iwMyeloma 2024 | Novel targets & agents in myeloma

Hi, everybody, I’m Faith Davies. I’m a physician scientist based in NYU Langone in New York. And today I am at iwMyeloma 2024, in Miami. And we have just finished an amazing session about new targets in myeloma, and particularly ones that are going to be therapeutically accessible. And I’m joined by two colleagues to discuss that in a little bit more detail. Mala, would you like to introduce yourself?

Hi. So, like Faith said, my name is Mala Shanmugam. I’m an associate professor at the Winship Cancer Institute of Emory University and excited to be here. And like Faith said, very interesting session on some newer directions we can be taking.

And Sikander.

Hi, I’m Sikander Ailawadhi from Mayo Clinic in Jacksonville, Florida. I’m a clinician, a professor of medicine over there and focused a lot on clinical trials, new drugs, different stages, and also healthcare disparities. It was indeed a very interesting discussion looking at novel targets. Where’s the field going? And a very good mix of preclinical and clinical studies talking about just what is in store for our patients and clinicians.

Excellent. So maybe we’ll start with the one that’s kind of closest to the clinic. So, we had a lovely talk by Paola Rodriguez from the Spanish group talking about some of her stuff. Maybe you want to tell us a bit more about that, Sikander?

Absolutely. Very exciting stuff, because we know that BCMA-targeting drugs have literally taken the field of myeloma with so much effect and have changed our patients outcomes tremendously. So, Paula talked about one of the newer agents in that same armamentarium, alnuctamab, which is another bispecific antibody targeting BCMA,

but talking about its combination with yet another novel class, CELMoDs. So she talks about, alnuctamab in combination with mezigdomide.

So the way it was very interesting was that we have these two brand new, very exciting and promising drugs, but designing a Phase I clinical trial of the combination, because there is certainly a lot of preclinical support data and efficacy signal, how does it pan out in the clinic? And Paula nicely talked about what our expectations are about the side effect profile, how to manage them, because there are some overlapping toxicities.

As we go into these newer agents, there will be some overlapping toxicities, but how can we manage them best so that these two very interesting and promising areas of BCMA-targeting and CELMoDs could be combined for the benefit of the patients.

Super. That’s great. And Mala, you presented some work, which I guess is kind of not far from the clinic, in the fact that you were looking at venetoclax resistant patients and their cells and a little bit more, I guess, about metabolism and how that might be important. Do you want to tell us a bit about that?

Yeah, sure. So, you know, we have had an interest in understanding how metabolites regulate therapy sensitivity and resistance mechanisms. And this particular research that I presented; we’re looking at venetoclax. And so what we find is that, whether it’s pathways or diets that increase oxidative phosphorylation or use of mitochondrial function and respiration, that in turn leads to resistance to venetoclax. And so through this work, we’ve revealed how heme, which is derived from both extrinsic sources such as diet, red meat and so forth, or through de novo synthesis pathways, how it promotes this increase in BCL2 function or dependence and resistance to venetoclax.

So, in the long run we still have some way to go, but it suggests that dietary modification or inhibitors that target these metabolic pathways can increase sensitivity in addition to promoting resistance to these important drugs.

And that kind of fits in really nicely with some work that I know has been going on at MSK, looking at patients’ diets and maybe the benefits of a plant-based diet over other diets.

Exactly, exactly.

And then there were kind of two talks, one by myself and one by Sikander. So I’ll maybe go first with mine, looking at some of the processes in cancer cells that we might be able to use to deliver drugs to a cell. And so I talked about a very specific process that occurs in RAS-mutant cells where they’re very reliant on something called macropinocytosis to take up molecules into the cell, and that’s how they would normally get their nutrients. And so I was discussing how you can hijack that pathway and maybe use that pathway to deliver a therapeutic target. We used MMA and we could show that it was very effective for myeloma cells that were dependent on RAS, be it KRAS or NRAS, and that we could show its activity in a myeloma mouse model and that there’s a young biotech company, who are called Tezcat, who are trying to develop this and take it to the clinic. Which is great news. And then you were talking about another pathway which is very intrinsic for cancer cells.

Yes. So the cellular structure has a phospholipid membrane which exists in all cells pretty much. But this particular mechanism is utilizing that phospholipid membrane and using what’s called PDEs or phospholipid-drug conjugates, so that a drug with a payload, which could be frankly any payload, could be given, these phospholipid ethers are internalized into the cell normally, and that payload can be delivered. Now the unique part is that, cancer cells have a higher abundance of these phospholipid ethers.

They have more stable structures so that the drug can actually attach and get internalized. And by that mechanism, a radioisotope, radioactive iodine, I-131, has been used as a part of this drug called iopofosine and delivered to myeloma cells.

So, I presented the Phase I clinical trial data where 31 patients were given this particular drug in the Phase I, and the Phase II is still ongoing, and we were able to show that every single patient had stable disease or better and the side effect profile was quite manageable, just hematological toxicities. So, to me that is a proof of concept not only for a drug, but for a whole platform which can be utilized to deliver effective payloads and drug molecules to myeloma and, frankly, to other cancers also.

And if I’m right, they’ve used that platform and have, I think, some approval with the FDA or beginning to start some work in Waldenström’s?

Yes. So they have actually completed their Waldenström’s trial. So, the way this clinical trial was set up, it had multiple different diagnoses going in. Through that initial Phase I study they identified that both myeloma and Waldenström’s would proceed further in specific trials. After the Phase I of myeloma was done, by that time they had received some very good initial signal in Waldenström’s. So as a smaller company, they decided to prioritize Waldenström’s. They have completed their pivotal trial, and that data is going to be submitted, hopefully, to the FDA sometime this year. So very exciting to bring in a completely different mechanism of action to plasma cell disorders.

That’s cool. And then the other talk in our session was maybe a little bit earlier, which was by Ryan Young from the NCI. Do you want to tell us a little bit about that?

Yeah. So that was beautiful work again here. Ryan did a very comprehensive, elegant CRISPR-Cas9 screen where he’s looking at fitness dependencies in the context of IRF4, and identified this novel gene or pathway that epigenetically regulates IRF4 function. Again, there’s, I think, a drug that’s in Phase I trials that can target this biology.

So really starting from very basic work to identifying this dependency and a drug that’s now in clinical trial. So, yeah, very, you know, elegant work. I think Ryan was also going to talk about RAS activation and so that also seemed to be like a theme in our session.

Because like I mentioned, heme also activates this pro-tumorigenic signaling, the RAS pathway. And both of the approaches proposed by Sikander, as well as yourself, using these monobodies, can take another much more proximal method of shutting down the entire pathway. And so it will be promising and I look forward to seeing how these approaches can overall encompass targeting more broader mechanisms in driving myeloma biology.

Yeah. And clearly I love my myeloma biology, but it is quite good as well because there’s been a lot of excitement over the last few years about bispecifics and the immune side of things, but I think it’s important not to forget that kind of cell biology side of things. And certainly one of the interesting things about Ryan’s work was, we know IRF4 is a good target, we know it because of our the work with IMiDs and so on. And so it’s actually been good to see that moving forward and to see within the session that we were targeting transcription factors, targeting metabolomics, thinking about processes within a cell that are important and very myeloma cell dependent.

So thank you so much for joining me today and thank you guys for listening, and we look forward to telling you some more about some of the interesting sessions at iwMyeloma. Thank you.