iwMyeloma 2025 | Novel targets in multiple myeloma & the role of the immune system in disease progression

Faith Davies:

Hi everybody, thank you for joining us. We’re at the iwMM meeting in Miami 2025 and we’ve just come from an amazing session and I’m fortunate to have two of the speakers with me today. So let me introduce Leo. You want to say a bit about yourself?

Leo Rasche:

Yeah, I’m Leo Rasche. I’m an attending physician at the University Hospital of Würzburg, and I’m also a scientist, so I’m running a lab, and I’m glad to be here.

Arun Wiita:

Thank you. Yeah, and I’m Arun Wiita. I’m a pathologist at the University of California, San Francisco, and my research laboratory focuses on novel target discovery for myeloma and other hematologic malignancies.

Faith Davies:

Excellent. Great to have you both with us. So, Leo, you had the keynote speech and everybody’s been talking about it. And one of the statements that kind of sat with me and I’ve remembered is that myeloma is a disease of a failure of immune surveillance. I think it’s what you said, something like that. Okay. Do you want to tell us a little bit about how you’ve come to that kind of conclusion?

Leo Rasche:

I think we were focusing a lot on the clonal architecture of myeloma and clonal evolution. And just recently, we started to think about the immune system that also goes through a co-evolution with the clones for 10, 20, even 30 years. And so one hypothesis is that the immune system is taking control for many, many years, but at some point it loses control and then you get symptomatic myeloma. The evidence for that is we see immune cell infiltration, what we call immune islands, in breakout lesions, also in extramedullary disease. We also see in CT scans osteolytic lesions without myeloma cells inside, but at the same time these are patients with active symptomatic myeloma. So the bottom line is, yes, the immune system failed to control the disease largely in our patients.

Faith Davies:

The other thing that really struck me was the way you were talking about the bone marrow as an organ in the body, whereas I’ve been thinking of the bone marrow essentially as the iliac crest where I go and do my bone marrow aspirate from. Okay, do you want to expand a bit more on that one?

Leo Rasche:

Yes, we are hematologists and we should be proud of our work. And if you Google it, then you will come up with the fact that the bone marrow is the second largest organ after the skin. And that’s why we have a 4,000 milliliter ecosystem with tumors and immune cells.

Faith Davies:

Yeah. I might add and some stromal cells in there as well, but that’s just my own bias. And then you also showed some beautiful data about patients who had not only been treated with the IMiDS and the proteasome inhibitors, the monoclonal antibodies, but also with our two new targets, GPRC5D and BCMA. Tell us a little bit about how you’ve been characterizing those, because that was really interesting.

Leo Rasche:

Yeah, well, so first of all, that’s a clinical dilemma. It’s a new setting because these patients who had been treated with all of the drugs you just named, they are existing. Now they come to us and they ask for new therapies. And usually, so that is at least my impression, they are in pretty good shape because they benefited from these new immunotherapies like the organ function recovered, the bone marrow function is quite well, but they run out of all options. And because pentarefractory disease is a term that we used in myeloma quite often, we’ve started to call this heptarefractory because it’s penta refractory plus GPRC5D and BCMA.

Faith Davies:

Yeah thank you so much and that’s a great place to start because Arun you were chairing a session about new targets and it seemed to be very much about new targets and potentially in the CAR T-cell world. Do you want to tell us a little bit about your own work to start off with?

Arun Wiita:

Right exactly, and I think Leo’s hit it on the head so much in terms of this is the challenge now for patients right, in terms of patients who have exhausted all of our current therapeutics. What can we do next? How can we still come up with novel agents? And the strategy we take in the lab is really thinking about new targets, new ways to go after. We particularly have been focusing on CAR T-cells because that’s our expertise in making CAR T-cells, but these could also be used for other immunotherapies, for things like bispecifics or ADCs that we know can be effective. I should say we’re not solely thinking we have to do CAR T-cells next. But we’ve been exploring that in the context of, we’ve used a technology called cell surface proteomics, which essentially what that means is it allows us to get the entire landscape of all the proteins on the membrane of those malignant plasma cells and things like BCMA, GPRC5D. These are also membrane proteins that we can target with therapies like CAR T-cells, like bispecifics. We’re trying to find alternative targets for patients who have become refractory to those therapies.

And so what I talked about today is a new target we found called CCR10. This target we think is quite interesting because we found it’s expressed widely on malignant plasma cells across myeloma patient tumors. It’s expressed minimally on other normal tissues, so we think it could be a safe target to go after. And what we particularly are trying to do is how can we engineer the therapy, how can we use protein engineering principles to find a therapy that could be more efficacious for patients. And so that’s really what we’ve been focusing on there. We have another new target I didn’t talk about today called CD70 that we found is particularly highly upregulated in high-risk cytogenetic subtypes of myeloma. These are the patients who, at least in the BCMA CAR-T space, tend to relapse more quickly, need new options as well. So those are really two targets that we found we’re really pushing forward, our hope is to clinically translate CAR T-cells within the next few years to patients, at least in early stage clinical trials. But we also think that there’s more targets out there as well. So that’s one solution to this challenge is finding new targets, make new therapies. There are other ones as well.

Faith Davies:

Yeah, no, that’s, I can say, so important when we come back to thinking about those patients that have received everything. I was really intrigued because during the talks, I think you asked Leo a question about why do we think that the CAR T-cells, I can say, don’t kill off all the myeloma cells and why is there… Do you want to just chat a bit more about that? Because I thought that was another fascinating area for me.

Arun Wiita:

Yeah. Do you want to start or what do you think?

Leo Rasche:

I can start with the question. So is a residual cell, a single cell or a dormant cell, is this refractory to CAR T-cells or bispecific antibodies just because the metabolic makeup is different, these cells maybe not really live, they are like in this dormant stage, or is there another reason why these cells cannot be killed?

Arun Wiita:

Yeah, exactly. I mean, I think when you think about that context of exactly this dormant cell state, I think what Marta Chesi also brought up in the discussion as well, you know, we know that these patients can receive therapies, be in remission for a very long time, and then relapse, as you showed so beautifully in the talk. And the question is, are they somehow de-differentiating, no longer look like plasma cells in their surface antigen repertoire, those proteins at the surface? They don’t have BCMA, they don’t have GPRC5D somehow. Is that how they’re escaping, or is there something else intrinsic? I’ll say definitely for both the CAR T-cell and the bispecific field, we know that you need the T-cell to be able to effectively engage the tumor cell, something called the T-cell synapse, where those two things contact. And so basically some tumor cells can also have other proteins that prevent that from happening very efficiently. So maybe these cells that are evading, they’re ones that T-cells, maybe they can touch them. As you mentioned, maybe they can say hello, but they can’t actually engage effectively to kill. So maybe that’s one of the resistance mechanisms. Maybe they no longer display their antigens. Maybe there’s something else intrinsic mechanistically. I think what’s most fascinating about your talk, Leo, is that thinking about how can we identify these cells? How can we characterize these incredibly rare cells? I think, Faith, some of the work you’re doing in terms of thinking about mouse modeling, I think could be a really important way to get to that strategy. But then, of course, we do want to figure out how can we find these rare cells in patients and actually characterize them and eliminate those last few cells that’s going to get us to the cure, right? That’s really, I think that’s really the goal right now.

Faith Davies:

No, thank you so much for joining me. It was great to talk to you and also a great session because although it was science, it was actually real key questions that we see on a day-to-day basis in the clinic and how we’re going to go about addressing those. So thank you so much for joining us, guys. We’ll sign off now from iwMM 2025.

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