Citations

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is a precursor to multiple myeloma and related diseases. The majority of MGUS cases are characterized by the expression of immunoglobulin heavy chain (IgH); however, approximately one-fifth of MGUS cases do not present with IgH expression. These individuals have light chain MGUS (LC-MGUS), a precursor to light-chain MM (LC-MM). LC-MGUS is characterized by an absence of IgH and an abnormal free light chain ratio (FLC-R), indicating excessive expression of either κ or ≤ free light chains. LC-MGUS has a prevalence of 0.8% in the general population over the age of 50, as compared with a prevalence of 3.2% for heavy-chain MGUS (HC-MGUS) (Dispenzieri, 2010). There is currently little understanding of the association between family history of HC-MGUS or multiple myeloma (MM) and LC-MGUS. We investigated whether the prevalence of LC-MGUS is elevated in first-degree relatives of patients with either HC-MGUS or MM. HC-MGUS probands expressed IgH and were recruited through a population-based study of Olmsted County residents; MM probands consisted of both HC-MM and LC-MM and were recruited through the Mayo Clinic Hematology practice. Serum samples were collected from first-degree relatives of probands older than 40 years of age and subjected to electrophoresis, immunofixation, and free light chain assay. Prevalence of LC-MGUS was calculated in all first-degree relatives combined, and in relatives from both HC-MGUS and MM families separately. We compared the prevalence in family members to that in a well-defined Olmsted County, MN cohort (Dispenzieri, 2010) of patients aged 50 and over. A total 911 relatives of 232 MM and 97 MGUS patients were studied. LC-MGUS was detected in 17/911 (1.9%) relatives, for an age- and sex-adjusted prevalence of 1.7% (95% CI, 0.9% to 2.6%). Prevalence among relatives of MM probands (age- and sex- adjusted rate 2.1%; 95% CI, 1.0% to 3.2%) was higher than among relatives of MGUS probands (age- and sex- adjusted rate 0.6%; 95% CI, 0.0%-1.6%). There was an increased risk of LC-MGUS in relatives compared to the reference population which was predominantly due to the increased risk among relatives of MM probands (risk ratio=3.4, 95% CI 2.0, 5.51) as opposed to relatives of MGUS probands (risk ratio=1.1, 95% CI, 0.3 to 4.5). Among MM probands, there was no significant difference between the prevalence increase in relatives of the 32 probands with LC-MM and that of the relatives of the 200 probands with HC-MM (3.8 vs 3.3, ratio=1.2, 95% CI: 0.3-5.1, p=0.85). We conclude that the prevalence of LC-MGUS is significantly higher among first degree family members of all MM probands compared to the general population. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5485. doi:1538-7445.AM2012-5485

AbstractTo further explore reports of association of alcohol dependence and response to acamprosate treatment with the GATA4 rs13273672 single nucleotide polymorphism (SNP), we genotyped this and 10 other GATA4 SNPs in 816 alcohol‐dependent cases and 1248 controls. We tested for association of alcohol dependence with the 11 SNPs individually and performed a global test for association using a principle components analysis. Our analyses demonstrate significant association between GATA4 and alcohol dependence at the gene level (P = 0.009) but no association with rs13273672. Further studies are needed to identify potential causal GATA4 variation(s) and the functional mechanism(s) contributing to this association.

Abstract It is believed that multiple genetic variants with small individual effects contribute to the risk of alcohol dependence. Such polygenic effects are difficult to detect in genome-wide association studies that test for association of the phenotype with each single nucleotide polymorphism (SNP) individually. To overcome this challenge, gene-set analysis (GSA) methods that jointly test for the effects of pre-defined groups of genes have been proposed. Rather than testing for association between the phenotype and individual SNPs, these analyses evaluate the global evidence of association with a set of related genes enabling the identification of cellular or molecular pathways or biological processes that play a role in development of the disease. It is hoped that by aggregating the evidence of association for all available SNPs in a group of related genes, these approaches will have enhanced power to detect genetic associations with complex traits. We performed GSA using data from a genome-wide study of 1165 alcohol-dependent cases and 1379 controls from the Study of Addiction: Genetics and Environment (SAGE), for all 200 pathways listed in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results demonstrated a potential role of the ‘synthesis and degradation of ketone bodies’ pathway. Our results also support the potential involvement of the ‘neuroactive ligand–receptor interaction’ pathway, which has previously been implicated in addictive disorders. These findings demonstrate the utility of GSA in the study of complex disease, and suggest specific directions for further research into the genetic architecture of alcohol dependence.

SummaryPreviously, 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.

Purpose Cardiac involvement predicts poor prognosis in light chain (AL) amyloidosis, and the current prognostic classification is based on cardiac biomarkers troponin-T (cTnT) and N-terminal pro–B-type natriuretic peptide (NT-ProBNP). However, long-term outcome is dependent on the underlying plasma cell clone, and incorporation of clonal characteristics may allow for better risk stratification. Patients and Methods We developed a prognostic model based on 810 patients with newly diagnosed AL amyloidosis, which was further examined in two other datasets: 303 patients undergoing stem-cell transplantation, and 103 patients enrolled onto different clinical trials. Results We examined the prognostic value of plasma cell–related characteristics (ie, difference between involved and uninvolved light chain [FLC-diff], marrow plasma cell percentage, circulating plasma cells, plasma cell labeling index, and β 2 microglobulin). In a multivariate model that included these characteristics as well as cTnT and NT-ProBNP, only FLC-diff, cTnT, and NT-ProBNP were independently prognostic for overall survival (OS). Patients were assigned a score of 1 for each of FLC-diff ≥ 18 mg/dL, cTnT ≥ 0.025 ng/mL, and NT-ProBNP ≥ 1,800 pg/mL, creating stages I to IV with scores of 0 to 3 points, respectively. The proportions of patients with stages I, II, III and IV disease were 189 (25%), 206 (27%), 186 (25%) and 177 (23%), and their median OS from diagnosis was 94.1, 40.3, 14, and 5.8 months, respectively (P < .001). This classification system was validated in the other datasets. Conclusion Incorporation of serum FLC-diff into the current staging system improves risk stratification for patients with AL amyloidosis and will help develop risk-adapted therapies for AL amyloidosis.

Abstract Immunoglobulin free light chains (FLCs) are the precursors of amyloid fibrils in primary amyloidosis (AL). We studied the relationship between FLC levels and clinical features in 730 patients with newly diagnosed AL. The plasma cell clone was λ in 72% patients, and κ in 28% patients. κ-AL had more GI tract and liver involvement, where as renal involvement was more with λ-AL. While the overall survival (OS) was similar for κ and λ-AL, the median OS for those without an identifiable serum heavy chain was significantly shorter (12.6 vs 29.9 months; P = .02). The OS was shorter among those with a higher dFLC (involved FLC−uninvolved FLC; κ > 29.4 mg/dL or λ > 18.2 mg/dL using median for cutoff); 10.9 vs 37.1 months; P < .001. In multivariate analysis, dFLC was independent of other prognostic factors. The type of light chain impacts the spectrum of organ involvement and the FLC burden correlates with survival in AL.

Abstract 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.

Abstract 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).

Abstract 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.