Welcome to The Myeloma Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc)! In this exclusive roundtable session, Irene Ghobrial and Sigurdur Kristinsson discuss screening for myeloma precursors, including updates from the iSTOPmm and PROMISE studies, and the key questions they have raised.
Featuring insights on the ISTOPMM & PROMISE screening studies, the clinical significance of precursor conditions, and the psychological impact of screening, this exclusive ASH 2021 discussion is not one to miss!
“Now we have screened more than 75,000 samples for MGUS and preliminary data show that 5% of our population have MGUS or light-chain MGUS. So we are following these individuals and trying to understand the impact of screening on overall survival.”
– Sigurdur Kristinsson
The clinical significance of precursor conditions
“The people who had MGUS, as well as the people who had a high level of MGIP, this new entity monoclonal gammopathy of indeterinant potential, which is similar to CHIP in a way we found that they actually have a worse overall survival. And they were associated with worse comorbidities, myocardial infarction, cardiovascular disease, autoimmune diseases. So it may not lead to myeloma unless we live for a thousand years, but it may also still lead to other things that we need to understand better in the future.”
– Irene Ghobrial
The psychological impact of screening
“You cannot just screen a population and dump a diagnosis on them without taking into consideration the potential harms of screening. And that really hasn’t been studied enough in general, in cancer screening. We screen for breast cancer, cervical cancer, and other cancers. And we really don’t know the negative effect of screening. So I think we are both taking that very, very seriously to monitor mental health over time because we don’t want to get people worried because they have a very, very low risk of a disease that they never knew even existed.”
– Sigurdur Kristinsson
My name is Irene Ghobrial. I’m from the Dana-Farber Cancer Institute in Boston, Massachusetts.
My name is Sigurdur Kristinsson. I’m from the University of Iceland. So the iStopMM study is called Iceland screens and treats and prevents myeloma. So basically we wanted to ask, “Should we screen for MGUS? Does that lead to an improvement in overall survival? So that’s basically what we’re doing. So we invited 148,000 centers back in 2017 to participate. And amazingly we got more than 80,000 patients that gave informed consent. And now we have screened more than 75,000 samples for MGUS and preliminary data show that 5% of our population have MGUS or light-chain MGUS. So we are following these individual and try to understand the impact of screening on overall survival, basically.
Absolutely. And I think it’s so complimentary to what Sigurdur has just shown us. What we’ve said is let’s try to look at people who are at risk of developing myeloma in the United States and ask the question, “If we screen people at risk or at high risk, will we find it much higher prevalence? And can we then say these are the people that potentially we can change the standard of care in the future for them?” Because we don’t want to keep screening the whole population. We want to ask questions specifically for certain people. So our Inclusion criteria for the promise study was people of African descent or Bback Americans or people who have a first degree family member with blood cancer. And by that we asked the question of people who can just donate their blood wherever they are. And then we went back to the mass general Brigham cohort, which is 125,000 people who gave their blood samples and their clinical data, all of their epic data over the last 10 years.
And we’re lucky because that’s a New England area where everyone basically goes to get their blood drawn. So many of us walk around and just give their blood either for voluntary reason for research or because we’re going to see our primary care physician. And from that, we got a collection of people who are also at risk. Black Americans first decree blood cancer. And together we have a cohort of 7,662 people definitely much less than the Iceland study but the diversity is important to ask that question. Now we were lucky enough to work with Binding Site and we use their new artificial intelligence algorithm to quantify the mass spectrometry at all different levels. So if we just put the data in perspective to what has been done by serum protein electrophoresis before Bob Kyle has shown us for many years, that it’s 3% in the general population over the age of 50 if you use serum protein electrophoresis.
If we look at this high risk population they’re much higher. We found that they are 6% also by serum protein electrophoresis. So that’s your standard showing that it is double. If we look by mass spectrometry and keeping it at that same level that you could potentially detect by SPEP, it was 13%. And that just tells you mass spectrometry is much more sensitive in detecting proteins, even if they are supposed to be detected by SPEP but it’s not just that sensitive. More interestingly, we found a large number of monoclonal gammopathies that were below that level of detection by immuno -ixation, but they were still quantifiable and they were all confirmed by LCMS. So it’s sort of the standard that this is truly a monoclonal protein. And we found that another 23%. So that age over 50, if you are black American, if you are a first degree family member, we have about a 40% of monoclonal gammopathies.
And that surprised us. That was like the first time I looked at it saying, “We’re all walking around with this.” But it was just an indication that just like many things that we’re seeing now with precursors and a normal phenotype with mutagenesis, we’re all walking around with cells that have p53 mutations that have mutations but that doesn’t mean that it’s cancer. That doesn’t mean that it has changed to a malignant phenotype. It’s still a normal phenotype.
And we still have so many questions to ask, what is this monoclonal gammopathy? We know that in those patients, because we have overall survival data on them because we followed many of those MGB cohort. The people who had MGUS, as well as the people who had a high level of MGIP this new entity monoclonal gammopathy of indeterinant potential, which is similar to CHIP in a way we found that they actually have a worse overall survival. And they were associated with worse comorbidities, myocardial infarction, cardiovascular disease, autoimmune diseases. So it may not lead to myeloma unless we live for a thousand years, but it may also still lead to other things that we need to understand better in the future.
Yeah. So I think that the Binding Site method of mass spec is very, very interesting and will come become more and more important. Because in the end we say that a lot of people have MGUS we have like 3% or 5%, and you might have seven or 8% in at risk persons. And then you add these 5% to the at risk persons. And I think it’s our responsibility and the responsibility of the myeloma community to try to understand what this means, because the more you look for things, the more things you find. And this is also our experience. Now we have done over 2000 bone marrow biopsies in aspirates. What we see is we have much more smoldering myeloma that anyone has even thought of. So 0.5% of individuals, 40 years and older actually have smoldering myeloma and talking about treating smoldering myeloma at this point.
So we really have to understand and use these two screening studies to understand what is really the impact of the MGUS or the Pre-MGUS or smoldering myeloma, per se. We cannot go and give guidelines on clinical cohorts of these individuals where the real truth lies in the screening course. I think that’s very important. That’s something that we need to discuss. And obviously the mass spec, I mean, you are way ahead of us there. But I think that’s a fantastic tool to be used in the future.
Yeah. And I totally agree. There is a difference between saying clinically what it means and what we should do. And I think both of us have that responsibility to say, “We should clinically follow up those patients and ask the questions. What is the significance? What’s the true significance clinically, and how do we manage those patients?” And I have to say, it’s impressive how the study has managed in the iStop study to say, “Let’s either screen them more carefully. Let’s identify who has higher risk MGUS or smoldering myeloma so that we can understand what to do with all of our patients.” But we’re starting to open up so many questions by screening people early and cancer screening does save lives. And the question is, who should be screened? Should we really screen the whole population or people at risk? Why are they at risk?
What makes them go at risk? And what is that significance? What is the clinical significance of having monoclonal gammopathies? And it may be that we just follow you very carefully or look for other comorbidities to make sure your bone health is good, your cardiovascular risk is good, but we’re not saying that you will develop multiple myeloma. And I think that whole area of understanding precursor conditions and what it means for us is so important because the population is getting older. All of us are going to be walking around with mutations. We know that from the CHIP mutations. It doesn’t mean that they’re always clinically significant but biologically we’re asking questions of “Does this regulate our immune system? Are we responding to infection is the same way or not.
So lots of questions to be asked for both of us. But the important question to our patients is don’t start asking, can I be screened because we’re not there yet to recommend a standard of care. We’re trying to carefully look at all our data and potentially come up with that answer in the future. Standard of care of screening in the future we need to identify exactly what it means.
I think that’s a very important point and I was very happy to see your oral presentation where you discuss a little bit about the mental impact of screening, because I think that’s another huge thing about screening. You cannot just screen a population and dump a diagnosis on them without taking into consideration the potential harms of screening. And that really hasn’t been studied enough in general, in cancer screening. We screen for breast cancer, cervical cancer, and other cancers. And we really don’t know the negative effect of screening. So I think we are both taking that very, very seriously to monitor mental health over time because we don’t want to get people worried because they have a very, very low risk of a disease that never knew even existed.
Correct. And people will see, oh, I have a precursor condition and will start asking so many questions and you don’t want to make them anxious for no reason. I think the most important the thing is we had an anxiety questionnaire built in into the promise study. And we also said, “We will never leave you alone.” If we diagnose you with MGUS, even if it’s a tiny MGUS or MGIP by mass spectrometry, we are here to take care of you throughout the journey.
So every patient is followed up by our team and we make sure they see a Hematologist/Oncologist. We make sure they get the routine testing every six months, every year, depending on your risk. We try to see if they can get a bone marrow biopsy, if they’re eligible and want to do it. And I’ve seen many of those patients personally, to make sure that we have that connection. We were lucky last year when we were able to see virtually many people that we were able to expand that. So I totally agree. You don’t just dump that diagnosis and leave it. And we need to educate physicians of what does it mean to have an early MGUS or MGIP, we don’t just let them get that diagnosis and leave them alone.
Yeah, I totally agree.
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