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The clinical significance of an abnormal free light chain (FLC) test, performed due to unspecific complains in the absence of a known plasma cell dyscrasia (PCD) or lymphoproliferative disease (LPD), is not fully elucidated. We investigated the importance of an abnormal FLC ratio (FLC-R) in this setting. Patients registered in the Maccabi Healthcare Services database, tested for FLC during 2007–2023 without previously documented PCD/LPD or increased total protein (TP) level, were reviewed. Demographics, co-morbidities, and laboratory tests were recorded. FLC-R was defined as normal (0.26–1.65) or slightly (slAb 0.1–0.26/1.65–4), moderately (mAbn 0.1–0.05/4–8) and significantly abnormal (sigAb- < 0.05 or > 8). Factors associated with PCD/LPD and overall survival were identified. In total, 8,661 patients, 2,215 (25.6%) with abnormal FLC-R [2,090 (24.1%)-slAb, 65 (0.75%)-mAbn and 60 (0.7%)-sigAb], were analyzed. Almost none had anemia nor acute renal failure. 14% had concomitant increased immunoglobulins. Within a median follow-up of 52 months, 943 were diagnosed with PCD (816-MGUS, 127-MM/Amyloidosis/plasmacytoma) and 48 with LPD. Median time to PCD and LPD were 19 and 28 months. Multivariate analysis found slAb (HR = 1.8, CI95%:1.53–2.12, p < 0.001), mAbn (HR = 6.3, CI95%:4.16–9.53, p < 0.001), and sigAb FLC (HR = 10.4, CI95%:7.0–15.35, p < 0.001), to be associated with PCD/LPD diagnosis. Decreased IgG, increased IgA, and concomitant comorbidities predicted PCD, whereas increased IgM predicted LPD. Older age, male gender, anemia, decreased albumin, increased IgG and concomitant comorbidities, predicted shorter survival. Our large study emphasizes the independent clinical significance of abnormal FLC-R as a predictor of PCD/LPD diagnosis even in patients with normal TP level, promoting early detection of PCD/LPD. [ABSTRACT FROM AUTHOR]

Purpose: Risk factors for monoclonal gammopathy of undetermined significance (MGUS), the asymptomatic precursor to multiple myeloma, are largely unknown. We hypothesized that low vitamin D levels might be associated with higher MGUS prevalence in a national cohort of U.S. Black women. Methods: We screened archived serum samples (collected 2014–2017) from 3896 randomly selected participants in the Black Women's Health Study ages 50–79 for evidence of MGUS; samples had been assayed for 25-hydroxyvitamin D [25(OH)D] shortly after blood draw. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between 25(OH)D level and MGUS status, adjusting for age, body mass index, and season of blood draw. Results: We identified 334 MGUS cases (8.6%) in the study population. The adjusted OR comparing women with vitamin D deficiency (25(OH)D < 20 ng/mL) to those with 25(OH)D levels ≥ 30 ng/mL was 1.27 (95% CI: 0.95, 1.72). Conclusion: MGUS was more prevalent among Black women with vitamin D deficiency compared to those with 25(OH)D ≥ 30 ng/mL; however, the association was not statistically significant. Future prospective studies are warranted to clarify the possible association between vitamin D and MGUS. [ABSTRACT FROM AUTHOR]

Today, Monoclonal Gammopathy of Undetermined Significance (MGUS) is known as a plasma cell malignancy susceptible to evolving into the life-threatening stage, multiple myeloma (MM), without prominent clinical manifestations. Despite the discovery of advanced therapies and multiple pathogenic markers, the complexity of MM development has made it an incurable malignancy. In this study, the microarray dataset was downloaded from the Gene Expression Omnibus (GEO) database and analyzed using the LIMMA package of R-software to determine differentially expressed genes (DEGs) in MGUS and MM compared to the control samples. Enrichment analysis of DEGs was evaluated using the GeneCodis4 software. Protein–protein interaction (PPI) networks were constructed via the GeneMANIA database, and Cytoscape visualized them. The Molecular Complex Detection (MCODE) plugin from Cytoscape was used to identify the key modules from the PPI network. Afterward, the hub genes were recognized using the cytoHubba plug-in in Cytoscape. Eventually, the correlation between hub-DEGs and MM-specific survival was evaluated via the PrognoScan database. A total of 138 (MM-normal) and 136 (MGUS-normal) DEGs were obtained from the datasets, and 62 common DEGs between MGUS and MM diseases (26 up-regulated and 36 down-regulated genes) were screened out for subsequent analyses. Following enrichment analyses and the PPI network's evaluation, FOS, FOSB, JUN, MAFF, and PPP1R15A involved in the progression of MGUS to MM were detected as the hub genes. The survival analysis revealed that FOS, FOSB, and JUN among hub genes were significantly associated with disease-specific survival (DSS) in MM. Identifying the genes involved in the progression of MGUS to MM can help in the design of preventive strategies as well as the treatment of patients. In addition, their evaluation can be effective in the survival of patients. [ABSTRACT FROM AUTHOR]

Summary: Acquired von Willebrand syndrome is exceedingly rare and accounts for only 1–3% of von Willebrand disease cases. In this short report, we present our own cases of acquired von Willebrand syndrome associated with monoclonal gammopathy. Both cases went into complete and sustained remission after intensive antimyeloma treatment. The first patient was not deemed fit for autologous stem cell transplantation and was managed with an extensive multidrug combination including daratumumab, carfilzomib, lenalidomide, cyclophosphamide and dexamethasone. After at least VGPR was achieved the coagulation studies rapidly normalized and remained normal after treatment de-escalation to lenalidomide/dexamethasone maintenance. The second patient successfully underwent ASCT after 5 cycles of induction with daratumumab, bortezomib, cyclophosphamide and dexamethasone and has remained in full hematologic and hemostaseologic remission ever since. The two cases highlight the efficacy of aggressive antimyeloma treatment in monoclonal gammopathy-associated acquired von Willebrand syndrome to achieve normalization of coagulation study, providing a possible way to manage these patients. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic plasma cell disorder characterised by a serum M protein level below 3 g/dL, percentage of bone marrow clonal plasma cells below 10%, absence of end-organ damage (hypercalcaemia, renal insufficiency, anaemia, bone lesions) and absence of any other disease known to produce M protein. MGUS may progress to myeloproliferative disorders or multiple myeloma, but very little is known about any modifiable risk factors or any preventative treatment that might delay this progression. Metformin has begun to be discussed as a potentially useful agent on the basis of the results of epidemiological and preclinical research showing that it may be beneficial in patients with leukaemia, lymphomas and multiple myeloma. Metformin studies dedicated to MGUS are currently very limited, yet it would appear that there may be hope for reducing progression of MGUS to multiple myeloma with metformin in type 2 diabetes mellitus. However, more data is needed until we reach a clearer view of what is to be gained with metformin in this setting. [ABSTRACT FROM AUTHOR]

Summary: Multiple myeloma (MM) remains incurable. Although early diagnosis improves outcomes, it has been unclear which populations to target for screening with serum electrophoresis, serum free light chains and urine electrophoresis. Here, we assessed the value of MM screening in a Fracture Liaison Service, finding that 1 per 195 fragility fractures has undiagnosed MM, which can be expedited to Haematology Services. Purpose: A key role of the Fracture Liaison Service (FLS) is screening for secondary causes of osteoporosis. In 2019, the Royal Osteoporosis Society recommended that all patients attending FLS who are recommended anti-osteoporosis therapy have universal screening for myeloma based on serum electrophoresis, serum free light chains and urine electrophoresis. Here, we examined the impact of universal myeloma screening within an FLS. Methods: We sampled all patients seen by the Oxfordshire FLS between January and April 2018. The completion rates and outcomes of screening were checked using the hospital and FLS databases. Results: Of 950 patients identified by the FLS, 628 were eligible for MM screening; 473 (75%) of these were female, and the average age was 78.4 years. Overall, 584 had some form of myeloma screening, of which 577 (92%) had serum electrophoresis, 525 (84%) had serum free light chains and 407 (65%) had urine electrophoresis measured. A total of 327 (59%) patients had complete screening. Three patients (0.5%) had newly diagnosed myeloma and were urgently referred to Haematology Services. Furthermore, 46 (8%) patients had a detectable serum paraprotein with a likely diagnosis of monoclonal gammopathy of uncertain significance (MGUS) and referred for community annual surveillance according to local guidelines. Conclusion: Addition of universal myeloma screening to laboratory testing identified myeloma in 1 per 195 patients, and its precursor state MGUS in 1 per 13 patients, which may have otherwise been missed. Further analysis with long-term follow-up is needed to clearly define the value of diagnosing MGUS within the FLS setting and establish the benefits vs. costs and methods to improve screening completion rates. [ABSTRACT FROM AUTHOR]

Tumour-associated macrophages (TAMs) support cancer cell survival and suppress anti-tumour immunity. Tumour infiltration by CD163pos TAMs is associated with poor outcome in several human malignancies, including multiple myeloma (MM). Signal transducer and activator of transcription 3 (STAT3) is over-activated in human cancers, and specifically within TAMs activation of STAT3 may induce an immunosuppressive (M2-like) phenotype. Therefore, STAT3-inhibition in TAMs may be a future therapeutic strategy. We investigated TAM markers CD163, CD206, and activated STAT3 (pSTAT3) in patients with MGUS (n = 32) and MM (n = 45), as well as healthy controls (HCs, n = 13). Blood levels of the macrophage biomarkers sCD163 and sCD206, and circulating cytokines, as well as bone marrow mRNA expression of CD163 and CD206, were generally increased in MGUS and MM patients, compared to HCs, but to highly similar levels. By immunohistochemistry, bone marrow levels of pSTAT3 were increased specifically within CD163pos cells in both MGUS and MM patients. In conclusion, macrophage-related inflammatory changes, including activation of STAT3, were present already at the MGUS stage, at similar levels as in MM. Specific increase in pSTAT3 levels within CD163pos cells supports that the CD163 scavenger receptor may be a useful target for future delivery of STAT3-inhibitory drugs to TAMs in MM patients. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathy of undetermined significance (MGUS), precursor of multiple myeloma, is an asymptomatic plasma cell disorder that overproduces serum monoclonal protein. Older age, male sex, black race, and family history of MGUS increase the risk of MGUS, yet other risk factors are known. We systematically reviewed observational epidemiological studies that examined sociodemographic, clinical, and behavioral risk factors for the development of MGUS. The protocol for this study was registered on the PROSPERO registry for systematic reviews. We identified epidemiological studies from PubMed and Scopus. Articles were limited to those written in English and published before February 2019. Five case-control and three cohort studies were eligible for data extraction. Studies evaluating factors associated with MGUS risk are limited, with conflicting conclusions regarding risk associated with obesity. Despite the limited research, a significant elevated risk for being diagnosed with MGUS was associated with several specific prior infections, inflammatory disorders, and smoking. The sparse existing literature suggests an increased risk of MGUS associated with several risk factors related to immune function. Further research is needed to explore the potential mechanisms underlying the development of MGUS and to confirm risk factors, both modifiable and non-modifiable. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant hematological condition arising from B‑cells, characterized by the presence of monoclonal immunoglobulin production, also known as paraprotein. It is found in up to 3% of individuals over the age of 50 years. The overall progression rate is low at around 1% per year, with most patients progressing to multiple myeloma (MM). Other diseases that may arise from MGUS include non-Hodgkin lymphomas, Waldenström macroglobulinemia, amyloid light-chain (AL) amyloidosis, POEMS (polyneuropathy, organomegaly, endocrinopathy, M‑protein, skin changes), cryoglobulinemia, monoclonal gammopathy of renal significance (MGRS), and additional paraprotein-driven diseases. Every case of monoclonal gammopathy warrants careful investigation to rule out the presence of a malignant form. In recent years, paraprotein-associated conditions such as MGRS have been increasingly recognized. Accurate diagnosis and work-up of these cases require a multidisciplinary approach, and it is paramount to accurately distinguish them from true MGUS in order to prevent end-organ damage. Follow-up of MGUS should be lifelong; however, a risk-adapted approach involving the primary care setting is recommended. [ABSTRACT FROM AUTHOR]

We performed a retrospective cohort study to analyze all 87 CAD patients with MGUS and 178 CAD patients without MGUS admitted in Zhongshan Hospital Fudan University from 2015 to 2017. Patients were followed up via regular patient visits or telephone, and the median follow-up period was 2.9 years. The end point of follow-up was the occurrence of major adverse cardiac events (MACE). CAD patients with MGUS had a higher risk of MACE than those without MGUS (log-rank P = 0.0015). After adjustment for other markers in the stepwise Cox regression model, MGUS was still related to the increasing risk of MACE incident (P = 0.002, HR = 2.308). Then, we constructed the nomogram based on the Cox regression model, and the concordance index (C-index) was 0.667. Hence, MGUS might be added into the risk model of CAD. [ABSTRACT FROM AUTHOR]

Purpose of the Review: Monoclonal gammopathy of undetermined significance (MGUS) is a highly prevalent precursor condition in the general population, with an approximate 1% annual risk of progression to multiple myeloma (MM) or a related disorder. Our understanding of MGUS and its association with myriad clinical disorders, its progression to MM, and the genomic alterations in the setting of a conducive or permissive microenvironment has deepened considerably. Recent Findings: Data from gene expression profiling studies have underscored the heterogeneity in the risk of progression of MGUS to MM. Ongoing efforts are being directed toward precise identification of high-risk factors for progression and addressing the role of screening for MGUS in populations at higher risk of MGUS in order to diagnose this precursor condition early, and target modifiable risk factors. Ongoing clinical trials are assessing the role of therapeutic interventions to prevent MGUS from progressing. Summary: MGUS is a heterogeneous precursor condition with a risk for progression to symptomatic disease. Future directions are focusing on identifying high-risk populations of MGUS and smoldering multiple myeloma that may benefit with screening and/or early intervention. [ABSTRACT FROM AUTHOR]

Knowledge of social inequalities in monoclonal gammopathy of undetermined significance (MGUS) will contribute to understanding multiple myeloma (MM) etiology, as MGUS consistently precedes MM. The aim of the present study was to examine whether socioeconomic position (SEP) is associated with MGUS in a population-based cohort including information on potential MGUS risk factors. Overall, 4787 study participants aged 45-75 years with information on MGUS were included. SEP indicators (education, income) and potential risk factors (i.e., body mass index, diabetes, smoking, dietary factors) were assessed at baseline. Overall, 260 MGUS cases were detected at baseline and prospectively over a 10-year follow-up. In age-adjusted logistic regression models, a lower chance of having MGUS at baseline or developing MGUS during 10 years of follow-up was indicated for groups of low SEP with odds ratios (OR) of 0.39 (95% confidence interval [95%-CI] 0.19-0.76) for women and 0.48 (95% CI 0.10-1.16) for men in the lowest compared to the highest educational group. After additionally including potential mediating risk factors in the regression models, the estimated ORs changed only slightly in magnitude. Similar results were obtained for income. Current smoking and low fruit consumption were associated with MGUS independently of SEP in women, but not in men. The present study indicates a lower MGUS risk in lower SEP groups. Supporting evidence is given that smoking and diet play a role in the development of MGUS independently of SEP, while it has to be assumed that risk factors unknown to date are responsible for the observed social inequalities in MGUS. [ABSTRACT FROM AUTHOR]

Objective: To determine the value of low-dose whole-body CT (WBCT) in the management of patients with multiple myeloma (MM) and precursor states.Materials and Methods: The study group comprised 116 patients (mean age: 68 ± 11 years, 48% women) who underwent WBCT for the work-up or surveillance of MM or MM precursor disease. WBCTs were reviewed for the presence of MM-related bone disease and incidental findings requiring therapy. The medical records, results from bone marrow aspirations and biopsies and follow-up imaging studies were reviewed to assess the influence of WBCT on patient management.Results: Whole-body CT led to a change in management in 32 patients (28%). Of those, 17 patients with MM precursor disease were found to have MM-related bone disease, 13 patients had progression of MM, requiring a change in treatment, in one patient hepatocellular carcinoma was diagnosed, requiring a change in therapy, and one patient had a rib lesion requiring intervention. In 65 patients (56%), WBCT was performed for surveillance of MM precursor disease or stable treated MM, and did not detect new lesions, thereby providing reassurance to the hematologist on disease status and management. In 15 patients (13%) WBCT was performed as a new baseline before a change or new therapy. In 4 patients (3%), WBCT was performed for a change in symptoms, but did not detect lesions that would lead to a change in management.Conclusion: Whole-body CT provides important information for disease monitoring and detection of incidental findings, thereby improving the management of patients with MM. [ABSTRACT FROM AUTHOR]

Demonstration of monoclonal immunoglobulin molecule in serum forms the mainstay in the diagnosis of monoclonal gammopathies. The major tests that help in this regard are serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (sIFE) and serum free light chain assay (sFLC). Our objectives were to study the accuracy of sFLC and sIFE in the diagnosis of monoclonal gammopathies and also to study the role of combination of SPEP + sIFE + sFLC in the diagnosis of the same. 46 patients who attended the hemato-oncology clinic with signs and symptoms suggestive of monoclonal gammopathy were enrolled in this study. SPEP, sIFE, sFLC and pre-treatment serum beta-2 microglobulin levels were analysed among the study population. Both SPEP and sIFE were performed in the Interlab Genios fully automated machine. Serum beta-2 microglobulin and sFLC were estimated by immunoturbidimetry in Beckman Coulter AU 2700 analyzer. The accuracy of sIFE came to be 80% with respect to sFLC assay. Sensitivity, specificity, positive and negative predictive value of sIFE with respect to sFLC were 81.3, 78.6, 89.7 and 64.7% respectively. It was observed that a combination panel of SPEP + sIFE + sFLC could detect all the cases of myeloma included in this study. Further testing in large samples is required for generalising the findings of this study. The pre-treatment beta-2 microglobulin levels were significantly higher in the group which was positive for myeloma. A combination panel of SPEP + sIFE + sFLC prove to be more useful than individual tests for the detection of myeloma. [ABSTRACT FROM AUTHOR]

Although anti-myelin-associated glycoprotein (MAG) antibody neuropathy is reported as a slowly progressive disease, it can lead to significant disability and impairment of health-related quality of life (HR-QoL) and social participation. The aim of this cross-sectional study was to evaluate the functioning and HR-QoL determinants in 67 patients with anti-MAG neuropathy in terms of the International Classification of Functioning, Disability, and Health (ICF). Evaluations included: Medical Research Council (MRC) sum score, Sensory Modality Sum score (SMS), Berg balance scale (BBS), Fatigue Severity Scale (FSS), Visual Analogue Scale (VAS) for pain, 9-Hole Peg Test (9-HPT), 6-min Walk Distance (6MWD), Impact on Participation and Autonomy (IPA) and the physical component score (PCS) and mental component score (MCS) of the short-form-36 health status scale (SF-36) HR-QoL measure. In the regression models, 6MWD was the most reliable predictor of PCS, explaining the 52% of its variance, while the strongest determinants of 6MWD were BBS and FSS, explaining the 41% of its variance. Consistently, VAS and BBS were good predictor of PCS, explaining together 54% of its variance. FSS was the most reliable determinant of MCS, explaining 25% of its variance. SMS and MRC were not QoL determinants. The results of our study suggest that 6MWD and FSS might be considered as potential meaningful outcome measures in future clinical trials. Furthermore, neurorehabilitation interventions aimed at improving balance and walking performance, fatigue management, and specific pain relief therapy should be considered to ameliorate participation in social life and HR-QoL in anti-MAG neuropathy patients. [ABSTRACT FROM AUTHOR]

Purpose of Review: MGUS (monoclonal gammopathy of undetermined significance) is a plasma cell disorder characterized by a moderate increase in serum monoclonal protein (≤ 3 g/dL), an increase in bone marrow plasma cell infiltration (≤ 10%) and the absence of any end-organ damage. Although MGUS is considered a benign condition, evidence for clinical consequences is increasing. In this review, we examine the most recent evidence regarding MGUS manifestations and risks and present an overview of MGUS population studies as related to bone disease. Data reveals important MGUS-related bone alterations that may contribute to disease pathogenesis.Recent Findings: MGUS patients present a rate of 1% per year risk of progression to the more aggressive multiple myeloma (MM) and therefore research has focused on the study of risk factors and the events leading to this progression. However, the exact health implications of MGUS itself and the mechanisms behind them remain unclear.Summary: It is now evident that the bone microenvironment plays a key role in hematologic cancers and other oncogenic processes leading to bone metastasis. [ABSTRACT FROM AUTHOR]

An uncommon association between multiple myeloma and Hodgkin lymphoma (HL) was observed in some case reports, while an association with monoclonal gammopathy of uncertain significance (MGUS) is exceedingly rare. We have diagnosed 110 HL cases from 2008 to 2018; here we report 4 HL cases associated with MGUS. MGUS was diagnosed before HL (1 case), together with HL (1 case) or after HL (2 cases). M-component was IgG/k (3 cases) and IgG/k and IgG/λ (1 case), MGUS was not influenced by HL treatment (2 cases), raised after therapy (1 case), while in the last case MGUS appeared after ASCT while HL was in complete remission. We suggest to further study a possible link between MGUS and HL and to perform serum immunofixation if protein electrophoresis shows a suspected discrete band. The comprehension of pathophysiology of this association and a possible role of cytokines such as IL-6 and antilymphoma therapies such as nivolumab or ASCT to MGUS development could represent an interesting research field that requires further investigations. [ABSTRACT FROM AUTHOR]

To characterize the clinical features, associated disorders, and treatment of necrobiotic xanthogranuloma (NXG), a rare non-Langerhans cell histiocytosis, we conducted a retrospective review of pathologically confirmed NXG at Mayo Clinic Arizona from 1987 to June 2017. Data on clinical findings, laboratory findings, associated disorders, therapy, and response to therapy were extracted. Nineteen patients were identified. Mean age was 54 years (range, 17-84) with equal gender distribution. Median follow-up was 5.5 years (range, 1-18). Most patients had a detectable monoclonal protein (84%), and IgG kappa constituted 58%. The most common cutaneous lesions involved the periorbital region (53%). The majority of patients had extracutaneous manifestations, most commonly affecting the liver (32%) and the sinuses (21%). Hematologic malignancies were diagnosed in 26% of patients and included Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), smoldering myeloma, and multiple myeloma. The most common treatment was chlorambucil with or without systemic corticosteroids. Response was seen in most patients (95%), and most patients received 1-3 lines of therapy (74%). NXG is a reactive histiocytic disorder that commonly involves multiple organ systems and requires a high degree of clinical suspicion for accurate diagnosis. Treatment decisions should be based on coexisting conditions and pattern of disease involvement. [ABSTRACT FROM AUTHOR]

High-count monoclonal B cell lymphocytosis (MBL) with a chronic lymphocytic leukemia (CLL) phenotype is a well-known entity, featuring 1-4% annual risk of progression towards CLL requiring treatment. Lymphoma-like MBL (L-MBL), on the other hand, remains poorly defined and data regarding outcome are lacking. We retrospectively evaluated 33 L-MBL cases within our hospital population and compared them to 95 subjects with CLL-like MBL (C-MBL). Diagnoses of L-MBL were based on asymptomatic B cell clones with Matutes score < 3, B cells < 5.0 × 103/μl, and negative computerized tomography scans. We found that median B cell counts were considerably lower compared to C-MBL (0.6 vs 2.3 × 103/μl) and remained stable over time. Based on immunophenotyping and immunogenetic profiling, most L-MBL clones did not correspond to known lymphoma entities. A strikingly high occurrence of paraproteinemia (48%), hypogammaglobulinemia (45%), and biclonality (21%) was seen; these incidences being significantly higher than in C-MBL (17, 21, and 5%, respectively). Unrelated monoclonal gammopathy of undetermined significance was a frequent feature, as the light chain type of 5/12 paraproteins detected was different from the clonal surface immunoglobulin. After 46-month median follow-up, 2/24 patients (8%) had progressed towards indolent lymphoma requiring no treatment. In contrast, 41% of C-MBL cases evolved to CLL and 17% required treatment. We conclude that clinical L-MBL is characterized by pronounced immune dysregulation and very slow or absent progression, clearly separating it from its CLL-like counterpart. [ABSTRACT FROM AUTHOR]

Purpose of review Several advances have been made on the pathogenesis and therapy of neuropathies associated with paraproteinemia (monoclonal gammopathy). It is important for the neurologist to understand the pathogenetic relevance of this association especially when the hematological disease does not require per se any therapy. Recent findings Treatment of the neuropathy in patients with malignant paraproteinemia is mainly addressed by the hematologist while the neurologist is mainly involved in the initial diagnosis and in deciding whether the neuropathy is caused by the disease or by the chemotherapy used for the disease. There is little evidence that the neuropathy is caused by the hematological condition in patients with IgG or IgA monoclonal gammopathy of undetermined significance (MGUS) unless there is an evidence of a reactivity of the paraprotein with nerve or evidence of its presence in the nerve. Patients with a chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)-like presentation should be treated as CIDP while there is no evidence that immune or chemotherapy may be effective in the other patients. In most patients with IgM paraproteinemia, that is usually a MGUS or an indolent Waldenström's macroglobulinemia, the neuropathy is induced by an immune reactivity of the paraprotein with nerve and particularly with the myelin-associated glycoprotein. There are now consistent data also from controlled studies that the anti-CD20 monoclonal antibody rituximab may improve the neuropathy in these patients. POEMS syndrome is a severe condition characterized by a disabling neuropathy whose prognosis has improved in the last few years with therapies against the proliferating plasma cell clone or vascular endothelial growth factor including local radiotherapy and chemotherapy followed by autologous stem cell transplantation. Other therapies are also available for patients not eligible or resistant to transplantation, including lenalidomide and possibly thalidomide or bortezomib. Summary Several new therapies are now available for patients with paraproteinemic neuropathy consistently improving the prognosis of these neuropathies. In most instances, however, their efficacy needs to be confirmed in controlled trials. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathy of undetermined significance (MGUS) is a clonal plasma cell disorder and precursor disease to multiple myeloma and other related cancers. While MGUS is considered a benign disorder, with a low risk of disease progression, patients have altered bone microarchitecture and an increased risk of bone fracture. In addition, alterations in immune function are regularly found to correlate with disease activity. Vitamin D, an important hormone for bone and immune health, is commonly deficient in multiple myeloma patients. However, vitamin D deficiency is also prevalent in the general population. The purpose of this review is to highlight the current understanding of vitamin D in health and disease and to parallel this with a review of the abnormalities found in plasma cell dyscrasias. While some consensus statements have advocated for vitamin D testing and routine supplementation in MGUS, there is no clear standard of care approach and clinical practice patterns vary. Further research is needed to better understand how vitamin D influences outcomes in MGUS patients. [ABSTRACT FROM AUTHOR]

Researchers globally are working towards finding a cure for multiple myeloma (MM), a destructive blood cancer diagnosed yearly in ~750,000 people worldwide (Podar et al. in Expert Opin Emerg Drugs 14:99-127, 2009). Although MM targets multiple organ systems, it is the devastating skeletal destruction experienced by over 90 % of patients that often most severely impacts patient morbidity, pain, and quality of life. Preventing bone disease is therefore a priority in MM treatment, and understanding how and why myeloma cells target the bone marrow (BM) is fundamental to this process. This review focuses on a key area of MM research: the contributions of the bone microenvironment to disease origins, progression, and drug resistance. We describe some of the key cell types in the BM niche: osteoclasts, osteoblasts, osteocytes, adipocytes, and mesenchymal stem cells. We then focus on how these key cellular players are, or could be, regulating a range of disease-related processes spanning MM growth, drug resistance, and bone disease (including osteolysis, fracture, and hypercalcemia). We summarize the literature regarding MM-bone cell and MM-adipocyte relationships and subsequent phenotypic changes or adaptations in MM cells, with the aim of providing a deeper understanding of how myeloma cells grow in the skeleton to cause bone destruction. We identify avenues and therapies that intervene in these networks to stop tumor growth and/or induce bone regeneration. Overall, we aim to illustrate how novel therapeutic target molecules, proteins, and cellular mediators may offer new avenues to attack this disease while reviewing currently utilized therapies. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a plasma cell disorder preceded by monoclonal gammopathy of undetermined significance (MGUS). Incidence of MM and MGUS is higher among patients with autoimmune disease. The aim of this study was to determine whether a history of autoimmunity has an impact on survival in MM and MGUS. Using high-quality national Swedish registries, we identified 8367 patients with MM, 18,768 patients with MGUS, and 110,251 matched control subjects, and obtained information on previous autoimmune disease in patients and controls. Cox regression was used to calculate hazard ratios (HRs) for overall survival with 95 % confidence intervals (CIs). In patients with MM and a prior autoimmune disease, the risk of death was significantly increased, HR = 1.2 (95 % CI 1.2-1.3) compared to MM patients with no history of autoimmunity. In MGUS patients, a prior autoimmune disease was associated with a significantly 1.4-fold elevated risk of death (95 % CI 1.3-1.4). When analyzing different types of autoimmune diseases, a history of ulcerative colitis had a stronger impact on survival in MM than in controls. Our findings that a history of autoimmune disease has a negative impact on survival in MM and MGUS could be due to shared underlying common genetic factors, or that patients with a history of autoimmunity develop more severe cases of MM and MGUS, or cumulative comorbidity in the individual. Our results suggest that more attention should be paid to comorbidity as a prognostic factor in MGUS and MM, and underlines the need for studies aimed at tailoring therapy according to comorbidity. [ABSTRACT FROM AUTHOR]

Objective: To determine abdominal adipose tissue parameters on PET/CT in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) that may serve as predictors of progression of MGUS to MM. We hypothesized that patients with MM had higher abdominal adiposity and higher fat metabolic activity compared to patients with MGUS.Materials and Methods: Our retrospective study was IRB approved and HIPAA compliant. The study group comprised 40 patients (mean age 64 ± 13 years) with MGUS and 32 patients (mean age 62 ± 10 years) with recently diagnosed MM (mean time since diagnosis of MM 3.0 ± 3.9 months) who had not undergone MM treatment. All patients underwent whole body FDG-PET/CT. Total abdominal adipose tissue (TAT), abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) cross sectional areas (CSA) (cm(2)) and metabolic activity (SUV) were assessed. Groups were compared using ANOVA. ROC curve analysis was performed to determine cutoff values for abdominal adipose tissue parameters to detect MM.Results: Patients with recently diagnosed MM had higher TAT and SAT CSA (p ≤ 0.03) and higher fat metabolic activity (p < 0.01). VAT metabolic activity showed the highest sensitivity and specificity for identifying patients with MM (area under the curve 0.95 with cutoff value of >0.34, sensitivity 90.6 %, specificity 92.5 %, p < 0.0001).Conclusions: Patients who were recently diagnosed with MM had higher abdominal fat CSA and higher fat metabolic activity compared to patients with MGUS. These parameters may serve as novel biomarkers of progression of MGUS to MM. [ABSTRACT FROM AUTHOR]

Anti-MAG neuropathy is a very rare form of acquired polyneuropathy associated with IgM monoclonal gammopathy of undetermined significance (MGUS). We conducted a retrospective review of 194 consecutive MGUS patients seen at the Penn State Hershey Cancer Institute. We identified six patients among 37 (16 %) with IgM MGUS with anti-MAG neuropathy. Interestingly, an additional patient had anti-MAG neuropathy without MGUS. Common clinical manifestations were numbness and paresthesias of the extremities and gait imbalance. All four patients treated with rituximab and none of the three untreated ones had a subjective improvement of their symptoms. We conclude that all patients with IgM MGUS and neuropathy should be screened for anti-MAG antibodies and, if positive, they should be offered treatment with rituximab. [ABSTRACT FROM AUTHOR]

Telomere length (TL) is currently used as an emerging biomarker in understanding the development/progression of hematological malignancies. The absolute quantitative PCR (qPCR) methodology has allowed the study of TL from a variety of mammalian tissues, but it has not been tested for bone marrow (BM) samples. In this study, we have examined the relationship between TL data generated by absolute qPCR versus those obtained by terminal restriction fragments (TRF) in 102 BM samples from patients with plasma cell disorders. A significant linear correlation between both methodologies was observed ( p < 0.0001; r = 0.70). Results were also analyzed in relation to clinical characteristics and significant associations between telomere shortening and parameters of adverse prognosis were observed. Furthermore, another set of 47 BM samples from patients with low quantity of DNA for TRF assay were suitably analyzed by qPCR, indicating the usefulness of the absolute qPCR methodology for the inclusion of patients with scarce material to the study. Taken together, these findings are of interest considering the importance of telomere dysfunction in the pathogenesis of cancer and give a new alternative to measure TL in hematologic disorders with substantial time and cost savings. [ABSTRACT FROM AUTHOR]

The link between myeloma and thrombosis is well established. Monoclonal gammopathy of undetermined significance (MGUS) has also been associated with an increased risk of thrombosis. It was recently demonstrated that patients with myeloma display changes in thromboelastometry that may indicate a prothrombotic state. There is little data with regard to changes in thromboelastography in patients with myeloma or MGUS. The aim of this study was to investigate the differing coagulation profiles of patients of patients with myeloma and MGUS by means of conventional coagulation tests and thromboelastography. Blood was taken by direct venepuncture from patients with myeloma, MGUS and normal controls. Routine coagulation tests were performed in an accredited hospital laboratory. Thromboelastography (TEG) was performed as per the manufacturer's protocol. Eight patients were recruited in each group. Patients with myeloma had a significantly lower mean haemoglobin level than patients with MGUS or normal controls ( p < 0.001). Pateints with myeloma had a significantly more prolonged mean prothrombin time than normal controls ( p = 0.018) but not patients with MGUS. Patients with myeloma had significantly higher median D-dimer levels than normal controls ( p = 0.025), as did patients with MGUS ( p = 0.017). Patients with myeloma had a significantly higher mean factor VIII level than normal controls ( p = 0.009) and there was a non-significant trend towards patients with MGUS having higher factor VIII levels than normal controls ( p = 0.059). There was no significant difference in thromboelastographic parameters between the three groups. Patients with MGUS appear to have a distinct coagulation profile which is intermediate between patients with myeloma and normal controls. [ABSTRACT FROM AUTHOR]

African Americans have two- to three-fold higher incidence of multiple myeloma and MGUS compared to other ethnic groups in the USA. Some physicians often perform diagnostic evaluations for plasma cell disorders (PCD) in African American patients on the basis of hematological abnormalities (thrombocytopenia, leucopenia, etc.) even in the absence of traditional triggers such as anemia, renal impairment, hypercalcemia, hyperglobulinemia, and lytic bone disease. Whether these nontraditional triggers have any significant association with PCD in African American population is not known. In addition, whether this approach could detect more asymptomatic PCD than black population prevalence is questionable. Moreover, the association between traditional triggers and PCD particularly in blacks has not been clearly delineated. Hence, we have carried out a retrospective study in an attempt to answer these questions. Two hundred fifty-four patients were eligible. Multiple myeloma workup based on parameters other than traditional triggers did not detect more asymptomatic PCD than what is expected of black population prevalence ( p = 0.19). Of traditional triggers, the finding of only anemia or hyperglobulinemia seemed to be nonspecific in black population ( p = 0.17 and 0.85, respectively). However, the presence of serum creatinine >2 mg/dL or corrected serum calcium >10.5 mg/dL or a combination of traditional triggers appeared to be strongly predictive of PCD (odds ratio of 6.9, 4.2, and 3, respectively). The number of trigger variables was positively correlated with the likelihood of PCD ( p < 0.001). Light-chain-only PCD, renal disease, and abnormal free light chain ratio seemed to be higher in black patients than their white counterparts. [ABSTRACT FROM AUTHOR]

Copyright of Wiener Klinische Wochenschrift is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Multiple myeloma (MM) is characterized by abnormal proliferation of clonal plasma cells or monoclonal plasmacytosis, resulting in accumulation of clonal immunoglobulins. Monoclonal gammopathy of unknown significance (MGUS) is considered a premorbid stage for developing MM. Studies have shown an increased risk of MGUS in first-degree relatives of patients with MM. Detection of immunoglobulin heavy chain gene ( IGH) rearrangement provides a useful tool for assessing clonality. The aim of this study was to determine clonality in peripheral blood samples from 61 healthy first-degree relatives of MM probands by sorting circulating lymphocytes and detection of the IGH rearrangements in these cells. We detected 16 out of 61 (26.2 %) relatives with monoclonal complete and incomplete IGH rearrangements; only three of them showed elevated monoclonal immunoglobulin in the serum protein electrophoresis. We conclude that this strategy is able to identify efficiently clonality in peripheral blood samples from first-degree relatives of patients with MM, who have a non-negligible risk of developing MGUS or other plasma cell dyscrasias. [ABSTRACT FROM AUTHOR]

Idiopathic Bence-Jones proteinuria (BJP) is a rare plasma cell dyscrasia, of which the clinical and biological characteristics are yet unclear. Historical data suggested that they are at higher risk of progression to multiple myeloma or other related neoplasms, while recent findings are contradictory. To address these open questions, we evaluated a series of both BJP and monoclonal gammopathy of undetermined significance (MGUS) with production of an intact immunoglobulin plus Bence-Jones proteinuria (MGUS+BJP) with long-term follow-up, regarding their clinical characteristics and progression to multiple myeloma, amyloidosis or other related B cell lymphoproliferative disorders. Two hundred and twenty-nine persons fulfilling the 2004 criteria of MGUS were included in the final analyses: 31 had BJP and 198 had MGUS+BJP. At the time of diagnosis, significantly more persons in the BJP group had renal impairment, anaemia and polyneuropathy. A more detailed analysis revealed discrepancies between the serum and urine light chain type in nine cases, reflecting clonal heterogeneity. The number of disease progressions was higher in MGUS+BJP ( n = 30) when compared to BJP ( n = 1), with a rate of 1.6 and 0.4 progressions per 100 person-years, respectively. In conclusion, BJP has distinct clinical characteristics and a lower risk of progression when compared to MGUS+BJP. Our data suggest that MGUS+BJP being closer to malignant transformation may be due to the higher portion of genetically heterogeneous, pre-malignant plasma cell subclones. [ABSTRACT FROM AUTHOR]

Objectives: Protein oxidation plays a key role in the pathogenesis of oncological diseases. In this study, we analyzed the oxidative stress in untreated multiple myeloma (MM) patients and in patients affected by monoclonal gammopathy of uncertain significance (MGUS). Methods: We evaluated serum levels of advanced oxidation protein products (AOPPs), advanced glycation end products (AGEs), and protein nitrosylation in patients with monoclonal gammopathy and in control subjects. Results: Serum levels of AOPPs and S-nitrosylated proteins were significantly increased in MM patients in comparison to controls and to MGUS subjects. Moreover, in MM patients the levels of AOPPs, AGEs and S-nitrosylated proteins were significantly higher in patients with bone lesions compared with those without lytic bone lesions. Conclusions: MM is closely associated with oxidative stress and further investigation might provide an insight to understand a putative causal link between oxidative stress and MM disease onset and progression or MM complications. [ABSTRACT FROM AUTHOR]

The aim of this study was to describe biological features and aetiology of monoclonal gammopathy diagnosed during a 10-year period in the biochemistry department of the Moroccan Military Hospital Mohamed V in Rabat. The study was performed from 1 January 2000 to 31 December 2009. The records of 261 patients living in the Rabat area in which either serum protein electrophoresis and serum and/or urine immunofixation were performed at the biochemistry department of Military Instruction Hospital in Rabat were analysed. A cohort of 182 (70%) men and 79 (30%) women, the mean ± SD (range) ages were 60.21 ± 12.56 years. All patients were Caucasian. Electrophoresis found that 211 (80.84%) of the patients had a monoclonal gammopathy. Immunofixation confirmed that 251 (96.17%) patients had a monoclonal band in serum. In our cohort, MM was the most frequent diagnosis, our patients were late diagnosed. [ABSTRACT FROM AUTHOR]

We determined the prevalence and progression rate of monoclonal gammopathy of undetermined significance (MGUS) and light-chain MGUS (LCMGUS) in Germany utilizing the biobank of the population-based Heinz Nixdorf Recall Study. The Heinz Nixdorf Recall Study comprises 4,814 men and women aged 45-75 years. To detect monoclonal proteins, standard serum electrophoresis was combined with parallel screening immunofixation using pentavalent antisera. Additionally, free light chains (FLC) were measured in all samples. Definition of MGUS included M-protein concentration, laboratory results, and disease history. LCMGUS was defined as abnormal FLC ratio, increase in FLC causing the abnormal ratio, and lack of intact immunoglobulin. One hundred sixty-five MGUS cases were identified among 4,702 screened samples (prevalence 3.5%, 95% confidence interval (CI) 3.0-4.1; median age 63 years, range 47-75 years; 103 (62%) male; IgG 59%, IgA 17%, IgM 17%, biclonal 4.8%, kappa 56%, and lambda 44%). Five cases progressed (0.6%/year, 95% CI 0.2-1.4). An abnormal FLC ratio was detected in 220 samples. Thirty-nine of these showed intact immunoglobulin. Thirty-four of the remaining met LCMGUS criteria (prevalence 0.7%, 95% CI 0.5-1.0). None of the LCMGUS cases progressed. We demonstrate a MGUS prevalence of 3.5% and a LCMGUS prevalence of 0.7% in the general population aged 45-75 years in Germany using a sensitive screening approach. [ABSTRACT FROM AUTHOR]

Peripheral neuropathy associated with monoclonal gammopathy is a rare but important cause of neuropathy that can herald serious underlying disease. IgM monoclonal gammopathy of undetermined significance (MGUS) is the most commonly found monoclonal gammopathy associated with neuropathy, with characteristic clinical, electrophysiologic, and pathologic features. The IgG and IgA monoclonal gammopathies are rarely associated with specific neuropathies. Standard immunomodulatory agents including steroids, intravenous immunoglobulin, and plasmapheresis have shown limited efficacy in IgM MGUS. Neuropathies associated with specific lymphoproliferative disorders may not respond to treatments aimed at that disorder. Case series had shown promising results with rituximab, a monoclonal antibody that targets the B cell surface antigen CD20 and results in a rapid and sustained depletion of B cells; however, two recent randomized controlled trials with rituximab failed to provide evidence of efficacy in primary outcome measures, despite reduction in antibody levels. Long-term studies looking at the association between specific immunologic markers and disease recurrence are needed to ultimately develop targeted therapies. [ABSTRACT FROM AUTHOR]

Hypogammaglobulinemia of the non-monoclonal immunoglobulin heavy chain classes has been reported in monoclonal gammopathy of undetermined significance (MGUS) patients. Whether low polyclonal immunoglobulin levels are associated with impaired specific antibody production and whether they represent a risk factor for the development of recurrent bacterial infections have not been established in this population. We determined the frequency of MGUS in patients referred to a tertiary care clinical immunology ambulatory care practice for evaluation of hypogammaglobulinemia, who were assessed for deficits in specific antibody production and the presence of recurrent infections. Of the 133 patients evaluated for hypogammaglobulinemia, 68 were screened for monoclonal gammopathy and 5 were found to have MGUS. Three had MGUS associated hypogammaglobulinemia in the absence of a defining primary immunodeficiency, one possibly had common variable immunodeficiency, and one had an uncertain diagnosis. Thus, MGUS may be uncovered in patients presenting with hypogammaglobulinemia even in those who lack an elevated serum level of IgG, IgM, or IgA. [ABSTRACT FROM AUTHOR]

Events mediating transformation from the pre-malignant monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are unknown. We analyzed gene expression data sets generated on the Affymetrix U133 platform from 22 MGUS and 101 MM patients using gene-set enrichment analysis. Genes overexpressed in MM were enriched for cell cycle, proliferation and MYC activation gene sets. Upon dissecting the relationship between MYC and cell-cycle gene sets, we identified and validated an MYC activation signature dissociated from proliferation. Applying this signature, MYC is activated in 67% of myeloma, but not in MGUS. This was further confirmed by immunohistochemistry (IHC) using membrane CD138 and nuclear MYC double staining. We also showed that almost all tumors with RAS mutations expressed the MYC activation signature, and multiple mechanisms may be involved in activating MYC. MYC activation, whether assessed by gene-expression signature or IHC, is associated with hyperdiploid MM and shorter survival even in tumors that are not proliferative. Bortezomib treatment is able to overcome the survival disadvantage in patients with MYC activation. [ABSTRACT FROM AUTHOR]

45-year-old Japanese woman had been diagnosed with monoclonal gammopathy of undetermined significance (MGUS) featuring urinary Bence-Jones protein of the lambda type (BJP-lambda) for 11 years. She then developed eyelid purpura, dyspnea, and flank pain. Abdominal CT scans revealed renal infarction. Biopsy of the kidney, heart, jejunum, and skin demonstrated amyloid deposits in the vessel walls, but not in the glomeruli. She was diagnosed as having AL amyloidosis with IgD-lambda monoclonal gammopathy and BJP-lambda. Autologous stem cell transplantation (SCT) was done after chemotherapy with vincristine, daunorubicin, dexamethasone (VAD), and high-dose melphalan (HDM). This reduced the IgD level from 156 to 0.1 mg/dL, along with the disappearance of BJP, despite cerebral infarction during chemotherapy. We recommend SCT for patients with IgD-associated AL amyloidosis. [ABSTRACT FROM AUTHOR]

There is limited understanding of the dysregulation of the innate immune system in multiple myeloma (MM). We analysed the expression of the activating receptor NKG2D on NK cells and T cells of MM patients and investigated the impact of soluble versus membrane-bound NKG2D ligands on the expression of NKG2D. NKG2D expression on NK cells and CD8+ αβ T cells from patients with MM or monoclonal gammopathy of uncertain significance and healthy controls was examined flow-cytometrically. Sera from patients and controls were analysed for soluble NKG2D ligands (sNKG2D ligands). Significantly fewer NK cells and CD8+ αβ T cells from patients expressed NKG2D compared to healthy controls (NK cells: median 54% interquartile range (IQR) 32–68 versus 71% IQR 44–82%, P = 0.017, CD8+ αβ T cells: median 63% IQR 52–81 versus 77% IQR 71–90%, P = 0.018). The sNKG2D ligand sMICA was increased in patients [median 175 (IQR 87–295) pg/ml] versus controls [median 80 (IQR 32–129) pg/ml, P < 0.001], but levels of sMICA did not correlate with NKG2D expression on effector cells. To elucidate the mechanism of NKG2D down-regulation, we incubated lymphocytes from healthy donors in the presence of sNKG2D ligands or in co-culture with MM cell lines. sNKG2D ligands in clinically relevant concentrations did not down-regulate NKG2D expression, but co-culture of effector cells with myeloma cells with high surface expression of NKG2D ligands reduced NKG2D expression significantly. These results indicate that MM is associated with a significant reduction in NKG2D expression which may be contact-mediated rather than caused by soluble NKG2D ligands. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older. The risk of progression to multiple myeloma, Waldenstrom's macroglobulinemia, AL amyloidosis or a lymphoproliferative disorder is approximately 1% per year. Low-risk MGUS is characterized by having an M protein <15 g/l, IgG type and a normal free light chain (FLC) ratio. Patients should be followed with serum protein electrophoresis at six months and, if stable, can be followed every 2-3 years or when symptoms suggestive of a plasma cell malignancy arise. Patients with intermediate and high-risk MGUS should be followed in 6 months and then annually for life. The risk of smoldering (asymptomatic) multiple myeloma (SMM) progressing to multiple myeloma or a related disorder is 10% per year for the first 5 years, 3% per year for the next 5 years and 1-2% per year for the next 10 years. Testing should be done 2-3 months after the initial recognition of SMM. If the results are stable, the patient should be followed every 4-6 months for 1 year and, if stable, every 6-12 months. [ABSTRACT FROM AUTHOR]

Aberrant DNA methylation is considered an important epigenetic mechanism for gene inactivation. Monoclonal gammopathy of undetermined significance (MGUS) is believed to be a precursor of multiple myeloma (MM). We have analyzed methylation status of p15 INK4B , p16 INK4A , ARF, SOCS-1, p27 KIP1 , RASSF1A, and TP73 genes in bone marrow DNA samples from 21 MGUS and 44 MM patients, in order to determine the role of aberrant promoter methylation as one of the steps involved in the progression of MGUS to MM. Methylation specific polymerase chain reaction assay followed by DNA sequencing of the resulting product was performed. SOCS-1 gene methylation was significantly more frequent in MM (52%) than in MGUS (14%; p=0,006). Methylation frequencies of TP73, ARF, p15 INK4B , p16 INK4A , and RASSF1A were comparable in MGUS: 33%, 29%, 29%, 5%, and 0%, to that observed in MM: 45%, 29%, 32%, 7%, and 2%. All patients lacked methylation at p27 KIP1 gene. In both entities, a concurrent methylation of p15 INK4B and TP73 was observed. The mean methylation index of MGUS was lower (0.16) than that of MM (0.24; p<0.05). Correlations with clinicopathologic characteristics showed a higher mean age in MGUS patients with SOCS-1 methylated (p<0.001); meanwhile in MM, methylation of p15 INK4B was more frequent in males (p=0.009) and IgG isotype (p=0.038). Our findings suggest methylation of TP73, ARF, p15 INK4B , and p16 INK4A as early events in the pathogenesis and development of plasma cell disorders; meanwhile, SOCS-1 methylation would be an important step in the clonal evolution from MGUS to MM. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathy of undetermined significance (MGUS) is one of the most common premalignant disorders in Western countries. Recent studies show that almost every multiple myeloma (MM) case is preceded by an MGUS stage. Interestingly, prevalence and incidence patterns for MGUS and MM show striking disparity patterns across ethnic/racial groups, most notably the two- to threefold increase in both these disorders in African Americans compared with Caucasians. In contrast, studies on Asian patients show lower prevalence/incidence for MGUS/MM compared with Caucasians. Familial aggregation for both MGUS and MM has been observed; the risk for MGUS or MM in family members with these disorders is increased about two- to three fold compared with the general population. Although underlying mechanisms remain unclear, there is evidence of heterogeneity among MGUS patients from different ethnic/racial groups. For example, compared with Caucasians, African-American and African MGUS patients have reportedly lower rates of immunoglobulin M (IgM) MGUS (versus IgG/IgA MGUS) and higher rates of unquantifiable immunoglobulins (Igs). This review focuses on racial disparity and familial aggregation patterns for MGUS and MM and discusses how these observations provide novel clues with regard to pathogenesis. [ABSTRACT FROM AUTHOR]

Gaucher disease type I, the most common lysosomal storage disorder, is associated with immunoglobulin abnormalities. We studied the prevalence, risk factors, pathogenesis, and effect of enzyme relation therapy (ERT) on gammopathies in an adult Gaucher disease type I cohort (N = 63) and related the results to a review of the currently available literature. Polyclonal gammopathies and monoclonal gammopathy of undetermined significance (MGUS) in our adult GD I cohort were found in 41% and 19% of patients. These results are similar to the data from the literature and correspond to the increased risk of multiple myeloma (MM) that has been described. The prevalence of MGUS in our cohort increased with age but was not associated with disease severity or exposure time. The serum levels of free light chains of immunoglobulins were measured and were not found predictive for the development of MGUS or MM. Levels of pro- as well as anti-inflammatory cytokines, growth factors, and chemokines, especially those involved in inflammation and B-cell function, are disturbed in GD I, with the most impressive and consisting elevations for interleukin-10 and pulmonary and activation-regulated chemokine. A beneficial effect of ERT on the occurrence and progression of gammopathies was suggested from longitudinal data. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in a geriatric population in Turkey and compare bone mineral densities and related laboratory parameters of MGUS patients with those who do not have MGUS. Among 1,012 patients enrolled, monoclonal band was detected in serum samples of 22 patients (2.17%), most of which were IgG type. Further tests revealed multiple myeloma and lung carcinoma in two patients. The remaining 20 patients were diagnosed with MGUS (1.97%). The clinical and laboratory parameters of patients with and without MGUS were mostly comparable; however, bone mineral density measurements of patients with MGUS were significantly lower than those without MGUS ( p = 0.007). We suggest evaluation of geriatric patients with MGUS for the presence of osteopenia/osteoporosis considering the high frequency observed in this study. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is the most common form of plasma cell dyscrasia, characterized by a marked heterogeneity of genetic lesions and clinical course. It may develop from a premalignant condition (monoclonal gammopathy of undetermined significance, MGUS) or progress from intramedullary to extramedullary forms (plasma cell leukemia, PCL). To provide insights into the molecular characterization of plasma cell dyscrasias and to investigate the contribution of specific genetic lesions to the biological and clinical heterogeneity of MM, we analysed the gene expression profiles of plasma cells isolated from seven MGUS, 39 MM and six PCL patients by means of DNA microarrays. MMs resulted highly heterogeneous at transcriptional level, whereas the differential expression of genes mainly involved in DNA metabolism and proliferation distinguished MGUS from PCLs and the majority of MM cases. The clustering of MM patients was mainly driven by the presence of the most recurrent translocations involving the immunoglobulin heavy-chain locus. Distinct gene expression patterns have been found to be associated with different lesions: the overexpression of CCND2 and genes involved in cell adhesion pathways was observed in cases with deregulated MAF and MAFB, whereas genes upregulated in cases with the t(4;14) showed apoptosis-related functions. The peculiar finding in patients with the t(11;14) was the downregulation of thea-subunit of the IL-6 receptor. In addition, we identified a set of cancer germline antigens specifically expressed in a subgroup of MM patients characterized by an aggressive clinical evolution, a finding that could have implications for patient classification and immunotherapy.Oncogene (2005) 24, 2461-2473. doi:10.1038/sj.onc.1208447 Published online 7 February 2005 [ABSTRACT FROM AUTHOR]

Molecular and genetic events associated with the transition from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are still poorly characterized. We investigated serial bone marrow specimens from 11 patients with MGUS who eventually progressed to MM (MM post-MGUS) by interphase fluorescence in situ hybridization for immunoglobulin heavy-chain gene (IgH) translocations and chromosome 13q deletions (del(13q)). In nine patients, IgH translocations were present both in MGUS and MM post-MGUS plasma cells, including three t(11;14)(q13;q32) and one t(4;14)(p16;q32), which was observed already 92 months prior to MM. Similarly, all five MM patients with del(13q) had this aberration already at the MGUS stage. Two patients without IgH translocation and del(13q) had chromosomal gains suggesting hyperdiploidy, but IgH translocations and/or del(13q) did not emerge at MM post-MGUS. IgH translocations and del(13q) are early genetic events in monoclonal gammopathies, suggesting that additional events are required for the transition from stable MGUS to progressive MM.Leukemia (2004) 18, 1879-1882. doi:10.1038/sj.leu.2403518 Published online 23 September 2004 [ABSTRACT FROM AUTHOR]

Copyright of Der Onkologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Multiple myeloma (MM) is a rare but uniformly fatal malignancy of antibody-secreting plasma cells. Although several key molecular events in disease initiation or progression have been confirmed (eg, FGFR3/MMSET activation) or implicated (eg, chromosome 13 deletion), the mechanisms of MM development remain enigmatic. Although it is generally indistinguishable morphologically, MM importantly exhibits a tremendous degree of variability in its clinical course, with some patients surviving only months and others for many years. However, measures of current laboratory parameters can account for no more than 20% of this outcome variability. Furthermore, the means by which current drugs impart their anti-MM effect are mostly unknown.The development of serious comorbidities, such as osteopenia and/or focal lytic lesions of bone, is also poorly understood. Finally, very little knowledge exists concerning the molecular triggers for the conversion of benign monoclonal gammopathy of undetermined significance (MGUS) to overt MM. Given that abnormal gene expression lies at the heart of most if not all cancers, high-throughput global gene expression profiling has become a powerful tool for investigating the molecular biology and clinical behaviors. Here I discuss recent progress made in addressing many of these issues through the molecular dissection of the transcriptome of normal plasma cells, MGUS, and MM. [ABSTRACT FROM AUTHOR]