Elsevier

The Lancet

Volume 375, Issue 9727, 15–21 May 2010, Pages 1721-1728
The Lancet

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

https://doi.org/10.1016/S0140-6736(10)60482-5Get rights and content

Summary

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, National Institute of Health.

Introduction

Monoclonal gammopathy of undetermined significance (MGUS) is a precursor lesion for multiple myeloma, which is an incurable malignant disease affecting bone marrow that has a yearly incidence of roughly 4·6 per 100 000 population.1 Historically, MGUS has been characterised by evidence of immunoglobulin heavy-chain (IgH) expression, but could therefore account for only 80% of cases of multiple myeloma, since in the remaining 20% no IgH (eg, IgG, IgA, IgD, or IgE) is secreted.2 The prevalence and risk of progression of the premalignant precursor entity for light-chain multiple myeloma is unknown.

We postulated that an equivalent of MGUS in which IgH is not expressed—ie, light-chain MGUS—is the premalignant precursor of light-chain multiple myeloma. We previously used a serum agarose gel electrophoretic screening method to show that the prevalence of standard heavy-chain-associated MGUS was 3·2% in the population aged 50 years or older in Olmsted County, MN, USA (a predominantly white population), but identified only two patients in 21 463 people tested who had free light-chain expression in serum without heavy-chain expression.2 We postulated that the serum immunoglobulin free light-chain assay,3 which can detect imbalances of unbound κ and λ light chains when circulating concentrations are as low as 10–30 mg/L,4, 5, 6, 7 might provide us with better sensitivity than would protein electrophoresis to detect this putative entity of light-chain MGUS. Clonality is defined as a ratio of κ to λ that is outside the reference range. This definition depends on the ratio, rather than the absolute concentration of either chain independently, because both renal disease and polyclonal activation of B cells can cause a diffuse increase of both κ and λ plasma cells, yielding raised absolute concentrations of free κ and λ chains, but maintaining a normal ratio. We aimed to use the free light-chain assay to estimate prevalence of light-chain MGUS in the large, well defined, Olmsted County cohort that was originally assembled to estimate prevalence and progression of plasma-cell disorders.2 We also described progression of this novel disorder to myeloma or related malignant disease.

Section snippets

Patients

We used a population-based cohort that we had previously assembled to estimate prevalence of MGUS.2 The original cohort consisted of 21 463 of the 28 038 enumerated Olmsted County residents aged 50 years or older on Jan 1, 1995 who had serum samples available. Written informed consent for the previous study included permission for further tests and studies on the samples, and for this study we did a serum immunoglobulin free-light-chain assay on all samples with sufficient remaining serum.

Procedures

After

Results

Sufficient serum for further analysis remained for 18 372 (86%) of the original 21 463 Olmsted County residents. Samples from 15 patients with malignant plasma-cell disorders were excluded.2 An abnormal free light-chain ratio was reported for 610 of the remaining 1857 participants (table 1). Serum immunofixation showed IgH expression in 213 of these 610 people, showing presence of conventional MGUS. These 213 patients included 57 for whom IgH expression was previously undetected with serum

Discussion

The term MGUS was coined more than 30 years ago at the Mayo Clinic in reference to asymptomatic individuals with an intact serum monoclonal protein concentration (both immunoglobulin heavy-chain and light-chain detectable) lower than 30 g/L and with less than 10% plasma cells in bone marrow.2, 17, 18 MGUS was shown to be the precursor lesion for intact immunoglobulin multiple myeloma.19 Roughly 80% of patients with multiple myeloma have IgH expression (ie, IgG, IgA, IgM, IgD, and IgE); no IgH

References (28)

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