MGUS and Thrombotic Events: iStopMM Study Results | Sæmundur Rögnvaldsson, MD, PhD | ASH 2023

Hello, my name is Simon de Rockholzson. I'm a physician and a postdoctoral researcher at Iceland's Green Streets or Prevent Multiple Myeloma Study or ICED.MMM study, which is ongoing at the University of Iceland in Iceland. So I'm presenting some of the findings of the ICED.MMM study here at ASH this year, both some headline results of the study, but also some of the more derived studies and some of the work that we're doing in monoclonal gemopathy in general. So the main objective of the ICED.MMM study is to look at screening, its benefits and potential harms. But in the meantime, we're also sort of collecting or creating a unique cohort of individuals with monoclonal gemopathy of undetermined significance. Or MGUS. So MGUS is an asymptomatic precursor condition, which precedes all cases of myeloma and related diseases. It's asymptomatic, but we know that in some cases, MGUS actually leads to disease. This is what we call monoclonal gemopathy of clinical significance. It's quite a sort of a wide area, wide field. And there is some confusion and there isn't a lot of clarity on precisely what disorders MGUS is actually associated with and what the clinical significance of these associations are. And that's due to some issues that come up when we're studying MGUS and its association with disease. Most importantly, usually when we diagnose MGUS, we diagnose it when someone goes to the doctor for something else, for example, heart disease or rheumatological disease. And when we compare these individuals who are showing up to the doctor to a control population, of course, we will find disease associations. But are they actually caused by MGUS? And that's something that we're trying to answer in the ICEDOT MEMS study, which is a screening study where we have now screened more than half of the population of Iceland over 40, 75,422 people. And using this data, we link it to high quality registries that we have in Iceland that include all clinical care that goes on in the universal Icelandic healthcare system. And using this data, we are now looking at disease associations of MGUS. And at this year's ASH, I'm presenting some data on the relationship of MGUS and thrombosis. So we thought for a while that MGUS leads to thrombosis. And there are cases where the monoclonal protein that individuals with MGUS have actually leads to thrombotic event. These are blood clots that go to the lungs, for example, or heart attacks and so on, or strokes. So these are very important health events, obviously. So we wanted to look at this in a screened population and whether this association was actually true and whether we could see an association with the concentration, with the amount of the monoclonal protein and a risk of thrombotic events. And what we see is that this effect is actually real. We see that individuals with MGUS have about a 30% increased risk or 1.3 fold risk of having venous thrombotic events. This is blood clots, for example, in the legs and blood clots that go to the lungs. But we don't see what we call arterial thrombotic events, thrombosis in the arteries, that's heart attacks, strokes and so on. So this association appears to be actually true. A second finding, which is very interesting, is that we find that the amount of the M protein is not correlated with the risk of thrombosis. And that sort of implies that it's not the M protein bulk or the disease activity of which the M protein is a marker, which leads to the thrombosis, but probably something else. And the current hypothesis is that this is due to these M proteins binding to some prothrombotic elements in the circulation leading to thrombosis. So the next step here is to find how to define some sort of subpopulation of individuals with MGUS who actually are probably driving this increased risk of thrombosis and seeing whether there may be something actionable there, maybe some way to prevent thrombosis in these individuals. Of course, thrombosis are extremely important health events, and if you can prevent some of them, that's something that we're doing really good and that's what we're trying to do.