ASH 2021: Multiple Myeloma Screening

A Conversation With Joseph Mikhael, MD

A Conversation Rafael Fonseca, MD

The interview has been edited only for clarity.

---

iStopMM Study

The Patient Story: Is it true that iSTOP is the largest screening of any cancer project in the world so far?

We learned that it is feasible to do a huge screening study.

Dr. Joseph Mikhael

As far as I know. The numbers are jaw dropping when we think about it. There were over eighty thousand people in Iceland who consented to participate in the study. That in and of itself actually is one of the most important things. We learned that it is feasible to do a huge screening study. They’ve already collected over seventy-five thousand samples trying to detect myeloma at its earliest stages.

As we know, myeloma has a precondition called MGUS (Monoclonal Gammopathy of Undetermined Significance), and there’s a lot still to learn about it.

• What is the true incidence of it?
• How should we follow it?
• Is there a way to detect it earlier?
• Is there something that puts certain people at risk?
• Does it mean something even if someone doesn’t ultimately develop myeloma?
• Only a very small subset of people will develop myeloma. So these are some of the questions that only a screening study of that magnitude could answer.

I think we had four different oral presentations from the iSTOP study -from the Iceland screening study- to be able to start to answer some of these questions. We still don’t have anything definitive. We’re not suggesting that we now go and screen everyone, but we’re starting to learn who is at higher risk, what MGUS really means. Ultimately, we hope to be able to detect it not only sooner, but maybe even know who’s really at risk and possibly even prevent it.

Takeaways from iSTOP

The Patient Story: What are some of the biggest takeaways from iSTOP?

Well, I think some of the biggest takeaways are that, as I mentioned, it’s feasible to do a big screening study, and that when we use our most sophisticated techniques, which includes mass spectrometry, we really do find that this is a common condition. And we know that with the Caucasian background of patients in Iceland, their risk tends not to be as high. And that’s why we’ll come to the PROMISE study in a minute.

And you know, although we have screening programs, for example, trying to detect things early in breast cancer and in colon cancer and many other areas, we really haven’t been doing that much in the hematology world. And so I think I stop is really starting to open the door towards that. We want to do it intelligently and appropriately. But it’s definitely taking us down that path.

Mass spectrometry

The Patient Story: Can you explain mass spectrometry?

Think of a mass spectrometer as just a really careful machine that can look at every tiny little protein in your blood and be able to quantify it very accurately.

Dr. Joseph Mikhael

So let me demystify it, because ultimately, I don’t think it’s going to be that expensive. I think it’s going to be cheaper in the long run. So when we look at a disease like myeloma, it’s a disease of proteins in the blood. And think of a mass spectrometer as just a really careful machine that can look at every tiny little protein in your blood and be able to quantify it very accurately.

If most myeloma patients or their caregivers saw how we measure some of the proteins in their blood or the M-spike, that monoclonal protein, we typically do it on what’s called a serum protein electrophoresis, which is just one way.

We put the blood on a plate and it runs over a period of time, and based on the weight of those different proteins, they kind of separate themselves out. And sometimes it’s like the hills here in Scottsdale, you know, they run into each other, and it’s hard to know how big one protein is versus the other.

Mass spectrometry is very precise, so it can detect low level proteins, which is really benefit number one– that it has that earlier detection. It measures them very accurately. It can also discriminate between different proteins sometimes.

Now, we use drugs in patients that themselves have a protein component, things like monoclonal antibodies, and they show up on a certain protein electrophoresis, and it can kind of confuse us. Like how much is the drug causing that, and how much is it actually the disease? The mass spectrometer is able to distinguish that difference.

Sometimes, unfortunately, in myeloma, proteins can change over time. And so mass spectrometry can know exactly which was the one that they had before and which is the one that they have now. So it’s really a fancy way of looking very carefully at these proteins.

With a mass spectrometer, we might be able to get people’s results literally within minutes. Right now, a lot of myeloma patients end up coming in a week before their visit or several days before their visit to get tested so that we can wait for all these results to cook in the lab. Here, we can do a much quicker turnaround.

Adoption of mass spectrometry vs. SPEP (serum protein electrophoresis)

It’s not been adopted universally yet. In fact, it’s not formally gone through the full FDA approval to be used yet.  We anticipate, though, that it may be available as early as the first quarter of 2023, so in a little over a year from now.

There are some centers that are using it as we’re validating the tool more and more at Mayo Clinic and other places. So it’s not yet ready for prime-time. It’s being used in some of these clinical trials, like in iSTOP. It’s being used in the PROMISE study, but it really is, I think, going to be mainline and a little over a year from now.

iSTOP and measuring kidney function

The Patient Story: I read something about a special tracking system with the light chain levels, and that iSTOP was able to provide information on people with reduced kidney function. Can you expand on that?

So again, going back to how the mass spectrometer works. It can be much more precise, and we do have sometimes a little difficulty following patients who have light chain myeloma. The protein that’s made in myeloma is this big immunoglobulin, or an antibody, that’s composed of a heavy chain and a light chain. Sometimes the whole thing remains intact. Sometimes there’s the heavy chains, plus the light chains. And sometimes, there’s just the light chains.

We have a light chain measurement that we do in the blood, but that’s sometimes skewed a bit by kidney function because typically our kidneys clear those light chains out of our system. So if the kidneys are not working as well, those light chains hover in the blood for longer. So we’re now just trying to understand the best way to measure them and what the implications are of those measures. And only in big studies like iSTOP can we capture all of that information.

Severity of COVID in MGUS patients

The Patient Story: Is it true that covid outcomes aren’t more severe in people with MGUS than in the general population?

It did not appear that MGUS status by itself heavily influenced someone’s risk of developing or being very sick from COVID.

Dr. Joseph Mikhael

One of the abstracts that was presented was trying to look at this. And they hadn’t had a massive outbreak, so the numbers are relatively small. But there were so many patients that they had diagnosed with MGUS that it did not appear that MGUS status by itself heavily influenced someone’s risk of developing or being very sick from COVID.

Now, obviously, we all know this is a moving target now with different variants and so on, but it is very important for us to evaluate this because it’d been such a source of stress for our patients and their families because we know that myeloma is a cancer of the immune system.

We know that people with myeloma’s immune systems aren’t as robust to fight off infections, or even to fully respond to vaccines. But we have seen when our patients get their vaccines and their boosters, it clearly confers some protection. They may be still at high risk compared to the general population, but I urge anyone who may be reading to ensure that they have gotten their original vaccinations and their booster.

Answers with iSTOP

The Patient Story: What are you hoping iSTOP will answer? And how long will that take?

Well, it is going to take years to get all the answers, but I think we’re going to learn in the shorter term what the true incidence of these conditions are, and if there could be certain populations that we should begin to screen for in an earlier capacity.

Also, part of iSTOP was not just collecting this information. Patients were randomized to different groups with a more intense versus a less intense follow-up. So this may influence the field even in the short term. How frequently should we follow our MGUS patients? And when do we not do bone marrow biopsies, and when do we do x-rays? And what are the psychological impacts of having MGUS?

People are more comfortable understanding [MGUS] than fearing they may have something that hasn’t been diagnosed.

Dr. Joseph Mikhael

One of the things that I think is particularly important to the study is that they do surveys with patients. Would patients rather know that they have MGUS? And does that induce more stress? And initially, it does not appear to induce that. 

People are more comfortable understanding it than fearing they may have something that hasn’t been diagnosed. So there are lots of things in the short term about the psychological impact of MGUS, how we follow MGUS, and whether or not we should be screening earlier in certain populations.

Diversity in Myeloma Care and Research

PROMISE study

The Patient Story: Can you tell us about the PROMISE study?

The PROMISE study is really a fantastic study, and I commend Dr. Ghobrial and her whole team. I happened to be a part of this program in the early days– we were planning it when I was still at Mayo Clinic.

PROMISE study goal of evaluating the impact of myeloma on diverse populations

I just think it’s a wonderful and important approach. In Iceland, obviously the numbers are massive, but we recognize that Iceland does not represent the diversity of what we see here in North America and in particular in people of color.

And so in the PROMISE study, they were looking to screen individuals and also use a large database that they have already existing in Boston to look at Black Americans and their true incidence of MGUS and myeloma, but also those individuals -independent of race and ethnicity- who are first degree relatives of myeloma patients.

This has always been a challenging question for us to know and really understand. ‘Familial myeloma’ is really quite rare, but are there ways to detect it more? And sure enough, we found that if, generally, MGUS is in about five percent of the population in patients over 40 or 50, that it really is double that in the African-American population and in those who are first degree relatives of myeloma patients.

Obviously, they’re not iSTOP numbers, and there’s still so much to learn, but I think it was really critical because in this group of individuals it demonstrates to us the greater incidence, and how these individuals are greater risk. And it speaks to us of the importance of health disparities in multiple myeloma that I know we’ll talk more about because there was great research presented within this field over the course of the meeting.

But I’m very thankful that the country, if not the planet, is starting to put a spotlight on health disparities. And the tragedy within the African-American community is that not only is disease more common, sadly, we do see that outcomes of survival are significantly reduced in this population.

And yet they don’t have to be, because there are studies that show that when African-Americans have the same access to therapies as Caucasians, their outcomes can be as good, if not better. So that tells us that there’s hope here, that there’s opportunity.

I think the PROMISE study is a step in that direction to really assess and understand the disease more fully as doctors.  Diagnosis always comes before therapy, right? So if we can fully understand the issue, then hopefully we’ll be able to do more about it, so that we’re not just talking about these things, we’re doing something.

The Patient Story: This mass spectrometry that’s being used in both of these studies– that plays a big part in getting better, more accurate numbers, right? Being able to detect more minute amounts of the M protein– is that part of this?

That’s absolutely part of it. Mass spectrometry has that ability to detect proteins at lower levels than we’ve traditionally been able to look for.

Risks found with screening

The Patient Story: The follow-up four and a half years after showed a slightly higher mortality rate in patients that had that and protein detected versus not, and also a higher risk of myeloma, other blood cancers and possibly things like heart attacks. Is that right?

Something that’s emerging from both the PROMISE study and the iSTOP study that we’re starting to understand a little bit more of is that we tend to think of MGUS as being a precursor to myeloma. And so the worry about MGUS is that someone develops myeloma.

And that, of course, is the central concern. But we’re starting to notice something else– that patients who have MGUS may have other associated conditions and that their overall survival may be compromised. We still don’t fully understand this.

I don’t want to raise too much of an alarm yet, because we’re still sorting it out. But there may be greater connections to certain kinds of heart or kidney or other disease, and we’re trying to understand the mechanism of that–  is it really driven by the MGUS, or is the MGUS just telling us something else that’s going on within the immune system or within the body?

And this is the kind of thing that really can only be fully assessed and understood in something like iSTOP. So that’s one of the things that we hope to have more answers about in the not-so-distant future.

Frequency of MGUS screenings in the US

The Patient Story: Can you talk about the frequency of MGUS screenings in the US?

So right now, whether it’s the International Myeloma Working Group, or our organization, the International Myeloma Foundation, or any other institution, no one is yet recommending that we just screen largely. I think the approach is that we’re learning more about this, and we’ll understand it better for the future.

I do, however, think it is really important for us to speak up when we identify people with signs and symptoms that could be consistent with myeloma. There’s a difference between screening the general healthy population and screening if someone has certain features.

The M-Power Initiative

This is part of the work that I do at the International Myeloma Foundation in our M-Power initiative, which is to educate the community and primary care docs about when to test for myeloma, how to recognize the signs and symptoms, and then what exact tests need to be done, which is the serum protein electrophoresis and the light chains like we talked about earlier.

So when people have a low hemoglobin count, or fatigue that is not otherwise explained, or bone or back pain in particular, that’s outside what we would expect, or their kidney functions off– there’s a whole series of things that kind of trigger this.

Thankfully, the majority of people with MGUS will not develop true myeloma. But now, as we have better techniques to measure it and better understanding of the disease, we want to keep an eye on it so that we can intervene when necessary.

Dr. Joseph Mikhael

Sometimes within the African-American community in particular, this isn’t thought of because these are many of the same things that we may see, for example, with diabetes. And some may say, “Oh, that’s just from your diabetes,” and not look a little bit deeper. But for those people who are reading and already have established MGUS, I think what it reminds us is that it’s important to continue to be followed.

Thankfully, the majority of people with MGUS will not develop true myeloma. But now, as we have better techniques to measure it and better understanding of the disease, we want to keep an eye on it so that we can intervene when necessary.

Follow-ups for MGUS patients

The Patient Story: What is the follow-up once someone has MGUS? And how long should it go on?

So the quick answer is that it depends on someone’s MGUS, and obviously they need to talk to their own physician about that. We have different groups that have provided different guidelines. In general, people with MGUS are seen either once or twice a year, so every six months or every 12 months. We have a sort of a grading system within MGUS of people who are higher risk and people who are lower risk.

This is also what we want to learn from iSTOP, because they have a strategy to look at how frequently people should be followed. Right now, it appears that people really do need to be followed indefinitely. It’s not like if you go five years and there’s no progression of MGUS to myeloma, you can stop looking. We see that people unfortunately can progress even after having MGUS for 19 years in their 20th year. It can happen, so it really is unfortunately a lifelong follow-up.

Future of screening

The Patient Story: What do you see for the future of MGUS screening?

I think it will take some time because the implications are huge, right? Massive screening programs are obviously very consuming and have to be done correctly if they’re going to be effective. And we don’t want to screen a whole group of people where it may not be necessary. So the day may come where we’ll say that at a certain age, or based on someone’s gender or ethnicity or race, that there may be a greater risk, and therefore it triggers the need to be screened.

That’s kind of how we do it now, right? We don’t screen everybody with mammography or with colonoscopies in their 20s and 30s. We set an age. If someone has family history, then their risk is increased. Someday, we’ll probably come to that. We’re just not there yet.