in 386 MM, 27 smoldering MM, and 179 monoclonal gammopathy of undetermined significance (MGUS) cases that secreted intact Igs. We recorded the highest levels of involved serum free LC, highest ratio of involved to uninvolved LC, highest concentration of involved LC per g of monoclonal Ig, and highest value for ratio of involved to uninvolved LCs divided by the monoclonal Ig concentration. Each data set was sorted into kappa- and lambda LC-associated lesions. Length of time, in months, between diagnosis and last contact with the patients having myeloma was recorded. RESULTS: Change point analysis of data revealed a subgroup of cases with distinctly higher levels of free LCs. In myelomas, including plasma cell leukemias, 16.4% of myelomas with kappa LCs and 22.3% of myelomas with lambda LCs, the LC secretion was distinctly higher than in the remaining cases, by a combination of 4 parameters, listed herein. Corresponding figures for smoldering myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS) were 12.5, 27.3, 3.8, and 6.8, respectively. Ten of the 13 (77%) cases of plasma cell leukemia) and all cases of IgD myeloma (n = 4) showed excess secretion of serum free LCs. Among IgG and IgA myelomas, including plasma cell leukemias, the LC-predominant lesions had shorter survival, by an average of 22.5 months. CONCLUSIONS: In total, 18.4% of MMs, including plasma cell leukemias, secrete distinctly higher amounts of serum free LCs than other intact Ig-secreting myelomas and confer significantly lower survival. Quantification of monoclonal serum free LCs may be useful in this subgroup in monitoring progress and potentially in ascertaining minimal residual disease. The findings also stress the need for separate criteria for kappa and lambda LC associated monoclonal gammopathic manifestations. The significantly shorter survival of patients with LC-predominant myelomas warrants consideration in prospective trials of treatments.

Risk of Malignancy in Spondyloarthritis: A Systematic Review.

Systematic inflammatory diseases, including rheumatoid arthritis (RA), are associated with an increased risk of malignancies. However, the pathogenesis of spondyloarthritis (SpA), which includes both ankylosing spondylitis and psoriatic arthritis, is different from RA, and the risk of malignancy and sites involved may also be different. It is important to better understand associations of SpA with site-specific cancers to facilitate appropriate cancer screening. The goal of this review was to examine the association of SpA with malignancy and the potential impact of therapy for SpA on development of malignancy.

Serum microRNA profiles among dioxin exposed veterans with monoclonal gammopathy of undetermined significance.

Previously an increased risk for monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma (MM), was reported among Vietnam veterans exposed to Agent Orange and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Dysregulated expression of certain microRNAs (miRNAs) was demonstrated in MGUS and MM. Given the important role of miRNAs in cellular homeostasis, the aim of this study was to determine if there was an association between serum levels of selected miRNAs and TCDD in 47 MGUS cases identified in our previous investigation using serum specimens and exposure data archived by the Air Force Health Study (AFHS). A total of 13 miRNA levels (let-7a, let-7i, miR-16, miR-20a, miR-21, miR-34a, miR-106b, miR-146a, miR-181a, miR-192, miR-205, miR-335, and miR-361) was measured in serum stored during the 2002 AFHS follow-up and the relationship to lipid-adjusted serum TCDD levels in 1987 was determined. miR-34a showed the strongest relationship with TCDD; after age-adjustment, this positive association was more pronounced. In contrast, the other 12 miRNAs displayed absolute values of age adjusted coefficient estimates below 1.16 and non-significant p-values. The observed strong positive association between high body burdens of TCDD and miR-34a, a tumor suppressor regulated by p53, in this MGUS population warrants clarification of the TCDD-miR-34a relationship and its role in the pathogenesis of MGUS and risk for MM.

Monoclonal Gammopathies After Renal Transplantation: A Single-center Study.

INTRODUCTION: Plasma cell disorders (PCDs) are clonal plasma cell disorders that include conditions such as monoclonal gammopathy of undetermined significance (MGUS), monoclonal gammopathy of renal significance (MGRS), multiple myeloma (MM), smoldering MM (SMM), solitary plasmacytoma, and light-chain (AL) amyloidosis. The risk factors associated with and the clinical course of PCDs after renal transplantation is not well established although immunosuppressive protocols may impact the incidence and natural history of PCDs posttransplant. PATIENTS AND METHODS: This single-center retrospective study evaluated patients with a history of renal transplant who developed a PCD between January 1, 2014-December 31, 2018. RESULT: A total of 41 patients met the inclusion criteria including 29 with MGUS and 12 with symptomatic PCD (4 with MM, 2 with SMM, 4 with MGRS, 1 with AL amyloidosis, and 1 with solitary plasmacytoma). The median follow-up of survivors was 41.6 months. Three patients (1 with MGUS and 2 with MGRS) progressed to MM during the follow-up period. There was a male preponderance in both groups. There was no correlation between the donor and immunosuppressive regimen and the development of a PCD. Patients with symptomatic PCD had higher serum creatinine and M-protein levels at diagnosis and higher free light chain ratio and plasma cell burden. There was also a higher percentage of allograft failure noted in the symptomatic PCD subset 50% (n = 6), whereas only 23% (n = 7) of patients had allograft failure in the MGUS group. CONCLUSION: This study shows the importance of considering monoclonal gammopathy in the differential of renal dysfunction after kidney transplant and the need to follow these patients closely to monitor for progression to symptomatic PCD.

Glucosylsphingosine but not Saposin C, is the target antigen in Gaucher disease-associated gammopathy.

In Gaucher disease type 1 (GD1), genetic deficiency of lysosomal glucocerebrosidase results in the accumulation of glucosylceramide and glucosylsphingosine (GlcSph), that underlie chronic lipid-mediated metabolic inflammation. An important age-related phenotype is high risk of monoclonal gammopathy (MG), including multiple myeloma. We identified GlcSph, a pathological lyso-sphingolipid exclusively elevated in GD, as a mediator of B cell activation and as an antigenic target for GD1-associated MG. Saposin C (SapC), is a lipid-binding protein and activator of lysosomal glucocerebrosidase, which when mutated, cause a rare variant of GD. Sera of GD1 patients with MG of diverse immunoglobulin types were compared to GD patients without gammopathy for reactivity against GlcSph and SapC. We show reactivity of clonal immunoglobulin in GD1 to GlcSph but not to SapC. In two patients with GD1 and gammopathy, GlcSph-reduction therapy with eliglustat resulted in reduction in clonal Ig. Together, our data show that GlcSph but not SapC is the antigenic target in GD1-associated MG and that therapy aimed at reducing the levels of immunogenic lipid resulted in reduction of clonal immunoglobulin in vivo.