MGUS Progression Risk: Immune Marker Alterations & FLC

Transcript: Simon Murray, MD: I know you wrote a recent article in JAMA about markers for myeloma, and it was a very provocative article. Could you just summarize that article for me?

Ola Landgren, MD, PhD: We did a large study based on the NCI [National Cancer Institute] prospective counsels screening to our published JAMA research in 2019. We had access to almost 100,000 individuals. This is a follow-up study from the one we did in 2009 with Dr Robert Kyle and his group at the Mayo Clinic. In this 2019 version, we tracked changes of serum immune markers, year by year, in more than 200 individuals who develop myeloma, and in more than 400 individuals who stayed stable with monoclonal gammopathy, or MGUS [monoclonal gammopathy of undetermined significance], for 10 or so years, to see if you could actually identify changes in the blood before myeloma happens. And the key findings are that in the patients who have myeloma, they previously had the monoclonal gammopathy; obviously we have shown that before. We also show that if you have high-risk signatures, as stipulated in this paper—there is a lot of detail I won’t go through now—if you have certain features, that’s when you are likely to progress. But if you look a year or 2 before you were high risk, you were low risk. So high risk is always preceded by low risk. But if you stay low risk the whole time, that is when you don’t progress. I think a key message really is the dynamics of the markers. We used to say this patient is high risk or this patient is low risk, but that is wrong.

The risk can unfortunately change. It can change only in 1 direction. It can go only from low risk to high risk. Clinically it’s important for you check these markers—the protein electrophoresis, the immunofixation, the serum free light chains, and the quantitative immunoglobulins. If you see that the markers are stable over time, that is the strongest clinically known predictor of non-progression. While you see the changes occurring, they can actually go on, we show in this study, up to 5 years before myeloma happens. There is a group of patients, 5% to 10%, where the changes were around a year or so. Most patients take a long time, but some patients have shorter responses. The last very important clinical message from this study is that, in the past, we didn’t really know if this so-called smoldering myeloma was an intermediate step between monoclonal gammopathy and multiple myeloma.

We always felt that this is probably not true because this definition for the so-called smoldering myeloma is quite artificial. What this study shows is if you have people with monoclonal gammopathy and you follow them year by year in the blood, only 20% of patients will have an M-spike [monoclonal protein]. That’s 3 g/dL or more. That means that only 20% of patients, based on your blood work, would fall into a smoldering myeloma before they develop multiple myeloma. The other 80% of the patients who go from monoclonal gammopathy to multiple myeloma, go from monoclonal gammopathy right into myeloma based on blood work. If you’re sitting waiting for smoldering myeloma, there is an 80% probability that it will not happen and that those patients will develop myeloma anyway. So don’t believe in this threshold for the monitoring. You have to look at all the other markers and stay on top of the game and probably do new bone marrow biopsy if there are changes.

Simon Murray, MD: Yeah, if I was told I had smoldering myeloma, I would think that would be worse than MGUS.

Ola Landgren, MD, PhD: Well, there could be patients with smoldering myeloma who are stable. The risk could probably be the same as the monoclonal gammopathy. But the changing pattern—that’s an indicator of progression. If you have change in the markers, you have to reassess. You could say these patients used to be low risk but now are high risk. If that continues to happen, that’s indicative that myeloma is about to happen.

Transcript Edited for Clarity