Raynell J. Clark

Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study.

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma-cell proliferative disorder associated with a life-long risk of progression to multiple myeloma (MM). It is not known whether MM is always preceded by a premalignant asymptomatic MGUS stage. Among 77,469 healthy adults enrolled in the nationwide population-based prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, we identified 71 subjects who developed MM during the course of the study in whom serially collected (up to 6) prediagnostic serum samples obtained 2 to 9.8 years prior to MM diagnosis were available. Using assays for monoclonal (M)-proteins (electrophoresis/immunofixation) and kappa-lambda free light chains (FLCs), we determined longitudinally the prevalence of MGUS and characterized patterns of monoclonal immunoglobulin abnormalities prior to MM diagnosis. MGUS was present in 100.0% (87.2%-100.0%), 98.3% (90.8%-100.0%), 97.9% (88.9%-100.0%), 94.6% (81.8%-99.3%), 100.0% (86.3%-100.0%), 93.3% (68.1%-99.8%), and 82.4% (56.6%-96.2%) at 2, 3, 4, 5, 6, 7, and 8+ years prior to MM diagnosis, respectively. In approximately half the study population, the M-protein concentration and involved FLC-ratio levels showed a yearly increase prior to MM diagnosis. In the present study, an asymptomatic MGUS stage consistently preceded MM. Novel molecular markers are needed to better predict progression to MM in patients with MGUS.

Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective population-based cohort study

BACKGROUND Monoclonal gammopathy of undetermined significance (MGUS) is defined by expression of heavy-chain immunoglobulin (IgH) and is the precursor lesion for 80% of cases of multiple myeloma. The remaining 20% are characterised by absence of IgH expression; we aimed to assess prevalence of a corresponding precursor entity, light-chain MGUS. METHODS We used a population-based cohort, previously assembled to estimate MGUS prevalence, of 21,463 residents of Olmsted County, MN, USA, aged 50 years and older. We did a serum free light-chain assay on all samples with sufficient serum remaining, and immunofixation electrophoresis was done for all samples with an abnormal free light-chain ratio or abnormal protein electrophoresis results from the original study. Light-chain MGUS was defined as an abnormal free light-chain ratio with no IgH expression, plus increased concentration of the involved light chain. We calculated age-specific and sex-specific prevalence and rates of progression to lymphoproliferative disorders for light-chain and conventional MGUS and assessed incidence of renal disorders in patients with light-chain MGUS. FINDINGS 610 (3.3%) of 18,357 people tested had an abnormal free light-chain ratio, of whom 213 had IgH expression that was diagnostic of conventional MGUS. 146 of the remaining 397 individuals had an increase of at least one free light chain and met criteria for light-chain MGUS. Prevalence of light-chain MGUS was 0.8% (95% CI 0.7-0.9), contributing to an overall MGUS prevalence of 4.2% (3.9-4.5). Risk of progression to multiple myeloma in patients with light-chain MGUS was 0.3% (0.1-0.8) per 100 person-years. 30 (23%) of 129 patients with light-chain MGUS were diagnosed with renal disease. INTERPRETATION We define a clinical entity representing the light-chain equivalent of conventional MGUS and posing a risk of progression to light-chain multiple myeloma and related disorders. FUNDING US National Cancer Institute.

Prognostic value of the serum free light chain ratio in newly diagnosed myeloma: proposed incorporation into the international staging system

To determine if the serum free light chain (FLC) ratio has prognostic value in patients with symptomatic multiple myeloma (MM), baseline serum samples from a well-characterized cohort of 790 newly diagnosed MM patients were tested with the FLC assay. FLC ratio was calculated as κ/λ (reference range 0.26–1.65). On the basis of the distribution of values, a cutpoint κ/λ FLC ratio of <0.03 or >32 was chosen for further analysis. Overall survival was significantly inferior in patients with an abnormal FLC ratio of <0.03 or >32 (n=479) compared with those with an FLC ratio between 0.03 and 32 (n=311), with median survival of 30 versus 39 months, respectively. We incorporated abnormal FLC ratio with the International Staging System (ISS) risk factors (that is, albumin <3.5 g/dl and serum β2-microglobulin ⩾3.5 g/l), to create a risk stratification model with improved prognostic capabilities. Patients with 0, 1, 2 or 3 adverse risk factors had significantly different overall survival, with median survival times of 51, 39, 30 and 22 months, respectively (P<0.001). These findings suggest that the serum FLC ratio at initial diagnosis is an important predictor of prognosis in myeloma, and can be incorporated into the ISS for improved risk stratification.

Serum immunoglobulin free light-chain measurement in primary amyloidosis: prognostic value and correlations with clinical features

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.

Suppression of uninvolved immunoglobulins defined by heavy/light chain pair suppression is a risk factor for progression of MGUS.

We hypothesized that the suppression of uninvolved immunoglobulin in monoclonal gammopathy of undetermined significance (MGUS) as detected by suppression of the isotype-specific heavy and light chain (HLC-pair suppression) increases the risk of progression to malignancy. This approach required quantitation of individual heavy/light chains (for example, IgGλ in IgGκ MGUS patients). Of 1384 MGUS patients from Southeastern Minnesota seen at the Mayo Clinic from 1960 to 1994, baseline serum samples obtained within 30 days of diagnosis were available in 999 persons. We identified HLC-pair suppression in 27% of MGUS patient samples compared with 11% of patients with suppression of uninvolved IgG, IgA or IgM. HLC-pair suppression was a significant risk factor for progression (hazard ratio (HR), 2.3; 95% confidence interval (CI) 1.5–3.7; P<0.001). On multivariate analysis, HLC-pair suppression was an independent risk factor for progression to malignancy in combination with serum M-spike size, heavy chain isotype and free light chain ratio (HR, 1.8; 95% CI, 1.1–3.00; P=0.018). The finding that HLC-pair suppression predicts progression in MGUS and occurs several years before malignant transformation has implications for myeloma biology.

Presence of monoclonal free light chains in the serum predicts risk of progression in monoclonal gammopathy of undetermined significance

We hypothesized that the presence of monoclonal free light chains (FLC) in the serum of patients with monoclonal gammopathy of undetermined significance (MGUS) is a marker of clonal evolution and a risk factor for progression. Forty‐seven patients with MGUS and documented progression to myeloma or related malignancy were compared with 50 age‐ and gender‐matched patients with MGUS and no evidence of progression after 5 or more years of follow‐up. The presence of an abnormal kappa/lambda FLC ratio in the serum was associated with a higher risk of MGUS progression (relative risk 2·5; 95% confidence interval: 1·6–4·0; P < 0·001).

Use of Nonclonal Serum Immunoglobulin Free Light Chains to Predict Overall Survival in the General Population

OBJECTIVE To determine whether the free light chain (FLC) assay provides prognostic information relevant to the general population. METHODS After excluding persons with a known plasma cell disorder, we studied 15,859 Olmsted County, Minnesota, residents 50 years or older in whom unmasked data and samples for FLC testing were available. Baseline information was obtained between March 13, 1995, and November 21, 2003, and follow-up status and cause of death were identified through June 30, 2009. The κ and λ FLC sum (Σ FLC) was evaluated for its ability to predict overall survival. Specific causes of death were also investigated. RESULTS In 158,003 person-years of follow-up, 4348 individuals died. A high Σ FLC was significantly predictive of worse overall survival; the risk ratio for death for those with the highest decile of Σ FLC (ie, ≥ 4.72 mg/dL) was 4.4 (95% confidence interval, 4.1-4.7) relative to the remaining study participants. Multivariate analyses demonstrated that this excess risk of death was independent of age, sex, and renal insufficiency, with a corrected risk ratio of 2.1 (95% confidence interval, 1.9-2.2). The increased mortality was not restricted to any particular cause of death because the observed-to-expected risk of death from most causes was significantly higher among those individuals with an antecedent Σ FLC of 4.72 mg/dL or higher, which is near the upper limit of normal for the test. CONCLUSION A nonclonal elevation of Σ FLC is a significant predictor of worse overall survival in the general population of persons without plasma cell disorders.

Racial disparities in the prevalence of monoclonal gammopathies: a population-based study of 12 482 persons from the National Health and Nutritional Examination Survey

Multiple myeloma (MM) incidence is markedly higher in blacks compared with whites, which may be related to a higher prevalence of monoclonal gammopathy of undetermined significance (MGUS). Our objective was to define the prevalence and risk factors of MGUS in a large cohort representative of the US population. Stored serum samples from the National Health and Nutritional Examination Survey (NHANES) III or NHANES 1999–2004 were available for 12 482 individuals of age ⩾50 years (2331 ‘blacks’, 2475 Hispanics, 7051 ‘whites’ and 625 ‘others’) on which agarose-gel electrophoresis, serum protein immunofixation, serum-free light-chain assay and M-protein typing were performed. MGUS was identified in 365 participants (2.4%). Adjusted prevalence of MGUS was significantly higher (P<0.001) in blacks (3.7%) compared with whites (2.3%) (P=0.001) or Hispanics (1.8%), as were characteristics that posed a greater risk of progression to MM. The adjusted prevalence of MGUS was 3.1% and 2.1% for the North/Midwest versus South/West regions of the United States, respectively (P=0.052). MGUS is significantly more common in blacks, and more often has features associated with higher risk of progression to MM. A strong geographic disparity in the prevalence of MGUS between the North/Midwest versus the South/West regions of the United States was found, which has etiologic implications.

Mutations in Specific Structural Regions of Immunoglobulin Light Chains Are Associated with Free Light Chain Levels in Patients with AL Amyloidosis

Background The amyloidoses are protein misfolding diseases characterized by the deposition of amyloid that leads to cell death and tissue degeneration. In immunoglobulin light chain amyloidosis (AL), each patient has a unique monoclonal immunoglobulin light chain (LC) that forms amyloid deposits. Somatic mutations in AL LCs make these proteins less thermodynamically stable than their non-amyloidogenic counterparts, leading to misfolding and ultimately the formation of amyloid fibrils. We hypothesize that location rather than number of non-conservative mutations determines the amyloidogenicity of light chains. Methodology/Principal Findings We performed sequence alignments on the variable domain of 50 κ and 91 λ AL light chains and calculated the number of non-conservative mutations over total number of patients for each secondary structure element in order to identify regions that accumulate non-conservative mutations. Among patients with AL, the levels of circulating immunoglobulin free light chain varies greatly, but even patients with very low levels can have very advanced amyloid deposition. Conclusions Our results show that in specific secondary structure elements, there are significant differences in the number of non-conservative mutations between normal and AL sequences. AL sequences from patients with different levels of secreted light chain have distinct differences in the location of non-conservative mutations, suggesting that for patients with very low levels of light chains and advanced amyloid deposition, the location of non-conservative mutations rather than the amount of free light chain in circulation may determine the amyloidogenic propensity of light chains.

Sharply Increased Serum Free Light-Chain Concentrations after Treatment for Multiple Myeloma

A 53-year-old woman presented to the orthopedic department with severe diffuse muscular and bone pain. An x-ray of her right upper extremity revealed a lytic destructive lesion in the right humerus. Computed tomography scans showed multiple lytic lesions in the spine and pelvis, and a biopsy confirmed the presence of 70% plasma cells, which were κ light chain restricted. The patient was referred to a hematologist. Although no monoclonal protein was detected in the serum by protein electrophoresis or by immunofixation electrophoresis (IFE),1 the κ free light chain (FLC) was increased at 47.2 mg/L (reference interval, 3.3–19.4 mg/L), with a κ/λ FLC ratio of 23 (reference interval, 0.26–1.65). Serum concentrations of β2-microglobulin and albumin were 248 nmol/L (reference interval, 59.5–153 nmol/L) and 37 g/L (reference interval, 34–47 g/L), respectively. The urine protein concentration was not increased, but protein electrophoresis revealed a small M (monoclonal) spike in the γ region (32 mg/24 h). In addition, IFE identified a monoclonal κ light chain (Bence Jones protein). On the basis of these findings, the patient was informed that she had stage I (International Staging System) oligosecretory/nonsecretory multiple myeloma (MM). The patient underwent surgical repair of her right humerus and was evaluated 1 month after her surgery. At that point, a second serum FLC measurement showed a κ FLC concentration of 68.2 mg/L. The patient’s hematologist recommended close observation in lieu of initiating therapy because of her lack of symptoms. The patient’s serum κ FLC concentration was monitored monthly and remained <50 mg/L for the next 3 months. Five months after diagnosis, the patient began to complain of mild fatigue, shortness of breath, and palpitations. A 10-fold increase in the urinary M protein to 333 mg/24 h was noted, along with a decrease in the blood hemoglobin concentration to 79 g/L …