Researchers from the Mayo Clinic con­firmed in a recent study that close relatives of people with multiple myeloma have a higher risk of devel­op­ing MGUS (mono­clonal gam­mop­athy of un­determined sig­nif­i­cance) than members of the general pop­u­la­tion.

In particular, the researchers found that "first-degree relatives" – parents, siblings, and children – of people with multiple myeloma were 2.4 times more likely to have MGUS than the general pop­u­la­tion.

This finding is in line with results of a pre­vi­ous Mayo Clinic study, which was smaller but in­cluded some of the same patients and relatives in­cluded in the latest study (see related Beacon news article).

Previous studies also have found that relatives of people with multiple myeloma are about 2.5 times as likely to develop multiple myeloma as people without a family history of the disease.

The authors of the new Mayo Clinic study also in­ves­ti­gated whether the risk of a close relative devel­op­ing MGUS was related in any way to a multiple myeloma patient's age, gender, type of multiple myeloma, chromosomal ab­nor­mal­i­ties, or M-spike level. The authors could not find any statistically sig­nif­i­cant rela­tion­ship between these personal and disease char­ac­ter­istics and the risk of a first-degree relative devel­op­ing MGUS.

That said, there were trends in the data that suggest that close relatives of a multiple myeloma patient may be more likely to develop MGUS if the patient has a higher M-spike (equal or greater than 1.5 g/dL, or 15 g/l) or if the patient has chromosomal ab­nor­mal­i­ties asso­ci­ated with inter­mediate- or high-risk disease.

At the same time, the researchers found that having a relative with MGUS did not have an effect on a myeloma patient's over­all survival. Myeloma patients with relatives who have MGUS lived as long as myeloma patients with no close family members with MGUS.

Given their findings, the authors of the new study believe that testing for poten­tial MGUS or multiple myeloma should be con­sidered for people who have more than one close relative with multiple myeloma. People with more than one first-degree relative with the disease are at a markedly higher risk of devel­op­ing MGUS or multiple myeloma. Screening for MGUS or myeloma in such cases is particularly likely to prevent com­pli­ca­tions due to undiagnosed disease, thereby improving survival.

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 bone marrow 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.

Previous research has shown that close relatives (parents, siblings, and children) of people with active or smol­der­ing multiple myeloma are more than twice as likely to have MGUS than the general pop­u­la­tion.

There is not much research, however, investigating whether the char­ac­ter­istics of a myeloma patient's disease are asso­ci­ated in any way with the risk of close family members devel­op­ing MGUS, or if a family history of MGUS is asso­ci­ated with better (or worse) over­all survival in myeloma patients.

Thus, the researchers from the Mayo Clinic sought to re-investigate the link between myeloma and the risk of MGUS in close family members while also assessing the connection – if any – between a myeloma patient's personal and disease char­ac­ter­istics and the risk of MGUS in first-degree relatives.

Study Design

For their analysis, the Mayo researchers used data from 430 multiple myeloma patients, 30 of whom had smol­der­ing multiple myeloma, and 1,179 first-degree relatives (siblings, children, or parents). The patients were recruited into the study between 2005 and 2015 at the Mayo Clinic's Rochester, Minnesota location. Family members had to be at least 40 years old to be in­cluded in the analysis; they were identified via questionnaires filled out by the myeloma patients when they entered the study.

Almost all multiple myeloma patients in the study (97 per­cent) were Caucasian, and the majority (86 per­cent) were between 50 and 79 years old. Approximately two-thirds (69 per­cent) had IgG multiple myeloma. Information about chromosomal ab­nor­mal­i­ties was avail­able for 70 per­cent of the multiple myeloma patients.

The majority of first-degree relatives (63 per­cent) were siblings.

The patient sample in­cluded more males (56 per­cent), whereas the relative sample in­cluded more females (59 per­cent).

Study Results

After adjusting for age and gender, the researchers reported that 5.8 per­cent of the myeloma patient's first-degree relatives were diag­nosed with MGUS. The rate increased to 7.9 per­cent when the researchers only con­sidered relatives over the age of 50.

The 5.8 per­cent risk of MGUS in first-degree relatives, the authors note, is 2.4 times higher than the age- and gender-adjusted risk in the general pop­u­la­tion, based on a pop­u­la­tion study involving participants similar in race and ethnicity to those in the current study.

The researchers found that the age of the multiple myeloma patient did not affect the relatives’ risk of MGUS.

Results of some pre­vi­ous research suggest that there might be a higher risk of MGUS in close family members in cases where someone is diag­nosed with multiple myeloma at a young age. The authors did not find any sup­port for this hypothesis in their results. In fact, if anything, the risk of MGUS occurring in close family members appears to higher – relative to the risk in the general pop­u­la­tion – in myeloma patients 55 years or older, compared to patients under the age of 55.

Patient gender and the type of their multiple myeloma (IgG or non-IgG) also did not affect the risk of MGUS in close relatives.

However, first-degree relatives of myeloma patients with an M-spike of 1.5 g/dl (15 g/l) or higher had a higher risk of MGUS than first-degree relatives of myeloma patients whose M-spike was below 1.5 g/dl. The difference in risk, however, was not statistically sig­nif­i­cant. (The risk of having MGUS was 2.7 times the risk in the general pop­u­la­tion for relatives of myeloma patients with a higher M-spike compared to 1.7 times the risk in the general pop­u­la­tion for patients with a lower M-spike.)

The researchers made the same observation in regard to the impact of a patient having one or more inter­mediate- or high-risk chromosomal ab­nor­mal­i­ties, defined as t(4;14), t(14;16), t(14;20), or del(17p), as determined by fluorescence in situ hybridization (FISH) testing of plasma cells from the patient's bone marrow.

First-degree relatives of myeloma patients with inter­mediate- or high-risk chromosomal ab­nor­mal­i­ties had a higher risk of MGUS, relative to the general pop­u­la­tion, than first-degree relatives of myeloma patients without those chromosomal ab­nor­mal­i­ties, although once again the difference in risk was not statistically sig­nif­i­cant. (The risk was 3.3 times higher than the general pop­u­la­tion in relatives of inter­mediate- and high-risk patients versus 2.3 times higher for relatives of patients with no inter­mediate- or high-risk chromosomal ab­nor­mal­i­ties.)

The researchers did not observe any sig­nif­i­cant difference in over­all survival between multiple myeloma patients with, or without, a first-degree relatives with MGUS.

For more in­­for­ma­tion, please see the study by Clay-Gilmour, A. I, et al., “Risk of MGUS in relatives of multiple myeloma cases by clin­i­cal and tumor char­ac­ter­istics,” in Leukemia, September 10, 2018 (abstract).