Monoclonal Gammopathy of Undetermined Significance (MGUS)
Sandra Mazzoni, DO, a hematologist at Cleveland Clinic Taussig Cancer Institute joins the Cancer Advances podcast to talk about monoclonal gammopathy of undetermined significance, known as MGUS. Listen as Dr. Mazzoni talks about this abnormal protein and explains when we can still effectively treat patients before it hits all the criteria for becoming multiple myeloma.
Monoclonal Gammopathy of Undetermined Significance (MGUS)
Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology.
Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic, overseeing our Taussig phase 1 and sarcoma programs. Today I'm happy to be joined by Dr. Sandra Mazzoni, a hematologist at the Taussig Cancer Institute. She's here today to talk to us about monoclonal gammopathy of undetermined significance, or MGUS. Welcome, Sandra.
Sandra Mazzoni, DO: Thanks for having me.
Dale Shepard, MD, PhD: Give us a little bit of an idea, what do you here at the Cleveland Clinic?
Sandra Mazzoni, DO: So, I'm kind of split between seeing a variety of different benign or classical hematologic entities, and then I also see the full spectrum of plasma cell disorders. So, from truly benign conditions like MGUS, or monoclonal gammopathy of undetermined significance, all the way through multiple myeloma, amyloidosis.
Dale Shepard, MD, PhD: And so, we have people that might be listening with varying degrees of sort of backgrounds in MGUS, and what that is. So, let's start very simple. What is MGUS?
Sandra Mazzoni, DO: That's a good question. So, as I said, it stands for monoclonal gammopathy of undetermined significance. That's a big mouthful. When I explain it to patients who have no medical background, I basically tell them that there's this protein that was detected on a blood test that looks to be potentially of significance. And so, we use these blood tests in order to look at basically a spectrum of proteins our body naturally produces. That particular test is called a protein electrophoresis, so what that does is it takes every protein that's in our bloodstream and it puts out a pattern. There's a normal pattern, and then it compares normal to the individual patient, and sometimes there is what's called a spike. It's a physical abnormality within this picture, so to speak. And they can then identify what that abnormal protein is, and give us a quantity, and also identify what type it is.
So, these proteins are actually different antibodies or immune globulins, to be more specific. So, part of our normal immune system. They're produced by cells that are also part of our normal immune system, by different types of B cells, B like boy. A normal B cell can produce this, or a mature form of B cell called the plasma cell can produce this. Now, our job as hematologists is to figure out, well, what does this mean? Is this a small quantity that can be seen, and is it truly something that is a benign condition? Or is this something that is of clinical significance? And that's where things have shifted. There's more association with clinical significance now than we originally thought.
Dale Shepard, MD, PhD: So undetermined significance, but we're learning more about the significance.
Sandra Mazzoni, DO: Correct.
Dale Shepard, MD, PhD: And so just give us a little perspective. So, somebody comes in and says, I have this M protein. My doctor sent me to see you. We might be looking at a patient with MGUS, which I think is relatively benign, and then you can fill me in on what exactly that means. But what else could it be? What else might they be worried about?
Sandra Mazzoni, DO: Yeah. So, this whole M protein, so M, we throw it around very casually. It basically means monoclonal. So, to tell someone that they really have a clone, you need to be able to detect that there is a clonal population, meaning that there's a B cell or plasma cell, so the mature B cell, that is making copies of itself, so to speak.
So, the way that we typically do this is we talk with the patient. We look at a timeline of events. So oftentimes these patients may come to us with a couple years of history of this M protein being watched. In other cases, it's a brand-new diagnosis. So now we need to figure out, okay, what type is this? What do we know about this so far? And there's different risk categories even for MGUS.
So, if you have an IgG, so I'm going to use some weird Greek terms here now, because everyone decided to use the Greek alphabet for all this, basically they break down the protein structure into heavy chains and light chains. So, the heavy chains come in multiple different flavors: IgG, IgA, IgM, et cetera. And those are all based off the Greek alphabet. And then there's light chains that are kind of attached to the top of the structure of this antibody. And they come in two flavors. Again, the Greek alphabet comes in play. Kappa and Lambda.
So, the lowest risk are the people who are going to be IgG Kappa. That's actually the most common. Those patients, you can typically watch. You look at all their symptoms, you do a thorough physical exam on these patients, and typically these are the patients who have what we call a 1 percent annual risk of them progressing to something that could be of clinical significance. Then you have other patients who could have a higher amount of M protein. So, anything greater than 1.5 puts you at a slightly higher risk. Anything non-IgG puts you in a higher risk. And then those light chains, that Kappa and that Lambda. If that ratio is shifted so it's abnormal in one direction or the other, that will be another risk factor. So, the more of these risk factors patients have, the more likely we are to talk about a deep dive into truly investigating if this is a clonal entity, if it's clinically significant, or what is the risk of this progressing to something like multiple myeloma?
Dale Shepard, MD, PhD: And I'm guessing that most people, if their primary care physician, for instance, tells them they have an M protein, and they get onto Google, they're going to come in and that first thing they're going to be worried about is, do I have multiple myeloma?
Sandra Mazzoni, DO: Correct. Correct. So that's part of our job too, is, where do patients fall on that spectrum from MGUS, to this in between stage called smoldering, which again breaks apart to low risk, intermediate, and high risk? And then who truly has active disease and needs treatment? Now what we're learning, though, is that there's people who will fall into this pre-meeting criteria for active disease, active myeloma, that have other clinical entities that need treatment. And that's where I have kind of developed a specialty at the clinic.
Dale Shepard, MD, PhD: So maybe let's go ahead and just talk a little bit about that. What are some of those factors we're looking at here?
Sandra Mazzoni, DO: So, the most common one is probably monoclonal gammopathy of renal significance. So, you'll notice a pattern here. They name all these things off monoclonal gammopathy, and then whatever organ system of clinical significance. So, there's monoclonal gammopathy of neurologic significance, dermatologic significance. I would argue there's one skeletal significance. Those are the main ones that we have really truly defined. There's probably even one of endocrine significance, but that's in the works, brewing, as far as what really is that entity, and how do we test for it, how do we monitor it, how do we look for it, et cetera.
Dale Shepard, MD, PhD: And so those essentially would be someone that happens to have an M protein, and then they have a dysfunction in a particular thing, like bone or kidney.
Sandra Mazzoni, DO: Not full-blown myeloma.
Dale Shepard, MD, PhD: Not full-blown myeloma, where they have multiple things.
Sandra Mazzoni, DO: So, these patients, the easiest one is to describe, let's pick monoclonal gammopathy of renal significance. So, this is a relatively newer term. I would say in the last 20 years, this has really come to being well-defined. And there's more and more different subtypes of this entity being defined, with the most recent one being defined in 2017. All these different entities, these patients don't necessarily have to have an abnormal creatinine, or an abnormal creatinine clearance. They can dump protein and have very high levels of protein in their urine. And what we need is, we need to get a renal biopsy on these patients. So, these patients will go through a thorough myeloma-style workup, including what we call advanced imaging. So not just a whole-body x-ray, which is called a skeletal survey, but they'll also get either a CT, a PET scan, or an MRI in order to look for boney abnormalities. In myeloma, the most common boney abnormality is a lytic lesion, or it looks like a little hole.
And then you have to do the blood work on these patients, so you can identify what type or what flavor of monoclonal protein is present. Then you need to do the kidney biopsy. And the kidney biopsy is key here, because based on the kidney biopsy, you're going to see different patterns of immune deposition that will match the same monoclonal protein that we're finding in oftentimes the bone marrow and the blood. And so that pattern alone, without the kidney being damaged in some way, or shape, or form, would not qualify as full multiple myeloma, but now we have this kidney damage that's happening from this small clone of abnormal B cells or plasma cells that's causing damage to the kidney. So that relationship's very important to establish.
Dale Shepard, MD, PhD: And I guess we commonly think about, when we see all the new therapies that are rapidly coming out for multiple myeloma, are there similar developments that are being helpful for patients with these sorts of individual, MGUS something?
Sandra Mazzoni, DO: Yes. Yes.
Dale Shepard, MD, PhD: Organ dysfunction.
Sandra Mazzoni, DO: That's a bit of a frustrating point, is that these entities are so rare. The one I mentioned with renal dysfunction is probably the most common that we find, and I think here we find so much of it because we work so closely with our nephrologist here, so we have easy access to kidney biopsies. So, we're finding a lot more of this than I thought initially we thought was out in the wild.
But the question about treatment, so a lot of this treatment is myeloma research focused. So based on what has worked traditionally to kill off a B cell, or kill off a plasma cell, tends to work with monoclonal gammopathy of renal significance, or MGRS for short. There's NCCN, National Comprehensive Cancer Network guidelines for this. There are guidelines within the International Myeloma Society, and we often treat this as active myeloma. So same chemotherapy protocols, and often we even consider transplant in some of these cases too.
Dale Shepard, MD, PhD: So, it's really monoclonal gammopathy of undetermined significance, but once you have some element of an organ dysfunction, even if it's not full-blown criteria for myeloma, we can still effectively treat patients.
Sandra Mazzoni, DO: Correct.
Dale Shepard, MD, PhD: Let's take a step back. Patients see you when someone has told them they have this abnormal protein, and you talk about electrophoresis and things. So, what are the patients, again, if people are listening in, and they're like, hey, maybe I'm missing things, who should be getting the testing to determine if they have a monoclonal gammopathy in the first place? Are we lagging behind and not diagnosing people that we really should, and being dismissive of symptoms and labs?
Sandra Mazzoni, DO: Yeah. That's a good question. So, the most comprehensive study was done by Dr. Kyle. He's with Mayo Clinic, and so he did basically a population study there in Rochester, Minnesota. But the population in Rochester, Minnesota is not representative of the population in, say, Cleveland, or most large cities in the United States. So, there's actually a project that is being developed here. It has funding, and it is going to start actively enrolling soon. It's going to go through our community outreach program, and it's focused specifically on our African American population, because that population, for some reason, we see more incidence of monoclonal gammopathy and full-blown myeloma in that population than other ethnic groups. So, we're trying to get real deal numbers on, what is the incidence of monoclonal gammopathy in African Americans? How should we screen them? How many of these patients are going to have clinically significant monoclonal gammopathy? That question is not answered. So yes, we have good data on mostly a Caucasian population, but not a population that really reflects the United States.
Dale Shepard, MD, PhD: And I guess you mentioned screening, and there's not anything that's really defined at this point from a screening because of the rarity.
Sandra Mazzoni, DO: Well, so the reason why a lot of people will get this test, so I actually did a project as a fellow looking at every single monoclonal workup that was done in the hospital over a period of 10 years. And the reasons varied all over the place. The things that we're taught in medical school would be the CRAB features: So, the elevated calcium, the renal dysfunction, the anemia, and bone lesions, or bone pain, even.
So the main reasons I was seeing monoclonal workups being ordered had to do with patients with anemia, patients with an elevated protein or a protein gap, so that protein gap is taught to us as these blood tests that routinely are drawn all the time, that can calculate a total protein in the blood, and then albumin, which should be the predominant protein in our blood. And then if there's a gap, meaning a difference of over five between the total and the albumin, that seems to be a trigger point to order this as well.
Unexplained kidney dysfunction is a big reason to order this, and elevated calcium. Those seem to be the main reasons people order this test. But I'll tell you, the ones that are getting missed quite often are the basic anemia workup. So, when it's not iron deficiency, it's not homolysis, quite often in the primary care setting, we're not seeing the monoclonal workup, and it's coming to us appropriately as a referral for anemia workup, and that's how we're catching it. Out in the region, I'm seeing a very similar pattern as well.
Dale Shepard, MD, PhD: So really more kind of unexplained anemia leading to this.
Sandra Mazzoni, DO: Correct.
Dale Shepard, MD, PhD: Gotcha. I know that I treat a couple of aggressive benign tumors, and this comes up as an issue occasionally. How do you deal with the psychosocial sort of aspects of someone being told they have something that's not right, it's not cancer, it could become cancer? How do you incorporate that into your practice?
Sandra Mazzoni, DO: Yeah, no. That's a very good question. So, I've had many, many patients, they have actually more anxiety about monoclonal gammopathy of undetermined significance than they do about real deal myeloma. Because when it's myeloma, it's very clear cut. But now they describe this as like a ticking time bomb sitting in them. So, I give them numbers, again, that are based mostly off of Dr. Kyle's research at Mayo, about what are the odds of this transforming or becoming an active problem? And in some cases, people who have lowest risk, it's 1 percent annually. If their numbers stay stable for five years, that's the best-case scenario. It's somewhere around, depending on the numbers you pull, like 5 percent to 8 percent over a 20-year period, it's going to become a problem. So that's very reassuring. But now you have that five-year waiting period of, oh, god. What's going to happen?
And then you have these patients who are smoldering. So, they're somewhere in that in between state, meaning they have a larger clone, so we did bone marrow on them, and they have somewhere between 10 percent and 60 percent plasma cells. And the closer they're inching to 60 percent, the closer you can see the anxiety levels rising, and those are the patients that you know something's going to happen. So, I have to make sure that my own anxiety about how often to monitor this, and make sure I catch it as soon as I can.
It's also relayed to the patient of, we're going to be watching this every three months as opposed to every six months. When we start to see that protein number rise, we will repeat some imaging, repeat some more blood work, potentially repeat bone marrow in order to get this thing as soon as it progresses to active disease.
Dale Shepard, MD, PhD: I must say, just the name smoldering must be anxiety provoking.
Sandra Mazzoni, DO: Provoking. Yes.
Dale Shepard, MD, PhD: Yeah. So, what does that look like? You mentioned things about repeating tests and things. What would be considered normal?
Sandra Mazzoni, DO: So normal for someone with MGUS, let's get away from the lowest of low risk MGUS. So that's your IgG Kappa patient. Let's say you have someone who has a different heavy chain, and it doesn't matter what the light chain is in this case. So, it could be like an IgA Kappa. That would be someone who I would screen thoroughly to make sure they don't have any unexplained skin rashes. I would gather urine studies on them, so I'd look back to see if they've been dumping protein in their urine in the past, if they have. I always do 24-hour urines over a spot urine in these patients, and just make sure that I'm doing my due diligence. Most importantly, it offers a bone marrow biopsy.
So, I know that bone marrow biopsies are very anxiety-provoking for patients, but here at the clinic, we have easy access to getting bone marrow done. And I think that is the best way to know 100 percent, for sure, that A, it's clonal, and B, you have a dedicated number system now. So, you have a percentage of clonal cells. You can get what's called a FISH study on these patients. So, a FISH helps determine also what's the risk of this progressing. Basically, you can look at the plasma cells themselves, and the different chromosomal changes within these plasma cells, so we know certain things are high risk and certain things are less likely to progress quickly. And that way you have a better timeline for these patients so that both you and their anxiety is treated appropriately.
Dale Shepard, MD, PhD: There we go. You talked about how often, as a hematologist, people come in with some sort of anemia, not knowing that they have MGUS. Who's the right patient to come in and see a hematologist? I mean, should everybody that has sort of these abnormal findings at least have a contact with the hematologist? And specifically at academic centers that are maybe more invested in these things?
Sandra Mazzoni, DO: Yeah. So that's also a very good question. When I first came here, we were bombarded with MGUS consults in our clinic as providers. And I looked at this, and it was a major access problem, because there was no filtration system between people who were newly diagnosed with amyloid, newly diagnosed myeloma, and these patients who had these tiny, small monoclonal proteins.
So, we developed a number of APPs who now subspecialize. So, APP is the advanced practitioner. So, the nurse practitioners, the physician assistants. And they're out in the region here, they're at Main Campus, but we meet every two weeks, and we go over all of the cases they see so that we can have better access for all of these patients. Because yes, a patient who has a non-IgG monoclonal protein should be evaluated by someone with this specialty training. They present them, and we make sure that we're not finding some sort of clinical significance. We came up with a recommendation about how often to be screening them going forward, how often to be seeing them, what testing to be getting next, et cetera, who to refer them to. So, there's some patients who have unexplained neuropathy, and they really need to see someone from our neuromuscular team, get EMGs, those sorts of things. So, this has been really nice, and it's been good for education too.
Dale Shepard, MD, PhD: Yeah. What are the biggest gaps? What needs to be addressed? What are the biggest questions that need to be answered?
Sandra Mazzoni, DO: So, the bigger thing is, no one really knows, with smoldering myeloma patients, the high-risk patients, it's very controversial about what to do with them. Do you start treating them early to try to prevent the organ damage, to try to delay the progression to true myeloma? Or is starting treatment early picking out the high-risk clone? Are we killing off the clone that's very treatment sensitive, and are we setting up a resistant clone for the future? That's going to be really tough to tackle. No one really knows. That's a big gap in research, but it's one of those things that a lot of people are looking into.
Dale Shepard, MD, PhD: That's great. Well, we certainly appreciate you being with us here today, and providing all this insight.
Sandra Mazzoni, DO: Okay. Thank you.
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