Miami Myeloma MRD 2025 | Novel technologies being explored for MRD detection in myeloma: CTCs, NGS & more

Benjamin Diamond

Hi, I’m Ben Diamond. I’m an Assistant Professor at the University of Miami. I’m joined today by esteemed colleagues, Dr David Coffey from the University of Miami and also Dr Hans Lee from MD Anderson Cancer Center. We were just attending a meeting where we had a bunch of different emerging MRD technologies that were introduced. These are technologies that are looking to really make their niche in the field now that MRD is becoming a much more established endpoint. And we have a lot of need for these new technologies, evaluating ways to improve what we already have in the bone marrow with our assays that are focused on seeing disease in its natural environment, as well as trying to look at MRD assays that are evaluating disease in the peripheral blood to make things a little bit easier for patients. And so we had actually eight different talks today discussing different avenues for our ability to detect these small clones in many different ways. And I’m joined today by two speakers who were attending the session. And so I want to open it up to discussion among us all so we can talk about some of the assays that we discussed. And maybe to start off, I can talk about some of the more established assays that we have been using. Dr Hans Lee, would you mind to talk about some ways that we might be optimizing some of the current assays and approaches that we use for MRD, how we can make them better for the future.

Hans Lee

Yeah, great points you make, Ben. So I think really the two ways that we assess MRD currently are through either bone marrow biopies with flow cytometry or bone marrow biopies using next-generation sequencing. So the two main types. And I think, you know, primarily I think the minimum threshold for MRD threshold detection is 10 to the minus 5 sensitivity. Perhaps NGS or next-generation sequencing has greater sensitivity, at least 10 to the minus 6 sensitivity. And so I think there’s some discussion about, can we further even optimize the sensitivity of NGS MRD detection? And so there’s a nice study, for instance, by Ben Derman, recently published at University of Chicago that really took it to 10 to the minus 7, and really doing a CD1 purification, essentially, of the bone marrow plasma cells prior to running the clono-seq assay to achieve that higher level sensitivity. So I think, again, we could potentially use the existing assays that we have, further optimizing them to achieve greater sensitivity. I think perhaps those tests might be needed in the future because we are having new therapies and new ways to treat multiple myeloma, they’re achieving greater percentages of MRD negativity. And so to discriminate between some of these therapies, I think it might be nice to see greater sensitivity.

Benjamin Diamond

Yeah, this is a really fantastic technology that is being piloted in Chicago. So Dr Derman is spearheading this effort. But we really like this. This is the idea behind taking your initial bone marrow and not just running the clono-seq assay on it, but using magnetic beads to enrich for those plasma cells so that you can make sure that what you’re testing is a more concentrated sample. And that has been able to get down to much deeper levels. But again, the issue is that we must go into the bone marrow to achieve sensitivity like this. And so tracking this over the long term can be difficult. So Dr Coffey, you presented some data on using circulating tumor DNA and multi-omic approaches to try to understand how we can maybe achieve some of the same information, if not some more biochemical information from the peripheral blood.

David Coffey

You’re right. Yes, Ben, it’s particularly challenging to do frequent bone marrow biopsies in patients. They’re painful. And patients don’t want to receive painful examinations frequently. So the idea is to try and investigate new technologies that are minimally invasive, like through a blood test. These technologies include cell-free DNA sequencing, circulating tumor DNA analysis, as well as clonotypic peptides using mass spectrometry to be able to identify very, very small levels of disease through molecular and proteomic type technologies. I today talked about some technologies that basically merge together multiple complementary technologies to look at both protein, DNA, RNA, all in the same assay, so that we can improve our biological understanding of the disease, not just be able to detect whether or not disease is presence or absence. We hypothesize that these new understandings will give us some insight into why the disease is relapsing and maybe even allow us to proactively make changes to therapies before patients go on and develop a clinical relapse.

Benjamin Diamond

And Dr Lee, you as well had presented some data on using circulating tumor cells to try to understand both disease biology and MRD. And so I wonder if you could comment on that?

Hans Lee

Yeah, so I discussed the potential of circulating tumor cells detected in the peripheral blood for assessment of both disease burden and also characteristic disease biology for our multiple myeloma patients. And I think this is a really, really promising approach that we have potentially, I think, hopefully more readily available in the future. I think as a standalone MRD test, compared to bone marrow MRD tests, there’s probably less sensitivity of peripheral blood circulating tumor cells to achieve that level of 10 to the minus 5 sensitivity compared to the bone marrow MRD assay. But I think in terms of two things really for CTCs, one is you can enumerate cells to characterize disease burden perhaps more accurately than doing conventional bone marrows just because there’s patchy bone marrow distribution. So you can essentially characterize disease burden also if the patient has extramedullary disease. And this has also been found to be prognostic in terms of both in response to treatment, but also even at diagnosis. But I think even more powerful is the potential to characterize CTCs on a molecular level in a non-invasive way. And so I discussed really new technologies to actually perform next-generation sequencing, also check copy number alterations that are recurrently assessed through myeloma FISH testing on peripheral blood tumor cells. And so I think this is really exciting because patients, I think, will benefit from having a less invasive way to characterize the myeloma cells. But then because it’s also less invasive, you can actually check it more frequently and serially. And so potentially then assess clonal dynamics more accurately. And it could also be important treatment decision in terms of tumor antigen profiling, for instance, BCMA GPRC5D to inform sequencing of these novel immunotherapies.

Benjamin Diamond

And just to get a little more granular on that, you know, we oftentimes think about CTCs as being a really phenomenal new addition to our armamentarium and how we can really fine tune a lot of our prognostication. But there remains a subgroup of patients that actually don’t have any CTCs. I think some of the data is basically saying about 90% of patients will have CTCs. And so that begs the question, how dependent on tumor burden are CTCs versus underlying disease biology? And that brings the question, do you think this is a technology we’ll be able to apply to everybody or just in select cases?

Hans Lee

Yeah, I think generally speaking, for instance, if you look at the FORTE study in patients who were diagnosed with multiple myeloma enrolled on the trial, about 70% of patients had detectable CTCs when assessed by uroflow. And of course, there’s different ways to assess for CTCs, but you’re absolutely right. Maybe about a third of patients may not have detectable CTCs at the time of diagnosis. And so I think a lot of these different methods are going to be complementary. And so we’re going to have different ways to assess disease burden and also disease biology. And for some patients, maybe peripheral blood CTCs would be a great option. For other patients, it may not be a great option. So one size won’t fit all. Just like our myeloma therapies, one size won’t fit all. Our diagnostics one size may not fit all.

Benjamin Diamond

I was kind of leading you down that road. But with that in mind, then I wanna ask Dr Coffey, I mean, what do you think in terms of complementary? We heard a bunch of different methodologies here. Some of them might make more sense to combine than others, we might have to combine bone marrow based testing and peripheral blood-based testing. What’s your take based on what we heard today?

David Coffey

Yeah, I agree. I don’t think a single technology that we looked at today is going to be the be all end all. I think we have multiple technologies that answer different questions. I like the words burden and biology. Some are very good at burden and some are very good at biology assessment. In fact, we also need to think about the immune microenvironment. As our treatments evolve more and more towards immunotherapies, we also need to be cognisant that in addition to studying the biology of the tumor cells, we also need to understand changes within the immune microenvironment that may enable a more progressive disease phenotype or perhaps a more resistant one versus a microenvironment that’s gonna be more responsive to immunotherapy. So I think each of the technologies offers different perspectives on the disease, the immune microenvironment, the biology of the tumor, as well as the burden assessment.

Benjamin Diamond

I completely agree with you. And to round out some of the other technologies that may not be represented by speakers here today. Some of the other things that we heard about today were to assess circulating tumor DNA by using targeted sequencing panels longitudinally, looking at actually very cool technology, looking at whole genome sequencing of circulating tumor DNA, basically doing a needle in a haystack approach, also looking at DNA longitudinally, and then finally looking at clonotypic peptides, in other words, proteins that are very specific, almost like a fingerprint for each patient’s unique myeloma and tracking those longitudinally. And I’ll add that for these technologies, what you really need is a baseline sample to inform your future samples. So very similar to like doing a clono-seq ID and a tracking assay. And so you can see here that regardless of the technology that we’re using, all roads lead to at least one bone marrow biopsy. And so with that in mind, I think, David, this might be a good opportunity for you to talk about how we might be able to sample more bone marrows over time. It seems like everybody’s gonna need one if we really wanna understand the disease in its totality and we can’t fully rely just on blood, unfortunately.

David Coffey

That’s true. You know, bone marrow biopsies are painful, as I mentioned, and that’s one of the reasons why we’re looking at minimally invasive ways to sample the disease through the blood. But there still is great value in looking at the bone marrow. we can’t completely replace the bone marrow with blood. So at the University of Miami, for example, we’re studying a new investigational device called the bone marrow port that allows one to place essentially a titanium screw into the bone marrow so that we can bypass the painful cortical bone marrow sampling and allowing for more easier sampling just directly through the subcutaneous tissue into the bone so that sampling can be less painful, less problematic for patients, so that we can do more frequent sampling, resulting in more dynamic assessment of the disease. If patients are interested in this technology, they can reach out to us and we can assess them for the trial.

Benjamin Diamond

I think that’s a good place to close for now. We had a really interesting meeting today. I think recordings will be available, but I think there’s a lot to be excited about for the future. We have a lot of technologies all vying for space, but likely we’re gonna see them all working together so that we can achieve the same goal of assessing MRD in the best way possible.

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