Mortality and causes of death in patients with monoclonal gammopathy of undetermined significance

To evaluate the mortality and causes of death in monoclonal gammopathy of undetermined significance (MGUS), we identified 1324 cases of MGUS in the period 1978-93 in North Jutland County, Denmark. Data on mortality were obtained by record linkage to the Danish Death Registry. There were 868 deaths in the MGUS cohort during 7785 years of follow-up vs. 409.6 expected, giving a standardized mortality ratio (SMR) of 2.1 (95% confidence interval 2.0-2.3). Malignant transformation was the cause of death in 97 patients vs. 4.9 expected, yielding a SMR of 20.0 (16.2-24.4), which explained about 20% of the excess mortality in the cohort. The mortality was increased for several other malignant and non-malignant causes of death during the first 4 years of follow-up. For late follow-up, 5-18 years after detection of the M-component, the overall SMR was 1.7 (1.5-1.9), and malignant transformation was the only cause of death with a substantial increase of SMR. Although malignant transformation is an important cause of death in MGUS patients, it did not entirely explain the increased mortality. MGUS patients often suffer from coexisting clinical conditions that increase the mortality, especially during the first years after detection of the M-component.     

Prognosis in monoclonal gammopathy of undetermined significance

Eighty-seven patients with monoclonal gammopathy of undetermined significance (MGUS) were followed for a period of 1–20 years, median 91 months. Transformation to multiple myeloma occurred in 14 patients of whom seven died as a consequence of the disease. There were 13 unrelated deaths. The actuarial probability of survival was 80% at 10 years and 44% at 15 years and the probabilities of malignant conversion for the same periods were 17% and 30% respectively. The most significant factor influencing the probability of malignant conversion was the increase of monoclonal protein above the level of 30 g/l during the observation period ( P <0.001), followed by an increase of M-protein to more than 50% above the baseline level ( P =0.02) and a decreased level of uninvolved immunoglobulins ( P =0.054).     

Survival of cancer patients with prior monoclonal gammopathy of undetermined significance

IntroductionIt is unknown whether a prior diagnosis of monoclonal gammopathy of undetermined significance (MGUS) affects cancer survival.Design and methodsWe linked data on 1652 cases of MGUS diagnosed during 1978–2006 in North Jutland County, Denmark with the Danish Cancer Registry and the National Patient Registry to obtain information on survival of cancer patients with a previous MGUS compared with that of cancer patients without MGUS, matched on cancer type, age, sex and year of diagnosis. Stratified Cox regression analysis was used to compute mortality rate ratios controlling for the matching factors and comorbidity.ResultsWe included 323 cancer patients with previously detected MGUS and 3154 comparison cancer patients without MGUS. The 5-year survival probability was 26.2% (95% CI, 21.2%–31.5%) in cancer patients with MGUS and 30.5% (28.8%–32.1%) in cancer patients without MGUS. The adjusted mortality rate ratio (MRR) was = 0.94 (95% CI, 0.82–1.09). Survival following a diagnosis of multiple myeloma, the cancer site of main interest, did not differ according to a preceding MGUS diagnosis. Among patients with immune-related cancers (liver, cervix, malignant melanoma and non-melanoma skin cancers), a preceding MGUS diagnosis was associated with reduced survival (adjusted MRR = 1.49 (95% CI: 0.96–2.31)). In contrast, for other non-haematological cancers a prior MGUS diagnosis was associated with a lower MRR (0.78 (95% CI, 0.63–0.96)).ConclusionOur study does not indicate that previously detected MGUS is a prognostic factor for cancer survival in general.     

老年人意义未明的单克隆免疫球蛋白血症的转归

目的 探讨老年人意义未明的单克隆免疫球蛋白血症(MGUS)的转归.方法 对我院14例MGUS患者转归进行回顾性分析,总结MGUS临床特征及转归时间,探讨单克隆免疫球蛋白浓度变化.结果 MGUS无多发性骨髓瘤(MM)的临床表现,从MGUS到MM转归时间为4～20年,平均10年;MM主要为IgA型和IgG型,其中IgA型6例,IgG型6例,轻链型2例;MGUS患者免疫球蛋白浓度总体呈现逐年上升趋势,呈折线型上升者占少数.结论 单克隆免疫球蛋白升高有向MM发展的可能,对于MGUS患者需密切观察,避免漏诊和误诊.     

Monoclonal gammopathy of undetermined significance

Significant advances have been made in our understanding of the natural history, pathogenesis, mechanisms of progression and prognosis of monoclonal gammopathy of undetermined significance (MGUS). Although the overall incidence of MGUS progression is 1 per year, it is now possible to more accurately predict the risk of progression based on a new risk-stratification model. However, it is still hard to design chemopreventive trials given that the absolute risk of progression per year is low, even in the high-risk group. Therefore, further improvements in estimating the risk of progression are needed. Roughly 50% of MGUS may originate from primary translocation events at the heavy-chain immunoglobulin locus at chromosome 14q32. In most of the remaining MGUS patients, the initiating event is associated with genomic instability that results in hyperdiploidy of certain odd numbered chromosomes. Cytogenetically distinct subtypes of MGUS may carry significant differences in the risk of progression to malignancy. New markers, such as measures of bone marrow angiogenesis and circulating plasma cells may be additional prognostic factors. A better understanding of the mechanisms underlying the transition of normal plasma cells to the MGUS phenotype, and the transition of MGUS to myeloma or related malignancy, will help identify new risk factors for progression and new targets for chemopreventive interventions.     

Helicobacter pylori infection and monoclonal gammopathy of undetermined significance

A recent report found resolution of monoclonal gammopathy of undetermined significance (MGUS) in nearly 30% of patients upon eradication of concomitant Helicobacter pylori (H. pylori) infection. We performed serologicalal testing for H. pylori on 93 MGUS patients and 98 control subjects. Seroprevalence of H. pylori was not significantly different between the two groups, 30% and 32% respectively. A retrospective review of Mayo Clinic records revealed identical diagnosis rates of H. pylori infection (33%) by serology, breath or stool testing between patients with MGUS and those with negative monoclonal protein studies. There was no evidence of resolution of MGUS with H. pylori therapy.     

Investigation and management of the monoclonal gammopathy of undetermined significance

This Good Practice Paper provides recommendations for the diagnosis, risk stratification and management of the monoclonal gammopathy of undetermined significance (MGUS). It describes the recently recognised entity of the monoclonal gammopathy of clinical significance (MGCS), and recommends how it should be managed. The potential for targeted population screening for MGUS is also discussed.     

Blood clonal B-cell excess in patients with monoclonal gammopathy of undetermined significance (MGUS): association with malignant transformation

Fifty-seven patients with monoclonal gammopathy of undetermined significance (MGUS) were analysed for the presence of blood clonal B-cell excess (CBE), defined as a lymphocyte surface membrane κ/λ light chain ratio outside the normal range (> 3.5 in κ-type MGUS and <0.9 in λ-type MGUS). 15 patients (26%) had a CBE. The patients were followed for a median time of 8.4 years (range 0.5–20.2). Eight of the 15 CBE⁺ MGUS patients (53%) developed a B-cell malignancy as compared to 7/42 patients (17%) in the CBE group and the difference in event-free (malignancy-free) observation time was statistically significant (P = 0.01). Cox's regression analysis showed that the presence of CBE was the most powerful predictor of progression to a malignant disease. Two patients with a normal κ/λ ratio at first test were analysed repeatedly during follow-up. Subsequently, a CBE appeared which gradually increased in size preceding the clinical diagnosis of a malignant disease.     

Chronic hepatitis C associated with monoclonal gammopathy of undetermined significance

BACKGROUND: Two patients were admitted to Mie Prefectural General Medical Center and diagnosed as chronic hepatitis C complicated with monoclonal gammopathy of undetermined significance (MGUS). METHODS: The MGUS class were immunoglobulin (Ig)G. The hepatitis C virus (HCV) RNA genotype was Ib. Based on these findings, they were diagnosed as chronic hepatitis C complicated with MGUS. RESULTS: Histological studies showed chronic hepatitis in the liver and a mild rise in plasma cells without dysplasia and abnormalities in the bone marrow. Serum examination for cryoglobulin was negative. CONCLUSION: Chronic HCV infection might play a pathogenic role in the multistage process leading to lymphoproliferative disorders.     

The prevalence and significance of monoclonal gammopathy of undetermined significance in acute medical admissions

Monoclonal gammopathy of undetermined significance (MGUS) affects 3·2% of adults aged >50 years. MGUS carries a life-long risk of progression to multiple myeloma and causes complications including infection and renal impairment; common causes of hospital admission. This study aimed to assess MGUS prevalence in emergency medical hospital admissions. Patients were recruited from unselected emergency medical admissions in a hospital in the United Kingdom. Serum protein electrophoresis was performed, with immunofixation of abnormal results. Reason for admission and routine test results were recorded. After education about MGUS and myeloma, patients chose whether they wished to be informed of new diagnoses. A total of 660 patients were tested and 35 had a paraprotein suggestive of MGUS. The overall rate of MGUS was 5·3%. MGUS prevalence in those aged >50 years was 6·94%, higher than the previously published rate of 3·2% (P < 0·0005). There were higher rates in those with chronic kidney disease (13·75% vs. 4·14%, P = 0·002), heart failure (14% vs. 4·59%, P = 0·012), anaemia (8·96% vs. 3·41%, P = 0·003) or leucocytosis (9·33% vs. 3·04%, P = 0·002). In all, 96% of patients wished to be informed of their screening results. The prevalence of MGUS in emergency hospital admissions is higher than expected based on previous population-based rates. This may suggest a selected population for screening.     

Risk of monoclonal gammopathy of undetermined significance: A case-referent study

A retrospective study was conducted in 285 cases of monoclonal gammopathy of undetermined significance (MGUS) and in 570 sex-and age-matched hospital controls in order to investigate the possible association between socioeconomic status, residence, alcohol and tobacco habits, occupation, occupational exposure to toxic substances, chronic antigenic stimulation, and risk of MGUS. Significant associations with the risk of MGUS were found for farmers (P < 0.005) and for workers in industry (P < 0.025). Occupational exposure to asbestos, fertilizers, mineral oils and petroleum, paints and related products, pesticides, and radiation was significantly (P < 0.05) associated with an increase in risk of MGUS. Chronic immune-stimulating conditions, when considered as a group, presented a significant (P < 0.025) association with the risk of MGUS, but no specific disease has been found to be significantly associated. These data are in agreement with the previous reports on multiple myeloma, suggesting that these factors may play an important role in the development of monoclonal gammopathies. However, these findings need to be confirmed in prospective larger population-based studies. © 1996 Wiley-Liss, Inc.     

Peripheral blood lymphocyte subsets in multiple myeloma and monoclonal gammopathy of undetermined significance

Summary. Peripheral blood lymphocyte subsets were analysed by flow cytometry and compared among 43 patients with untreated multiple myeloma (MM), 16 patients with monoclonal gammopathy of undetermined significance (MGUS) and 26 controls. The age and sex distributions of the patients and controls were comparable, which is important, since in the controls there was a significant effect of age and/or sex on the number of CD3⁺, CD57⁺, CD8⁺57⁺, CD16⁺ and CD3^-56⁺ lymphocyte subsets, and on the CD4⁺/CD8⁺ and CD4⁺Leu–8⁺/CD4⁺ ratios. In MM, the number of CD8⁺ and CD57⁺ cells and the CD4⁺/CD8⁺ ratio were related to the clinical stage. The number of CD20⁺, CD3⁺, CD4⁺, CD16⁺ and CD3^-56⁺ cells and the CD3⁺/CD20⁺ ratio were significantly different in MM patients compared to age- and sex-matched controls as was the number of CD3¹ and CD4¹ cells of MGUS patients compared to controls. Further, there were significant differences in the CD3^-/CD20⁺ ratio between MM and MGUS patients and between stage I MM and MGUS. The role of peripheral blood lymphocyte subsets in differentiating monoclonal gammopathies merits further study.     

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意义未明单克隆免疫球蛋白血症(monoclonal gammopathy of undetermined significance,MGUS)指血清中出现单克隆免疫球蛋白,但缺乏浆细胞病或其他相关疾病,如Waldenstr(o)ms巨球蛋白血症(WM)、原发性淀粉样变(AL)、B细胞淋巴瘤(B-NHL)、慢性白血病(CLL)的证据和特征.曾一度被称作为"良性单克隆免疫球蛋白病(benign monoclonal gammopathy,BMG)",后证实一部分病例可发展演变为恶性疾病,故以MGUS命名之.     

Prognostic factors in monoclonal gammopathy of undetermined significance

A retrospective evaluation of 285 patients with monoclonal gammopathy of undetermined significance was performed to identify variables associated with progression, actuarial progression free survival (PFS) and overall survival (OS). Three variables, level of uninvolved immunoglobulins (HR 4.98, CI95% 2 -12.4, p=0.0006), monoclonal protein concentration (HR 4.04, CI95% 1.6-10.34, p=0.004), and erythrosedimentation rate (HR 3.94, CI95% 1.33-11.6, p=0.01), showed independent prognostic significance. With a median follow-up of 66 months (range 6-378), PFS and OS at 10 years were 89% and 91% respectively.     

Genomic abnormalities in monoclonal gammopathy of undetermined significance

Translocations involving immunoglobulin (Ig) loci and chromosome 13 monosomy (Delta 13) are frequent cytogenetic findings in multiple myeloma (MM). Similar chromosomal aberrations have been identified in the monoclonal gammopathy of undetermined significance (MGUS), but their prevalence and significance remain uncertain. Bone marrow from 72 patients with MGUS (n = 62) and smoldering MM (n = 10) was evaluated for translocations between the Ig heavy chain (IgH) and chromosomes 4, 11, and 16, translocations involving Ig light chain-lambda (IgL-lambda, and Delta 13. Fluorescence in situ hybridization (FISH) analysis was done on clonal plasma cells (PCs) detected by immunofluorescence (cIg-FISH) of the cytoplasmic light chain. We also studied cells for cyclin D1 and FGFR3 up-regulation by immunohistochemistry and immunofluorescence, respectively. Twenty-seven (46%) of 59 patients had IgH translocations, and 4 (11%) of 37 had an IgL-lambda translocation. A t(11;14)(q13;q32) was found in 15 (25%) of 59 patients, a t(4;14)(p16.3;q32) in 9% of patients, and a t(14;16)(q32;q23) in 5% of patients. All patients with t(4;14)(p16.3;q32) tested (n = 3) had intense cytoplasmic fluorescence with an anti-FGFR3 antibody. PC nuclear staining of cyclin D1 was only observed in patients with t(11;14)(q13;q32); Delta 13 was detected in the clonal PCs in 50% of patients. The percentage of abnormal PCs varied with any given abnormality. No obvious clinical or biologic correlations were associated with these chromosome abnormalities. Similar translocations are found in both MGUS and MM, including t(4;14)(p16.3;q32) and t(14;16)(q32;q23). Moreover, Delta 13 is common in MGUS and unlikely to play a predominant role in the evolution of MGUS to MM.