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Joseph Mikhael, MD, MEd: Hello. I’m Dr Joseph Mikhael and this is season 2 of the Medscape InDiscussion Multiple Myeloma podcast series. Today, we are going to discuss one of my favorite topics: screening for multiple myeloma. We’ve specifically titled the topic, “Is It Time to Screen for Multiple Myeloma?” The answer is no, but why?
I honestly cannot think of anyone on the planet who has a better understanding and appreciation of screening, who has led the largest study ever in screening for multiple myeloma. That, of course, is Dr Sigurður Kristinsson, a very good friend of mine. Don’t hold that against him, but he is a wonderful individual.
He comes to us as a professor at the University of Iceland. He has led the largest myeloma screening study in the world — the iStopMM: Iceland Screens, Treats, or Prevents Multiple Myeloma project, where nearly 100,000 people are involved in this study. And he’ll explain to us what that means. He has really been leading the whole world effort in myeloma of understanding the principles of screening, and how ultimately we may or may not be screening for multiple myeloma. Welcome to the Medscape InDiscussion multiple myeloma podcast.
Sigurður Kristinsson, MD, PhD: Thank you so much, and thank you for this kind introduction, and of course, to Medscape for having me. I’m really looking forward to our discussions today.
Mikhael: It’s a really fun environment to be able to have this sort of free-flowing discussion, and I’m looking forward to listening to you. I’m not saying it to butter you up, but honestly, I learn so much from you every time we have these kinds of discussions because you have spent so much of your career and time and thinking through this topic. I am very thankful that you have the ability and time to spend with us today.
So let me just tee it up a little bit because I think what happens is sometimes we just assume that myeloma is a disease where the average patient sees their primary care provider three times with signs and symptoms consistent with myeloma before the diagnosis is made. Yes, there are those incidentalomas where people may get diagnosed because they had a blood test for another reason, or insurance reasons, or whatever, but the vast majority of our patients get diagnosed after having symptoms over a long period of time.
And it’s even longer, especially here in the US, in certain populations like African Americans and Latino Americans. So, some of us would naturally think, “Oh, well, then we should be screening for myeloma.” Why don’t we just catch it early? Isn’t that what we’re doing in cancer in general? But of course, we’ve come to realize that you can’t just willy-nilly screen. It has to be done in a very systematic way. I wonder if you can share with us a little bit about the principles and the concept of screening, even before we get into myeloma.
Next week I’m going to have a colonoscopy. Sadly, my father died of colon cancer, and so I have colonoscopies more regularly, but long before we knew the best way to do colonoscopies or to screen for colon cancer, we had to have the data to prove it — same thing with breast cancer and mammography. Maybe you can tell us about what some of those principles are that guide us as we think about screening for any disease, let alone myeloma.
Kristinsson: Sure. You bring up a very important topic. One thing is to identify a disease when it’s already symptomatic. Like in myeloma, people have symptoms on average 6 months before they’re diagnosed. What we are really talking about here is screening asymptomatic individuals. We know from the literature and other cancers that there is a benefit of screening for breast cancer, cervical cancer, and some say for colon cancer as well. So there’s evidence for that. But there are criteria that you should use. These are called the Wilson-Jungner criteria, which were established in the 1960s and have been updated once or twice since.
They pinpoint 10 important points or criteria that a disease, a test, and the population should fulfill before you even consider screening for them. Sure, it makes sense. It’s probably true for all diseases. It’s better to diagnose them early, rather than late. It makes sense. But we cannot screen for all diseases all the time. It’s ineffective. It costs a lot and it can cause side effects. There can be invasive procedures, there can be mental health impacts, and so on. So the literature is pretty firm on breast cancer and these other cancers.
What they have essentially done is randomized clinical trials. So you randomized from screening to nonscreening, and then you see if this leads to an improvement in outcome. Then the key is, what is the outcome? Usually, the outcome is overall survival. So if you screen, it should lead to an improvement in overall survival. Not just that you find more cases, and the few that are diagnosed with a disease sort of get a little bit better prognosis.
The other thing is that in order to raise awareness for a rare disease like myeloma, you should know the symptoms. If you have an individual with anemia, renal failure, or back pain, think about myeloma and do the testing. But that’s not really screening. That’s not what we’re talking about today. And so, the Wilson-Jungner criteria, this is what some people are discussing at the moment in myeloma — that we should just go ahead and screen. We’ll have a little discussion about that today. I have my opinion about that and the literature is something that you really cannot debate or even have an opinion on there. It’s pretty straightforward. But, in general, you should do the studies around much clinical trial. Check the Wilson-Jungner criteria. It will show that it’s superior to not screen in terms of overall arrival. Yes, let’s screen, but then we have to implement that. But if not, we should definitely not do it.
Mikhael: This is extremely helpful. You brought up so many outstanding points and I think it’s really important for our audience to grasp this because I know many of us can sometimes almost exchange the words screening and testing. For example, a lot of the work that I do in health disparities, and even through the International Myeloma Foundation, we’re raising awareness, as you said, of myeloma. We’re teaching primary care doctors. If someone has anemia, renal insufficiency, and pain that doesn’t make sense, then you test for myeloma. That’s not truly screening in the big picture that we’re looking at, because then you are focused on a sign or a symptom.
Secondly, I really like how you brought out a very important point that we need to do this systematically to see an improvement in survival. It’s not just catching more cases. Dr Robert Kyle showed this to us almost 50 years ago now by screening a population near Mayo Clinic in Minnesota that the precursor to myeloma is inordinately common. And so we have to be particularly careful. Maybe I’m biased here a little bit from my Canadian training, where we’re always trained that testing actually can hurt somebody. Here in the US, we just love to order tests, but there are implications, as you said, psychological implications, cost implications. And typically, if a test is either equivocal or positive, it might lead to more testing, and there can be other issues with it. So, putting in summary what you’ve said is we do have principles of screening, and really, if we’re going to embark on screening, we have to look at overall survival as being the endpoint if we’re going to be able to do this en masse.
Now, if only we had a large, national screening study of tens of thousands of patients to guide us. So tell us about iStopMM. I can remember being with you in Scotland at an evening event, and you and I, Dr Carl Ola Landgren, and a few other people were writing on the back of napkins, coming up with this sort of basic concept. But you’ve taken it to a level that is almost indescribable. Please describe it for us.
Kristinsson: Stephen Harding was a key member there as well. The idea actually came across in Edinburgh in 2015. We started the whole concept of screening Icelanders in October 2016. Basically, we invited all Icelanders, 40 years and older at the time, to participate in this iStopMM study, which, as you said, stands for Iceland Screens, Treats, or Prevents Multiple Myeloma.
We really wanted to screen Icelanders for the precursor and see if we could evaluate the effect of screening. There are 146,000 Icelanders that are more than 40 years or older, and 80,742 individuals gave informed consent for screening. During the next 3 years, we managed to screen 75,422 individuals. The Binding Site in Birmingham performed the assay. So they did protein electrophoresis and free light chain analysis. Those who would be diagnosed with MGUS (monoclonal gammopathy of undetermined significance), either light chain MGUS or classic MGUS — IgG, IgA, or IgM — were then entered in a randomized clinical trial with three arms.
Arm 1 is basically the placebo arm, if you will, or the standard of care, which is not screening. They had MGUS but were not notified. Arms 2 and 3 had MGUS, and we met them in our clinic. We informed them, we tested them, and we did bone marrow in some and not others, according to the protocol. The whole concept is comparing arms 2 and 3 (those people have MGUS, and they’re worked-up and followed) compared to arm 1, which does have MGUS but they’re not being actively followed.
So if MGUS screening makes sense and improves survival, arms 2 and 3 together should have an improved overall survival compared to arm 1. This is the primary outcome. We also have secondary outcomes, which compared the number of cases, and we are looking at the mental health impact; we take that super seriously. So we do a lot of questionnaires, and we do biobanking and all kinds of questionnaires and testing.
So that’s the whole concept. We are currently around 5 years down on the average or a median follow-up time. It’s still too early to say if the overall survival is different, but we have some very interesting findings that sort of indicate that it is beneficial. But we haven’t reached the primary endpoint yet.
Mikhael: Just the sheer numbers of it become a little bit overwhelming. I’m helping with coordinating a study here in the US in the Charlotte, North Carolina, region. Our chief objective this year is to screen 1000, let alone 80,000. It’s just amazing what you’ve done. Maybe you can also tell us what is sort of unique about Iceland that allows this to happen the way it does? I know you have an incredible deCODE Genetics lab. There’s sort of a philosophy among the individuals of Iceland that they would be more willing to participate. This is a tremendously positive thing, because I assume that you’re going to be able to gain a lot of other genetic information through this — is there something that predisposes and the like. But by contrast, I’ll also ask you, does that mean that we can’t apply this to other nations or other countries that don’t have the same, similar background to the Icelanders? But let’s start with what makes Iceland so unique and why this study can therefore be even more powerful.
Kristinsson: Iceland is a beautiful country with a fantastic landscape and fantastic people. Secondly, there is a tradition here and sort of the philosophy, if you will, that Icelanders really like to participate in science and if they can sort of contribute to new knowledge. That’s very important. This is not only true for the iStopMM study, this is true for the genetic studies and there are many large epidemiological studies with high participation rate. Maybe not quite as high as this one, but still, when we reached out, we didn’t really know — would we have 30,000, 50,000 or 80,000, but it just really exploded. I met every single one with MGUS or smoldering myeloma. They have been donating blood, they are participating in all these, they have a t-shirt with a sign of different scientific projects, and so on. So, I think that’s a very important thing here in Iceland that they want to participate. Also, when we tell them that we need another test, or we want to do a bone marrow to evaluate this and that, they don’t ask first if it’s beneficial to themselves. They really say, “If it’s important for you and my future kids and grandchildren, then I want do it.” Most people are like that, so I think that’s very important.
Mikhael: It would be quite different here in the United States, so that is really remarkable.
Kristinsson: The other thing is that since we are collaborating with other health authorities here, and deCODE as you mentioned, we already have a lot of information, clinical information — like every disease that all the 80,000 people have been diagnosed with since the beginning of digitalized era.
So we have now every pneumonia, every hyperthyroidism, every colonoscopy, every blood test, every thyroid and cholesterol level. We know all this for all 80,000 individuals since the year 2010. We update this twice a year, every cancer and so on. We also have collaboration with the genetic information. I think that’s very important that we do not have to collect all these samples and clinical information ourselves. This is already in the system.
The most important thing is, what’s the external validity of what we see? What’s the generalizability? I think then it’s important to think that the prevalence of MGUS and myeloma in Iceland is similar to other Western or predominantly White populations. Survival is similar in myeloma compared to other populations. Both the germline genetics, which we have looked at, and also the somatic-like changes that happen in myeloma over time — they’re exactly the same here as everyone else. So even if Icelanders themselves, their personalities are different to the rest of the world, I think that’s a positive thing.
But I have to admit that, when it comes to MGUS, we are basically the same. Having said that, all the findings that we have that can be validated in other populations should be validated. Not everyone can do the randomized clinical trial and do lots of bone marrow, but what can be done (eg, changing criteria, prevalence of smoldering), all this needs to be validated. This is what we are doing. We have also seen in the literature that there’s a lot of interest in different cohorts to validate. Everything that we have published that can be validated has been validated. So no one is finding strange, different things than what we are. I think in the end, when we have the final verdict — it’s only one verdict of them all — it should be screened for MGUS or not. I think people just have to rely on that.
Mikhael: You’ve raised so many points, and I love the fact that it’s sort of the nirvana of the medical record that you could have it all integrated into one. That’s one of the greatest challenges we face here often in the United States — “bits and pieces” of health information. You have it all integrated, which is wonderful. But I really appreciate your comments about the generalizability because I have very often heard people say, “Iceland is a very unique country. Genetically speaking, it reflects a small group of White individuals. Can this really be applied?” So I think your comments about generalizability is really important. I think of one of the individuals who helped you, especially in the early days, my former boss, Dr Brian Durie, would say, “It sounds very simple, but myeloma is myeloma.”
Kristinsson: That’s what he loves to say. Myeloma is myeloma. I love that. It’s true. What we have done has been validated in African American populations in the US, in the Bronx, in Israel, in China, and in Sweden. Wherever you look, this can be validated and ensued.
Mikhael: I think the point you make is so important to distinguish between a greater incidence of something doesn’t necessarily make the disease different per se in that individual. As an African American man, I know I’m at twice the risk of getting myeloma, but it doesn’t mean that we can’t learn from that.
Well, as we come into our last 5 minutes or so here, I would love for you to share with us. I know that you said obviously the final verdict, should we be screening? Does it save lives? Right. Does it improve overall survival? That verdict is not out yet. The jury is still meeting behind closed doors. We need more time for that. But, in the interim, we’ve learned a lot of things from your study, and I know it’s impossible for you to summarize them in a couple of minutes. But can you give us a couple of highlights of things that we’ve already learned through iStopMM?
Kristinsson: One of the most important findings we had was that since we did bone marrow in every single person in arm 3 of the study, which is about 1100 individuals. We found that we could evaluate the prevalence of smoldering myeloma, which no one had done before. So we could see that 0.5% of Icelanders 40 years and older have smoldering myeloma. That was a surprise that smoldering myeloma is so common. I know you have an episode on smoldering myeloma, so I think that’s a key thing. Only 8% of them had high-risk smoldering myeloma, which some people claim should be treated. This indirectly proves that you shouldn’t treat everyone with smoldering myeloma. You can’t treat 0.5% of the population with chemotherapy.
We have also changed the definition of light-chain MGUS, which was a bit off. No one has been publishing anything about light-chain MGUS since the definition paper in The Lancet more than 10 years ago. Hopefully, we can start to understand more about that.
Also we found — a little bit surprisingly — that autoimmune disease is not a risk factor for MGUS and myeloma. I know that a lot of rheumatologists and internal medicine specialists are screening all their cases of autoimmune disease for MGUS and myeloma. But the hazard ratio was actually 1.0. So I think that proves that you shouldn’t look actively for myeloma in everyone with rheumatoid arthritis or SLE (systemic lupus erythematosus) and so on.
One of the unpublished findings is the mental health impact. When people gave informed consent, 70,000 of the participants gave us their email address. We have been sending at least once a year, usually twice a year, questionnaires about anxiety, depression, satisfaction with life, and worries. So just after they gave informed consent, like 5 minutes later, they told us if they were worried and anxious and so on, using these validated questionnaires.
Immediately after we told part of the people they had MGUS, they told us again. And then also the people that do not have MGUS. Everyone is answering these questions all the time. My mother and all her friends are doing this, and they send me a text when they have. So we can see that using these validated questionnaires, now 5 years later, that we are not causing a mental health crisis in Iceland. People, on average, are not more worried, depressed, or anxious, and so on. So I think that’s a huge secondary outcome of the study: If you give them the diagnosis, you tell them the plan, it’s not a death sentence. Most people with MGUS will never develop myeloma and will never need any treatment. So when you deliver the diagnosis in that fashion and you follow them for years, people are okay.
Mikhael: That’s amazing. I mean, so many huge lessons there. I’m particularly interested in the autoimmune disease, by the way. Back in the day, when I was in Canada, I had an MGUS clinic, and it happened to be right next to the rheumatology clinic. And so we would always have these discussions, whether or not it was “incidental-oma” — incidentally found because these are sort of sicker patients that are getting more tests.
I think that really sheds a lot of light, and I think the psychological impact aspect of your study is going to be extremely important going forward. When we think of the implications of potentially screening millions of people here in the US and across the world, I think it’s going to be important to have that.
Granted, as you said already, the philosophy of thinking is a little bit different in Iceland than it would be in the US. I love it when you tell me that you send out a survey that takes almost an hour to fill out, and they do it. Here, we’d be lucky to get surveys done that take 5 minutes. So, I really want to commend you and your leadership and work in not only conceiving this idea but also fulfilling it.
I think it is going to have a massive implication in the myeloma community. Well, it’s hard to believe our time has already gone, but I want to take a moment to thank you again for your incredible insights today.
The major lessons we’ve learned are understanding the principles of screening, that we have to do it in a very calculated and careful manner, with the goal of overall survival. The iStopMM study has consented over 80,000 individuals and in 5 years has learned great lessons, but is still waiting for the final verdict, as it were, as to whether or not screening is truly going to save lives. And we hope to have that answer from you within the next couple of years.
I’d like to thank Dr Kristinsson for joining me today. It’s just a pleasure to have this conversation with you. Thank you all for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on multiple myeloma. This is Dr Joseph Mikhael for the Medscape InDiscussion Multiple Myeloma podcast. Thanks again so much.
Listen to additional seasons of this podcast.
Resources
Screening in Multiple Myeloma and Its Precursors: Are We There Yet?
International Myeloma Foundation
Prevalence of Monoclonal Gammopathy of Undetermined Significance
Monoclonal Gammopathy of Undetermined Significance
Mode of Progression in Smoldering Multiple Myeloma: A Study of 406 Patients
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Cite this: Is It Time to Screen for Multiple Myeloma? - Medscape - Nov 20, 2025.
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