Multiple Myeloma Podcast

Avoiding the Cliff: Screening for Early-Stage Multiple Myeloma

Joseph Mikhael, MD; Irene Ghobrial, MD


May 03, 2022

This transcript has been edited for clarity.

Joseph Mikhael, MD: Hello. My name is Dr Joseph Mikhael, and welcome to Medscape InDiscussion: Multiple Myeloma. Today we're talking about screening for early-stage multiple myeloma, and I think this is a particularly important topic. For so many years, we only defined myeloma as being present when patients had organ damage and the classic CRAB criteria (calcium elevation, renal insufficiency, anemia, and bone disease). But over the past several years, we've been changing that definition to try to catch the disease earlier. Sometimes I give this analogy because I'm a runner: If I'm running toward a cliff, hopefully someone will catch me before I fall off the cliff and run into trouble. And that's kind of what we've done with myeloma. We only used to define myeloma after someone had fallen off. But we want to catch patients earlier and earlier. Not too early, because maybe they'll never make it to the cliff, but early enough. And understanding that sweet spot is really the focus of our discussion today: when we should do so and how we should do so. My guest today is a world-known myeloma expert and also a very dear friend, Dr Irene Ghobrial. Dr Ghobrial is a professor at Harvard Medical School and is a hematologist at Dana-Farber, and she has dedicated much of her working career to understanding this field. So, welcome, Irene. It is always good to be with you.

Irene Ghobrial, MD: Thank you, Joe. It's a pleasure to be with you.

Mikhael: We have so much going on now with new treatments and new approaches. What drew you to this area of understanding earlier disease and maybe even screening for myeloma? What was the impetus to draw you to that?

Ghobrial: It started with the grandfather of myeloma, Bob Kyle. I trained at Mayo Clinic almost 17 years ago now, and Bob Kyle was the first one to coin the name "monoclonal gammopathy of undetermined significance (MGUS)." He and Jan Waldenström first described it. They saw those asymptomatic people, and I think Jan wanted to call it the benign gammopathy. But Bob Kyle said, "Well, they may actually involve myeloma. Let's track this. Let's look at what's going on in those people and see if they will develop myeloma." And he wanted to call it "undetermined significance" because of the potential of developing cancer. He had this amazing insight of 50 years in advance, to truly understand the precursor condition to define it early and to track it for 50 years. We're very lucky that we have so much information about the precursor condition just because Bob Kyle saw it 50 years ago.

Going back to why would I do that… I've had my share of seeing many people with multiple myeloma, and it hurts sometimes to see people coming in with fractures or anemia. Then we start to work up the diagnosis and then we tell them, "You do have multiple myeloma; let me treat you." And if you ask those people, "If I had diagnosed it a few years ago, would you have wanted to know that? If I diagnosed you 4 or 5 years ago, when you didn't have the fracture or the anemia or the kidney failure and you didn't need dialysis, would that make a difference for you?" I can tell you that 100% of people would say yes. If you think about it, every single patient with multiple myeloma who comes today to see us must have had an earlier precursor condition of MGUS or smoldering myeloma, and we did not diagnose it because we don't go looking for it. Shame on us if we can do something about that and change that, if we can change the perspective — let's diagnose it early when it's still asymptomatic and let's intervene early before the fracture, anemia, and renal failure. Wouldn't that make a huge difference not only for their survival but also for their quality of life and for their own idea of "I am not suddenly being diagnosed with something and it's falling apart"? Let me plan for it. Let me be proactive about it.

Mikhael: Wow, that's fantastic, Irene. I love how your passion comes through with this and your history of where we've been in myeloma and where we're going. Thank you for that insight. As we start to dive into this conversation, I thought of you this week when I saw a patient in clinic. I saw a patient in clinic who was relatively recently diagnosed with multiple myeloma, and her community oncologist wanted my opinion about whether we should take her to stem cell transplant. She was accompanied by her sister and her sister said something very fascinating to me. She said, "We know it was many years ago, but our father had something in his blood. We never knew what it was before he passed away. And I went and got tested, and I have this thing called M-G-U-S. Do you know what that is, doctor?" And of course I said yes. I was also very close to Dr Bob Kyle when I was at Mayo Clinic, and it got me thinking because she looked at me and said, "We have another sister; should she be screened for myeloma?" I know that may be one extreme example, to have two siblings with this. But I think it raises the issue and shines a light on a lot of the great work that you have done recently on trying to understand if everyone who has myeloma previously had MGUS, when should we start looking for it? Especially because we know that MGUS is so common. We think of myeloma as being a rare cancer, maybe 1%-2% of all cancers. But I could argue that it's maybe one of the most common cancers in the world because 5% of people over the age of 40 — if we look for it, we find it. If you don't take the temperature, the patient won't have a fever; so if you don't look for something, you're not going to find it.

So let's dive in. Irene, I've heard you talk about this topic and it's so valuable now. What are the implications of early screening? I know that "screening" is a word we use a lot in breast cancer and colorectal cancer, but it's not been in the terminology of the myeloma world. Talk to us a little bit about that.

Ghobrial: You're right. Cancer screening saves lives. We know that if you can detect cancer early, this is when you can potentially cure it. And the idea that we should wait for people to fall apart, to have all of the cancer cells and all of the immune system dysregulated and then we treat them — that's probably where they are metastatic already and it's too late to treat it. So, early detection and early interception for all cancers in general makes a difference. Now, how can you detect it early and think of screening for those people? If we can detect that monoclonal protein, that MGUS, early in the high-risk population, the we don't have to screen the whole population because, as you said, it's about 5% of the people over the age of 40 or 50. But if I can detect people who are either of African descent, Black Americans here in the United States, or if we can detect it in people who have a family history of blood cancer — although we don't know very well which mutations can make us at risk of developing that. But if we know that I have a sister or brother or a father with myeloma or leukemia or lymphoma, I am at a higher risk of developing MGUS. Those are the people that you want to screen for.

And indeed, this is what we did with the PROMISE study. We started screening over 3 years ago, and we just published our data of 7600 people where we looked for it in those high-risk populations. We found that, indeed, you have it in almost 30% of people over the age of 50. That's a huge number of people having monoclonal gammopathies that are true and may indeed go on to myeloma or to lymphomas or to other things. The numbers are much higher than what we expected. And this is because, again, it's a high-risk population. If we use the old traditional way of serum protein electrophoresis, you will find that in 6% of those people. It's double what we would expect in the general population. And that alone can help us say people at risk — African American or with a family history of blood cancer — let's consider thinking of screening for them because the positive value of knowing early and preventing myeloma can make a huge difference. I would say that a blood sample is much easier than going through colonoscopy or mammography. So why wouldn't we want to make screening something that we have available for everyone, detecting it for everyone?

Mikhael: You make an impressive case, Irene. I can't deny that. Let's unpack a couple of things you said there. It was a privilege to be a part of the PROMISE study with you. For our audience, can you discuss how you defined family history of hematologic malignancy, and what was the age cutoff for the PROMISE study?

Ghobrial: We started the PROMISE study with age 40 and above, specifically for that reason that we've seen in prior studies — that age 40 and above can increase your chances of monoclonal gammopathies. And we defined the family history as a first-degree relative of someone who has a blood cancer. Originally, we had someone who has myeloma or a plasma cell disorder. We noticed that the recent studies have shown that having a blood cancer relative, whether leukemia or lymphoma as a first degree, can also increase your risk for monoclonal gammopathies. We changed the study to allow having a first-degree relative of a CLL lymphoma, leukemia, myeloma, and others. And indeed, we are finding that this is relatively high risk of developing monoclonal gammopathies.

Mikhael: Indeed, it was only just one family member that had that, not more than one.

Ghobrial: If you have multiple family members, we just changed the study now to allow screening all of your family members — first- or second-degree relatives — and even going down all the way to age 18 to see what the risk is.

Mikhael: Excellent, very helpful. There's another point out of what you mentioned that I want to clarify for everyone, which I think was really important. Obviously, you did a lot of advanced testing, but the serum protein electrophoresis has been the historical — if I can even put it in quotes — "screening test." We used to give these talks to the primary care physicians on when do you order a serum protein electrophoresis (SPEP)? When do you order this? When you think unexplained anemia, unexplained renal insufficiency, suspicious bone lesions, whatever it may be or bone pain that draws someone in. I know you did a lot of advanced testing, but talk to us just very briefly for a moment about how you went beyond just the serum protein electrophoresis to include light chain testing, which we think is standard, but even doing mass spectrometry.

Ghobrial: Right. And I have to say that I give you all the credit because when we designed the PROMISE study 3 years ago, you said, "Why don't we do a mass spectrometry instead of just doing serum protein electrophoresis?" And indeed we did. Because of your insight into that, it made a huge difference in understanding those very early monoclonal gammopathies, which we term now as "MGIP monoclonal gammopathies of indeterminate potential," which are very early monoclonal proteins that may in the future lead to MGUS or smoldering myeloma or others, but are also associated with increased cardiovascular risk, increased autoimmune diseases, and association with other hematologic malignancies. It's opening the door for us to understand, in an earlier event of immune dysregulation in many of us, what happens and why we are developing those earlier. And it's opening the door again for so many epidemiologic studies in the future. Now, mass spectrometry is a much more sensitive way of looking at the monoclonal protein. If you think about it, SPEP, or serum protein electrophoresis, was a technology that was developed 50 years ago, and hopefully we are doing much better than that. Mass spectrometry hopefully will be the future not only for detecting early monoclonal gammopathies, but hopefully even replacing the way that we use serum protein electrophoresis, because it's also not very accurate in the development of our prediction of response, resistance, or MRD, but also in some cases like the IgA monoclonal proteins or the IgM monoclonal proteins, which may not be very accurate in SPEPs.

Mikhael: That's really helpful and I think a little prophetic of the future. I really do see a day where we're going to abandon SPEPs and light chains and just go straight to mass spectrometry. Before we move on to risk stratification, one point here, because I did a press interview recently and one of the people said that they had interviewed another prominent hematologist in the myeloma world who is a little bit suspicious of this MGIP idea and said, "Oh, we may be overcalling it." That's always a risk of screening, isn't it? You don't want to have it, for example, in colon cancer; you don't want to have all sorts of people with tiny, little benign findings that may never lead to colon cancer to be overinvestigated, or benign changes in mammograms. What is your response to someone who says, "Oh, if you dig too deep and Irene looks too carefully, they're finding these tiny little things that may never be an issue." How do you respond to that?

Ghobrial: Science is what leads us, instead of us having our opinions. And science matters a lot. When Bob Kyle decided to think of MGUS, a lot of people told him it doesn't matter either, and it is benign until we understand it better. And whether it is MGIP or MGUS, most people will never develop myeloma, and that's the good news. The question is why and how can we make the other people who will develop myeloma become like them, become like MGUS? So a couple of things. Yes, we are detecting very early monoclonal proteins. They are real. These are not polyclonal. They are true monoclonal proteins at a much more sensitive level compared with another test that is less sensitive. What is the implication? If, truly, there is a strong association with other things, like cardiovascular disease, inflammation, autoimmune diseases, then we should know about it because it's about your whole health and not just about developing cancer. If I can prevent your next heart attack, or if this could be a biomarker of your autoimmune diseases, then why not discover that and understand it better, and let the science lead us rather than us telling ourselves what to do with it? And yes, most of the people will not develop cancer. But if we can prevent cancer and if we can understand better biologically who will develop it and why are they developing it, then we can develop the therapy to prevent that. So I think we do need to allow science to tell us what to do with it and not add to it our own understanding of things.

Mikhael: I completely agree with you, Irene. You had me at MGIP. I completely agree with you. I think this has been corroborated by the massive iStopMM study, where literally over 80000 samples have been collected throughout Iceland now. Obviously not the same risk stratification that we're going to come to in a moment because they really are very rare individuals of African descent in Iceland. But they demonstrated a similar concept that even in those MGUS patients who never developed myeloma, their outcomes were inferior. It speaks of something else going on, whether it's in the immune system or the whole health — that's the phrase you used, which I really like. I commend you on wanting to capture this a bit earlier. Let's think for a moment about risk stratification. We do this in all screening, right? We don't screen every female in the world, right? We wait until people reach a certain age for breast cancer, for colon cancer. We don't do a colonoscopy on everybody; we wait until a certain age. But like myself with a positive family history, I had to start my colonoscopies earlier. Help us understand this risk stratification for screening and how it is in your mind. I know that we don't have formal recommendations yet to screen on a large scale, but if we were to go in that direction, my gut feeling is that we would start with those at highest risk. And it looks like you identified in the PROMISE study those two particularly high-risk phenomena, of being of African descent and having a family history of hematologic malignancies. But tell me more about your thinking in that risk-stratification process.

Ghobrial: You can think of risk stratification for screening, but also risk stratification of when I diagnose a case of MGUS or even smoldering myeloma. What do I tell this patient? That's important because we have said already that not every patient would develop cancer. You want to understand: Is this MGUS more of a benign one, more of a normal phenotype? You have developed a clone that has expanded but has not developed all of the factors, all of the hallmarks of cancer that will go on to develop myeloma. And in that case, you may feel more comfortable watching carefully. In another person with the same tumor burden, with the same cancer cell number and M spike, they may already be developing this malignant phenotype and they're going toward myeloma. And these are the ones, like you said, running toward the cliff — let's try to make sure we prevent it and intercept it early. If I have two cases of MGUS or smoldering myeloma looking the same, I want to risk-stratify them better by looking at multiple other factors so I can give them in a more precise way. Where is their own risk of developing cancer and how can I then also precisely intercept it? Going back to screening: Right now, we're using very crude things like, are you of African descent? Are you someone who has a family history in the future? We may improve on this because ancestry is such an important thing, and we want to get off this idea of, if my skin color is brown or black or white then I am at the certain risk. I want to understand more my own ancestry and whether that can affect my risk. And as we are all starting to see germline sequencing here and there and 23andMe, the new generation of people really want to know a lot more about their own risks and understand their own inheritance and their own ancestry more than anyone else. It will come to a point where whether you are Black or White or brown, if you have certain ancestral genes that predict or can predispose you to developing cancer, you may want to know about those and understand it better rather than using our skin color.

Mikhael: That's extremely helpful. Especially since you and I come from the same ancestry, so I want to learn from you as we go through. What I'm hearing from you also is that it's not just the presence or the absence or even the size of the MGUS. There are different MGUSes in terms of those that have a more benign clone vs a malignant phenotype. This is extremely insightful. But before we wrap up, I do want to ask you an important question. Going back to my analogy of running toward a cliff, I hope that if you see me running toward a cliff, you're going to pull me away before I fall over. And one of the greatest questions we struggle with in myeloma right now is, it's one thing to prognosticate around this, but when do you treat? Do you see us moving? If I use the analogy again of running, we used to say, you don't have myeloma until you fall off the cliff. Well, when we changed the CRAB criteria to SLiM CRAB criteria 7 years ago, almost 8 years ago now, we drew a line, let's say, 50 feet short of the cliff and said, if you cross this line, you're so close to falling off the cliff. Do you see us moving that line even further away from the cliff and closer to the city with the tools in the testing that you've been demonstrating?

Ghobrial: Two things. We are using now markers like the 2/20/20, which is wonderful to tell us who's that close to the cliff and we need to improve on it. As you can think of it, it's more like one picture, and we want the whole video. We want to see the whole thing happening. Dynamic assessment of people as they progress, taking it into the genomics, taking into the immune, and being more precise in our prediction of who would develop myeloma can be very helpful because you don't want to overtreat and you don't want to undertreat people. Then the second thing is, how do you intervene? Because if you use drugs that are so-so, then you don't expect to have an amazing response and potential cure. You want to also be precise in your interception, and certain people may require three drugs, four drugs. What we use for myeloma. Certain patients may require only lenalidomide and dexamethasone, and some people may require more immune therapy. More interesting things about modulating your immune system and harnessing it like bispecific antibodies, CAR-T, and other things to truly get to that cure in smoldering myeloma. So, there is a potential for developing multiple things. Think of 11;14 translocation. Wouldn't it be nice to bring in venetoclax early on? Think of someone who has a 17p deletion. You may not want to treat that patient with lenalidomide/dexamethasone alone. So there are so many things about us being more precise in our interception, rather than saying everyone will get the same treatment.

Mikhael: Well, that was a beautiful summary and a take-home message that you've left with the crowd. I'll reword it and say it really is multiple myeloma because there are multiple diseases in one here, from the level of MGUS, to the level of smoldering, to the level of active myeloma, and "one size fits all" is clearly not going to be the way we're going to be treating this disease in the short term, in the long term. So, thank you so much, Irene, for your brilliance, for your insight, for your dedication to this topic that we've learned so much about today. For our listeners, I would try to summarize it this way and say that we are coming to recognize that in general in cancer, we want to catch it early. We now have insights into how we may be able to do so in multiple myeloma, especially in particular high-risk populations with certain ancestries and certain family histories, but also better techniques to detect it so that we not only detect it, but we can learn appropriately how to intervene. Can we just wait and watch longer? Should we intervene aggressively, less aggressively? It's a beautiful description of what precision medicine is meant to be, that we don't just treat every patient the same way. As I always say, I don't treat myeloma; I treat people. And this kind of work that Dr Ghobrial and her team are doing clearly emphasizes that. So thank you so much for your time and your passion and your energy, Irene. It's always a pleasure to hear from you, and we trust that this will be beneficial for those who have listened today.

Ghobrial: Thank you, Joe.


Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance

Prevalence of Monoclonal Gammopathies and Clinical Outcomes in a High-Risk US Population Screened by Mass Spectrometry: A Multicentre Cohort Study

Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM): A Population-Based Screening Study for Monoclonal Gammopathy of Undetermined Significance and Randomized Controlled Trial of Follow-up Strategies

International Myeloma Working Group Updated Criteria for the Diagnosis of Multiple Myeloma

The IMWG 2/20/20 Risk Stratification Model for Smoldering Multiple Myeloma

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