← The Fellow on Call: The Heme/Onc Podcast
The Fellow on Call: The Heme/Onc Podcast
Episode 140: Myeloma Series, Pt.1 - Intro to Testing and MGUS (2025)
Ronak Mistry, Vivek Patel, Dan Hausrath
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- [00:00]
Dan
Foreign.
- [00:04]
Roanoke
Welcome to another episode of the Fellow on Call, the Hemong Podcast. We're coming at you from Rouleau University Medical Center. I'm Roanoke. Actually, it's just me today and I just wanted to pop on here and introduce our next series. Believe it or not, it's been almost three years since our first Myeloma series, one of our most highly anticipated and most listened to series to date. And in that time, the Myeloma landscape has changed quite a bit. We could have just released a couple of updates in Myeloma episode, but that wasn't good enough for us. Instead, we've gone back to the drawing board and meticulously combed through all of our old episodes and re recorded any and all episodes that had updates since then. Along the way, our old content that's still applicable will also be re released. This way, whether you're here as a refresher or you're a new listener, you'll be able to follow along in the same TFOC way. And as always, thanks for being a loyal listener. So in our first episode, which is a rerelease, we talk all about the basics, including definitions and workups of plasma cell dyscrasias. So without further ado, let's roll that show. And happy learning.
- [01:17]
Ronick
Guys. How are we doing?
- [01:19]
Vivek
Doing pretty good. I have a new show recommendation that I want to throw out for everybody right now and it is trashy. It is very trashy. Are youe the One? Anybody heard of this?
- [01:31]
Dan
I think I've seen it scrolling. Is it on Netflix?
- [01:34]
Vivek
You know, there's on Netflix and Hulu. It's an MTV produced show and you know, that's gotta be good. If it's MTV produced, that's high quality. It's high quality television. And what the premise of the show is is that there are 20 people or 22 people. It's either 10 couples or 11 couples. And the idea behind this game is that these people are all thrown into a house together and they have to find their quote unquote perfect matches. And it's based on the producers interviewing their family and themselves and some other people. And the producers choose their perfect matches and these people have to find their perfect matches and date each other. Lots of drama, lots of intrigue. Highly recommend. It's really high up there. We've really been binging a lot of those seasons, so. Highly recommend. Are you the one, Vivek?
- [02:27]
Ronick
I must say, at least there's a consistent theme with the genre of television that you like to watch. So I'm Glad that you're not losing sight of who you really are. That's really, really what's important here.
- [02:37]
Vivek
It's all total trash, which is very important.
- [02:42]
Ronick
Well, you know, how about we switch gears just a little bit before we lose the interest of our audience? Let's say something that we see all the time as hematology fellows is workups for people that are suspecting a plasma cell dyscrasia in their patient. And I'm talking about that spep, and it seems like so many different specialties tend to send SPEPs, and when that information comes back slightly abnormal, no one really knows what to do with that information. And so they get a referral to hematology. And I think that this is a perfect opportunity for us to provide some education about how we interpret these tests, what they're really used for, and use this as we start moving into a discussion about the various types of plasma cell dyscrasias. And I know this is a huge topic, there's a lot of nuances in this field, but I think, and I'm hopeful that as we've done with so many diseases thus far, we'll be able to break it down and really help our audience and understand the fundamentals of plasma cell neoplasms.
- [03:43]
Dan
Yeah, you know, you're absolutely right that we do see these referrals come in all the time. And it's just because the workup of so many common conditions can involve sending off some of these paraprotein studies. Anytime you're faced with working up an anemia or someone with new unexplained neuropathy or even renal failure of an unclear cause. That workup can include evaluation for an abnormal serum protein like the ones we're going to be talking about.
- [04:10]
Ronick
And this is exactly, almost exactly what had happened. And I actually have a patient that is in my clinic that I had seen and I think that he provides a good opportunity for us to have a discussion. If you guys are open to hearing a case.
- [04:23]
Vivek
Yeah, let's do it.
- [04:25]
Ronick
So I have a case of a 73 year old gentleman. He had a past medical history of hypertension, hyperlipidemia and diabetes, and he had been observed for about the last year by his PCP for a normocytic anemia. The patient had no symptoms. He had a normal colonoscopy just a few years prior. No family history of any colon cancer or anything like that. And truly asymptomatic. So this 73 year old gentleman with normocytic anemia. And so after a Year of this not getting any better. His primary care doctor did nutritional studies, as we discussed in our prior anemia episode. And then when all of those came back normal, his PCP went ahead and ordered a spep, and that came back with an m spike of 1.2. And so, given this abnormality, the patient was referred over to hematology. And I think what's interesting about this case is I suspect that at some point in your training, you've probably seen something like this either as an inpatient consult or in the outpatient setting. This is not that uncommon. So maybe we should just take a step back and just. Let's just talk about what the normal function of a plasma cell is, because it's been a few years since I've done immunology, and so I think I, for one, need a refresher.
- [05:40]
Vivek
The plasma cells function is really the humoral immunity in producing antibodies. So remember, the antibodies are the proteins that flag pathogens for destruction and that help signaling processes for the immune system. And normally you have multiple populations of plasma cells that produce many different types of immunoglobulins or these antibodies. So for the rest of the discussion, it's important to know that an immunoglobulin and antibody are synonyms for each other. So these plasma cells are producing a heterogeneous group of a variety of different antibodies or immunoglobulins. And remember that that antibody or immunoglobulin has a Y shape to it. And the base of the Y shape is what we call the heavy chain. What I mean by a heavy chain on this is that it can be either igg, iga, or IGM are the most common ones that you see. And that's the heavy chain of that Y shape of an antibody. And then if you looked at a diagram of a nanobody with a Y shape, you have two little chains hanging off the edge, and those are what we call the light chains. And that can either be kappa or lambda. And here's the important thing. As the B cell terminally differentiates into this plasma cell to produce antibodies, it chooses either kappa or lambda. And because we have a heterogeneous grouping of cells in a normal functioning immune system, we have a certain proportion of kappa cells and a certain proportion of lambda. And it's not that we have an overabundance of one type of cell, which really is. What do you think about that clonal process that you think you had a mutation that caused a plasma cell to clone itself and proliferate? And specifically, choose to only produce one type of heavy chain and one type of light chain. And that could be, for example, IgG Lambda or IgG Kappa, for example, or IgA Lambda. And that's when we have what we call a plasma cell dyscrasia. And, and that's when you, again, you have these plasma cells which are choosing either kappa or lambda. In the normal setting, you have both kappa and lambda, and you don't have an overabundance of one or the other, but in a clonal process, you might have an overabundance of one type of the protein, which we'll get to as we discuss this case.
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Ronick
So when we use the term plasma cell dyscrasia, it's essentially a population of plasma cells gone bad, for lack of a better term, correct?
- [08:11]
Vivek
Yeah, that's right. It's a population of plasma cells that have gone bad in a sense that now they just want to constantly proliferate and preferentially choose to secrete a specific type of heavy chain and light chain. And in some cases, the plasma cell could only produce the light chains. It could only produce capellite chains, for example. And that can happen as well. But again, it's gone bad and only producing one specific type of protein.
- [08:39]
Dan
And oftentimes you may hear the phrase kappa or lambda restriction. And that's just referring to the idea that these clonal populations of cells are just producing that one type of light chain, either kappa or lambda. So a kappa restricted plasma cell population is simply a plasma cell clone that's only producing kappa light chains.
- [09:00]
Ronick
So if the normal function though of the immunoglobulin is to provide protection, protection against pathogens, then what is the issue with producing a monoclonal protein? What's the issue with having this clonal process if you're just getting protein production that typically serves a purpose in the body?
- [09:18]
Vivek
I think there are multiple things that go on here, and it really depends on which type of plasma cell dyscrasia we're talking about. But just to keep things, for example sake, let's, let's just go through some examples. When you have an excess quantity of a specific type of immunoglobulin, there can be downstream consequences. For example, that abundance of immunoglobulin can cause disruption of your normal osteoclast and osteoblast homeostasis and have things like lytic lesions. The classic thing we think about with myeloma in the bone lesion criteria, there can be disruption in the erythropoiesis in the bone marrow, resulting in anemia. You could have excess immunoglobulin deposition or a light chain cast nephropathy, resulting in renal failure. And then in some cases, and we see this in one of the types of plasma cell dyscracia is known as Waldenstrom's macroglobulinemia, where you have an abundance of IgM production, where that's often associated with an immune mediated neuropathy. So there are multiple downstream effects, almost. Think about this like an autoimmune type of effect, which is also important to note that if a patient has an autoimmune disease, there is an association with some of these of also having a monoclonal gammopathy, meaning that a gammopathy too much of one type of immunoglobulin, monoclonal gammopathy, one type of immunoglobulin, as opposed to a polyclonal gammopathy, where you're producing multiple different types of immunoglobulins, which is normal.
- [10:46]
Dan
Yeah, and it really is. Remember, the powerful thing about the immune system and the humoral immune system is the body's ability to recombine those variable regions of the heavy and light chain to respond to any pathogen that the immune system might encounter as a result of that. When something goes wrong with these cells, it's basically luck of the draw as to what protein that plasma cell is going to be producing. Like Vivek said, it could have functional effects. It could interact with autoantigens, it could precipitate in a certain way in the kidney and cause problems there, or the light chains could misfold and cause amyloid proteins to form. So it's. It's all about what whatever protein that plasma cell that went bad and became clonal happened to be making. And it could cause a problem just from being itself, and it could cause a problem from simply the abundance of protein that's being produced.
- [11:43]
Ronick
Well, that makes a lot of sense, and thanks for clarifying that. And, you know, I think the part that confused me initially when I started.
- [11:50]
Roanoke
Fellowship was that there's so many different.
- [11:52]
Ronick
Types of disease manifestations under that umbrella of a plasma cell dyscrasia. So, you know, we'll define all of these as we go through the series for our listeners. But just so you all have heard them at least once as we, as we move through that, you can see anything from an mgus, which is a monoclonal gammopathy of undetermined significance. And we'll talk a little bit more about that later in this episode. Next time we'll also talk a little bit more about smoldering myeloma, the than multiple myeloma. There's also this thing called Waldenstrom's macroglobulinemia that we just mentioned moments ago. And this is a disease associated with IgM and neuropathies that we can see. And then one of them also mentioned amyloidosis. So that is this disorder by which misfolded proteins cause disruption in the body. And that can have a whole host of different manifestations depending on where those proteins settle. So stay tuned. We will go into that in more detail. But just know that plasma cell dyscrasias is a pretty broad term with a lot of different manifestations of disease. All right, guys, so, so just to remind us all of what we're talking about here, recall that this is the case of a 73 year old gentleman with a normocytic anemia. And his PCP had ordered an SPEP because of the persistence of his normalcytic anemia despite a negative, otherwise extensive workup. And that M spike had shown a value of 1.2. So understanding that this possibility of a plasma cell dyscrasia and the presentation of a plasma cell dyscrasia can be so heterogeneous, what do we make of this SPEP and how do we interpret this? So can we just talk a little bit about this test? Because, you know, again, we see it all the time, but what does it really mean?
- [13:38]
Dan
So the SPEP stands for serum protein electrophoresis. The way that we run this test is we use electricity to help us separate the proteins in the bloodstream. And the result that we get from that, the sort of direct readout on that test is a series of peaks that show us how much protein is present at different sizes. Essentially, the largest peak on that usually represents albumin, the most abundant protein in the blood. Then there are two alpha peaks, a beta peak, and finally a gamma peak. So gamma, which is where we get the term gammopathy or, you know, monoclonal gammopathy, Gamma is where our immunoglobulins are found. And all these peaks that we see on our readout are fairly uniform and fairly smooth looking. But if there's a clonal group of plasma cells all producing identical immune proteins, there's a large, large peak in the gamma range on the protein electrophoresis readout. And that, that peak, it's, it's sharp because all the proteins again are exactly the same. So they're all going to run at the same place on our electrophoresis gel. And so it looks like a spike. And that's why we get the term M spike. M for monoclonal and spike, because that's just what it looks like on the readout. You can use measurements to quantify exactly how much of that protein is there based on the area underneath that spike. And we're able to quantify the M protein in that way. So the more protein there is, the taller the spike.
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Vivek
And.
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Dan
And we're able to actually use that to figure out how much disease is, is present in a person.
- [15:19]
Ronick
Dan, I just wanted to. To highlight one thing that you said that I thought is super key. And spep, you said is quantitative. Correct. So it tells you how much of a protein is present, not which protein is present.
- [15:35]
Dan
Really good point. If we want to figure out what type of protein that that spike represents, we have to do some additional testing. And that's where immunofixation comes in. This is where we can use some additional testing to try and suss out what type of immune protein is being produced in that M spike. And that can tell us what type of light chain is being produced. Is this a kappa or lambda immunoglobulin? And it can also tell us the immunoglobulin class. So is it an IgM, an IgG or an IgA? IgG is certainly the most common. IgM is the rarest. And we'll get into this in later episodes. There are some implications for prognosis based on what class of immunoglobulin is present in the N spike. But immunofixation, and there is additional testing that has to be done if you want to know what's in the spike. And often these tests are run together these days, usually when you're ordering serum protein electrophoresis at most centers, it's going to be an electropheresis that comes with an immunofixation. You'll get a readout on, on what the M spike is made of.
- [16:44]
Vivek
Yeah. And Dan, I wanted to point out one thing and that's really important for everybody to hear this. When you read a report for an spep, I was always confused when I looked at that because it would be, it would say something like, well, you have the albumin, the gamma peak, the beta peak, the alpha peak, there's another alpha peak. And I was always like, which of these really matter? And what is happening here is that there's a very smart pathologist who's looking at the curve and looking at the distribution of these spikes and interpreting that to give us a result of is there an M protein, yes or no? And identifying how much there is and what type of M protein is it? Is it an Igg kappa, an IGA kappa, something like that? Is it too small of an amount to really quantify exactly how much? But I can detect it through this immunofixation. So I can tell you there is something present, but I can't give you a quantity to it. And that's really important. So forget about the other peaks. You really can only interpret those other peaks and those values if you're looking at the curve as a whole. So really just look at what is the interpretation. Is there an M spike? How much is there, and what type of light chain and or heavy chain is being produced.
- [18:05]
Ronick
So often when these patients get referred over to our clinic, you know, the one thing that tends to be missing from this workup is the serum free light chains. And so I just want to talk a little bit about that and provide some clarity to our listener. Why do we have to worry about sending these if we already have the SPEP and the immunofixation?
- [18:26]
Vivek
So this is so, so important. We talked about the heterogeneous presentation of plasma cell dyscrasias. And here's the thing that you heard from us. If you're sending an sbap, you should always send serum free light chains to identify the ratio of kappa light chains to lambda light chains. And I'll explain why. So this test will quantify how much kappa light chain you have. It'll quantify how much lambda light chain you have, and then you'll get a ratio of the two. Why is that important? Well, these are cleared in the body and one of the clearance mechanisms is through the kidneys. So, for example, if somebody had renal dysfunction, you would have elevation in kappa chains and lambda chains because you're not clearing it as much. But the ratio is what matters. In addition, kappa chains are more renally cleared than lambda chains are. So if you have renal dysfunction, you might have a preferential elevation in your kappa light chain over your lambda light chain. And understanding that ratio is incredibly important. When a patient is sick, they may have elevations in their kappa and or lambda light chain. So that value is hard to interpret. But why do we get this and why is it so important? It helps us define how risky this patient with a monoclonal gammopathy is for having something like multiple myeloma. So it risk stratifies our patient and without that information, oftentimes we don't have enough to risk stratified to determine the next steps on what to do next for the workup.
- [19:58]
Ronick
So it holds really important risk stratification and thus prognostic information and potentially treatment implications as well. So you've heard it from us, SPEP with immunofixation. And then you also want to always order serum free light chains, especially at the point where they're being referred over to a hematologist and you're trying to complete this workup for a potential plasma cell dyscrasia. So going back to our case, recall once again that our patient had a normosic anemia with an SPEP that showed an m spike of 1.2. And in his case, the immunofixation suggested that it was Igg kappa. So at this point, what do we do with this information? Does this guy actually have myeloma? Do we call it mgus? Where would we go from here?
- [20:50]
Vivek
So one other important concept that we need to talk about is that for these patients with a monoclonal gammopathy, you will see that a common part of the workup is a 24 hour urine protein electrophoresis test. And you also get a quantitative 24 hour urine protein collection. This is very important and I'll explain why right now. So in the same way that the serum protein electrophoresis that Dan beautifully explained gives you these peaks and identifies if you're making too much of a specific type of protein, well, if you got that in the urine, it will tell us, are those glomerular pores messed up? Are they now allowing these larger immunoglobulins to get through? Do you have renal dysfunction that's getting through? Do you have an overwhelming amount of immunoglobulin to that kidney that's now passing through and you can detect it in the urine, a spot UPEP is pretty much clinically useless. You should always do a 24 hour urine protein electrophoresis. The spot test doesn't really give us much information at all. And we use the 24 hour values for again, diagnostic and prognostic purposes. And it can tell us, well, if you have a positive upep, that makes us more concerned that this patient might have something like myeloma. To the next question, which is, what does this patient have? So they have an m spike of 1.2 and we have no idea. Does this patient have myeloma? What do we tell them? Why are they seeing a hematologist? Especially if you're in primary care or now you're the hematologist. How do you counsel this patient? So it's first important to define what multiple myeloma is. So, Dan, how do we define multiple myeloma?
- [22:30]
Dan
So to make a determination on what your patient actually has, you really do need a bone marrow biopsy. That's, that's very important. Next diagnostic step. There are some clinical and pathological criteria that we use together to help determine whether or not we can assign a diagnosis of overt multiple myeloma or one of these other related diagnoses like smoldering myeloma, or mgus that we'll get into in later episodes. In very broad strokes, you need greater than 10% clonal plasma cells, along with some clinical criteria that define multiple myeloma or wild overabundance of plasma cells in the bone marrow greater than 60%. There's a whole list of these criteria that again, we're going to get into in a separate episode. But it all starts with that bone marrow biopsy.
- [23:17]
Ronick
So, guys, that's helpful. So essentially you're saying that a bone marrow biopsy is important for the true diagnosis of someone having a myeloma. But does that mean that every single patient with an abnormal M spike on their SPEP automatically warrants a bone marrow biopsy?
- [23:37]
Vivek
This is an excellent question. And it really gets to the crux of what happens for an inpatient with an abnormal spep. What is the urgency in their evaluation? Do we need to do a bone marrow biopsy? Right now? Let's talk about what is exactly what is an mgus? So first important thing, mgus is incredibly common in the adult population. We've done population based screening studies and have found that the prevalence of MGUs is roughly 3% in adults over the age of 50. These are asymptomatic adults who just incidentally have been found to have MGUs in the African American population. It can be up to about 6% of that population. And this was a great study. Vincent Rajkumar, who's done a lot of work in multiple myeloma, New England Journal of Medicine, 2006, published this, which was really, really helpful for us to understand what is the prevalence of MGUs and not everybody. It's not like multiple myeloma is prevalent in those same numbers in the overall population. So that's one important thing, that MGUs is incredibly common. And we don't need to do a bone marrow biopsy on all of these patients because mgus is common and not all of these patients get Multiple myeloma. Some of the older studies said that, well, okay, so the prevalence is common. We looked at how many of these patients progressed to overt myeloma. And there was a study done in 2002 that was an observational study that showed that it's about 1% per year for patients with MGUs. But then we said, wait a minute, it can't be that simple, right? It can't just be 1% per year. There has to be something else that tells us if a patient is more likely to develop myeloma. This isn't a homogeneous entity. It's very heterogeneous in the same way that the classification of plasma cell dyscrasias are very heterogeneous. And that's why the serum free light chains are critical in helping us understand whether a patient needs a bone marrow biopsy, because they are at the high risk for actually having multiple myeloma. So there are criteria that use the light chains. The type of M spike that's produced, whether that's igg versus non igg, with non igg being higher risk, and also the quantity of that M spike. If it's greater than 1.5, that's a higher risk feature. And if you have evidence of one of these higher risk features, we know the data suggests that that's the time we need to do more workup and go ahead and do something like a bone marrow biopsy.
- [26:10]
Ronick
Essentially, our job as the hematologist seeing these patients for the first time, is to interpret all these data, putting it in the context of these criteria, and then deciding if a further workup is warranted. If a patient does not necessarily meet this criteria, for instance, if they have, you know, igg, in our case, it's igg kappa with an m spike of 1.2. It's okay to forego the bone marrow biopsy at this time, but that this patient should probably be observed and, you know, should there be any major changes in their serologic testing that there'd be a low threshold to consider one in the future. Is that safe to say?
- [26:49]
Vivek
Yep, that's right. We would need to know what their light chains were. And if they had an abnormal free light chain ratio, then even with that lower IG, that IgG M spike, that's less than 1.5, if they had an abnormal free light chain ratio, we would go ahead and still do that bone marrow biopsy.
- [27:06]
Ronick
I see. So that. That really does change things. And now I understand why you said we always need to get a free light chain ratio. That makes perfect sense.
- [27:13]
Vivek
That's exactly right. And so everybody remember again, you will link this to our show notes, one of the MD calc options that you can use to calculate this to determine what your risk is of your MGUs. And if you have a low risk MGUs, no need for further workup. But if you have an intermediate to a high risk MGUs, that's when we do the bone marrow biopsy and imaging studies.
- [27:35]
Ronick
Can we briefly talk about imaging studies really quickly? So what is the recommended imaging studies that we need? I remember back from studying for step, they used to say skeletal survey. And I think that was just like a bunch of X rays. And to my understanding, and at least our practice at Rouleau, I don't really think that we do that anymore. So what is the current guidelines about that?
- [27:58]
Dan
Basically skeletal survey? You're absolutely right. It is just a whole bunch of X rays. They do the extremities, they do the axial skeleton, including the calvarium or the skull. Skull is a pretty common place for these lytic lesions. If they're going to pop up these days though, we have more sensitive imaging options. So our top two choices are either going to be whole body pet, PET ct, so FDG based PET imaging or mri. MRI is also incredibly sensitive for these lytic lesions. That's something that we do so we can figure out is this patient already showing signs that they may have an overt multiple myeloma? If there are lytic lesions present, we're going to have to do a little bit more work to fully define what their disease is.
- [28:46]
Ronick
So I think what I'm hearing is once again, in this initial visit with a patient with an abnormal M spike, our job is to one, make sure that all the different types of testing that's required for us to decide whether or not this patient has an MGUs or something else is completed. So that includes the Spep, the immunofixation, the free light chains, to consider doing a 24 hour urine as well. And then if these things start to show abnormalities as defined by the criteria that Vivek previously mentioned, that is where we also decide whether or not this patient should then be scheduled for a bone marrow biopsy in the near future and also be referred for additional radiologic imaging. And I think collectively that then helps us stratify whether or not patients truly are showing the signs and symptoms of someone with clinical multiple myeloma or, or some variation in between. Does that just about encapsulate kind of the spirit of what we were just.
- [29:43]
Vivek
Discussing that was perfect, Ronick. And I think now's a good time to take a pause. And for next episode, we can really get into the nitty gritty on how do we survey MGUs? How do we think about something like a light chain only MGUs? And what is smoldering multiple myeloma?
- [29:59]
Ronick
I think that sounds like a good deal. This was a lot of really great fundamental, but such high yield information. I definitely learned a lot. So. So thank you guys as always, and hopefully our listeners feel the same way. All right, guys, any final thoughts?
- [30:14]
Vivek
Watch more trash tv.
- [30:16]
Ronick
Our listeners can't see the screen, but Vivek looks like he's inching towards the door ever so slightly. I think it's probably time for him to get back to his Netflix and chill.
- [30:25]
Vivek
That's exactly right. That's exactly right.
- [30:27]
Dan
Yeah. All right, well, send more free light chain ratios. That's. That's what I'll say.
- [30:33]
Ronick
That sounds good. Noted. All right, guys, well, until next time. We'll see you all later.
- [30:38]
Vivek
See you later.
- [30:39]
Dan
Peace.