iwMyeloma 2025 | Genomics & epigenomics in multiple myeloma: key updates and potential clinical applications

Gareth Morgan:

Hello, my name is Gareth Morgan. I’m Professor of Medicine at NYU in New York City. I’m here in Miami with my two colleagues at the International Workshop on Multiple Myeloma 2025.

Benjamin Barwick:

My name is Benjamin Barwick. I’m from Emory University. I’m an assistant professor there studying drug resistance and genetics and epigenetics.

Lawrence Boise:

Hi, I’m Larry Boise and I’m also from Emory University where I’m a professor in the Department of Hematology and Medical Oncology.

Gareth Morgan:

So, we’ve had a great session and what I would say is probably the best session on genomics and epigenomics I’ve ever sat through and I think what we need to do is kind of distil that into something that people understand about what this means for the clinical care of patients.

So, there’s been a lot of talk of high-risk myeloma – you two guys are very expert on that area. So, Larry, what do you think we’re going to use genomics and epigenomics for in the field of higher-risk myeloma?

Lawrence Boise:

You know, Gareth, I think one of the things is, in this case, learning more about what these changes are. We’ve known some of the changes associated with high-risk myeloma for some time, including chromosomal translocations. But what we haven’t really understood is how does that lead to high-risk myeloma? And I think some of the talks we heard today really started to drill down on one particular translocation, the one that is chromosome 4 to chromosome 14, resulting in the increased expression of an oncogene that we refer to as NSD2. And we heard several talks about this, I think three in our session that really started to look at what are the consequences and what is the function of NSD2. And I think thinking about that in terms of patient care, it gets you to what are the therapeutic opportunities or what are the vulnerabilities of having a 4;14 translocation that we can take advantage of for treating our patients?

Gareth Morgan:

So, I think one of the take-home messages was that the PRC2 complex that kind of shuts off genes broadly is one of the major contributors, and you both showed cool examples how you might target that feature. And so, especially Ben, looking at the methylation status of the genome.

Benjamin Barwick:

Yeah. So, I think we were here six years ago, or we were in San Diego at this meeting six years ago, and Leif Bergsegel stood up and said, we’ve identified the drivers, there are no targetable, no drugs, that hit these drivers. And we have one now for NSD2. Whether or not that actually is efficacious in patients, I don’t know if we’ll see that. And I think you touched on a really interesting thing. There’s this antagonism between NSD2 and EZH2 or polycomb, and they do have EZH1 and 2 inhibitors. And so whether or not those are actually going to be effective, we’ve kind of played around with them in the lab some. But I think we’re a long way from really knowing if there are, you know, if they’ll be effective in myeloma in general or maybe in a given subtype, perhaps the t(4;14) subtype. I think we’re still a long way from knowing that.

Gareth Morgan:

So there’s the concept of synthetic lethal. It’s difficult to explain, but it means if you have something, you’re sensitive to something that you weren’t sensitive to before. And so Larry showed a really cool example of synthetic lethality. Would you like to?

Lawrence Boise:

Sure. So our idea was that if you had NSD2, or in this case, what we showed was if you even inhibited NSD2, how did that make the cells from these patients more susceptible to other types of therapeutic approaches? The one we focused on was really understanding how cells die through the process of apoptosis. And this is controlled by a set of genes, the BCL2 genes, and what we found was that inhibition or loss of NSD2 actually resulted in greater dependence on one of these BCL2 proteins, and that protein is currently targetable and using in clinical trials with an inhibitor. So it really sets up the possibility of combinations where we inhibit the NSD2, which by itself may or may not have an effect on killing cells, but it may leave them susceptible to this new dependency. And I think Ben actually had a really nice example of synthetic lethality as well.

Benjamin Barwick:

So what we saw with the NSD2 high cells, the t(4;14) translocations, that they have this higher level of DNA methylation. And with these hypomethylating agents that are approved in MDS, we saw that the cells were more sensitive to this, and that was through an interferon response. And you can imagine that that could basically work very well with common immunotherapies used in myeloma. And so we have more work to do. But I think it’s not just about new drugs. It’s about knowing how to use the existing drugs. And the biology can really help us understand how to use those better.

Gareth Morgan:

So it would be really great if you could make a compelling use to use those widely used hypomethylating agents in a subset of myeloma. I mean, that’s the exciting thing. If you could use those, they’re available, and you may get better responses in this more aggressive subset of disease.

Benjamin Barwick:

Yeah, we’re pretty excited about the data, but we have a long way to go to actually get it to-

Gareth Morgan:

Yeah, get it to the clinic.

Benjamin Barwick:

Yeah.

Gareth Morgan:

Do you want to make a concluding remark, Larry?

Lawrence Boise:

Yeah, I think, you know, for me, what was so exciting about what we saw today was that, again, we know NSD2 was the target in case of these 4;14 myelomas. But now, through understanding the biology of this and more about the genomics of it, we have ways to treat, to potentially treat, this high-risk form of disease, and I think that’s really exciting and that’s something we really haven’t seen at previous meetings like this. So I was really excited.

Gareth Morgan:

Ben?

Benjamin Barwick:

Yeah, I would be… you know, it was great to see everyone’s talk from Francesco to Brian, but you know, I think, you know, the studies on the big scale studies on the genomics and looking at the differences in populations and from New York and whatnot, I think we can learn a lot about the disease by looking at the different biologies associated with it, whether it’s African-Americans and Caucasians, but I think understanding that, I think that’s gonna be beneficial in ways that we can predict and ways that we can’t predict.

Gareth Morgan:

So one of the conclusions was it’s complex and our job is to appreciate that complexity, but to reduce it to simple ideas that you can translate into the clinic. And I think from my two colleagues here, I think you’ve heard a number of examples where we will be able to do that and improve the outcome for myeloma patients in general. And so signing off here from this first session and thank you very much for your attention.

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