Saad Usmani:

Hello, everyone. My name is Saad Usmani. I’m the Chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center. And I’m joined by my two wonderful colleagues to take you through some really interesting new and emerging data focused on GPRC5D. Let me welcome both Doctors Hansen and Bal. 

Susan Bal:

I’m Susan Bal. I’m an associate professor of medicine here at the University of Alabama in Birmingham. I’m delighted to be here today. Thank you also for the kind invitation. 

Doris Hansen:

My name is Doris Hansen. I’m at the Moffitt Cancer Center in Tampa, Florida, and also very excited to be a part of this conversation. 

Saad Usmani:

But certainly, you know, it’s become a cliché to say that this is a very exciting time in myeloma therapeutics. And to be a myeloma doctor and researcher, we have, especially in the last, I would say, six to seven years, seen major advances in T-cell redirecting therapy with both the antibody-based platforms as well as cellular therapy. And, you know, it’s not too long ago that we actually had the first description of GPRC5D as a target, Eric Smith had published that paper when he was still a fellow at MSK, and since then, we have seen several T-cell-directed redirecting therapies come to the fore, targeting GPRC5D as well as CAR. So, you know, I want to just ask both of my colleagues, you know, what do you think about GPRC5D as a target? And then, you know, maybe, you know, start talking about more of the clinical data. Susan, maybe I can start with you, and feel free to call me Saad. 

Susan Bal:

Thank you so much. You know, GPRC5D is a target that has been explored now since 2019. As you mentioned, Dr Smith, he was at MSK at the time, and we were fortunate enough to learn from some of his early work when he first described this as a sort of independent target that was mutually exclusive to BCMA. And it’s sort of expression that was limited to malignant plasma cells with limited expression on vital organs and predominantly was present on hard keratinized tissues. After that time, around the same time, bispecific antibody trials looking at GPRC5D as a target took off. And we had some of the first data from talquetamab, which is a GPRC5D-directed bispecific antibody that was used in patients with heavily pretreated multiple myeloma, showing response rates at two different dose levels that were studied, roughly in the order of 65% to 70% of the different doses that were studied, and was remarkable to see how some of these very relapsed and late-line patients did with this drug. It was remarkably effective. And even now, I think we consider this a very exciting approach for patients with high-risk cytogenetics and extramedullary disease. It’s really shown a lot of promise. After its availability in the late-line setting, it was used in novel ways and has been used as an approach for bridging therapy with CAR T-cells, and continues to be a very important agent for relapsed multiple myeloma.

Saad Usmani:

So, Doris, what’s been the most exciting early with GPRC5D that you thought, wow, I think that this will be a good target for myeloma? And I’m going back four, five, six years when the first initial clinical efficacy data were coming out. What was the wow moment for you? 

Doris Hansen:

Well, I think for me, just as Susan mentioned, I think having this novel target has been so very exciting because we have so many BCMA-directed therapies or targets in terms of bispecifics. We have CAR T-cell therapies, but really being able to have this different type of target and being able to give our patients excellent responses, whether it be bridging therapy so we can optimize their CAR T-cell therapy, or in heavily pretreated patients, giving another bispecific with a different target that gives them excellent outcomes. I think for me, that’s been incredible, right, in the early 2020s. But then beyond that, in terms of early-line data, Dr. Voorhees had a very exciting presentation at EHA showing us some data on MonumenTal-3. So in MonumenTal-3, patients were treated essentially in earlier line. This was a combination of talquetamab, either with daratumumab or with pomalidomide compared to standard of care options. And we saw significant improvement in terms of responses with talquetamab-based combination, significant improvement in survival in terms of PFS for these patients. I think that’s been incredible to be able to have not only great responses in late-line, but also moving these therapies earlier in the disease course and still seeing, you know, quite impressive efficacy outcomes. 

Saad Usmani:

Yeah, I’m reminiscing this, you know, and I want to take you guys back with me to, you know, the early 2020. So this was, you know, at the height of the pandemic. And I recall that, you know, we had both teclistamab and talqueatamab in first in human phase one studies back in 2018, 2019. And the data was just maturing for MajestTEC-1 and one, you know, and then eventually for MonumenTal-1 as well. AndI had the privilege of presenting the tec data for the first time at ASCO in the virtual ASCO of June 2020. So it would have been nice if we were all in person. But I was thinking, wow, these therapies are really great. And I’m really looking forward to the MonumenTal-1 data, which got presented at ASH 2020, which was also virtual, and Ajay Chari had presented it. What was most striking to me in that experience was we had a lot of BCM-exposed patients, either with ADCs or with ide-cel or with Teclistamab or with even, you know, Elra was also in early phase clinical trials, who went on Talquetamab. And these patients had, you know, wonderful responses, even after having progressed on BCMA. So for me, the wow, you know, thing was that, yeah, this is a legit target, you know, and we are all excited about BCMA. We were, you know, in awe when the initial ide-cel data was presented and then when we had presented the cilta-cel data, but then, you know, you had the GPRC5D data and, you know, responses looked really promising. And Doris, like you said, you know, since then, you know, we’ve had Tal approved by the FDA for late relapse patients, but then now we have early relapse data as well. So, you know, maybe we can talk, you know, we’re all excited about, you know, the efficacy, but what are the unique side effects that you see in clinic with talquetamab and how do you manage them? 

Susan Bal:

Happy to take that on. Before I get there, I also want to share a wow moment for myself. Back in 2021, when we first opened a CAR T-cell study that was targeting GPRC5D, we were not sure what to expect at the early dose level. And we had this one patient that I’ll never forget who had been on every kind of clinical trial that was available, including FCRH5, and had been on everything that we could have given to them. And they were about to go to hospice because while they were fit and functional, we had nothing to offer them. And they went on the lowest dose level of one of the GPRC5D-directed CAR T-cells and had a long-lasting remission with minimal toxicities. And at the height of the pandemic, he used to go dancing. So I really feel like, to me, that was a personal wow moment for that patient that, you know, after everything was sort of already expelled, you know, we didn’t have any other options that for somebody to have that quality and quantity of life was really amazing. And then the quality of life kind of brings us back to the question of toxicities that we see with GPRC5D therapy. And they’re predominantly because of the expression profile. As we just talking, the expression in addition to malignant plasma cells is also on hard keratinized tissue. So we see a lot of skin changes, rashes, nail toxicities, nail peeling. We see dysgeusia, which I think is one of the most important quality-limiting toxicities that we see with these therapies. And with the bispecific, because we give continuous dosing, it can be quite frequent. And because of the ongoing dosing, I think these toxicities can be anywhere from 50% to 70% of the patients and can be quite challenging. I think overall to manage those, I think dose holds, dose reductions go a long way. And one of the things that I’ve noticed in particular, and some data already points in that direction, is some of our African-American patients may have a slightly higher risk of some of these hard keratinized toxicities. So, you know, as we hopefully understand better about this target, we can better understand how to mitigate these. 

Saad Usmani:

So Doris, has your experience been the same? And, you know, with the late relapse, you know, one thing, again, I’m going off script here, you know, from the real-world perspective, we know that there are two doses that were approved, but are we really adhering to those doses or schedules, you know, to mitigate these side effects? I would say that we are already modifying the schedule based on these adverse events that we’re seeing in our clinical practices. And I’m also very open to alternate dosing for these patients because even the first-in-human studies, you know, you did have patients responding to the lower doses below 0.4. So if someone is responding and they’re having side effects, I think, you know, there is flexibility for both the dose that you’re giving as well as, you know, giving it less frequently. Doris, what are your thoughts? 

Doris Hansen:

Absolutely. So I very much agree with both of you. Dr Bal very nicely pointed out that these patients do have quite a few toxicities, whether that be skin changes, nail changes, skin rashes, whether they had dysgeusia, they experienced weight loss. And generally speaking, these are very difficult toxicities for patients. And we commonly do not stick to the dosing recommendations. Generally, we will start with every two-week dosing, but if patients have these toxicities, we might even consider doing monthly dosing or even more alternative dosing. But importantly, we also will consider fixed-duration therapy as well. First, we start out with spacing out the dosing, but should patients be on treatment, let’s say for several months or let’s say up to a year, we can get into an MRD-negative CR and the patients are doing well, I think we can even consider perhaps early discontinuation. We are seeing still durable responses with this. Another consideration in terms of toxicities, for these patients, we have also seen some ataxia and dizziness-type symptoms or dizziness ataxia. Some of our colleagues have described, like Dr. Janakiram from the City of Hope and others. So as has been pointed out, generally what we do for these patients is we may hold the dosing. Potentially, we can re-challenge them with a lower dose, and certainly, we can observe their response or consider alternative T cell-directed therapies if needed. But generally, a majority of them will resolve. 

Saad Usmani:

And then now with that late relapse experience, you know, you also shared some of the excitement about the MonumenTal-3 data that were presented looking at the combination of talquetamab with daratumumab or with daratumumab and pomalidomide and compared that to dara-pom-dex. It looks like the MRD negativity rate, progression-free survival, as well as overall survival were all positive in favor of the Tal combination arms. What lessons did we learn from that late relapse setting to early relapse setting? And what do you think about these combinations? Do you think there is… what makes more intuitive sense? Is it anti-C38 with a bispecific, an IMID, or both? 

Doris Hansen:

So that is really a great question. I do think we’ve learned a lot from the late relapse and we’ve brought these learnings to the early setting in terms of MonumentTal-3, as you very nicely pointed out, right? The combinatorial strategies were either with a CD38 alone or a CD38 and an immunomodulatory drug, or pomalidomide. And really what we saw in terms of response, very similar when we had either the CD38 with talq or with CD38 and pom, responses were very similar. Survival was very similar, regardless if you use the doublet or a triplet, if you may. But what we saw differences in were safety events or toxicity events. Generally, what we observed is that in patients who you added the immunomodulatory drug to, they tended to have generally more cytopenias, more infections. So again, this is my personal opinion. We do not have any approvals in this setting, but I think perhaps just the two-drug combination strategies such as talquetamab and daratumumab alone may be sufficient for these patients to minimize the toxicity profile.

Susan Bal:

I have a little bit of a different take because, you know, a lot of these later early line studies that we’re looking at, you know, have often used Dara in patients who may not be Dara-naive or exposed. And so a lot of times, you know, when we are trying to understand and phrase this data in our clinic and our clinical practice, it becomes a little tricky when we are trying to anticipate the expected PFS for those patients, given that a lot of our patients don’t fit that bill. Dr. Usmani has presented fantastic data from quad combinations up front and really led the way for those things. And now that we use Dara for everybody, I often struggle with understanding what the role of sort of Dara retreatment for these patients is. So I find that a little bit tricky in my clinic when I’m trying to understand where all of this data fits. And so I struggle a little bit with that question. Perhaps, you know, I remain very excited about the MonumenTal-6 data that’s going to have a Tal-Tec arm. And I feel like perhaps those combinations for high-risk patients make more sense. Where CD38 combos sit in an era where everybody is CD38-exposed or refractory is, I feel, a personal challenge for me to kind of extrapolate that data in clinic and try to explain that to patients. 

Saad Usmani:

No, absolutely. And, you know, I’m glad that you bring up that point because how do we apply that data to our patients today? The way that I think about this is that, you know, we all have those patients who got a triplet or a quad, with or without transplant, and then went on just a single drug maintenance. And so they had anti-C38 exposure, but, you know, they did not receive anti-C38s subsequently or they stopped after a little while. So for whatever reason, you know, this is different from the MAIA-like patients who got dara-len continuously, right? So we have those patients and if they’re progressing, then I think an anti-C38 being added on to a bispecific makes, you know, good sense. It looks like, you know, there were patients who were anti-C38 exposed, even though they were small, but they were exposed, not refractory. So if you have that exposure, it looks like, you know, you may be able to use this treatment. But I completely agree. I think, you know, for those patients who are actively on anti-CD38s and progressing, you would agree that many of those patients are probably functional high risk, you know, because if you look at the Cepheus and Perseus data, the people who respond well, you know, they keep on responding. So, and it’s really that functional high risk or even IMS, IMWG 2025 high risk who’s going to progress early. So, for those patients, you know, you really want to change up the mechanism of action. That’s where, you know, we might be favoring something like cilta-cel early on or if they’re just not eligible for CAR for any reason or it’s an access issue, then it’s probably going to be, you know, the bispecific without the anti-C38 or potentially even with an IMiD, you know, once that gets approved. So, you know, we’ve been talking a lot about talquetamab. Susan, I want to give the floor to you and you can talk about, you know, Arlo-Cel. And again, that’s, you know, so I have to put the plug in that, you know, it was the construct that, you know, Sham and Eric had worked on at MSK that, you know, is eventually getting commercially developed. And you had led the phase one study, presented it, published it, and now, you know, it’s heading into, in fact, you know, data may be maturing for regulatory purposes as well. So Susan, can you walk us through some of that? And Doris, please feel free to chime in as well. 

Susan Bal:

Yeah, I think that, you know, it’s really been an exciting journey. As you said, I definitely want to shout out to Eric and Sham. I was a fellow with Sham in his clinic accruing to the initial phase one study, so really, this was a full circle moment for me when I came out to UAB and I had a chance to work on the arlo-cel project. And as I mentioned, we had some excellent early experience and we were fortunate to have a chance to present this data. Arlo-cel, as is known to this audience, is a GPRC5D-directed CAR T-cell therapy. It’s currently not FDA-approved for this indication, but in the phase one study, with more than half of our patients, or roughly half of our patients having been previously BCMA-exposed, we saw very impressive response rates, 87% for the entire study and at the two recommended phase two doses, we saw response rates that were upwards of 90%. With a median PFS in the late-line setting, that was about 18 months, and a median OS to me, which was very encouraging, which was roughly 90% at 12 months, really unheard of in this very late-line, previously BCM-exposed population. I think two reasons why it looks so good. One is I think the mortality and NRM on this CAR-T is quite low because patients don’t get bad infections. They get minor heart epithelial toxicities, which usually will resolve given the one-time nature of the CAR-T. But a lot of the non-relapse mortality is actually quite limited. So even if patients have, you know, sort of 18 months of progression-free survival, they remain alive and well to then go on to kind of experience some of the benefits of other development that are occurring in myeloma fields. So this is currently being studied based on the positive phase one results in the QUINTESSENTIAL study, which is a phase two study looking at quad class exposed multiple myeloma, and I think BMS released the top line results sharing that the study looks positive. I do not have any more data beyond that, but we are all excited to learn more, and hopefully this can be an option for our patients soon. 

Saad Usmani:

Doris, your thoughts about this CAR-T construct, especially with the prior GPRC5D bispecific experiments in mind. 

Doris Hansen:

Yeah, I mean, I think this is such an exciting study and such an exciting time in myeloma to be able to have a one and done treatment after a BCMA exposure, which you mentioned was a lot of these patients and to have that median progression-free survival of 18 months or so is really incredible. And really being able to see that some of those on-target off-tumor toxicities generally were mild and resolvable, at least for skin, nails, et cetera. I think that’s really great from a quality of life perspective and patients who might not have had a chance to make it that long in the first place. I think very, very exciting target and development. 

Saad Usmani:

Speaking of, you know, going beyond just single antigen targeting, you know, we have bispecific data with the Tec-Tal combination in the RedirecTT-1 study, which was focused more on looking at the safety, eventually saw a signal in EMD and then expanded the EMD population. And that combination is also being examined in the MonumenTal-6 study, which apparently is supposed to be positive. You know, the news came out, maybe the data will be presented at ASH, maybe by Pete Voorhees again, who knows, you know. So, you know, we’ll see what that data looks like. But, you know, a lot of excitement. So, you know, your experience and thoughts, you know, about the dual targeting? 

Doris Hansen:

I can start. I really am very excited about the dual targeting Tec and Tal combination. I do believe that, as you mentioned, the extramedullary disease patients have really been a population of a highly unmet need. So being able to have that type of therapy where we’re seeing response rates of like 80%, we’re seeing complete remission rates in these patients exceeding 50%, I think that’s really quite incredible for such a high-risk population. And whether we use that, you know, in the relapse setting, whether maybe we consider additional, consolidative, perhaps fixed-duration, spaced-out duration for patients who have, let’s say, functional high-risk disease, EMD, or some other immunotherapies such as CAR-T. I mean, I think these are all very exciting to be able to dual-target to overcome that resistance. And if we can optimize safety a little bit more via these fixed-duration strategies, I think that would be beneficial. 

Saad Usmani:

Then we have the trispecifics too, Susan. So they’re coming. Do we need two different antibodies being given at the same time, or can we just one? 

Susan Bal:

I think the trispecific data is so exciting to us because, you know, especially kind of looking at some of the late-line Ramantamig data, the response rates are really astounding, particularly in those who are GPRC5D and BCMA naive, a 100%. I think the development of that particular agent is one that I think we should all study at how wonderfully it was done, all in the context of a single study, trying to sort of understand every aspect of optimization, whether that’s one dose step up, whether that’s outpatient dosing, whether that’s really the incredible efficacy of these agents. And I think everybody is looking forward to developing these trispecifics in earlier-line settings to achieve our goal of cure together. 

Saad Usmani:

And then, you know, at least in the preclinical domain, there are other trispecifics that may be combining, you know, that are coming up as well. So there was this second tri-specific beyond romantimic, I think it was the IBI3003; I think that was presented showing, you know, almost similar kind of results. It’s further, you know, behind in terms of clinical development, but that one is coming up. And then, you know, we also have dual-targeting CARs that are in development. So, you know, so I think that may be, you know, the wave of the future as we try to get these therapies to the front line so that we can really cure myeloma. Doris, cure. We’ve been hearing a lot about that too. So dual-targeting CARs, will they get us there? 

Doris Hansen:

I really hope that they do. I mean, I think what’s impressive, even if we think about ramantamig, so like multi-antigen targeting ramantamig and dual-targeted CAR T-cell therapies, what’s really exciting is that we do see encouraging efficacy for these patients in later lines, but what’s most impressive is their efficacy in patients who are, let’s say, BCMA/GPRC5D-naive. I mean, we’re seeing responses with these agents of 100%. We’re seeing MRD negativity rates of 100%. And CR rate, at least for the dual CAR, was 88%, with responses continuing to deepen over time. Similar for ramantamig. I think this is really quite incredible. I know we’ve talked, as you mentioned, about a functional cure. The question here is some of this data is a bit not mature yet. We still have, we need longer follow-up. But in theory, all of this multi-antigen targeting should overcome resistance, should get us deep and more durable responses. I think time will tell. But I do believe that these have perhaps the most potential to get us and our patients to a functional cure, maybe a definitive cure. I’d love to see that. 

Saad Usmani:

So Doris, one of the things that we have not talked about, we will focus more on T-cell redirecting therapies, but antibody-directed conjugates are still a novelty, I think, in myeloma. We have ADCs that have been around on the solid tumor side and lymphoma, but, you know, for myeloma, we’ve only had one ADC. But, you know, apparently, you know, there is an ADC that’s targeting GPRC5D. And there’s, you know, some clinical development, you know, on that, and, you know, do you know anything about that compound and others? 

Doris Hansen:

Yes. So that’s a great question. I do believe that there is some development with ADCs in terms of targeting GPRC5D. I don’t know that we have a lot of data in that space, but I think it will be exciting to be able to have a potential option that patients could get in the community, could get different frequency and dosing durations, may not necessarily perhaps need the academic center or the different complexities that come with T-cell redirecting therapies. But I look forward to seeing some of that data from, you know, an efficacy, safety, and sequencing perspective as we have more and more therapies come into the pipeline and as BCMAs move earlier in lines of therapy. 

Saad Usmani:

And Susan, you know, with GPRC5D being a lucrative target for both these kind of T-cell redirecting therapies, there’s also potential of combining other antigens with GPRC5D for the trispecific approach or even for cellular therapy approaches. So, you know, what would you be more excited about? You know, if BCMAs are, you know, moving upfront, what else can be combined with GPRC5D for multi-agent targeting? 

Susan Bal:

Absolutely. I think that as the landscape changes yet again for our myeloma patients and we have more data, particularly some of the MajesTec-5 data that shows upfront bispecifics targeting BCMA moving up and creating an opportunity for us to have 100% MRD negativity, even in limited numbers. I think that the next question and the next unmet need that we’re going to have to address as a field is going to be what to do with these very early BCMA-exposed or refractory patients. And I think, Dr. Usmani, as you mentioned, I think GPRC5D is definitely an option for these patients, both by itself as well as in combination as a trispecific approach with other antigens such as FCHR5 or CD38. So, for example, if we are not exploiting or creating CD38 refractoriness early on, then perhaps, you know, those different combinations could serve us well in the early relapse setting in those situations. But look forward to ongoing developments. 

Saad Usmani:

Thank you both. Thank you, Dr Hansen, Dr Bal, for joining me for this discussion. I hope the audience enjoyed these updates focused on GPRC5D as a target in myeloma, both the current data and the future developments that we all look forward to.

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