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Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal disorder that progresses to multiple myeloma (MM), or other plasma-cell or lymphoid disorders at a rate of 1%/year. We evaluate the contribution of body mass index (BMI) to MGUS progression beyond established clinical factors in a population-based study. We identified 594 MGUS through a population-based screening study in Olmsted County, Minnesota, between 1995 and 2003. Follow-up time was calculated from the date of MGUS to last follow-up, death, or progression to MM/another plasma-cell/lymphoid disorder. BMI (kg/m 2  < 25/≥25) was measured close to screening date. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of BMI ≥ 25 versus BMI < 25 with MGUS progression and also evaluated the corresponding c-statistic and 95% CI to describe discrimination of the model for MGUS progression. Median follow-up was 10.5 years (range:0-25), while 465 patients died and 57 progressed and developed MM (N = 39), AL amyloidosis (N = 8), lymphoma (N = 5), or Waldenstrom-macroglobulinemia (N = 5). In univariate analyses, BMI ≥ 25 (HR = 2.14,CI:1.05-4.36, P = 0.04), non-IgG (HR = 2.84, CI:1.68-4.80, P = 0.0001), high monoclonal (M) protein (HR = 2.57, CI:1.50-4.42, P = 0.001), and abnormal free light chain ratio (FLC r ) (HR = 3.39, CI:1.98-5.82, P < 0.0001) were associated with increased risk of MGUS progression, and were independently associated in a multivariable model (c-statistic = 0.75, CI:0.68-0.82). The BMI association was stronger among females (HR = 3.55, CI:1.06-11.9, P = 0.04) vs. males (HR = 1.39, CI:0.57-3.36, P = 0.47), although the interaction between BMI and sex was not significant (P = 0.15). In conclusion, high BMI is a prognostic factor for MGUS progression, independent of isotype, M protein, and FLC r . This association may be stronger among females., (© 2022. The Author(s).)

We and others have shown increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first-degree relatives of patients with multiple myeloma (MM). Whether familial risk of MGUS differs by the MM proband's age at onset, tumor or clinical characteristics is unknown. MM and smoldering MM (SMM) cases (N = 430) were recruited from the Mayo Clinic in Rochester, Minnesota between 2005-2015. First-degree relatives over age 40 provided serum samples for evaluation of MGUS (N = 1179). Age and sex specific rates of MGUS among first-degree relatives were compared to a population-based sample. Cytogenetic subtypes were classified by Fluorescence in situ hybridization. MGUS was detected in 75 first-degree relatives for an age- and sex- adjusted prevalence of 5.8% (95% CI: 4.5-7.2). Prevalence of MGUS in first-degree relatives was 2.4 fold (95% CI: 1.9-2.9) greater than expected rates. Familial risk did not differ by proband's age at diagnosis, gender, isotype, IgH translocation, or trisomy. This study confirms first-degree relatives of MM cases have a significantly higher risk of MGUS compared to the general population, regardless of age, gender, or tumor characteristics. In selected situations, such as multiple affected first-degree relatives, screening of first-degree relatives of MM cases could be considered for follow-up and prevention strategies.

Objective: To determine the prognosis of patients with non-secretory myeloma., Methods: We studied 124 patients diagnosed with multiple myeloma who had no monoclonal protein detected on serum and urine immunofixation at diagnosis and on all subsequent follow-up testing (non-secretory myeloma). The overall survival (OS) of patients with non-secretory myeloma was compared with 6953 patients with typical myeloma seen during the same time period in whom a monoclonal protein was detected at the time of diagnosis., Results: One hundred and twenty-four patients met criteria for non-secretory multiple myeloma. The median follow-up was 102 months (range, 1-204 months). The median progression-free survival with initial therapy was 28.6 months, and the median OS was 49.3 months. There was a significant improvement in OS since 2001; median survival 43.8 months (prior to 2001) vs. 99.2 months (2001-2012), P < 0.001. OS was superior in patients with a normal baseline FLC ratio (n = 10) compared to patients with an abnormal ratio (n = 19), medians not reached in both groups. Prior to 2001, OS was similar in non-secretory myeloma (n = 86) and secretory myeloma (n = 4011), median 3.6 vs. 3.5 yr, respectively, P = 0.63. However, among patients diagnosed between 2001 and 2012, OS was superior in non-secretory myeloma (n = 36) compared to secretory myeloma (n = 2942), median 8.3 vs. 5.4 yr, respectively, P = 0.03., Conclusions: Non-secretory myeloma is an uncommon subtype of multiple myeloma. In the last decade, there has been an improvement in the survival of non-secretory myeloma and appears superior to secretory myeloma., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Previously, we reported increased risk of heavy-chain (HC) monoclonal gammopathy of undetermined significance (MGUS) among first-degree (1°) relatives of multiple myeloma (MM) or HC-MGUS probands. This study investigated whether there was comparable risk for light-chain (LC) MGUS among 911 relatives of the same HC-MGUS/MM probands versus a reference population of 21 463. Seventeen 1° relatives had LC-MGUS (adjusted prevalence = 1·7%, 95% CI = 0·9–2·6%). There was increased risk of LC-MGUS in relatives of MM probands (RR = 3·4, 95% CI = 2·0–5·5). We saw no increased risk in relatives of HC-MGUS probands. We conclude that the prevalence of LC-MGUS is significantly higher among 1° relatives of MM probands compared to the reference population.

During the course of multiple myeloma (MM), new monoclonal proteins of an isotype distinct from the original clone, referred to as secondary monoclonal gammopathy of undetermined significance (MGUS), have been described. We report on the frequency, characteristics, and outcome of secondary MGUS. Of the 1942 patients with MM, 128 (6.6%) developed a secondary MGUS, at a median of 12 months from the diagnosis of MM. The median duration of secondary MGUS was 5.9 months. Secondary MGUS was more common in patients after stem cell transplantation than in those who had not undergone such treatment (22.7% vs 1.6%, P < .001). Overall survival was significantly superior in MM patients who developed secondary MGUS compared with the rest of the cohort (73 vs 38 months, respectively; P < .001). The time of onset and the duration of secondary MGUS, as well as failure to resolve spontaneously, had an effect on overall survival and require further study.

Monoclonal gammopathy of undetermined significance (MGUS) is associated with a long-term risk of progression to multiple myeloma (MM) or related malignancy. To prevent serious myeloma-related complications, lifelong annual follow-up has been recommended, but its value is unknown. We reviewed all patients from southeastern Minnesota seen at Mayo Clinic between 1973 and 2004 with MGUS who subsequently progressed to MM. Of 116 patients, 69% had optimal follow-up of MGUS. Among these, abnormalities on serial follow-up laboratory testing led to the diagnosis of MM in 16%, whereas MM was diagnosed only after serious MM-related complications in 45%. In the remaining, workup of less serious symptoms (25%), incidental finding during workup of unrelated medical conditions (11%), and unknown (3%) were the mechanisms leading to MM diagnosis. High-risk MGUS patients (≥ 1.5 g/dL and/or non-IgG MGUS) were more likely to be optimally followed (81% vs 64%), and be diagnosed with MM secondary to serial follow-up testing (21% vs 7%). This retrospective study suggests that routine annual follow-up of MGUS may not be required in low-risk MGUS. Future studies are needed to replicate and expand our findings and to determine the optimal frequency of monitoring in higher-risk MGUS patients.

The current definition of complete response in multiple myeloma includes a requirement for a bone marrow (BM) examination showing less than 5% plasma cells in addition to negative serum and urine immunofixation. There have been suggestions to eliminate the need for BM examinations when defining complete response. We evaluated 92 patients with multiple myeloma who achieved negative immunofixation in the serum and urine after therapy and found that 14% had BM plasma cells more than or equal to 5%. Adding a requirement for normalization of the serum-free light chain ratio to negative immunofixation studies did not negate the need for BM studies; 10% with a normal serum-free light chain ratio had BM plasma cells more than or equal to 5%. We also found that, on achieving immunofixation-negative status, patients with less than 5% plasma cells in the BM had improved overall survival compared with those with 5% or more BM plasma cells (6.2 years vs 2.3 years, respectively; P = .01).

We examined whether monoclonal gammopathy of undetermined significance (MGUS) is increased in first-degree relatives of multiple myeloma (MM) or MGUS patients. Probands were recruited from a population-based prevalence study (MGUS) and the Mayo Clinic (MM). Serum samples were collected from first-degree relatives older than 40 years and subjected to electrophoresis and immunofixation. The prevalence of MGUS in relatives was compared with population-based rates. Nine-hundred eleven relatives of 232 MM and 97 MGUS probands were studied. By electrophoresis, MGUS was detected in 55 (6%) relatives, and immunofixation identified 28 additional relatives for an age- and sex-adjusted prevalence of 8.1% (95% CI, 6.3 to 9.8). The prevalence of MGUS in relatives increased with age (1.9%, 6.9%, 11.6%, 14.6%, 21.0% for ages 40-49, 50-59, 60-69, 70-79, >/= 80 years, respectively; P < .001). Using similar MGUS detection methods, there was a higher risk of MGUS in relatives (age-adjusted risk ratio [RR], 2.6; 95% CI, 1.9 to 3.4) compared with the reference population. The increased risk was seen among relatives of MM (RR, 2.0; 95% CI, 1.4 to 2.8) and MGUS probands (RR, 3.3; 95% CI, 2.1 to 4.8). The increased risk of MGUS in first-degree relatives of MGUS or MM patients implies shared environment and/or genetics.

Background: Smoldering (asymptomatic) multiple myeloma is an asymptomatic plasma-cell proliferative disorder associated with a high risk of progression to symptomatic multiple myeloma or amyloidosis. Prognostic factors for the progression and outcome of this disease are unclear., Methods: We searched a computerized database and reviewed the medical records of all patients at Mayo Clinic who fulfilled the criteria of the International Myeloma Working Group for the diagnosis of smoldering multiple myeloma between 1970 and 1995. Bone marrow aspirate and biopsy specimens were studied, and patients were followed throughout the course of disease., Results: During the 26-year period, 276 patients fulfilled the criteria for smoldering multiple myeloma. During 2131 cumulative person-years of follow-up, symptomatic multiple myeloma or amyloidosis developed in 163 persons (59%). The overall risk of progression was 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% per year for the last 10 years; the cumulative probability of progression was 73% at 15 years. At diagnosis, significant risk factors for progression included the serum level and type of monoclonal protein, the presence of urinary light chain, the extent and pattern of bone marrow involvement, and the reduction in uninvolved immunoglobulins. The proportion of plasma cells in the bone marrow and the serum monoclonal protein level were combined to create a risk-stratification model with three distinct prognostic groups., Conclusions: The risk of progression from smoldering multiple myeloma to symptomatic disease is related to the proportion of bone marrow plasma cells and the serum monoclonal protein level at diagnosis., (Copyright 2007 Massachusetts Medical Society.)

Background: Previous studies have indicated that the incidence and mortality rates for multiple myeloma have increased in the United States. The authors reported on the incidence of multiple myeloma in Olmsted County, Minnesota, between 1991 and 2001 and on trends in multiple myeloma incidence over the last 56 years., Methods: Using the files of the Mayo Clinic and the Olmsted Medical Center (Rochester, MN), the authors identified all residents of Olmsted County who had multiple myeloma, suspected myeloma, or a related disorder. Reports of all laboratory determinations, in addition to autopsy findings and death certificates, were obtained. The criteria for the diagnosis of multiple myeloma have not changed during the last 6 decades., Results: All but 1 of the 47 residents with multiple myeloma first diagnosed between 1991 and 2001 were recognized antemortem. Fifty-five percent had a previous monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or solitary plasmacytoma before multiple myeloma was diagnosed. From 1991 to 2001, the overall annual incidence rate, age-adjusted to the 2000 U.S. population, was 4.3 per 100,000 (95% confidence interval, 3.0-5.5 per 100,000). Poisson regression analysis showed no statistically significant trend in Olmsted County incidence rates over 56 years. In similar fashion, the authors adjusted multiple myeloma incidence rates from nine other studies worldwide for which adequate data were available and documented similar findings in each case, except for one study that included patients with smoldering multiple myeloma., Conclusions: The overall incidence of multiple myeloma in Olmsted County, Minnesota, has not changed in almost 6 decades. The apparent increase in incidence elsewhere is unexplained but probably is attributable to improvements in diagnostic techniques, particularly in older patients., ((c) 2004 American Cancer Society)

Objective: To study the clinical course of patients with multiple myeloma (MM) that relapses after initial therapy., Patients and Methods: Patients with MM, seen at the Mayo Clinic in Rochester, Minn, between January 1, 1985, and December 31, 1998, were identified from a prospectively maintained database. Our study population consisted of 578 patients with newly diagnosed MM who were followed up and monitored throughout their clinical course at our institution., Results: The median age of the 578 patients with MM was 65 years (range, 26-92 years); 228 patients (39%) were women. The median follow-up of 71 surviving patients was 55 months (range, 0-202 months). The overall survival (OS) for the 578 patients at 1, 2, and 5 years was 72%, 55%, and 22%, respectively; the median OS from initial therapy was 28.4 months. The median OS of 355 patients who experienced relapse after initial treatment was 17.1 months from initiation of the second therapy, and 84% died within 5 years. The duration of response decreased consistently with each successive regimen. Patients with a high plasma cell labeling index (> or = 1.0%), low platelet count (< 150 x 10(9)/L), high creatinine level (> or = 2.0 mg/dL), and low albumin level (< 3.0 g/dL) had a poorer prognosis., Conclusions: Our study revealed decreasing response duration with increasing number of salvage regimens, probably reflecting acquired drug resistance and an increasing proliferative rate of the myeloma cells. Patients who experienced relapse after initial treatment and received salvage therapy had a median survival of nearly 1.5 years. This must be remembered when making treatment decisions for these patients and must be factored in when assessing the efficacy of new therapies.

Objective: To determine the clinical and laboratory features of newly diagnosed multiple myeloma., Patients and Methods: Records of all patients in whom multiple myeloma was initially diagnosed at the Mayo Clinic in Rochester, Minn, from January 1, 1985, to December 31, 1998, were reviewed., Results: Of the 1027 study patients, 2% were younger than 40 years, and 38% were 70 years or older. The median age was 66 years. Anemia was present initially in 73% of patients, hypercalcemia (calcium level > or = 11 mg/dL) in 13%, and a serum creatinine level of 2 mg/dL or more in 19%. The beta2-microglobulin level was increased in 75%. Serum protein electrophoresis revealed a localized band in 82% of patients, and immunoelectrophoresis or immunofixation showed a monoclonal protein in 93%. A monoclonal light chain was found in the urine in 78%. Nonsecretory myeloma was recognized in 3% of patients, whereas light-chain myeloma was present in 20%. Conventional radiographs showed an abnormality in 79%. The plasma cell labeling index was 1% or more in 34% of patients. Multivariate analysis revealed that age, plasma cell labeling index, low platelet count, serum albumin value, and the log of the creatinine value were the most important prognostic factors., Conclusion: The median duration of survival was 33 months and did not improve from 1985 through 1998.

Background Cardiac complications following hematopoietic stem cell transplantation ( HSCT) are emerging as a significant concern given the increasing utilization of HSCT for a variety of hematologic malignancies. Methods We utilized an existing database to determine the frequency of cardiac dysfunction ( CD), namely a decrease in left ventricular ejection fraction, following conditioning with high-dose melphalan ( HDM) and autologous HSCT for multiple myeloma ( MM) and systemic amyloidosis ( AL). We then performed a case-control study to examine variables associated with increased risk of CD in this population. Results In MM patients undergoing HSCT, the rate of CD was 1.6% (17/1050, 95% CI: [0.9, 2.6]). None of the examined pre- HSCT variables or HDM dose were significantly associated with development of CD in this population. In patients with AL, the rate of CD was 5.6% (24/426, 95% CI: [3.6, 8.3]). On univariate analysis, decision to administer an HDM dose <200 mg/m2 [odds ratio ( OR): 4.59 (1.27-16.57) P = 0.02], pretransplant left ventricular ejection fraction <60% [ OR: 17.78 (2.29-138.33) P = 0.006], and documented amyloid involvement of ≥3 organs [ OR: 4.0 (1.03-15.6) P = 0.046] were associated with the development of CD in the AL population. No other examined peri-transplant factors were associated with development of CD. Conclusion To our knowledge, this is the first series to report a significant rate of CD following HDM conditioning and autologous HSCT in patients with AL. [ABSTRACT FROM AUTHOR]

Primary systemic amyloidosis (AL) is a plasma cell disorder characterized by deposition of monoclonal light chains in different organ systems. Although multiple and complex numerical chromosomal abnormalities have been described in patients with multiple myeloma, it is currently unknown whether such changes occur in systemic amyloidosis. Bone marrow samples from 21 patients with AL were studied by standard cytogenetics and interphase fluorescence in situ hybridization (FISH) for the presence of numerical chromosomal abnormalities. We tested for six chromosomes (7, 11, 9, 15, 18 and X) using centromere-specific probes. The monoclonal plasma cells were identified by simultaneous fluorescent staining of the monotypic cytoplasmic immunoglobulin. We compared these results with those obtained from 19 patients with monoclonal gammopathy of undetermined significance (MGUS) and normal controls. Multiple numerical chromosomal abnormalities were detected in AL by interphase FISH, including trisomy of chromosomes 7 (42%), 9 (52%), 11 (47%), 15 (39%), 18 (33%) and X (13% in women and 54% in men). Monosomy of chromosome 18 was seen in 72% of cases. Previous exposure to alkylator therapy did not appear to correlate with these abnormalities. No significant difference was observed in the prevalence of these abnormalities between AL and MGUS. Multiple chromosomal numerical abnormalities were detected by interphase FISH analysis in patients with AL, especially monosomy of chromosome 18. Aneuploidy in the monotypic plasma supports a neoplastic nature for the disorder. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathies (MG) constitute a spectrum of disorders starting from a monoclonal gammopathy of undetermined significance (MGUS) to active disease requiring therapy such as multiple myeloma. MG are characterized by proliferation of clonal plasma cells (PC) secreting a monoclonal protein either as intact immunoglobulin or free kappa or lambda free light chains (FLC). We hypothesized that a polyclonal elevation of serum FLC may indicate an inflammatory state that precedes development of MG. We studied 15,630 individuals from Olmsted county, who did not have MGUS based on baseline screening studies. At a median follow-up of 18.1 years, 264 patients had developed a clonal PC disorder; 252 with MGUS, 1 with SMM, 8 with MM, and 3 with amyloidosis, translating to an annual incidence of development of a MG of 0.1%. We examined the baseline polyclonal ΣFLC (kappa + lambda FLC) from the initial screening and grouped them into deciles. The highest decile group had a 2.6-fold (95% CI; 1.8, 3.7) increase in the risk of developing a MG, P < 0.001. We demonstrate for the first time, the increased risk of developing MG in patients with elevated serum FLC, suggesting that an underlying inflammatory state may play an etiologic role. [ABSTRACT FROM AUTHOR]

The article details a study which investigated the prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance (MGUS). The study included 21,463 residents, aged 50 years and above, from Olmsted County, Minnesota. Light-chain MGUS was characterized as an abnormal free light-chain ratio with no immunoglobulin H (IgH) expression. Study authors found 0.3 percent risk of progression to multiple myeloma in patients with light-chain MGUS, and 23 percent risk of renal disease. They concluded that MGUS poses risk of progression to light-chain multiple myeloma and related disorders.

OBJECTIVES: To determine the prevalence of monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma (MM), in Ghanaian men vs white men and to test for evidence to support an underlying race-related predisposition of the 2-fold higher prevalence of MGUS in African Americans vs whites. PARTICIPANTS AND METHODS: Between September 1, 2004, and September 30, 2006, 917 men (50-74 years) underwent in-person interviews and physical examinations. Serum samples from all participants were analyzed by electrophoresis performed on agarose gel; any serum sample with a discrete or localized band was subjected to immunofixation. Age-adjusted and standardized (to the 2000 world population) prevalence estimates of MGUS and 95% confidence intervals (Cls) were computed in the Ghanaian men and compared with MGUS prevalence in 7996 white men from Minnesota. Associations between selected characteristics and MGUS prevalence were assessed by the Fisher exact test and logistic regression models. RESULTS: Of the 917 study participants, 54 were found to have MGUS, yielding an age-adjusted prevalence of 5.84(95% Cl, 4.27-7.40) per 100 persons. No significant variation was found by age group, ethnicity, education status, or prior infectious diseases. The concentration of monoclonal immunoglobulin was undetectable in 41 (76%) of the 54 MGUS cases, less than 1 g/dL in 10 patients (19%), and 1 g/dL or more in only 3 patients (6%). Compared with white men, the age-adjusted prevalence of MGUS was 1.97-fold (95% Cl, 1.94-2.00) higher in Ghanaian men. CONCLUSION: The prevalence of MGUS in Ghanaian men was twice that in white men, supporting the hypothesis that race-related genetic susceptibility could explain the higher rates of MGUS in black populations. An improved understanding of MGUS and MM pathophysiology would facilitate the development of strategies to prevent progression of MGUS to MM. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine the relative diagnostic contribution of urine assays as part of the screening algorithm for monoclonal gammopathies. PATIENTS AND METHODS: We Identified 428 patients with a monoclonal gammopathy and monoclonal urinary protein at initial diagnosis of plasma cell dyscrasia who had also undergone serum immunofixation and serum free light chain quantitation within 30 days of diagnosis. The laboratory results for serum protein electrophoresis, serum immunofixation, serum free light chain, urine protein electrophoresis, and urine immunofixation were reviewed. RESULTS: The patients had diagnoses of multiple myeloma, primary amyloid, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, solitary plasmacytomas, and other less frequently detected monoclonal gammopathies. All 428 had a monoclonal urine protein, 85.7% had an abnormal serum free light chain κ/λ ratio, 80.8% had an abnormal serum protein electrophoresis, and 93.5% had an abnormal serum immunofixation result. All 3 serum assays were normal in only 2 patients, 1 of whom had monoclonal gammopathy of undetermined significance (Idiopathic Bence Jones proteinuria) and 1 whose urine sample contained an intact monoclonal immunoglobulin but whose serum and subsequent urine samples showed no evidence of a monoclonal gammopathy. CONCLUSION: Discontinuation of urine studies and reliance on a diagnostic algorithm using only serum studies (protein electrophoresis, immunofixation, and free light chain quantitation) missed 2 (0.5%) of the 428 monoclonal gammopathies with urinary monoclonal proteins, and these 2 cases required no medical intervention. [ABSTRACT FROM AUTHOR]

Background: A monoclonal gammopathy of undetermined significance (MGUS) occurs in up to 2 percent of persons 50 years of age or older. Reliable predictors of progression have not been identified, and information on prognosis is limited. Methods: We identified 1384 patients residing in southeastern Minnesota in whom MGUS was diagnosed at the Mayo Clinic from 1960 through 1994. The primary end point was progression to multiple myeloma or another plasma-cell cancer. Results: During 11,009 person-years of follow-up, MGUS progressed in 115 of the 1384 patients to multiple myeloma, IgM lymphoma, primary amyloidosis, macroglobulinemia, chronic lymphocytic leukemia, or plasmacytoma (relative risk of progression, 25.0, 2.4, 8.4, 46.0, 0.9, and 8.5, respectively). The overall relative risk of progression was 7.3 in these patients as compared with the white population of the Iowa Surveillance, Epidemiology, and End Results program. In 32 additional patients, the monoclonal protein concentration increased to more than 3 g per deciliter or the percentage of plasma cells in the bone marrow increased to more than 10 percent (smoldering multiple myeloma) but without progression to overt myeloma or related disorders. The cumulative probability of progression was 12 percent at 10 years, 25 percent at 20 years, and 30 percent at 25 years. The initial concentration of serum monoclonal protein was a significant predictor of progression at 20 years. Conclusions: The risk of progression of MGUS to multiple myeloma or related disorders is about 1 percent per year. (N Engl J Med 2002;346:564-9.) [ABSTRACT FROM AUTHOR]