iwHRMM 2024 | Defining high-risk multiple myeloma: recent advances in the field & future considerations

Ken Anderson:
I’m Ken Anderson here honored to chair a session related to the advances in high-risk multiple myeloma and I’m joined by a distinguished panel and I’ll let them introduce themselves.

Francesco Maura:
Thanks Ken, my name is Francisco Maura from University of Miami.

Simon Harrison:
And I’m Simon Harrison from Peter McCallum Cancer Center in Australia.

Ken Anderson:
So as you all know, know we’ve had major advances in multiple myeloma, 19 drugs in the last 20 years. And in fact, in the most recent study, the PERSEUS trial, where four drugs, quadruplet therapy, are used initially in newly diagnosed patients, transplant, consolidation, and maintenance, the progression-free survival now is 16 years projected. Nonetheless, this conference that we’re attending today is really so central because there are high-risk multiple myeloma patients who either present with genetic features that makes them high-risk, high response rates but early relapses, or eventually with subsequent relapses patients acquire high-risk myeloma features. So we’re here discussing in really a roundtable format so that we can understand the obstacles to progress and try to propose collaborative efforts to solve them. So maybe I can ask Francesco first, but he has a wonderful paper in Journal of Clinical Oncology where he’s looked at deep sequencing and looked at, I think, 12 different genomic groups, subgroups in myeloma and how they respond differentially to different treatments. But maybe you can expand on that and talk about high-risk myeloma and how we can personalize care for myeloma patients using your model.

Francesco Maura:
Yeah, thanks. So yeah, our work, we leverage almost 2,000 patients to first define which are the genomic drivers involved in myeloma. And I think we have a good picture. It’s not perfect. There are a lot of genes, as some of the ones that you presented also today, that are not included in the model or not considered involved by DNA mechanisms and other genes that are just not based on DNA and we still don’t know or immune factors that may be independent so those are not part of the model right now, but what is important is that high-risk is not just one single bucket but is extremely heterogeneous population. As we know in clinic patients with the bad alteration can actually [have] very long responses and patients with non-high risk features can actually have a very aggressive disease, so clearly there is a gap in our knowledge in our understanding. And I think our paper in putting together so many different features, you know, the 12 groups plus 150 genomic drivers plus treatment and genomic and clinical factors, ECOG, age, try to kind of like create a model that takes into account the whole patient, not just like an aspect of it, and try to use the information to predict the outcome. And what’s emerging? There are clearly some patients that don’t benefit or are not benefitting from these progresses. An example, patients with this high APOBEC, this kind of like bad mutagenic process active in high-risk myeloma cells, the overall survival is three years with VRd. So that’s not PFS, it’s overall survival. So it means that these patients have a disease that doesn’t respond to anything. And I think it’s important to identify these patients because we cannot wait five, ten years to get you know the good drugs like CAR-T and bispecifics approved for every patient and having these patients die so early and not responding. So we need the – and I think IMS and IMWG and all the organizational information are trying to push this like more focused trials on high-risk and better identifying them so we can accelerate drugs for patients not enrolled in clinical trials.

Ken Anderson:
Fair enough. And one of the real features of this workshop is not only the decharacterization of the tumor cell itself, but it’s also trying to understand changes in the microenvironment that might correlate, be associated with, or even causative for standard risk disease versus high-risk disease. Maybe you could comment on your wonderful talk in terms of changes in the microenvironment that may be targets for novel treatments to try to improve our outcomes?

Simon Harrison:
Yeah, I think Ken, that the newer therapies like CAR-T and bispecifics really kind of interact with both the tumor and the microenvironment. So the bad biology in the tumor interacts with, or leads to bad biology in the microenvironment. And I think in your data around simple things like beta 2 microglobulin and its impact on the dendritic cell compartment, which seems to be really important to get entry of the T-cells into the tumor microenvironment to deal with the malignant clone. And so that might be one of the answers to say when the patient expresses the antigen, be it BCMA or one of the other newer antigens, but they still don’t respond, we still really don’t understand that kind of dynamic. You know, patients should respond, they have antigens, they’re having a targeted therapy against that. And how do we understand to pick out these patients who we think should be responding and are not? And then what’s the difference between the bone marrow tumor microenvironment and the extra-medullary disease microenvironment, which really is very poorly understood. So I think there’s lots of information and targeted biopsies and really having a focus on that area is going to be really important to move that field.

Ken Anderson:
Wonderful. And I’ll just mention I was charged with trying to talk about the future of genomics, immunomics, and the microenvironment in a short time. And I was trying to be very positive, which I am, about taking the wonderful work of Francesco and applying sequencing across not only the different myeloma categories clinically, but correlating with clinical features and outcome, but also with changes in the microenvironment, particularly the immune profiling and other changes with accessory cells in the microenvironment that may be in fact very important in promoting the tumor cell growth, survival of drug resistance, or conferring immunosuppression. And I mentioned, you know, most of the sequencing studies or profiling studies we’ve done have been RNA-based and now we’re switching to sequencing. But there are early studies suggesting that proteomic profiling may be possible. I mentioned a couple of examples where I think epigenomic profiling looking at mechanisms that the myeloma manifests as a consequence of changes in the myeloma cell or binding to the bone marrow microenvironment. I mentioned that there’s an adverse stromal signature that is induced or triggered when myeloma cells bind to stroma for example. And then I just mentioned what is one of my favorite topics and yours too, of immunogenic cell death, the idea that if you can kill a myeloma cell with traditional or novel therapies or immune therapies, and the dying myeloma cell can in turn trigger what looks like a viral mimicry of type 1 interferon response, and those patients who get in fact that immune response tend to do better. And the idea is how can we exploit that I think we’re doing it with immunotoxins, you mentioned low-dose radiation treatment as a possibility, and I mentioned a research question so far but whether something like beta 2 microglobulin levels either on the myeloma cell or free circulating can be immunosuppressive by blocking this immunogenic cell death, blocking the ability of the dendritic cell to function or migrate to the appropriate areas, or blocking the effector NK and T-cells too. So, there’s factors in the host that we need to understand to understand truly high-risk myeloma, and it brings up new targets for possibilities for therapy as well. So I think one question, maybe I’ll just finish with this one, but this is, you know, we’re all so excited about the progress that’s happening in myeloma. It’s honestly extraordinary. And the question that was brought up repeatedly was, you know, just as an example, we have a new definition of high-risk multiple myeloma that we as an academic community with the International Myeloma Society, International Myeloma Working Group, we have consensus and this will soon be published. It’s important so everybody uses the same system, clinical trials so we’ll know that we’re testing the same kinds of patients. But much of it depends on sequencing and right now everything is really predicated on FISH testing, as you know. So how are we going to actually in the real-world make advances and get sequencing-based technology out in the real-world so that we can appreciate better the biology, categorization, and most importantly get the right treatment for our patients? So, any thoughts about how we can increase education awareness and actually use of sequencing in the community?

Francesco Maura:
So there are like different levels one what is the optimal sequencing and one is what the minimal sequencing that is required. So in terms of optimal sequencing, of course, whole genome sequencing will be the optimal for many different reasons. It’s more accurate, more comprehensive, more granular, but despite I love it, it’s impossible right now because there are technical issues like storage, analysis and things that no one can do it right now on large scale. Different is the clinical trial. For the targeted panel or whole exome sequencing, I think as a new thing, people are concerned about insurance, about how to do that in daily life and daily activity. But we have so many examples of cancers where this is already done automatically, like breast cancer that has so many women every year with cancer and most of them get a screening for mutations or colon cancer for MSI and there are multiple companies that have the FDA clearance so I think it’s after the first shock that people hear and say, “Oh I need to do sequencing today how can I do it?” then I think people will realize that it’s actually much easier than what they think that to just detect… then if we go more and say replacing FISH with NGS completely, that might be more difficult because we have the immunoglobulin region and that’s why I think there are some discussions both at the EMN, here, but also in the IMS with Nikhil Munshi about trying to develop a consensus panel for the community, something that every center can look and say okay that’s the minimum requirement to get the good stamp of enough and then computational type and the people can just run easily without doing too much manipulation or time-consuming experiments. I think these aspects are needed. I don’t see them as a big limitation as soon as people will realize how important they are. And as soon as we have treatment for high-risk, people will really rush to do that because that would be of course a game changer for patients.

Ken Anderson:
Now I think those are such good points and we can learn from our solid tumor colleagues. Lung cancer is another example, so it can be done. The other thing I just would bring up is the cost, you know, we use these technologies for research, the cost is coming way down so it’s becoming much more practical.

Simon Harrison:
Yeah and in the Australian context in a universally reimbursed healthcare system, cost is a really important driver of what technologies are brought in and FISH is actually really expensive. It’s labor intensive, you need myeloma cells rather than DNA and I think there’s a very rapid switch in our jurisdiction to go with the DNA-based technologies. So I think that’s the other part of that question. One of the points I wanted to kind of think about is when we’re looking, thinking about the tumor microenvironment, clearly that’s a dynamic situation and what happens early and what happens later on is really important and so time is an important variable in the equation to look at tumor and microenvironment interactions. And so, you know, we tend to do biopsies at the start, but what we tend not to do are sequential biopsies even at relatively early time points to really see what the dynamic changes are when we’re using immune based therapies and a lot of changes are happening within the first month in terms of debulking of the tumor, tumor cell, immune cell infiltrate and those kind of things. And I think trials in particular need to take that into account and so biopsying, having multiple biopsies and multiple biopsies over short periods of time I think is going to be essential for us to really understand the changes in the microenvironment due to eradication of the tumor, but also the impact of the novel therapies on the microenvironment, both positive and negative, because T-cells get affected by the tumor microenvironment, and when they’re interested early, they can be turned off by the tumor microenvironment. And understanding some of those mechanisms and circumventing them, I think is going to be really important to move the field forward. And Jeremy, my PhD student, who’s producing those really nice time course images in the mouse models is going to be presenting some of that data at ASH.

Ken Anderson:
No, it’s wonderful. So, in summary, I think what we’re seeing here, and again, in this conference/workshop, just beginning, but the excitement is palpable because we’ve actually made together as a community such progress for our patients. But we’re really honestly in the unprecedented time of opportunity for more in-depth analysis of the tumor, more in-depth analysis of the microenvironment, measuring both of them over time serially, as you nicely mentioned, and maybe not only understanding of pathogenesis, but when we think about MRD negativity for the cancer, we should be thinking about some metrics. Have we actually normalized or at least corrected abnormalities in the bone marrow microenvironment? So I hope that you’ve enjoyed this. And I think it goes a long way to making sure that the advances that we’ve made together in science, diagnosis, prognosis, and treatment will get to the caregivers and ultimately to the patients who desperately need them. Thanks very much.