iwHRMM 2025 | Mechanisms of resistance to immunotherapy in HRMM and overcoming it with multiple antigen targeting

Peter Voorhees:

It’s Pete Voorhees from Atrium Health Levine Cancer Institute in Charlotte, North Carolina. And I am here at the International Workshop on High-Risk Multiple Myeloma. And with me today is my good friend and colleague, Holly Lee from Calgary. 

Holly Lee:

Hi, my name is Holly. I’m a clinician scientist from University of Calgary in Canada. 

Peter Voorhees:

Very good. So Holly, you and your team in Calgary have led the charge as far as identifying mechanisms of resistance to T-cell redirecting therapies. You want to give us a bit of an overview as to kind of what you guys have gleaned from the research that you’ve done in your lab. 

Holly Lee:

Yeah, of course. So the main focus of our research is really trying to understand what are the different mechanisms of resistance. And of course, there is, you know, tumor extrinsic, T-cell tumor microenvironment related factors. But the main focus of our research has been understanding tumor intrinsic factors. And primarily, especially in the setting of acquired resistance to bispecifics, it appears to be hinging on antigen expression and antigen escape. So across BCMA and GPRC5D targeting bispecifics, we’re seeing antigen escape rates of around 60-70%. And that comes in various forms. Studying that, genomically, we see that it’s either copy number losses but perhaps more frequently retained expression of the molecule on the cell surface but with the mutation, so altering the target epitope. So yesterday in our session we had a great discussion about how that could lead to functional impact and kind of differing sensitivities to different anti-BCMA and anti-GPRC5D targeting agents that we have. But of course, the discussion went beyond that into a discussion of T-cell related factors, as well as tumor microenvironment factors by the other presenters. 

Peter Voorhees:

Yeah, no, incredible work. Do you want to speak to, you know, any potential differences, you know, in this phenomenon of antigen escape with regards to CAR T-cell therapy, BCMA and GPRC5D-directed CAR T-cell therapy, as opposed to a bispecific antibody treatment? 

Holly Lee:

Yeah. So what we’re seeing is that for CAR T-cell therapy, the rates of antigen loss seem to be relatively lower. And it mainly comes in the form of biallelic deletion. So complete loss of the antigen. I believe for BCMA, that’s about 5%. For GPRC5D, perhaps more frequent. And bispecifics, it’s predominantly mutation-based antigen escape that we’re seeing. There is also a distinction between BCMA and GPRC5D. So for BCMA, again, it’s that retained surface expression with epitope change. But for GPRC5D, a lot of the mutations that we’ve cloned and tested in vitro are showing just entrapment of that mutant protein within the cell, so that never comes up to the cell surface. 

Peter Voorhees:

Yeah, absolutely. So with all of that in mind, for a patient relapsing who is fit and potentially eligible for CAR T-cell therapy, based on the work that you and others have done, any thoughts about optimal sequence as far as CAR T-cell therapy followed by bispecific antibodies versus the other way around? 

Holly Lee:

I think we’re learning that if you’re exposed to a BCMA bispecific and you get any kind of subsequent immune targeted therapy, the response rates tend to be lower and suboptimal compared to patients that are completely naive and get it for the first time, and that is with respect to both the depth of response as well as the duration. So perhaps that is partly explained by the biology that we’re seeing with this antigen escape. But also, again, I don’t want to completely ignore the fact that there’s T-cell fitness as well as durability, the tumor microenvironment – I think all of these factors do play a role. So in terms of how we sequence and even combine these therapies, I think those factors all need to play a role. And that’s also where the genomics and the functional studies come in to be able to really understand the biology that underlies these subsequent response durations and depths. 

Peter Voorhees:

Yeah, no, absolutely. And I think, you know, as we kind of move forward into this whole new domain of T-cell redirecting therapy, I think it’s going to be critical that we start doing whole genome sequencing on our patients, you know, who are relapsing after CAR T-cell therapy or after they’ve received bispecific antibody therapy to determine what the deletion status is, what the mutation status is, and what sort of a candidate they are for subsequent repeat BCMA-targeted therapy, for example. 

Holly Lee: 

Yeah, exactly. 

Peter Voorhees:

Incredibly important work. Now, based on the work that you guys have done and the 60% to 70% presence of antigen escape for folks that are on bispecific antibody therapy. Obviously, from a clinical research perspective, the obvious thing to do is to target multiple tumor-associated antigens. And in that regard, we had the opportunity at our center to participate in several, I think, very important clinical trials that are ongoing. One is the RedirecTT-1 study, which is a study that’s looking at the combination of the BCMA bispecific antibody teclistamab in combination with the GPRC5D bispecific antibody talquetamab. The initial phase one dose escalation occurred in Europe, but then subsequently was expanded, you know, into other regions of the world, including the United States. And to make a long story short, at the recommended phase two dose, they saw a very impressive overall response rate of 80% with the combination, which is better than one would have expected, you know, with the 60 to 70% response rates that we typically see with one or the other used alone. And I think very early days, but the duration of response and progression-free survival that we’re seeing with the combination is quite remarkable. During the phase one dose escalation, it was very intriguing to see the signal of activity in patients with extramedullary disease where we know those patients aren’t going to do as well with a single agent bispecific antibody-based approach, so there was an expansion cohort that was introduced into RedirecTT-1, you know, looking specifically at patients who had true extramedullary disease, not paramedullary disease, these are myeloma tumors completely outside of bone. And what we’ve seen in that cohort of patients, which was 90, really quite a remarkable effort in a difficult, you know, to treat patient population. Overall response rate, again, was around 80%, but more importantly, you know, the median progression-free survival extends, you know, well beyond a year, which is far better than what one would expect with just a single bispecific alone. So it really kind of gets at this idea that, you know, tumor antigen escape is real and multi-antigen targeting is really a promising way forward to kind of get around at least that aspect of resistance. 

So, and I think that the other, you know, very interesting sets of data in the clinical domain, as far as multi-antigen targeting is in the trispecific antibody space. You know, so we have, you know, the J&J, GPRC5D-BCMA triispecific antibody, you know, which at the recommended phase two dose in patients who’ve not received previous BCMA-targeted therapy yields a response rate of 100%. And the one-year progression-free survival and duration of response is well over 90%. So we’re starting to feel the tangible benefits of what you and others have uncovered in the lab. And then lastly, you know, as far as another very interesting trispecific antibody is one that’s targeting both CD38 as well as BCMA. Now, when this first came along, I was thinking, gosh, targeting CD38, that’s going to be a bit challenging. 

Holly Lee:

Especially after daratumumab. 

Peter Voorhees:

Yeah, exactly. And yeah, with daratumumab we now have evidence that tumor antigen escape with CD38 targeted therapy happens as well. So, but not only that, but the fact that CD38 is expressed on, you know, more lineages, you know, than just the plasma cells. But, you know, really quite remarkably, when you look at, you know, the phase one dose escalation phase of that study, you know, at dose levels three through nine, you’re seeing, again, overall response rates approaching 80%. And this is a very heavily pretreated patient population with many of the patients in the study having received prior BCMA-targeted therapy. So you would have expected this group of patients not to do as well as they did. And some of them had even had talquetamab, GPRC5D-targeted bispecific antibodies. So it’ll be really fascinating to see how that agent moves forward in the clinic. 

Holly Lee:

Yeah, I think it’s a really exciting time in myeloma, as you said, and with these multiple agents coming in at different time points of the disease phase as well, as you mentioned, in newly diagnosed, relapsed/refractory, and in more terminal. And so I think, yeah, we’re at a really exciting time. And I think there’s a lot to understand about translating these clinical benefits into understanding how they’re happening with the biological side, and then kind of putting it all together to see if we can really achieve that cure. 

Peter Voorhees:

Yeah, yeah, absolutely. Just one last question. So, you know, obviously, targeting multiple tumor-associated antigens appears very promising in early looks at the data, but, you know, at the end of the day, that’s likely not the only reason for resistance to these T-cell redirecting therapies. So how do you see the field, in addition to targeting multiple antigens, how do you see the moving forward? So to overcome intrinsic resistance that we see with some of the bispecific antibody therapies, again the response rate is 60–70% so 30–40% of these patients don’t respond right from the get-go, and then you know acquired resistance in many cases is due to antigen escape but again 30–40% of the time it’s not. So what are your thoughts about how the field will look like in the next five, 10 years? 

Holly Lee:

So I think, yeah, we also look outside of the tumor. I think there’s a lot of focus and interest in looking at tumor microenvironment and then the T-cells. One of the presentations yesterday was talking about immunogenic cell death, that even though we’re targeting BCMA or GPRC5D, maybe the subsequent and kind of the expanding immune effect is whether it may be antigen spreading and other epitope related immunity that may be at play. I think there’s a lot to learn in terms of mechanisms of how that initial response happens, but also how it spreads. And for those patients that are primarily refractory, I think we can’t ignore the disease burden aspect. Patients who have the very high proliferative and high-risk disease upfront, maybe they’re the ones that are having poor effects. So there is a unmet need in terms of targeting those patient populations more effectively, again, with different combinations or sequences. So I think that’s where the field is also headed and we should also look further into. 

Peter Voorhees:

Yeah, I could not agree more. You know, with progress comes many questions, but, you know, it’s really an exciting time in the field of multiple myeloma and very hopeful for patients. So thank you for the work that you do on the lab side of things. And we will keep pressing forward on the clinical research side of things and continue to make progress for our patients. 

Holly Lee:

Great. Thank you very much.

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