In a recent roundtable discussion led by Todd Druley, Chief Medical Officer at Mission Bio, three distinguished clinical researchers shared their groundbreaking work in leukemia and myeloma using single-cell technology. Comprising of Prof. Hervé Avet-Loiseau from IUCT Oncopole, France, Prof. Felipe Prósper from Clínica Universidad de Navarra, Spain, and Dr. Cedric Dos Santos from Genentech, US, the panel explored the potential clinical impact and future horizons of single-cell analysis in acute myeloid leukemia (AML) and multiple myeloma (MM), drawing from their experience across clinical, academic, and pharmaceutical sectors. Here we summarized some of the key questions posed by Todd and the insightful responses provided by these experts.
To watch the full roundtable, visit here.
The transcript has been lightly edited for brevity and clarity.
Tell us about the work your team is doing around single-cell technology in your respective fields.
Hervé: For two decades, our focus has been identifying risk factors in myeloma, aiming to differentiate patients at high risk of early relapse from those with prolonged progression-free survival. With access to more immunotherapies and CAR-T bispecifics, if we can identify these patients as early as diagnosis and not wait for the relapse to occur 18 months later, that will be a huge progress for the patients.
Using Mission Bio’s single-cell technology, we were able to, in about one-fourth of patients, identify what we call “high-risk subclones” at the single-cell level (e.g. 17p deletion, 1q gain, 1p32 deletion). These subclones can be very small (e.g. 3-5% of the cells), so with bulk analysis, you don’t see anything. It’s in progress, so I don’t have the definitive results yet, but at least in more than 15 patients, we show that these very small subclones are responsible for relapse occurring 12, 18, to 24 months later. We need to work on more patients, and we have more than 100 patients being analyzed with a single-cell tech.
Felipe: One main question we’re trying to address with your technology is whether it is useful in measuring minimal residual disease (MRD). We selected a very complicated set of samples: cryopreserved mononuclear cells from patients with AML. We focused on samples at the MRD stage to see whether the technology was able to pick up MRD in cases where we also had flow cytometry data and, in some cases, NPM1 RNA data. I’ve been very surprised by the robustness of the technology. Even in these cryopreserved samples, we were able to pick up some nice signals, point mutations, and specific mutations in individual cells.
We’re also trying to measure the quantity of MRD, working with your team to come up with the best way to quantify MRD and compare it with what we see with FACS. A clear advantage [of these molecular technologies] is that you can get a more solid and specific measurement of MRD where you always have some interpretation one way or another.
The second thing is around clonal evolution. With the single-cell tech, you don’t have to make any assumptions. You can really tell which clones are driving MRD and are driving relapse… Even if you have very few/small clones, you can monitor that clone through time and see whether it’s growing and whether you have to intervene. These are choices that we didn’t have before. When you complement single-cell [analysis] with antibodies, that is also very attractive in terms of better understanding and targeting the disease.
Cedric: We’ve been working with you and Hervé on developing an assay to look at clonal revolution mostly in multiple myeloma. In general, at Roche Genentech, we are very keen on developing these kinds of assays to enrich and better select the populations that will benefit the most from the different therapies.
In multiple myeloma, there are point mutations occurring in patients who have been treated with BCMA therapy. And those mutations that are in the extracellular domain are disrupting the interaction of the drug with BCMA. With this application combining single-cell and immunophenotyping, you can clearly address those kinds of questions in a real-time fashion, and think about adapting therapy and switching targets from that aspect.
I can say that most pharma companies have moved away from “one drug fits all patients” into a precision medicine era. And I think that the best example so far in the heme space is AML where the disease and patients are very much fragmented based on mutations. IDH inhibitors and FLT3 inhibitors are currently approved in the frontline setting, and that’s the way patients get treated. So [Mission Bio’s tech] has a lot of potential from an early disease intervention standpoint.
What is the potential for monitoring pre-cancerous conditions (such as MDS, CH, MGUS, or smoldering myeloma) with single-cell technology?
Felipe: It would be nice to be able to [use this technology] for clonal hematopoiesis in patients with CHIP, where you can identify whether those mutations do evolve while you follow those patients. But still, the clinical value of that is just very complicated. The same goes for low-risk MDS because those are situations in which identifying a specific clone with specific mutations may help us know what may happen with these patients. But still, we need to accumulate a lot of data, a lot of sequential data, from these patients to be able to answer that question. I see a lot of potential, but I still see that we need to do a lot of research in that area.
We’ve also done some studies in non-Hodgkin’s lymphoma, both follicular and DLBCL, and the results are very interesting because we get the cells from lymph nodes, and we are seeing the same cells with several mutations and the consecutive acquisition of different mutations. As a scientist, I’m really excited about what I’m seeing with the technology but I’m still not sure what is going to be translatable to clinical application. That, for me, is the question we need to address.
Cedric: The simple answer is “yes”. As Felipe mentioned, we need more data. Early intervention is the key theme in oncology these days, and the sooner you can anticipate and prevent the full-blown development of myeloma or AML, the better it is for patients. One of the questions people have with respect to clonal hematopoiesis is, let’s say you have TP53 mutation, the importance is on quantifying how much VF because 2% VF for TP53 is quite different from 20 to 50%. And that goes back to Hervé’s point about the detection of minor subclones that you’re missing with bulk sequencing.
And with this [single-cell] technology, you don’t miss it. That gives you an advantage over bulk sequencing as you can better pay attention to these particular patients and ultimately adjust the therapy. So for me, for us in general, I think early disease intervention is the way to go. There are a lot of trials now in myeloma aimed at treating asymptomatic myeloma patients ( SMM and MGUS with different therapies, including immunotherapy). So I think the field is moving to earlier detection.
Hervé: Currently, the prognostic models we have in our hands [for smoldering or MGUS trials] are not perfect. We have 20 to 25% of smoldering patients who are classified as high-risk who will never develop myeloma. So it’s difficult to propose very aggressive treatments for patients who may not progress. Nowadays, for a [pharma] company that wants to register a drug for frontline patients with a median PFS of more than 10 years, it is almost impossible. This is very problematic for the patients and the companies. So I think in the future, it’ll be about designing trials for high-risk patients, including patients who have minor subclones that will evolve very quickly.
What kind of data do you think is needed to demonstrate the clinical utility of single-cell technology?
Hervé: I can come back to the project we have going currently. We did single-cell analysis on ~150 myeloma patients at diagnosis, all treated in a clinical trial for the same treatment. And we found what I call high-risk subclones in about a quarter of them. Of course, we’ll follow these patients [through the disease course], but if we show that these subclones are responsible for relapse, I think that in the future, we’ll have to qualify these patients as high-risk (with 17p deletion detected on the bulk).
The question now is, “Will immunotherapy have a better impact on these high-risk patients than traditional chemotherapy we’re using now?” We don’t have the answer, but again, we need to dedicate some trials to answer these questions.
Felipe: We are now using MRD for designing therapies for patients with AML. What we need to do with this [single-cell] technology is to compare it with the standard of care (which is FACS in general for AML) and see whether there is any advantage in predicting which patients are going to progress early or are going to relapse. Once we can demonstrate that the technology adds significant value to this, that would be the time to implement it in clinical application. So getting data both retrospectively and using this technology in new clinical trials is what I would like to do.
It’s a similar situation as in myeloma, where we use the quantification of MRD as one of the strongest prognostic factors. We’re also introducing CTCs in peripheral blood as another factor. We really need to use these technologies in clinical trials and demonstrate that they add to patient care (with the prediction of relapse and survival), and after that, you can really implement them in the clinic. I don’t think it’s a too long way to go, but it’s still some way to go.
Cedric: Ideally, you want to use an assay that will enrich your population of interest and enhance the response rate. So [clinical utility demonstration] is highly relevant and of interest. I agree with Felipe, it’s a combination of retrospective and prospective studies to further validate the platform in comparison to the existing methods and assay. I think the Tapestri single-cell MRD Assay for AML is very good in terms of sensitivity, 10-4. There will be a debate, but I think it’s probably one log better than the current flow-based assays that most people are using.
But it has to be compared in a head-to-head fashion or in a retrospective fashion, which means a large number of patients need to be analyzed and compared across the different methods.
As the roundtable discussion unfolded, it became evident that single-cell technology is a transformative force in leukemia and myeloma research and therapy development. The insights shared by the panelists highlight its potential in shaping therapy development, early intervention, and personalized medicine in the future. While these key topics were covered, the panelists delved into various other subjects, including regulatory landscapes of different countries, immunotherapy, and the potential of machine learning. For a comprehensive overview, watch the full roundtable here.