The term, MGUS, was coined at the Mayo Clinic over 30 years ago in reference to asymptomatic individuals with an intact serum monoclonal protein (both immunoglobulin heavy and light chain detectable) less than 30 g/L and with fewer than 10% bone marrow plasma cells.2, 16, 17
MGUS was observed to be the precursor lesion for intact immunoglobulin MM.18
Approximately 80% of MM cases have IgH expression (i.e., IgG, IgA, IgM, IgD, and IgE); in the remaining 20%, there is no IgH expression. Prior to our original description of LC-MGUS,19
a premalignant lesion for LC-MM corresponding to MGUS had not been systematically described. However, a condition called idiopathic Bence Jones proteinuria was defined in 7 patients who had at least one gram of urinary monoclonal protein without evidence of MM or related disorders.20
In the parlance of the current manuscript, these 7 patients could be considered the first cases of LC-MGUS, but prevalence was not addressed. Herein, we have shown that LC-MGUS comprises 19% of the total cases of MGUS and LC-MGUS, consistent with the proportion of LC-MM cases among newly diagnosed MM patients, 21
and that an estimated that 0.8% of the general population age 50 years and older has LC-MGUS.
Recognition and description of this entity is important for two reasons. First, it provides insight into an additional precursor lesion for MM, a devastating malignancy. Second, the natural history of LC-MGUS, which affects 0.8% of the Caucasian population age 50 years and older—likely more than 750,000 Americans—needs to be understood to promote appropriate testing on these patients who have a relatively benign condition. Patients with LC MGUS had a progression rate of only 0.3%/year, which is lower than their conventional MGUS counterparts, who have an overall annual risk of 1.0%/year, but 23% of them have or will develop renal disease. This low progression rate was perhaps unexpected in the context of our prior observation that patients with intact immunoglobulin MGUS, but who also have an abnormal FLC-R, are at higher risk of progression than are their counterparts with a normal FLC-R.12
We demonstrate, however, that the progression rates of the low-risk conventional MGUS patients (i.e. those without coexistent abnormal FLC-R) and the LC-MGUS patients were similar.
Whether differential risks of progression among patients with conventional MGUS or LC-MGUS are a function of tumor burden, biology, or a combination of the two is unknown. It is conceivable that the transforming events that produce a LC-MGUS and a conventional IgH MGUS (with a normal FLC-R) are the same, whereas conventional IgH MGUS combined with an abnormal FLC-R is a manifestation of another “hit” and therefore one step closer to full transformation to active MM.22
It is also plausible that the cases of LC-MGUS are being detected at an earlier time point (i.e., at a point of earlier tumor burden) given the relatively higher sensitivity of the serum FLC ratio determination (which can detect involved FLC of less than 10–30 mg/L) compared to the serum protein electrophoresis screening (1–2 g/L).3,8
In this study, we detected an additional 57 unrecognized MGUS patients by FLC assay, increasing the prevalence of IgH MGUS from 3.2%2
to 3.4% and defining the prevalence of LC-MGUS plus MGUS as 4.2%. A final explanation could be that a small fraction of our LC-MGUS cohort, i.e. those with the least abnormal ratios, does not have a true clonal disorder, but merely renal dysfunction or polyclonal activation.
Our description of the LC-MGUS entity is supported by three recent observations. Landgren et al., in collaboration with our group showed that the either MGUS or LC-MGUS is present in over 96% of MM patients more than 6 years prior to the diagnosis of their malignancy.23
If LC-MGUS were excluded, only 93% of MM patients had a premalignant MGUS preceding the diagnosis. This shows that there is a small subset of MM patients in whom the precursor lesion is not MGUS, but rather LC-MGUS. A second similar study showed that LC-MGUS was the preceding premalignant lesion in LC-MM.24
These results support our previous report that IgH MGUS progresses only to MM with IgH expression. Taken together, they lend strong support to the findings of the present study. Finally, in a slightly different vein, Tsai et al found that among a cohort of 109 CLL patients, the prevalence of an abnormal FLC-ratio prior to CLL diagnosis was 38% (95%CI 29–47%);25
none of the LC-MGUS cases in our cohort has yet evolved to CLL.
For the purposes of disease definition, we excluded from the LC-MGUS category those individuals with an abnormal FLC-R who had no elevation in the involved light chain. This group, constituting 63% of all individuals with an abnormal FLC-R and absent IgH expression, may include a subset of patients with true LC-MGUS, but were felt to be false positives based on two arguments. First, since an abnormal FLC-R in the context of B-cell disorders is used as a surrogate for clonality, abnormality in the FLC-R due merely to relative suppression of the other immunoglobulin FLC seems insufficient evidence for a clone. Second, when we explored the prevalence of abnormal FLC-R with neither elevated κ or λ concentrations, the age distribution was the inverse of what is seen in MGUS.
A more specific definition of LC-MGUS could include only that subset that were immunofixation positive (26 of the 146 LC-MGUS cases), but such a definition would have missed all 3 cases of LC-MGUS that progressed to MM in this series. Since the FLC-R is more sensitive at detecting free light chains than serum immunofixation;4–7, 9
relying on immunofixation alone would also greatly underestimate the true prevalence of LC-MGUS. Our trust in the FLC-R to detect clonal disorders in the setting of a negative immunofixation to is supported by the report of Weiss et al.24
In their series, among the 30 patients with MM who had pre-diagnostic serum available for retrospective testing for monoclonal gammopathy from 2.2 to 15.3 years prior to MM diagnosis, the first evidence of a plasma cell clone was the FLC-R alone in 6 patients, two of whom subsequently had an IgH detected by immunofixation prior to their diagnosis of non-LC MM.
Another “more specific” definition of LC-MGUS might employ the renal reference range.15
This exercise increased the number of λ cases by 57 and decreased the number of κ cases by 69, which did not significantly change the prevalence rate, but did dramatically alter the population at risk. Because the current definition of renal range does not take into account degrees of renal dysfunction,15
it was not possible to select those patients to whom the renal reference range should have been applied. Employing the normal reference range rather than the renal range, albeit imperfect, allowed for the greatest consistency in the setting of this large population study. Another confounder of our prevalence estimates is that the recognition of MGUS—be it conventional MGUS or LC-MGUS—is dependent on the screening methods used. As the sensitivity of the screening technology increases, the prevalence of an entity also “increases.” In the case of conventional MGUS, our detection rates have increased with increasing sensitivity of the screening method as we have evolved from paper electrophoresis,16
to agarose gel electrophoresis2
to FLC measurements.
In summary, we define a new clinical entity representing the light chain equivalent of MGUS, namely LC-MGUS. LC-MGUS is prevalent in almost 1% of the general Caucasian population age 50 and older, is associated with increased progression to MM or related malignancy. An important limitation of this study is the absence of an African American presence with the Olmsted County cohort. Conventional MGUS is 2–3 times as common in African Americans as it is in Caucasians, and our population study does not provide information about the prevalence of LC-MGUS in African Americans.26
We also found an association with renal disease that needs further study. We do not recommend screening for this disorder; however, we expect patients to be identified incidentally when a FLC assay is ordered as part of a diagnostic evaluation for a variety of symptoms and laboratory abnormalities such as anemia, hypercalcemia, or renal failure. If LC-MGUS is identified in the context of one of these abnormalities, as with MGUS we recommend excluding a diagnosis of MM, amyloidosis, and related conditions by performing a bone marrow examination with clonality testing, imaging studies, renal biopsy, and/or Congo red staining of fat or other tissue as clinically appropriate. If no malignant condition is recognized, the free light chain assay should be repeated in 6 months and yearly thereafter; no therapy is indicated as long as there is no progression. Our data would suggest that monitoring renal function periodically is prudent given the fact that 23% of these patients either have or will develop renal disease. LC-MGUS patients are at risk for LC-MM, amyloidosis, and renal disorders and hence will need further evaluation if symptoms suggestive of these disorders are encountered during follow up. We hypothesize that LC-MGUS occurs as a consequence of translocations involving the immunoglobulin heavy chain region at chromosome 14q32 which results in total suppression of heavy chain production.27