Light chain mono­clonal gam­mop­athy of undetermined sig­nif­i­cance (MGUS) has a very low probability of progressing to symp­tomatic multiple myeloma, accord­ing to the results of a new study by researchers in Germany.

The German researchers found that, with a median follow-up time of 11.5 years, none of the 75 people in their study who had light chain MGUS saw their MGUS progress to symp­tomatic multiple myeloma, amyloidosis, or a related disease.

In fact, in more than half of the 31 cases where the nec­es­sary laboratory results were avail­able, study par­tic­i­pants who initially met the criteria for a diag­nosis of light chain MGUS were found to be free of the disease upon sub­se­quent testing.

These findings are in line with those of a key study of light chain MGUS published by U.S. researchers in 2010. The earlier study found that the risk of pro­gres­sion to symp­tomatic myeloma for patients with light chain MGUS was only 0.3 per­cent per year, com­pared to 1 per­cent per year for people diag­nosed with conventional MGUS.

The group of light chain MGUS patients in­ves­ti­gated in the new study were par­tic­i­pants in a more general health study involving German men and women aged 45 to 75. The over­all survival of the study par­tic­i­pants with light chain MGUS was the same, the authors found, as the over­all survival of the study par­tic­i­pants who did not have light chain MGUS.

Based on their findings, the German researchers conclude that light chain MGUS is “a rel­a­tive­ly benign con­di­tion with a high disappearance rate … and normal over­all survival.” They there­fore recommend that initial laboratory tests suggesting a diag­nosis of light chain MGUS be repeated again, perhaps in three months, to con­firm the initial diag­nosis.

Background

MGUS is a disorder similar to multiple myeloma in that both con­di­tions involve the presence of ab­nor­mal (“clonal”) plasma cells in the body. These dysfunctional plasma cells typically, but not always, produce mono­clonal (M) immuno­glob­u­lins and free light chains, which are measured using tests such as serum protein electrophoresis and serum free light chain analysis.

Where MGUS and multiple myeloma differ, how­ever, is that MGUS almost by definition is a more benign disease. Conventional, non-light-chain MGUS is clin­i­cally defined as disease that produces a mono­clonal protein level (M-spike) less than 3 g/dL (30 g/l), involves a clonal plasma cell per­cent­age less than 10 per­cent, and causes none of the organ damage typically found in multiple myeloma patients (for example, bone lesions, anemia, or kidney damage).

Whereas a multiple myeloma diag­nosis almost always leads to treat­ment of the disease, this is rarely the case with MGUS. Instead, the typical ap­proach to MGUS is “watch and wait,” in which patients are monitored but not treated.

The “watch and wait” ap­proach is pursued due to the frequently benign nature of MGUS and the fact that people diag­nosed with conventional MGUS progress to symp­tomatic multiple myeloma at a rate of just 1 per­cent per year.

Light chain MGUS is a sub-form of MGUS in which patients do not have an M-spike, but they do have an ab­nor­mal free light chain (kappa-lambda) ratio and either an elevated kappa, or an elevated lambda, free light chain level.

Previous research found the prev­a­lence of conventional MGUS and light chain MGUS to be 3.3 per­cent and 0.8 per­cent, re­spec­tive­ly, in people 50 years of age and older in Olmstead County, Minnesota.

The authors of the new German study also have pre­vi­ously esti­mated the prev­a­lence of light chain MGUS. They found it to be 0.7 per­cent among the German men and women, 45 to 75 years of age, who partici­pated in the Heinz Nixdorf “RECALL” (Risk Factors, Evaluation of Coronary Calcifi­cation, and Life­style) study.

The RECALL study, which involved almost 5,000 par­tic­i­pants, was organized to in­ves­ti­gate factors that might affect the devel­op­ment of heart disease.

Since the German researchers’ initial look at light chain MGUS among par­tic­i­pants in the RECALL study, data from the study have matured. Thus, the researchers decided to use the study results to in­ves­ti­gate the rate of pro­gres­sion of light chain MGUS to symp­tomatic multiple myeloma over long periods of time.

Study Design

For their analysis, the German researchers used data from the initial examination par­tic­i­pants had when they entered the RECALL study (between 2000 and 2003), and from the five-year (between 2006 and 2008) and 10-year follow-up examinations (between 2011 and 2015).

The RECALL study in­cludes 4,814 men and women be­tween the ages of 45 and 75 years who live in three large neighboring cities in western Germany. The study par­tic­i­pants were ran­domly recruited from statutory lists of residents. The median age of the study par­tic­i­pants was 56.9 years.

The median follow-up time was 11.5 years.

Study Results

The researchers identified 75 RECALL study par­tic­i­pants who had light chain MGUS at one or more of their three study examination times; 32 of the cases were detected at initial examination, 10 be­tween initial examination and the five-year follow-up examination, and 33 be­tween the five-year and 10-year follow-up.

After the median follow-up time, none of the study par­tic­i­pants with light chain MGUS saw their disease progress to symp­tomatic multiple myeloma. However, three case of light chain MGUS evolved into conventional MGUS during follow-up, and one case of light chain MGUS was seen in a study par­tic­i­pant who initially had conventional MGUS.

Intriguingly, the researchers also found that light chain MGUS disappeared in 17 of the 31 patients for whom the nec­es­sary test results were avail­able across multiple time points.

This 55 per­cent disappearance is very high, the authors note, com­pared to disappearance rates of only 2 to 5 per­cent seen in pre­vi­ous research involving patients with conventional MGUS.

In the 17 patients in the RECALL study whose light chain MGUS disappeared, the initial con­cen­tra­tion of the involved (elevated) free light chain was lower than in patients whose light chain MGUS persisted. The involved free light chain level was a median of 9.1 mg/l in study par­tic­i­pants whose light chain MGUS disappeared, versus 20.3 mg/l among those whose MGUS persisted.

Overall survival for the study par­tic­i­pants with light chain MGUS was the same as for the 4,705 RECALL par­tic­i­pants who had normal free light chain test results at all times during the study.

There is some evi­dence in the RECALL data that over­all survival may be lower for lambda light chain MGUS than for kappa light chain MGUS. There is a noticeable dif­fer­ence in over­all survival be­tween the lambda and kappa light chain MGUS patients in the study, and the dif­fer­ence is statistically sig­nif­i­cant.

That said, there were only 10 cases of lambda light chain MGUS in the study, so these survival findings need to be viewed with caution.

Although there was no dif­fer­ence in over­all survival be­tween the light chain MGUS study par­tic­i­pants and others in the RECALL study, the par­tic­i­pants with light chain MGUS had a 1.5 higher likelihood of devel­op­ing solid tumor cancers. This finding, the authors note, is in line with pre­vi­ous research that has reported an in­­creased rate of cancer in patients with conventional MGUS.

For more in­for­ma­tion, please see the study by Pelzer, B.W. et al., “Light chain mono­clonal gam­mop­athy of undetermined sig­nif­i­cance is char­ac­ter­ized by a high disappearance rate and low risk of pro­gres­sion on longitudinal analysis,” Annals of Hematology, April 9, 2018 (abstract ^[1]).

The Beacon's forum ^[2] also has a section focused on MGUS ^[3], and in it there are many discussions about the risk of pro­gres­sion in people with MGUS ^[4].