iwHRMM 2024 | Bispecific antibodies in the treatment of HRMM: optimizing therapy and combination strategies

Thomas Martin

Hi, I’m Dr Thomas Martin from the University of California, San Francisco.

Ajai Chari

Hi, Ajai Chari, University of California, San Francisco.

Niels Van de Donk

Niels Van de Donk, University of Amsterdam.

Saad Usmani

Saad Usmani, Memorial Sloan Catering Cancer Center, New York.

Thomas Martin

So we’re here in Charleston, South Carolina at the iw High-Risk Multiple Myeloma Conference, and we just had a very nice session talking about five specific T-cell engager antibodies as treatment of high-risk myeloma. And so Dr Usmani, you talked about, you know, do bispecifics actually work? Are they good therapeutics for patients that have high-risk multiple myeloma?

Saad Usmani

Yeah, so I think that that was a challenging topic because if we look at each of the single arm studies that have led to the accelerated approval of the bispecifics we have, as well as other combinations, we have small subsets of high-risk patients. And what we’ve recognized is that high disease burden patients, high-risk disease extramedullary myeloma patients, they tend to either not respond or respond for a short duration of time. So it’s really a data-free zone. And what I was more interested in learning in this session is how best to optimize the bi-specific antibodies as a technology, paying attention to either the molecule itself or the immune microenvironment, or doing some combinations and trying to see if we can make those therapies work better for high-risk patients. And so this was the crux of what I had to discuss in my talk.

Thomas Martin

Yeah, and unfortunately what we thought is perhaps that these immunotherapies that have been so wonderful for all of multiple myeloma CAR-T’s and bispecifics that they work just as good in the high-risk scenario. And unfortunately, we’re finding that that’s not true, right? We’re going to have to probably do other things. So, and that leads us to you, Dr Chari, because you actually gave a talk, a really nice talk on optimizing therapy with bispecifics. You know, we can optimize for everybody, but we also can hopefully optimize for the high risk. So what did you talk about?

Ajai Chari

I think as Saad mentioned, these are single arm studies that we have so far. So it’s really hard to interpret because when we talk about high risk, ideally, we want randomized Phase III studies. But of course, that doesn’t stop us from, you know, pontificating on what might be. So the ways you could optimize is looking at the structure of the molecule. Can you do more than one binding site? But a couple of examples with BCMA and GPRC don’t seem to support that. Can you alter the T-cell affinity? Maybe that might mitigate the CRS, but doesn’t seem to change efficacy. And having more than one target, perhaps, maybe doing GPRC and BCMA, but we don’t have clinical data. Preclinical data looks good. Then you could also change the cell that you’re targeting in the immune system, right? Right now, we’re talking about T-cells, but can you target NK cells? and we have some products in the clinical trials that we don’t have data for yet. Then you could also target both of those, the immune cells as well as the myeloma. And the best example of that would be combination strategies. And there, the challenge is how do you balance safety and efficacy? So the BCMA combinations have shown preliminarily good response rate, but we don’t have PFS, and they’re coming with more neutropenia and infection issues. So I think we need to optimize that. For the GPRC, tal, interestingly, monotherapy has shown the high-risk PFS as comparable to standard risk. And the combination data looks quite encouraging with daratumumab, with dara plus pom, with teclistamab, latter potentially overcoming EMD in particular with the REDIRECT study, longest follow-up I’ve seen in a myeloma study where median PFS has not reached at 18.2 months. So I think the combination strategy. And lastly, I talked a little bit about dosing, which is, you know, there’s this feeling that immunotherapy, you can be very lackadaisical about dosing. But when you do look at the Phase I studies, you need that initial dose to get a response, get the T-cell activation. But perhaps after that initial dose, you can back off a little bit because that mitigates T-cell exhaustion. And that may be why, for example, tal every two week dosing gives better PFS. So those are some of the strategies we have, I think, in our arsenal right now.

Thomas Martin

Very good. And so Niels, you talked about resistance to bispecifics. And so we have primary resistance in that maybe 60 to 70% of patients actually initially respond. But we also have secondary resistance, meaning patients respond, but then all of a sudden they lose their response. So what did you talk about in your talk?

Niels Van de Donk

Yeah, in my talk, I focused on T-cell related factors and how they contribute to resistance, but there’s much more. There is also tumor-related factors that are related to development of resistance like high tumor burden or maybe a very small subclone that has already bi-allelic BCMA deletion that eventually gets selected under pressure of a BCMA-targeted bispecific antibody or a CAR-T. And then there is the microenvironment, which is full of immune suppressor cells in multiple myeloma, and these cells can also impair the efficacy of bispecific antibodies. So in my talk, I discussed that both laboratory studies and clinical studies point to the importance of the effector T-cell, in this case, to target myeloma cell ratio. So a better effector to target ratio typically results in a higher response rate, a better progression-free survival. And I tried to discuss some ways of improving the effector target ratio. For example, first sort of debulking strategy before you move to the bispecific as is now being used in studies where the bispecifics are used as a maintenance strategy. I also discussed that it’s not only the frequency of the T-cells but also T-cell fitness is of importance. In the MajesTEC-1 study, it has been shown that responding patients have more fit T-cells, less activated T-cells. And in a MajesTEC-1 study, it has also been shown that a better T-cell fitness is associated with a better progression-free survival. So maybe combination strategies that are keeping the T-cells in a good state, for example, bispecifics with CELMoDs, IMIDs or co-stimulatory agents will further improve the efficacy of bispecific antibody-based therapy. And then I briefly discussed the role of regulatory T-cells. In vitro studies, clinical studies have shown that regulatory T-cells are bad guys. They confer resistance. And well, we already have very interesting promising data of tal plus dara, as Dr Chari alluded to, a medium progression-free survival of approximately 18 months in heavily pretreated patients. Half of them was already BCMA exposed. Most of them were CD38 antibody refractory. So, a very poor patient population, but 18 months is very promising. And maybe we think that daratumumab eliminates the CD38 positive regulatory T-cells. And that may be the mechanism whereby this combination is so effective and attractive. And follow-up studies, which also have a randomized design, in the end, will hopefully shine a more bright light on this question, on this issue.

Thomas Martin

I think in high risk, we’re all thinking that it is probably going to be combinations, even though today we only have a single agent that we can deal with. But we did see some other data with combinations too. I’ll ask the whole panel, do you guys have a favorite combination that you think might be the one that’s ahead of the others in terms of treatment of high-risk myeloma with bispecifics? We can go down the line.

Saad Usmani

Yeah, so I would say that the dual antigen targeting probably is going to be the optimal strategy and whether we decide to add or sequence a CELMoD into that picture to kind of augment the response that we want to get for our high-risk patients. I think that’s something that all of us talked about. One thing that was raised in the session was also how to overcome, identify and overcome this T-cell exhaustion, you know, phenotype from the beginning. Can you do something different? And, you know, whether debulking patients, you know, would actually make a little bit of sense before you employ treatment. So I think we have several things that we need to work on, but yeah, It will probably be dual targeting.

Thomas Martin

Yeah. It was, I thought, at IMS when Yael Cohen, when she presented the tec plus tal data, showing a really high response rate, right? 96% or so in the combination. But in the high risk, still over 80%. But I was a little disappointed with the PFS of just over six months, right? Yeah. So, Niels, how are we going to make that better?

Niels Van de Donk

I think in patients with extramedullary disease, the tec and tal combination was promising, but you’re right, progression-free survival was still on the low side compared to the overall patient population. Maybe incorporation of radiotherapy will be beneficial to shrink the tumor so that penetration is improved. Maybe it leads to T-cell activation. Maybe it also leads to immunogenic cell death that further improves the efficacy of the double targeting combination. And I think also the trispecific antibodies are very promising in high-risk disease, because they not only target two different antigens, but they also have an avidity effect. They targeted two antigens at the same time. One molecule targets two antigens. So there’s not only, well that avidity effect probably also potentiates the efficacy of this dual targeting approach so the trispecifics are I think also very promising hopefully also leading to a more targeted approach with less toxicity but this has to be seen from the ongoing clinical studies. And I also like, if you talk about the most interesting partners, I also like the CD38 combination because TRIMM-2 and prior BCMA exposed patients looked really very promising because patients with prior BCMA bispecific and then getting tal have a PFS of approximately four months and now we are talking about a much better PFS by adding daratumumab so that’s also something that we have to follow up on.

Thomas Martin

And Ajai, your favorite?

Ajai Chari

I do like the dual target for extramedullary disease based on REDIRECT. But I’m not sure. And then of course, you could do it either in two molecules with tal plus tec or in one molecule with a tri specific and we’ll have to see that data, we don’t have clinical data. But putting EMD aside, I think one thing I wanted, we haven’t talked about explicitly is another really high risk, perhaps maybe the most high risk is prior bispecific failures, right? Because if you’re progressing on one bispecific, what do do you do? And we know that tal, for example, the PFS for a naive patient is around 12 months, but if you’ve had a prior BCMA bispecific, it drops to four months. And I agree with Niels, where this is where the tal-dara really shines. And in that data set, it was 19 months, including patients with prior bispecific. So I think what also is good about that combination is you don’t have the cytopenias. You don’t have the infection, neutropenia. Like all of that, the toxicity profile is not very different from tal monotherapy. So I think that makes it quite an exciting compound that I would reach for as soon as we could get approved.

Thomas Martin

All right. I have one last question for you guys. And that is, so it’s Simon Harrison brought up in our session. Based on your talk on looking at the T effector to T target ratio, what about pulling out some of those stem cells? What about giving alkylator-based therapy and pulling out some of those stem cells and giving back? Not just stem cells, but they have a lot of more naive T-cells in that group. So Niels, how will we help our T effector to target ratio? Is that something that you think would work?

Niels Van de Donk

I don’t know. I think we have to evaluate this to see whether this really makes a difference because I don’t know how much T-cell numbers will in the end increase by giving a stem cell boost. But this is for sure something that we should evaluate. In clinical practice, when I have a patient with very high tumor burden, I try to debulk with polychemotherapy before going to the bi-specific. But this is also based on small numbers. And we do not know whether this is really contributing to better clinical outcomes or not. So I think there are still lots of open questions, including the potential value of the stem cell T-cell boost.

Thomas Martin

Yeah. Very good. Well, thank you very much, you guys. It’s been a nice discussion.