← The Fellow on Call: The Heme/Onc Podcast
The Fellow on Call: The Heme/Onc Podcast
Episode 144: Myeloma Series, Pt. 5 - Myeloma Risk Stratification and Response Criteria (2026)
Ronak Mistry, Vivek Patel, Dan Hausrath
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Hey, friends.
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This episode of the Fellow on Call.
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Is not meant to be used for medical advice and is intended for educational purposes only. Patient information has been modified to ensure privacy. The views expressed in this episode do.
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Not necessarily reflect the views of our employers. Enjoy.
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Welcome to another episode of the Fellow on Call, the hemok podcast. I'm Vivek.
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I'm Dan.
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And I'm Sean.
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And as you know, this sounds a lot different than before because Ronuk is lazy and he's taking the day off, but today we're really excited to get into another episode. Really? Last week we talked about smoldering multiple myeloma. This week we're going to recap what we talked about then and introduce everybody into important key concepts into multiple myeloma. Right before we get into the treatment episode, we're going to talk about response definitions, risk stratification, diagnostics criteria, all of the really important things that you need to know as we get into these future episodes.
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C
Yeah, it should be a good show. I mean, we're going to get to talk about some basic science. VDJ recombination rears its ugly head. So I'm excited to talk about that. Let's do it.
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A
All right, everybody. Only Dan likes that, but let's go ahead and roll that show. All right, guys, really excited to be back today. I'm glad Ronick's not here so we don't have to do the fluffy intro because we can really cut down on time. I think our listeners are going to be happy. We'll do one quick thing really fast. So here Sean, as everybody met last week, he went from fellow to attending. He's a guest host on our show. Really excited to have him. Longstanding show note writer and really helped us make this podcast. So, Sean, give us a fun fact about yourself. We haven't done this. A lot of our listeners know a lot about my trashy tv. But, Sean, what do you like to do?
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Giving no warning, by the way. Yeah, just adding.
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So I actually used to play tennis all throughout when I was growing up, playing through high school, I played on my varsity team. I quit that for many years, all the way through med school and through residency. But in fellowship, I started to pick it up again and now usually play about once or twice a week. It's been great. And also started watching it more and had a chance to go to the US Open earlier this year for my second time. Would highly recommend. Definitely a great trip, even if you're not a huge tennis fan. It's just a great atmosphere A lot of fun watching the matches, especially at night.
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I just had that on tap. Very impressive. Have you seen Challengers, the movie in 2021?
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I have not seen Challengers yet, but all the people that when I tell them I play tennis, that's their first thought.
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Hugely outstanding film. Really, really well done. It is not the usual slop that hits theaters these days. Like whoever made this film actually cared about filmmaking. It's wonderful.
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So if you stop here, watch that movie. All right, everybody watch the movie. But to move things along, let's go ahead and get started on the episode today talking about the introduction to multiple myeloma. So I'm going to kick it off with a case. We have a 63 year old female with an IGG kappa m spike of 2.2 Kappa light chains at 70 and Lambda light chain at 7 with a ratio of 10. The S PEP and light chains were sent because she had a normocytic AN with a hemoglobin of 9.5 and a normal nutritional workup. She notably had a normal calcium and creatinine. Remember to always get light change with that spep. As we've discussed previously, we also always get a 24 hour upep for patients who have a higher risk MGUs like this patient in order to risk, stratify and obtain a better understanding of their baseline disease status. This showed 600mg over 24 hours of monoclonal protein excretion recall. This is a synonym for the Bence Jones protein, which essentially means there's an overwhelming amount of protein to the kidney resulting higher levels of detectable excretion. She ended up then getting a bone marrow biopsy because she did have this high risk MGUs. And remember the criteria for that. Any abnormal free light chain ratio, M spike greater than 1.5 or a non IGG M spike and her marrow showed 60% clonal plasma cells by IHC. We then got a PET CT which showed lytic lesions in her T5 and L3. Notably she was asymptomatic. So now we clearly have a patient who has symptomatic multiple myeloma. So let's talk a little bit about our diagnostic testing here. So can one of you go through a little bit about what we do to diagnose these patients in terms of the bone marrow biopsy?
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C
Absolutely. So like you'd said, you know, our patient got this bone marrow biopsy because of the elevated M spike, the abnormal free light chain ratio. And when we do that we get an aspirate and a core Specimen. So if you haven't done a bone marrow biopsy before, there's sort of a multi part. We sample first a liquid part of the marrow and then an actual chunk of usually some trabecular bone and the actual tissue of the marrow. In the aspirate, we are able to get a smear, so just like a peripheral blood smear, but smearing out those little, they call them spicules of marrow that you get in the aspirate. And we'll also be able to sort of run cell counts on that and some ancillary testing, including flow cytometry, cytogenetics, and molecular testing. So this sample is kept alive. It's not put into a fixative. Right. So we're able to do all that sensitive testing. On the core biopsy. We get a sense of the architecture of the bone marrow, its structure, its cellularity. And this is the specimen that we use to do immunohistochemistry, or ihc. And that will also help us enumerate specific types of stells based on whatever stain is being done. Remember that the flow cytometry, clinically, we're looking at multiple cell surface proteins that are expressed on live cells in suspension. And with that, we can identify the immunophenotype. IHC looks at protein expression by staining cells on a fixed specimen. So you kind of stain the cells, and they'll turn brown based on whatever surface marker you're looking for. With that, you can use the percentage that are stained versus the percentage not to estimate a percentage of cells that are positive for the marker you're looking at.
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So our patient's report said there were 60% plasma cells. How did we really get to that number? And so recall everybody in our heme path series, first series we ever recorded, one of our most popular series, we discussed all of these methods for blast enumeration. But what about for plasma cell enumeration? Shaun?
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Yeah, so we use a combination of different methods that serve different purposes here. And so if you'll recall from that earlier episode, when we do flow cytometry, oftentimes plasma cells don't survive that process very well. And that can lead to underreporting on flow, the amount of plasma cells that are actually in the sample. And so what we typically will need to do is use IHC staining on that core biopsy specimen to get a better sense of how many plasma cells are in that specimen. Plasma cells typically express unique markers like CD138. And so we can use stains for that to Determine the plasma cell percentage. Patients with myeloma can have a patchy distribution of bone marrow plasma cells, and so that can make it a little bit difficult to determine the overall percentage in general when you're just looking at specific portions of the core biopsy. Flow cytometry does still have a purpose, though. So remember that flow cytometry has the advantage of looking at multiple surface markers on each individual plasma cell rather than just looking for one protein at a time, which you would get when you do ihc. And so when we run flow on these plasma cells, we can see if there's an abnormal expression of different patterns of cell surface markers compared to what we would expect for normal plasma cells. That allows us to identify if there is an aberrant immunophenotype on these cells. And that's what really makes us confident that these are myeloma cells and not just regular plasma cells. The other part of this that we look at is that with the combination of IHC and flow cytometry, we're also looking to see that there's a restriction in either kappa or lambda. And so if you're seeing a relatively equal amount of those two, that may tell you that this is more of a polytypic process rather than a monotypic one, which is what we expect in myeloma and the other monoclonal chemopathies.
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And, Shawn, that's really, really important. We always talk about kappa restricted populations, lambda restricted populations. In general, our cells should choose either kappa or lambda. But if they're all choosing K, all choosing lambda, that's suggestive of clonality. So that's really, really important. So in addition to that, on this bone marrow biopsy, we end up getting CD138 enriched plasma cell enriched fish testing. And that's really important that we enrich our specimen for plasma cells before running our FISH testing to get accurate results on a fish myeloma panel. So, Dan, can you tell us a little bit about risk stratification using fish? And why do we also get an LDH and beta 2 microglobulin albumin? Why? Do those other labs mean something?
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Sure. And I'll just give a spoiler here that, of course, things always get a little bit more complicated. And so we've had some recent updates to this, and I'll let Shawn speak to that since he's sort of really at the bleeding edge of all this. But speaking more basically, we use that FISH testing to kind of help us out. And we look at the translocation 14, 16, and 4 14. And of course also the deletion 17p. Pretty much no matter what malignancy you're talking about, if you're seeing deletion 17p or loss of P53, you're in kind of a high risk territory. And then also the amplification 1q. So greater than three copies of 1q. We also want to point out sometimes you may see on the report a gain of 1Q21 that may be reported out that is not the same as 1Q amplication, which is definitely a high risk thing. This 1Q21 is a separate entity and we also can use in addition to risk stratifying multiple myeloma, we can sometimes use that fish testing to help us try and understand which smoldering myeloma is going to be higher risk as we referenced in our last episode.
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Another important rearrangement that I want to point out is translocation 1114 myeloma is complicated, but that translocation has shown to be sensitive to Venetoclax based regimens. We'll talk about this in a future episode, in a relapse refractory episode, but really wanted to update our listeners on that in this updated series. And when it comes to the LDH albumin and beta 2 microglobulin, these are our prognostic. And you'll see that these have been incorporated into the ISS and the revised ISS scoring systems. The revised ISS adding high risk cytogenetics, which is an important variable. And so remember that these replace the much older Durie salmon staging that was developed in 1975. And so those are no longer really relevant. But you'll see some of those referred to in the literature if you're reading older myeloma studies. But remember that an elevated beta 2 microglobulin greater than 5.5 is a true high risk feature. And that's really important that we identify high risk patients with multiple myeloma as it does inform our consolidation and maintenance strategies. And that's very important in 2025. So Dan had mentioned 1416, 414 deletion 17p, there's amplification 1q, that's four or more copies gain 1q. And he said, well amplification 1q was higher, was definitely higher risk. And these are sort of older things. And we also had translocation 1420. So Sean, can you tell us some updated criteria for this? And remember our listeners, this will all be in our show notes but Sean, can you tell our listeners what the updated high risk myeloma features are, of course.
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Yeah. So in 2025, there was actually an updated definition of high risk multiple myeloma that was put out by the International Myeloma Society and the International Myeloma Working Group. And so this is now the new consensus genomic staging for high risk multiple myeloma that we are now going to be using going forward. And so, again, the whole idea of these risk stratification systems is to get a better sense of which patients are at highest risk for progression and be able to tailor our treatments, ideally to be best fit for patients based off their risk stratification. So there's a lot of things that we've understood previously that contribute to that risk, but it's not as simple as if you have this, you're automatically high risk in a lot of cases. We've realized that a lot of these risk factors actually interplay with one another. And having multiple risk factors together is what really increases the risk significantly in many situations. So, again, we'll list the full criteria in our show notes. But just as a summary, if you have deletion 17p or a mutation in TP53 that you see on NGS, that is still high risk, as is often the case for many of the cancers that we treat, if you have a translocation that we mentioned, so 4, 14, 1416 or 14 20, that would be considered high risk if you also have either gain or amplification in 1q or deletion in 1p, if you have a deletion in 1p, if that is also paired with gain in 1q, or if it's a biallelic deletion in 1p, that counts as high risk. And then finally, if you have a high beta 2 microglobulin, so greater than 5.5 milligrams per liter, and that's in the setting of a normal creatinine less than 1.2, that also is one of the criteria that you can meet to be high risk. So overall, there is a combination of different ways that you can meet the high risk definition. I think it's always important to keep in mind that if you're looking back at definitions of high risk for older trials, especially if they use high risk as an inclusion or exclusion criteria, you want to go back and look at what they use for that trial specifically, since these definitions are changing over time.
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And, Sean, it's really important that you highlight that. And I think this is the most complex thing about multiple myeloma. So remember, pathophysiologically, we have this MGUs. What is that? That means that for some reason you had an aberrant plasma cell population. Often this is a trisomy. Actually, when we look at the older data, we see this is a trisomy. So we have this patient who's got some sort of an aberrant abnormal plasma cell clone that's mildly proliferating. Then for some reason, it develops another mutation, another hit happens. And the things that Sean described are the mutation, the hits that tend to lead to a more resistant multiple myeloma clone. A multiple myeloma clone that's more likely to relapse after treatment, more likely to come back quickly rather than come back later. And so all of these things are really important. And don't memorize these. Look them up. And so if you have a patient in front of you, look up these criteria. Super important. So you can listen to this. Also look at our show notes and look at this, because it's really important as you think about treating these patients. So let's move on and talk about response criteria and MRD testing. Don't worry about these treatment details as we talk about some of these cases as we'll go through this more in future episodes. So our patient was transplant eligible, and she got Dara VRD based on the pivotal Perseus trial, and she had a planned autologous stem cell transplant and consolidation. So I had this patient in my fellowship, and she got four cycles of Dara VRD and she achieved what my attending said was a vgpr. So what exactly does that mean? What does a very good partial response mean? I mean, when you think about myeloma response, you're like, what are they talking about? So can one of you go through what these response criteria actually mean?
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So when we talk about response in myeloma, it can actually be a little bit of a confusing topic. So again, always refer back to the IMWG response criteria, which we'll link in our show notes. And so there are actually defined ways of quantifying a response in myeloma. And so we can have a partial response, a very good partial response, a complete response. And then we can also talk about things like MRD negative and MRD positive complete responses. And so first off, let's talk a little bit about disease progression as well, because that's important for us to consider as we're talking about patients who are getting treatment, maybe in one of these remissions, and then at some point down the road, their disease may start misbehaving again. And so again, there is a defined Criteria for what constitutes progressive disease. In general, it's a greater than 25% increase from the lowest response value or the nadir for whichever metric that we're tracking for a patient's disease. So for patients with a detectable M spike, a greater than 25% increase from their lowest M spike. And if that's undetectable, then that's zero. The absolute increase must be at least half a gram, though if there's an increase in the urine M spike, that also counts. For patients that are free light chain only disease, there has to be a greater than 25% increase in the difference of their involved and uninvolved free light chain levels. And again, the absolute increase must be at least 100 milligrams per liter. The bone marrow plasma cell percentage can also come into play. And so a greater than 25% increase as long as it's at least over 10% in total. And if there's any new evidence of any new bone lesions or plasmacytomas or progression in any existing bone lesions that we know about, those also count as potential criteria to meet for progression.
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And I think that's really important that you defined progression first. And remember, to our listeners, progression can be asymptomatic lab value elevations. And that's what makes it challenging. On who in multiple myeloma do you really, really need to treat right now? And who in multiple myeloma can you still watch under active surveillance? And that's very, very challenging. There's no right answer. The trajectory of these labs matter, how quickly these labs change matter. And that's a little bit more of a nuanced discussion. But these are the definitions for progression, particularly when you think about trials and things like that. So I'll go on to talk about what these other response are. So in general, it's a good rule of thumb to remember it's always best to get to at least a VGPR prior to transplant. That's really what you want to do. Occasionally you'll take that PR patient to a transplant, but you want to get to this very good partial response vgpr. So what is that? That's basically like barely any M spike left, greater than 90% reduction in your M spike. And I think that's the easiest way to think about it. And it's important to note that the free light chain ratio does not have to be normal. So it's really a greater than 90 reduction in your M spike. So barely any M spike left, partial response is a 50% reduction. So if I got 50% down. I'm a partial response. If I got 90% down, barely anything left, I'm a very good partial response. And then if I no longer have a detectable M spike, that's a complete response. There used to be this thing called a stringent complete response where you do a bone marrow biopsy and if they had no plasma cells left over, that was called stringent complete response. But really in the modern times, that's really not as relevant as we think about things like MRDT testing, which Dan's about to talk about in just a second. So one important thing, just to reiterate here, that if a patient is undergoing induction therapy and you're planning on consolidating them with a transplant, you need to collect those stem cells, ideally after about four cycles of therapy. I think that's the sweet spot when it comes to many of these studies and how this is done so that you can get a good collection of their stem cells. So just keep that in mind. Early referral to transplant is very important in these patients with multiple myeloma. And we'll talk about the nuances on two transplant, not two transplant, how MRD is involved in future episodes. So I've mentioned a lot now about mrd. Dan, can you walk us through what MRD means? What is this measurable residual disease? Why is this more important than just a cr, no more M spike?
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So essentially I like to think about it like just increasing the power of our microscope. Right. We're looking deeper and deeper, just like we do in other hemologic malignancies to see is there any sign that there's some of this plasma cell clone left and if so, how much of it is left? And there's a few different platforms out there looking at this, but basically the goal is to try and understand who has just a little sliver of detectable disease left and who doesn't. Because there's some thought that MRD negativity is going to be a surrogate for improved overall survival and potentially opening door towards determining whether or not someone's really been cured of this disease. And in myeloma, there's, like I mentioned, two different platforms. We're going to see next generation flow or next generation sequencing based MRD assessments, depending on who's running the trial and what their platform is. I'm going to talk a little bit about flow first. And so flow cytometry, it's something we already do on bone marrow biopsies all the time and it's really good. It's Got great sensitivity. But I don't know if any of y' all have experience reading flow. It's kind of like reading druidic runes. It's like there's these little clusters of cells. They're antibody panels with different fluorophores. There's a lot of sort of inter lab variability. And so next generation flow, the goal was to try and standardize these panels a little bit more, automate the process as much as possible, and with that, improve sensitivity from about one in 10,000 all the way down to one in a million with the next generation version. Now it does require live cells because it's a flow cytometry platform. And so you need to run the testing quickly within 24 to 48 hours of collecting the specimen. And it can't really determine whether there's been clonal evolution or not because we're not looking at the actual genetic sequencing. We're just looking for those signature cell surface markers that tell us about the plasma cell clone. Now, you may recall from earlier in the episode where we were talking about the aspirate, the plasma cells just don't survive as well. Could that affect sensitivity? Ultimately, this is a sensitive enough assay that we're not worried about a little bit of difference here and there between the aspirate and the core. Were looking well below the threshold of being able to see anything visibly. NGS or next generation sequencing is the sort of competing platform here. And it's something we've talked about in terms of being able to use molecular testing, looking at the genetic sequence to identify about one in a million cells left over of residual disease. There's actually even some emerging data published at ASH that suggests we may even be able to get down to 1 in 10 million cell sensitivity. So really, really, really fine grain basically, in these B cell malignancies, plasma cell malignancies. Remember that to get to the point of being a plasma cell, that heavy chain variable region, or light chain variable region had to undergo recombination. That's sort of what allows these B cells to express B cell receptors that can detect all sorts of different antigens. And so that heavy chain or that light chain variable region has undergone VDJ recombination. And it has this unique genetic code that's going to be expressed in all the different copies of that cell that get made, all the different parts of that plasma cell clone, and it's going to be expressed by all the daughter cells of the plasma cell clone. Right in that way, it serves as a sort of barcode on these malignant cells. And so this NGS platform uses universal primers, their conserve regions and the V and J regions that will serve as a template for those primers to connect to. And it just sequences all of the sort of variable regions that it can find. And basically it's able to identify which of these particular barcodes is dominant. And that serves as the sort of clonotype, as they call it. This is the molecular signature of that patient's tumor. And for that reason, you do need sort of a baseline to be able to say what their disease actually is. Fortunately, most of these platforms can actually look back at that original biopsy, even if it was done a little while ago, and pull that genetic data and figure out what the dominant clone is. But once you have that, you will be able to say, okay, if we're detecting this genetic sequence, we know that there's some residual disease left around. And again, because this is genetic data that we're getting, genetic sequencing, some of that finer grain detail that you get might help you determine has there been clonal evolution, what population of sub clones is being generated. Some of the other advantages, you don't need to process this immediately because, again, we're talking about extracted genetic data and not live cells. It's able to capture almost all IG gene rearrangements. And like I said, it uses those universal primers for clonality detection, and it's been standardized by adaptive biotechnologies. And so it's a really sort of universal and available platform. On the downside, it is expensive and it does take a little bit longer to come back. So slow cytometry results, remember, come back quickly. This, we're talking probably more five days, two weeks, somewhere in that time range.
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Dan, that was really, really good overview there. So keep in mind, you could listen to the different techniques and how they're running. We're just getting a deeper level of detection. Is there any scrap of this multiple myeloma left? We know that patients with multiple myeloma inevitably relapse, right? That's what we know. We see this as a chronic malignancy. It's something that we think we can obtain, quote, unquote, functional cures, meaning the patient is doing well. They might live a decent life expectancy in some ways, a relatively normal life expectancy if they're older patients with treatment. But we do know the myeloma's lurking in there somewhere. And so we know if we can't detect this at a one in a million threshold, obviously that patient's Gonna have a better prognosis. Their clone, whatever genetics were in that clone were more responsive to that treatment. Right. That's probably not your higher risk patient that we had talked about that. Sean talked about the updated cytogenetic criteria for that. So it has been shown to be significantly correlated to progression free survival, keeping the patient in remission for as long as possible, whether it's going to correlate to overall survival. You would need decades of time to figure that out. Right. And so this is why now, in 2025, MRD is now a surrogate marker for drug approval in multiple myeloma because we know it's so highly correlated with progression free survival. And when it comes to these patients, they're living so long now, fortunately, we want to give these patients the best access to drugs as possible. And that was the argument that was made during the ODAC sessions at the fda. And it was pretty much unanimously voted to be accepted that we use MRD as a surrogate for drug approval and multiple myeloma. So this is very, very important, really important to understand in clinical practice. We don't really know how to use it yet entirely. And we're going to go through that in our treatment episodes. We'll walk you through the data. Really excited to get into that. But Sean, I'm going to let you finish out with any closing thoughts you have on what we talked about today.
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Yeah. So with mrd, I think this is a very exciting area of research for a couple of reasons. So again, we know it's a very strong correlation with sort of the overall prognostics for a patient. We have actually pretty good evidence which we'll link in our show notes from a meta analysis showing why we can use it as a sort of an intermediate endpoint for these trials. And that is so important when you think about the fact that we've had so many advances in how we treat myeloma, our patients are not just living longer, but staying in remission for so much longer that it's becoming increasingly hard to actually measure things like PFS in a reasonable timeframe. So for example, if you look at the data from Perseus, the progression free survival at four years for patients who were getting quad therapy was over 80%. And so we need a way to be able to get a more immediate way to evaluate new treatments as they're being introduced. This is a really helpful way for us to be able to evaluate that for. And there's a lot of exciting things in terms of studies that are currently ongoing to help look at whether MRD can be useful for clinical decision making. One of the areas that we're looking at is whether MRD negativity that's sustained can be used as a way to identify patients that may be able to discontinue therapy and switch back to observation. And so rather than just being on maintenance for an indefinite period of time until they progress, we may be able to identify patients that might be lower risk for progression and can be closely monitored. And so that is an area that's an active interest. But there is some exciting data that's already been published so far. And so we can expect that over the next few years we may see more information about how to use MRD to identify which patients we can potentially deescalate therapy on.
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A
And I think that's the key that Shawn is pointing out here. It's a very useful tool for de escalation of therapy. Whether flipping a patient from MRD positive to MRD negative, meaning escalating therapy. That is a difficult question to answer. And we've seen from. We talked about this in our colorectal cancer series. Didn't work in Dynamic or Dynamic 3, where we just escalated treatment for CTDNA positivity. Obviously a different disease, but that's the challenge. And I think we need to remember one of the most important trials in Hodgkin lymphoma was response adapted treatment in Hodgkin lymphoma. The RATHL study where you used PET scans, if they're PET negative, drop bleomycin. And I think that mantra is really, really important when we think about multiple myeloma. Let's de escalate therapy. And I think starting there with MRD testing is very logical. Makes a ton of sense. That is likely the patient you're okay with de escalating that therapy for. And I think that's really going to improve the quality of life living longer and living better. And if we're making patients live longer, let's make them live as best as possible during that time period. So really well said, Sean. Really excited to look into the data. And guys, I think that's a pretty good episode for today. You think we're done?
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C
Yeah, let's call it.
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B
Yeah, I think we had a great discussion.
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A
Really excited to get into our next episode, which is treatment in the frontline setting for multiple myeloma. We're going to break it up into multiple parts to make it digestible. We're going to give you all of the updated information and re release our old episodes. For historical context. If you're a nerd and you're interested, all that stuff's going to be there. So excited to see everybody next week. And until then, we'll see you later.
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C
Peace.
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B
See you later.