Reflections on the unexpected laboratory finding of hemorheological alterations observed in some haematological disorders.

Hyperviscosity syndrome is a clinical condition characterized by the slowing of blood flow through the vessels and it may be associated with several diseases. The nosographic classification of primary hyperviscosity conditions (Wells classification 1970) divided the primary hyperviscosity syndromes in polycythaemic, sclerocytemic and sieric. Recent and personal laboratory observations have highlighted an unexpected behaviour of the erythrocyte deformability observed in some haematological disorders such as polycythemia vera, multiple myeloma and monoclonal gammopathy of undetermined significance. The interest of this observation depends on the fact that up to now, according to the Wells classification, the hemorheological alteration present in PV was related to the increase of RBC mass while that present in MM and MGUS was attributable to the abnormality of plasma or serum viscosity only. Through an extensive research among the literature, using MEDLINE/PubMed to identify all published reports on the hyperviscosity syndromes, issues that until now have been dealt with separately will therefore be analyzed in a unique paper, allowing a global view. The aim of this paper is to provide some suggestions for reflection and emphasizing the need of a nosographic framework of hyperviscosity that, probably, deserves to be reviewed.

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.

Bone tissue quality in patients with monoclonal gammopathy of uncertain significance.

INTRODUCTION: Monoclonal gammopathy of uncertain significance (MGUS) is highly prevalent in older adults and affects bone structure, with osteoporosis and increased risk of fractures in up to 14% of affected patients. Dual-energy X-ray absorptiometry (DXA), the standard technique for diagnosing osteoporosis, is ineffective to reveal microstructure and bone quality in this disease. MATERIALS AND METHODS: We conducted a cross-sectional study of patients with MGUS, recruited consecutively from the Hematology and Internal Medicine Departments of Hospital del Mar, Barcelona, between January 2011 and January 2018. Medical records, clinical results and spinal X-ray images were collected. Bone mineral density (BMD) at hip and spine was measured by DXA and Bone Material Strength index (BMSi) by impact microindentation on the tibial mid-shaft. RESULTS: Thirty-nine patients with MGUS and 65 age-matched controls without previous fractures were included. In the MGUS group, 11 (28.2%) patients had prevalent fractures, nearly half of them vertebral (n = 5, 45.45%). Compared to controls, MGUS patients had significantly lower BMSi, a mean (SD) of 70.72 (9.70) vs. 78.29 (8.70), p = 0.001, and lower spinal BMD values (0.900 [0.159] vs. 1.003 [0.168], respectively, p = 0.012), but no significant differences at femoral neck and total hip. No association was observed between BMSi and DXA. Bone remodeling markers (procollagen type-1 N propeptide, bone-alkaline phosphatase and C-terminal telopeptide of type I collagen) did not differ between the two groups. CONCLUSIONS: Spinal BMD and mechanical properties of bone tissue, as measured by impact microindentation, were impaired in patients with MGUS. These changes in bone tissue mechanical resistance were independent of DXA levels.

[Monoclonal Gammopathy Of Unknown Significance - A Common Incidental Finding - What is to be thought of? What has to be done?] / Monoklonale Gammopathie unklarer Signifikanz ­ ein häufiger Nebenbefund.

Monoclonal gammopathy of unclear significance (MGUS) is detected at high frequency in a variety of disciplines as an incidental finding. MGUS can be associated with non-malignant diseases, but it also can be a precursor of malignant lymphoproliferative disorders (multiple myeloma, Waldenstroem's disease, other non-Hodgkin's lymphoma, light chain (AL) - amyloidosis). However, many of these patients remain asymptomatic throughout their lives. Screening is performed by serum protein electrophoresis, immunofixation and determination of quantitative immunoglobulins and free light chains in serum. Currently, general population screening is not recommended. There are three subtypes with different rates and types of progression: IgM-MGUS, non-IgM-MGUS, and light-chain MGUS. The scope of further diagnostics and follow-up is based on the clinical findings and risk stratification (monoclonal protein in serum < or ≥ 15 g/l and normal or abnormal free light chain ratio in serum). If paraprotein-associated disease is detected, gammopathy is of clinical significance and should not be referred to as MGUS.

Cytomegalovirus infection with pulmonary embolism, splenic vein thrombosis and monoclonal gammopathy of undetermined significance: a case and systematic review.

A 62-year-old immunocompetent woman was admitted with cytomegalovirus (CMV) infection, pulmonary embolism, splenic vein thrombosis and monoclonal gammopathy of undetermined significance (MGUS). Anticoagulation therapy was started. Two months later, seroconversion of CMV IgM to IgG was observed, while the monoclonal protein was no longer detectable. This suggests a relationship between acute CMV infection, transient MGUS and thrombosis. In accordance with current best practice guidelines for provoked venous thromboembolism (VTE), anticoagulation therapy could be discontinued after 3 months instead of 6 for unprovoked VTE, thereby reducing unnecessary time at risk of bleeding complications. While the relationships between CMV and both MGUS and thrombosis have been described independently, we are first to describe these three conditions occurring simultaneously.Furthermore, we provide a systematic review on the relation between CMV, MGUS and thrombosis.

Disrupted radial and tibial microarchitecture in patients with monoclonal gammopathy of undetermined significance.

Patients with monoclonal gammopathy of undetermined significance (MGUS) had abnormalities in volumetric BMD (vBMD), microarchitecture, and stiffness at both the radius and tibia by high-resolution peripheral quantitative CT compared to matched controls. This is the first report demonstrating that patients with MGUS have microarchitectural deficits at multiple skeletal sites. INTRODUCTION: Fracture risk is elevated in patients with monoclonal gammopathy of undetermined significance (MGUS). However, the pathogenesis of bone disease in these patients is poorly understood. Prior work using high-resolution peripheral CT (HRpQCT) demonstrated abnormal microarchitecture at the radius, with predominantly cortical abnormalities. We hypothesized that patients with MGUS have abnormal microarchitecture at both radius and tibia compared to controls, reflecting global skeletal effects of the disease. METHODS: This case-control study enrolled 36 subjects; patients with MGUS (n = 12) were matched 1:2 by age, sex, and race to controls (n = 24). Areal BMD (aBMD) was measured by DXA, vBMD, and microarchitecture by HRpQCT, and whole bone stiffness by finite element analysis. Serum was drawn for markers of bone metabolism and inflammation. RESULTS: By DXA, MGUS patients had lower aBMD at the lumbar spine, femoral neck, and 1/3 radius. Markers of bone metabolism and inflammation did not differ. By HRpQCT at the radius, MGUS patients had lower total, trabecular and cortical density, lower trabecular number, and greater trabecular separation and heterogeneity. At the tibia, MGUS patients had lower total and trabecular density, lower trabecular number, greater separation and heterogeneity, and lower whole bone stiffness. CONCLUSIONS: Patients with MGUS had lower vBMD, cortical, and trabecular abnormalities at the radius compared to matched controls. At the tibia, trabecular abnormalities predominated. These results suggest that in addition to previously described cortical deficits, deterioration of trabecular bone may contribute to a generalized skeletal fragility in patients with MGUS.

What is the significance of monoclonal gammopathy of undetermined significance?

Monoclonal gammopathy of undetermined significance (MGUS) is characterised by the presence of a monoclonal paraprotein in the blood, without the characteristic end organ damage seen in multiple myeloma. MGUS is more common in older age groups and has a risk of progression to myeloma of 1% per year. Population screening is not currently recommended, but retrospective studies have suggested improvements in myeloma outcomes in those under MGUS follow-up; in addition, MGUS has associated complications, including fracture, osteoporosis, renal disease and infection, which can be treated. Given this increasing evidence of disease related directly to MGUS, strategies for early identification might be needed. In this review, we discuss the complications of MGUS and whether MGUS fulfils the criteria needed to implement a screening programme. We also highlight areas where more evidence is needed, including identification of a higher risk population to make screening more practical and economically viable.

Monoclonal gammopathy in prostate carcinoma: a case report and review of literature.

BACKGROUND: Monoclonal gammopathy is commonly associated with plasma cell dyscrasia. However, monoclonal gammopathy without bone marrow plasmacytosis in prostate carcinoma has rarely been reported. The association between the two conditions is not clearly established. CASE PRESENTATION: We report a case of metastatic prostate carcinoma in a 65-year-old Indian man with the unusual phenomenon of monoclonal band in gamma globulin region without evidence of bone marrow plasmacytosis. CONCLUSIONS: Monoclonal gammopathy in solid tumor has seldom been reported. This case report highlights the rare association of monoclonal gammopathy with malignant prostatic carcinoma. Therefore, while investigating a case such as this, in an elderly male patient, we should always keep a lookout for any solid tumor foci after excluding multiple myeloma.

Association of resilience with health-related quality of life and depression in multiple myeloma and its precursors: results of a German cross-sectional study.

OBJECTIVES: To investigate the relation between resilience, health-related quality of life (HRQOL) and depression in multiple myeloma (MM) and its premalignant stages. MM is one of the most frequent haematological disorders. It is regularly preceded by asymptomatic stages of the disease namely monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM). Survivors have to cope with mental and physical impairment in terms of HRQOL and depression. The concept of resilience refers to a person's ability to adapt to adversity. DESIGN: Cross-sectional study. SETTING: MM outpatient department at a University Hospital in Germany (tertiary care). PARTICIPANTS: 292 consecutive patients from our MM outpatient department. OUTCOME MEASURES: HRQOL, depression and psychological resilience were assessed with validated questionnaires. RESULTS: Regression analyses were performed to determine associations between resilience, HRQOL and depression. 98 patients (33.6%) had a new diagnosis of active MM, 106 patients (36.3%) were already treated for MM and 88 patients had the diagnosis of a precursor (MGUS or SMM; 30.1%) of MM. Multivariate linear regression analyses revealed a strong positive impact of resilience on physical (b 7.20; 95% CI 4.43 to 9.98; p<0.001) and mental (b 12.12; 95% CI 9.36 to 14.87; p<0.001) HRQOL. Ordered logistic regression analysis showed that the odds for higher depression severity were lowered for individuals with a high level of resilience in comparison to the individuals with a low level of resilience (OR 0.11; 95% CI 0.06 to 0.19; p<0.001). CONCLUSIONS: Resilience may be a protective factor in the disease trajectory of MM and its precursors. As a next step, future research should focus on longitudinal assessments at various time points to elucidate the role of resilience in one of the most frequent haematological malignancies.

Antigen-mediated regulation in monoclonal gammopathies and myeloma.

A role for antigen-driven stimulation has been proposed in the pathogenesis of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) based largely on the binding properties of monoclonal Ig. However, insights into antigen binding to clonal B cell receptors and in vivo responsiveness of the malignant clone to antigen-mediated stimulation are needed to understand the role of antigenic stimulation in tumor growth. Lysolipid-reactive clonal Ig were detected in Gaucher disease (GD) and some sporadic gammopathies. Here, we show that recombinant Ig (rIg) cloned from sort-purified single tumor cells from lipid-reactive sporadic and GD-associated gammopathy specifically bound lysolipids. Liposome sedimentation and binding assays confirmed specific interaction of lipid-reactive monoclonal Ig with lysolipids. The clonal nature of lysolipid-binding Ig was validated by protein sequencing. Gene expression profiling and cytogenetic analyses from 2 patient cohorts showed enrichment of nonhyperdiploid tumors in lipid-reactive patients. In vivo antigen-mediated stimulation led to an increase in clonal Ig and plasma cells (PCs) in GD gammopathy and also reactivated previously suppressed antigenically related nonclonal PCs. These data support a model wherein antigenic stimulation mediates an initial polyclonal phase, followed by evolution of monoclonal tumors enriched in nonhyperdiploid genomes, responsive to underlying antigen. Targeting underlying antigens may therefore prevent clinical MM.

DEVELOPMENT OF GANGLIONOPATHY AND TABETIC VISCERAL CRISES ON THE BACKGROUND OF POLYRADICULONEUROPATHY ASSOCIATED WITH MONOCLONAL GAMMOPATHY (CASE REPORT).

The article presents an analysis of the clinical occurrence of development of chronic polyradiculoneuropathy associated with monoclonal IgG/k (kappa) gammopathy of the undetermined significance. The peculiarity of this occurrence is the uniqueness of the development of the symptoms which are characteristic of tabes dorsalis in this pathology with episodic severe visceral crises and also with ganglionopathy. The example describes the clinical polymorphism of the course of visceral crises, the problems of their diagnosis and as a consequence of inadequate treatment with the development of severe social maladaptation. The importance of timely diagnosis and treatment of such conditions is discussed.

Monoclonal gammopathy of undetermined significance and bone health outcomes: a systematic review and exploratory meta-analysis.

Monoclonal gammopathy of undetermined significance (MGUS) is a common condition in the elderly. A number of studies have investigated the relationship between MGUS and bone health outcomes including bone mineral density (BMD), osteoporosis and fractures, but no meta-analysis exists. We conducted a systematic review and exploratory meta-analysis comparing bone health outcomes in patients with MGUS. Two independent authors searched PubMed and Scopus from inception until 19 October 2016. A meta-analysis of cross-sectional and longitudinal studies investigating fractures and BMD was conducted. Standardised mean differences (SMD) ± 95% confidence intervals (CIs) were calculated for BMD, and risk ratios (RRs) were calculated for prevalent and incident fractures. Of 174 initial hits, 10 studies of moderate methodological quality were eligible, including 8711 individuals with MGUS vs. 52,865 controls. Compared to controls, subjects with MGUS showed significantly lower values for radial cortical volumetric BMD (1 study; SMD = -5.45, 95% CI: -7.24 to -3.66), but not at the lumbar spine, femoral neck or hip. The incidence of fractures was higher in people with MGUS (n = 7466) vs. controls (n = 52,304) (RR = 1.36, 95% CI 1.28-1.44, I 2 = 0%) over a median of 12.5-year follow-up. The incidence of vertebral fractures was particularly elevated (RR = 2.50, 95% CI 1.53-4.06) although limited to two studies. In conclusion, although with limitations, our preliminary meta-analysis suggests that patients with MGUS are at higher risk of fractures despite evidence for differences in BMD being equivocal. Future longitudinal research is required to confirm our findings and determine if fracture prevention interventions are warranted in people with MGUS.

Sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance.

PURPOSE OF REVIEW: Sporadic late-onset nemaline myopathy (SLONM) with monoclonal gammopathy of undetermined significance (MGUS) is a rare subacute progressive muscle disease. The prognosis is poor due to severe respiratory insufficiency. Recently, however, autologous stem-cell transplantation following high-dose melphalan has been shown to be effective unless there is delay before the treatment. Therefore, early recognition of the disease is important. This review gives an overview of recent advances in SLONM-MGUS, which could help to understand clinical and pathological features and treatment. RECENT FINDINGS: Efficacy of autologous stem-cell transplantation following high-dose melphalan has been demonstrated in a long-term observation study. Subsequently, reports from other groups also have supported it. Furthermore, efficacy of chemotherapy toward plasma cell dyscrasia without stem-cell transplantation have been reported as well. A few case reports have suggested the presence of cardiac involvement related to SLONM-MGUS. SUMMARY: SLONM-MGUS is now considered as a treatable disease. Antiplasma cell dyscrasia therapy is a promising therapeutic option. Meanwhile, the pathomechanic link between muscle degeneration and monoclonal gammopathy remains unclear and further investigations are warranted.

Electrophysiologic features of POEMS syndrome compared with MGUS-related neuropathy.

INTRODUCTION: Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome and monoclonal gammopathy of undetermined significance (MGUS) are paraproteinemic disorders that can cause demyelinating polyneuropathy. Herein we assessed the findings of nerve conduction studies (NCS) in patients with POEMS syndrome and MGUS-related neuropathy to determine whether the NCS characteristics can help differentiate between these conditions. METHODS: We enrolled 24 POEMS and 37 MGUS-related neuropathy patients. NCS parameters, including compound muscle action potential (CMAP), motor conduction velocity (MCV), and terminal latency index (TLI), were evaluated. RESULTS: Compared with MGUS-related neuropathy patients, POEMS syndrome patients demonstrated a greater reduction in both the upper and lower limb CMAPs and a greater reduction in the median and ulnar MCVs. The TLIs were significantly higher in POEMS patients. DISCUSSION: NCS can help distinguish POEMS syndrome from MGUS-related neuropathy. Reduced CMAPs, slow MCVs, and high TLIs are indicative of POEMS syndrome rather than MGUS-related neuropathy. Muscle Nerve 56: E73-E77, 2017.

Vitamin D and plasma cell dyscrasias: reviewing the significance.

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.

Crystalglobulinemia manifesting as chronic arthralgia and acute limb ischemia: A clinical case report.

RATIONALE: Crystalglobulinemia is a rare disease caused by monoclonal immunoglobulins, characterized by irreversible crystallization on refrigeration. It causes systemic symptoms including purpura, arthralgia, and vessel occlusive conditions to be exacerbated by exposure to cold. We report a patient with crystalglobulinemia associated with monoclonal gammopathy of undetermined significance (MGUS) manifesting as chronic arthralgia and recurrent acute arterial occlusion. PRESENTING CONCERNS: A 61-year-old man, who had been diagnosed with MGUS and who had arthralgia of unknown origin, presented with recurrent acute limb ischemia after surgical thromboembolectomy. Refrigeration of his serum formed precipitates that looked like needle-shaped crystals. These crystals did not dissolve with warming, which is not a characteristic of cryoglobulins. Skin biopsy results showed crystal-liked eosinophilic bodies in small vessels and we diagnosed crystalglobulinemia. INTERVENTION AND OUTCOMES: Although he underwent above-knee amputation, he was treated with a bortezomib and dexamethasone-based chemotherapeutic regimen, following lenalidomide maintenance therapy. Finally, he achieved complete remission and serum crystalglobulins diminished. LESSONS: Monoclonal gammopathy, previously diagnosed as MGUS, can cause systemic symptoms and thrombotic conditions by producing pathologic immunoglobulins, such as crystalglobulins. In such situations, MGUS, even when it has not progressed to multiple myeloma, can be a target of aggressive chemotherapy. Crystalglobulinemia should be considered for patients with monoclonal gammopathy manifesting as systemic and thrombotic symptoms exacerbated by cooling.

[Expression of microRNA-221/222 in patients with monoclonal gammopathy of undetermined significance and multiple myeloma].

Objective: To detect the expression of miR-221/222 in serum and plasma cells in patients with monoclonal gammopathy of undetermined significance(MGUS) and multiple myeloma(MM), and to explore the possibility of miR-221/222 as biomarkers in the diagnosis and prognosis predicting of MGUS and MM. Methods: Bone marrow and serum samples from 14 patients with newly diagnosed MGUS, 81 patients with newly diagnosed or relapsed MM and 10 controls were collected from Sir Run Run Shaw Hospital of Zhejiang University and Tongde Hospital of Zhejiang Province during January 2013 and December 2015. The expressions of miR-221/222 in serum and in sorted CD138 positive plasma cells were detected by qRT-PCR, and the relative expression of miR-221/222 (Δct) was compared between the groups. Serum levels of miR-221 before and after treatment were compared in both remission group (n=22) and refractory group (n=13) in MM patients, and its correlation with serum level of ß2-MG was assessed using Pearson's correlation analysis. Results: Serum levels of miR-221/222 in MGUS and MM groups were significantly higher than those in control group (all P<0.01), while miR-221/222 levels in plasma cells were significantly lower in MGUS and MM groups than those in the control group (P<0.05 or<0.01). No significant difference in miR-221/222 levels in serum and plasma cells was observed between MGUS group and MM group (all P>0.05). There was no correlation between miR-221/222 levels in serum and plasma cells (r=0.024 and -0.127, all P>0.05), but miR-221 levels were correlated with miR-222 levels in both serum and plasma cells (r=0.534 and 0.552, all P<0.01). Receiver operating characteristic (ROC) curves showed that the areas under the curve (AUCs) of serum miR-221/222, plasma cell miR-221/222 in diagnosis of MGUS/MM were 0.968, 0.976, 0.801 and 0.727, respectively. There was no significant difference in serum level of miR-221 among MM patients with different paraprotein isotypes (P>0.05), but serum level of miR-221 in patients with relapsed MM was higher than that in patients with newly diagnosed MM (P<0.01). Compared with the patients with MGUS or MM stageⅠ and Ⅱ, patients with MM stage Ⅲ were of higher serum levels of miR-221 (P<0.01). Serum level of miR-221 decreased after chemotherapy in the remission group (U=51.5, P<0.01), but such decrease was not observed in the refractory group (U=67.5, P>0.05). Serum level of ß2-MG was positively correlated with serum level of miR-221 (r=0.524, P<0.01). Conclusion: miR-221/222 in serum and plasma cells may be biomarkers for early diagnosis of MGUS, and are helpful for diagnosis and efficacy evaluation of MM.

Molecular pathogenesis of multiple myeloma.

Multiple myeloma (MM), one of the most intractable malignancies, is characterized by the infiltration and growth of plasma cells, the most differentiated cells in the B-cell lineage, in the bone marrow. Despite the introduction of novel therapeutic agents, including proteasome inhibitors and immunomodulatory drugs, the prognosis of patients with MM is still worse than that of most hematological malignancies. A better understanding of the molecular pathogenesis of the disease is essential to achieve any improvement of treatment outcome of MM patients. All MM cases pass through the phase of asymptomatic expansion of clonal plasma cells, referred to as monoclonal gammopathy of undetermined significance (MGUS). It has long been believed that MM evolves linearly from MGUS to terminal phases, such as extramedullary tumors and plasma cell leukemia via the accumulation of novel mutations. However, recent studies using next-generation sequencing have disclosed the complex genomic architecture of the disease. At each step of progression, the acquisition of novel mutations is accompanied by subclonal evolution from reservoir clones with branching patterns. Each subclone may carry novel mutations and distinct phenotypes, including drug sensitivity. In addition, minor clones already exist at the MGUS stage, which could expand later in the clinical course, resulting in relapse and/or leukemic conversion. The ultimate goal of treatment is to eradicate all clones, including subclonal populations with distinct biological characteristics. This goal could be achieved by further improving treatment strategies that reflect the genomic landscape of the disease.