Early Diagnosis of Myeloma: Guideline Compliant Testing - Episode 3

The Clinical Significance of MGUS

April 9, 2020

Simon Murray, MD: Could you tell me how you define MGUS [monoclonal gammopathy of unknown significance]? And what is the significance of MGUS?

Ola Landgren, MD, PhD: In a nutshell, there was discussion back in the 1960s whether these proteins that we have been talking about, the abnormal monoclonal proteins, were related to multiple myeloma or were benign? And there were 2 schools of thought. One school of thought said that these are benign proteins. It was actually John Waldenström, who discovered Waldenström macroglobulinemia. He said this was a benign monoclonal protein. There was another school of thought that said this was premyeloma. In the late 1970s, Bob Kyle from the Mayo Clinic said, “Let’s say it’s unknown.” He declared monoclonal gammopathy of undetermined significance, so the 2 schools of thought could agree to that.

But over time it has been found that about 1% of patients progress into myeloma per year. These are the statistics, so that’s where the acronym comes from. But we know much more today. There have been a lot of recent genomic discoveries. There are ongoing studies as we speak, indicating that there probably are some people who are quite unfortunately predisposed for progression, while others probably have an extremely low likelihood. My thinking is that it is maybe monoclonal gammopathy or it is a high predisposition for myeloma. These are not yet agreed-upon conventions, but I think that’s where the field is going.

Simon Murray, MD: There is a rare form of genetic multiple myeloma I believe too. I don’t understand the genetics of it, but I think there is a genetic form that is known to exist, familial form at least.

Ola Landgren, MD, PhD: We did studies years ago. I used to work in Washington, DC, at the NCI [National Cancer Institute] for 10 years before I came to New York. And we did familial aggregation studies where we looked in large data sets. We actually looked in Scandinavia and places like that. And taking advantage of huge population-based multigenerational dialysis. We were able to show that the familial increase could be as high as 2-fold. That sounds quite high if you just hear the number 2 there. But you have to be very careful when you think about these things because the actual risk for myeloma in the population is maybe 6 per 100,000. If you double down if you’re talking 10 to 12 cases per 100,000. So the absolute risk in the family is still very low. There is also an increased risk for monoclonal gammopathy in family members with myeloma. But it’s clinically very important that there is no increased risk for transformation from the monoclonal gammopathy to myeloma, if you have a family member, for example with myeloma or with monoclonal gammopathy. So that’s important.

Simon Murray, MD: If 1% of people with MGUS progress per year to myeloma, that’s 1 thing, but is it not true that 100% of myeloma patients had MGUS at 1 time.

Ola Landgren, MD, PhD: That is true. We actually did that study together with Bob Kyle. In 2009, we published in Blood a large study based on something called NCI PLCO [Prostate, Lung, Colorectal, and Ovarian] Cancer Screening Trial. Almost 100,000 people participated in this trial. They were cancer-free and they had to be 55 to 74 years of age, men and women, followed over time. And they gave blood once a year for many years. In that study we identified any individual who had been diagnosed with myeloma to 10 years from study start. Then we got permission to go back and take all the blood samples. And we looked to see if there were abnormal proteins, and we showed up every person had these monoclonal gammopathy.

Simon Murray, MD: That’s great. You found 71 cases, I believe?

Ola Landgren, MD, PhD: That was the original study.

Transcript edited for clarity.