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Beyond BCMA: How GPRC5D-Targeted Therapy Fits into Multiple Myeloma Care Today

Intro: 

Hello and welcome to the Decera Clinical Education’s Oncology podcast. I’m your host, Hannah Powell. Today’s episode features Dr. Jesus Berdeja from Tennessee Oncology in Nashville, Tennessee and  Dr. Amrita Krishnan from City of Hope Orange County in Irvine, California.

They are going to be discussing the use of GPRC5D-targeted bispecific antibodies in Relapsed or Refractory Multiple Myeloma, such as recent clinical trial data, patient selection, safety considerations and where GPRC5D-targeted bispecific antibodies best fit in current and future treatment strategies.

This episode is part of a larger educational program titled, “GPRC5D-Directed Bispecific Antibody Therapy in RRMM: Clinical Evidence and Practice Implications” For more information about the presenters along with a link to the larger educational program, please visit the show notes for this episode.

Now let’s get started and hear what the experts have to say about this important topic.

Dr. Jesus Berdeja (Tennessee Oncology): I was just thinking of maybe just start with GPRC5D. A lot of the new immunotherapies are BCMA directed. There is another great target in myeloma called GPRC5D. Would you mind telling us a little bit about what GPRC5D is? Then we can start talking about some of the therapies that we have targeting that antigen.

Dr. Amrita Krishnan (City of Hope): Sure. GPRC5D is an interesting target because it is, we discovered that it is on myeloma cells. It is actually expressed in other tissues in the body. For example, on keratinized tissues, so your nails express next to taste buds as well. The question is what does it really do? I am not sure that we really understand its purpose, but we do know that it is highly expressed on myeloma cells, which is what we exploit when we look at GPRC related targeting strategies. The real question then becomes, I am going to ask you, do we really need? I thought you fixed everything with your BCMA CAR T cells.

Dr. Berdeja: Unfortunately the short answer is yes, we do. Although there is a lot of excitement about the possibility of some of these therapies maybe being curative for a subset of patients. The majority of patients still relapse even after BCMA targeted therapy. I do really believe that we need a lot more directed therapies. I think GPRC5D lends itself well to that. Like you said, GPRC5D we do not know exactly what it does or why the cells need it, which is very different from BCMA. 

BCMA is very important for the plasma cells, and so unfortunately it is expressed on all plasma cells, both the malignant and benign cells whereas GPRC5D the nice thing about it is actually it is expressed much more avidly in malignant cells and not so much in the benign cells. I think that is one of the attributes of this antigen is that it is much more targeted towards malignant cells. Perhaps that may be the reason why we are seeing a little bit less of an infectious problem with these products that target GPRC5D. 

Maybe we can actually talk about what products we are talking about is what is FDA approved that targets GPRC5D currently?

Dr. Krishnan: In that sense, it is much easier because there is only one FDA approved GPRC targeted therapy and that is talquetamab. I think that is easy if you have to go to your cupboard of therapies. You have decided on a GPRC5D therapy. Really that is the only thing you can pick. The question becomes this whole idea of therapeutic sequencing. Where do we put this before, after, alongside BCMA directed therapies?

Dr. Berdeja: No, that is a good point. But maybe we could start by actually, you know this data incredibly well, but somebody else may not know this data incredibly well. How did talquetamab get approved? I believe it was the MonumenTAL-1 study. 

Dr. Krishnan: Yeah, exactly. MonumenTAL-1 was of course advanced relapsed disease. What we show in patients with median of four prior lines of therapy, including prior BCMA directed therapies. There was a cohort that was allowed to have prior T cell redirecting therapy, so that could be either bispecifics or CAR T. They could still respond to a GPRC directed therapy. Overall, the progression free survival MonumenTAL-1 in patients with a median of four prior lines of therapy was around 11 months. 

That prior BCMA directed cohort, it was a little bit less. It was about 7.7 months, but it still suggested that you can use this after BCMA directed therapy. Of course, since that trial came out, we have learned a lot more about sequencing and probably we can optimise its use after BCMA directed strategy.

Dr. Berdeja: Do you think it should be relegated to the BCMA space?

Dr. Krishnan: That is a great question. I think that is where we struggle, because MonumenTAL-3, which, was pretty exciting data that was presented at EHA was just after one prior line of therapy. It was fairly agnostic, and the PFS data from MonumenTAL-3 three was pretty good. The MRD negative CR rate also extremely high. That was a combination of talquetamab and dara or talquetamab, dara, or pom. 

I do not necessarily think it has to be relegated to post-BCMA. I think it becomes this idea of patient selection to your point about less infectious toxicity with talquetamab, for example, versus BCMA directed therapies.

Dr. Berdeja: Go ahead.

Dr. Krishnan: I was going to say where have you been using it?

Dr. Berdeja: I completely agree with you. I think it is just as potent therapy as the BCMA directed therapies, but like, as you alluded before, because of some of the off tumour expression in the surface of the tongue and the highly keratinized tissues, it does have these toxicities that are basically expected. That can be a little bit more difficult as opposed to the BCMA directed therapies where,  my patients say they do not even know they are on therapy. 

It really comes down to a quality of life and this discussion with the patient about the side effects and  where they stand with the caveat that I think it is true. I think as we get more and more data, we do see that the GPRC5D directed therapies are not as plagued as much as the BCMA directed therapies with severe infections. The problem I have with the bispecific antibodies is that at least right now, all the bispecific antibodies are given to a progression. 

Which means that the infectious risk does not go away until the patients offer therapy, even six months later, we have to be careful about the patients still being high risk for infections with BCMA directed therapies. In a patient where we are very concerned about infection, I agree with you. I think the GPRC5D targeted therapies make more sense. 

I have to say if that is well-managed for the most part, I am using a BCMA first and then the GPRC5D. I think part of that is also just because it is almost easier. We only have one book that we can use as opposed to several drugs that are directed against BCMA. I think almost that by itself relegates it to later use, but I do not think we know the answer. 

Dr. Krishnan: No, but I think we are all aligned there so that obviously with CAR T being approved in the second line setting now with MajesTEC-3 BCMA bispecific approved in the second line setting, Talquetamab is still only approved after four lines of therapy. Just by default, it is still right now in that post-BCMA space. To me, I think you alluded to the differences in side effect profile. I think that is where the biggest education really has been to patients as well as to community providers of not being afraid of it. 

Forewarned is forearmed, and I think if patients understand these things could happen, they are manageable and they improve with time that they are less afraid unless it sounds less onerous. It is just the taste changes can be managed with dose and schedule adjustments, The nail and skin toxicities. We used to send everyone to a dermatologist. We never do that now. 

We have a handout for patients in terms of using nail hardening agents and emollients for their skin, things like that. I think all of that has helped to make it a much more manageable therapy for patients.

Dr. Berdeja: I think you are right. I think, you and I were both in MonumenTAL-1. When we first started using it, we were not expecting these toxicities. It was like, "Whoa, what is going on? What is happening?" Even we were a little scared of what are we doing to our patients? I have to say, once we realized that this was an off tumour on target effect, and also we started realizing that at least when you look at some of the data, the patients that had these side effects also seem to be the ones that responded. 

It is like cytokine release syndrome with CAR Ts where we are like, "We want a little bit. We just do not want too much." I think you are right. I had patients who really benefited from talking to other patients who were on the drug to help them navigate that whole first cycle. Because I think that first cycle is the hardest where the side effects are new, and it almost seems like they are almost a little stronger. 

Then like you said, they tend to get better with time. I do not know if that is just because the patient gets used to it or because truly you are no longer redirecting to those low level expressions of those tissues. Maybe it is less. We have learned also that with increasing the interval of the drug significantly helps with those. I think you are right. It is the expectation is making sure that everybody is educated about the expectation of these potential side effects, which I think are unique.

Dr. Krishnan: I think in a way, the community doctors, they did such a great job with checkpoint inhibitors.. You and I do not give them because it is not myeloma, but they have a fair amount of skin toxicity, other side effects. I actually think talquetamab is a much easier drug to give than a checkpoint inhibitor. The toxicities are pretty directed. As you said, relatively manageable with dose and schedule adjustments and supportive care.

Dr. Berdeja: I agree. What is interesting is there are other GPRC5D directed therapies that are being tested including an antibody drug conjugate. I think the one that is the most advanced is a CAR T that is directed against GPRC5D. I do not know if you are involved in that phase I study. Were you involved in the phase I study for arlo-cel.

Dr. Krishnan: Yeah, we were here.

Dr. Berdeja: I have to tell you, the very first patient I dosed, I was very scared because I was worried that knowing that these potential toxicities with the bispecific and the bispecific is given slowly. You step it up and then you do it every two weeks and you can stop. If there is significant toxicity with the CAR T, as you know is the CAR Ts go in and they expand. My concern was that expansion, that patients were going to get these really severe cutaneous toxicity and tongue toxicity and it was going to be terrible. 

What is interesting is actually that has not panned out, which is really nice. I think that it is just a different kinetics, I think of the two different therapies, but the good news is that at least from that standpoint, the other modalities targeting this antigen are moving forward and appear to be safe. I think it is good, but none of those are approved. We will have to wait for more long term data as to howwell they actually work.

Dr. Krishnan: I think, the other thing I did want to bring it back to this sequencing idea because in that original MonumenTAL study, I think we did not really understand that going from one bispecific directly to another bispecific is probably not optimal just because of not just target, but also the immune environment. There is a lot of controversy. Do T cells get exhausted or not? I think the data does-

Dr. Berdeja: They are damaged anyway.

Dr. Berdeja: They are affected.

Dr. Krishnan: I think that is a fair. They are tired.

Dr. Berdeja: I think you are right. This whole sequencing thing is very intriguing. I think most of us in our mind think if we go from one, if we change a target that is better than going to the same target, and theoretically that is true, but I think you are right. I think it really depends on what the prior therapy was immediately before changing your target. Again, we do not know this, but I think we will know this for some time as we are moving this earlier in line, is it going to be the same for a patient who gets second line BCMA directed CAR T and now gets talquetamab third line four years later? 

Is that going to be the same in terms of the effects on talquetamab as someone who just finished BCMA directed bispecific and is progressing and you put them on talquetamab? We know that that is not a great scenario. Going from bispecific to bispecific. It is not completely clear. Do you agree that changing antigen is probably the best if you have that option, it is probably the best way to proceed after you received one or the other?

Dr. Krishnan: I think that is what most of us do. I do think the best case scenario is relapse after BCMA CAR T then going to talquetamab. Even there, the data that we have is retrospective data. There is some data suggest six months after your CAR, but to me that is more a function of your disease biology and less a function of the time interval.

Dr. Berdeja: That is true. A patient whose myeloma responds and stays in response longer, it is always going to do better than a patient that progressing quickly. It is always challenging to know, are those therapies specific or myeloma specific issues. No, you are right.

Dr. Krishnan: Then maybe we should talk about combinations, because I think, most of us, yes, these were all approved as single agent. Do you want to speak to MonumenTAL-3 because that is kind of the first combo phase III.

Dr. Berdeja: You are right. I think just like everything in myeloma, we think everything works better in combination, and there are some rational combinations with these T-cell redirecting therapies. With other of our therapies like anti-CD38 antibodies or even like the IMiDs and CELMoDs that tend to potentiate the T cells and cause immune modulation that may really work very well in conjunction with these T-cell redirecting therapies. 

To that effect, we saw that it started with the BCMA bispecifics and MajesTEC-3 with the combination of daratumumab and teclistamab being incredibly effective and superior to standard of care. Now we are seeing the same thing with MonumenTAL-3, which you just alluded to. These are patients who  had had one or more prior line of therapy, and were randomised to receive talquetamab with daratumumab plus-minus pomalidomide versus standard of care. 

The curse of both the talquetamab arms are well superior to the standard of care. Again, reinforcing the idea that the combination makes the drugs more potent. In that scenario, I also wonder, is it the combination or is it moving it earlier in the line of therapy? Because we also saw with MajesTEC-9, with a single agent, teclistamab also performed the standard of care in one to three prior lines. 

I think the verdict is still out, but I think especially talquetamab I think it lends itself very well to combinations to potentially make this a much more powerful treatment for our patients. What is your take on the combination study so far?

Dr. Krishnan: I think MonumenTAL-3 data, you are right. The 24 month PFS, 81% in the tal, dara, pom. 77% in the tal, dara arm. I agree. I think it is just using a bispecific in the second line setting is where you see the biggest benefits of anything. Then it becomes more nuanced of which one do you choose? I am going to put you on the spot and ask you. Here the question is, how much do you need to do tal, dara, pom versus just tal, dara? Because the trial did not compare those two arms. 

Dr. Berdeja: Yes, you are right. The short answer is, I think you can do either. I think the question is, is there really a significant increase in efficacy by adding pomalidomide on top of daratumumab? That is what we do not know. I think numerically it seemed like it was superior, but the problem was also there were more toxicity, more hematotoxicity, more infections. You have to weigh whether the added toxicity is sufficient for that perhaps increase in efficacy, given that the two drugs are superior. 

I probably would not do the three drugs in most patients. I may consider it in a patient that just has bulky disease where I am trying to really get them control where I know that the tal-dara- pomalidomide combination will work as an antimyeloma therapy as well. Not just as a potentiator for the T cell redirecting. I might consider it then, but I think in most patients I will probably go with a doublet instead of the triplet. 

Then I will put you on the spot next since you put me on the spot about that one is all these phase III trials we are talking about dose the bispecific antibody until progression. In your mind, are you going to be dosing this talquetamab, for example, after MonumenTAL-3 once assuming it gets an FDA indication, are you going to be dosing until progression or are you thinking limited therapy?

Dr. Krishnan: Oh, that is a good question. I think in the first relapse setting, you will be much more willing to limit duration of therapy. If you have sustained MRD negative CRs, I do not know what that duration of therapy will be. My guess is somewhere between two years to three years, and then one would envision stopping. Because I think many of us are already doing this. MonumenTAL-1  , we have extended duration. We have been too chicken to stop because that is a patient who has had four or five relapses.

Dr. Berdeja: No, I think that is an excellent point. I think we all talk about limited duration, but I think we really have to be thinking about the patient. If it is a patient that really is relapsed refractory is gone through everything we have and they have a response to this and it is tolerable, I would be cautious about stopping therapy in that patient. Like you said in a patient that if and when they were to relapse after something like MonumenTAL-3 based therapy, you know have options after that. 

I think that is where quality of life and the idea of how much do we need is important. I agree with you. Two to three years sounds like a lot to me. I suspect that as we move forward that we will find that after a year, if you are not in a MRD negative that maybe do you really need to continue the therapy? I think patients achieve responses so quickly. 

It is unclear to me how long they need it, but I think definitely from a quality of life standpoint I think this especially something like actually both but talquetamab just given some of those side effects that patients do not like. I think if they know it is limited duration, it is going to get them to a remission and then they get a treatment free period. I think that is going to be the best way moving forward, but obviously we still have to study that and do it cautiously.

Dr. Krishnan: Then the other point, allegedly higher incidence of GPRC resistance than you see with BCMA, because GGPRC has multiple mechanisms of resistance. I do think also fixed duration of therapy may help also reduce the emergence of resistance.

Dr. Berdeja: I think that is an excellent point and something we did not really talk about when we were doing sequencing. With BCMA after CAR T, it is unheard of. That you lose BCMA although there are case reports. The majority of patients retain BCMA, presumably later on, you can then sequence. With bispecifics, that is a little bit of a higher incidence in terms of BCMA, but it is most of the time it is mutations. 

As long as you have something that binds, perhaps you can overcome the mutation, but with GPRC5D their early data is looking like patients who relapse after a GPRC5D therapy. The majority of patients will lose GPRC5D? Is this a one and done type of therapy or are we going to be able to sequence? We actually do not know but I like your thinking that if you stop it early, maybe you will prevent that from happening for these patients.

Dr. Berdeja: Is there anything else? Any final thoughts on this, we discussed most of these issues, I believe.

Dr. Krishnan:I know you work with a lot of community sites as well. What do you tell them just as a practical to start? It is not just GPRC5D bispecifics, which is bispecifics in general.

Dr. Berdeja: I think, talquetamab it is no different than the BCMA bispecific from a standpoint of the need for step up dosing before you get to the final dose. Most of the cytokine release syndrome and potential ICANS happening during that step up in first dose. Which is why with the REMS is required. I think for the most part right now, most community, like small community practices are not doing the step up. 

As you know, when often they will send them to a tertiary center like yours to do the step up to the first dose and then you send them back. Hopefully they are ready to then continue dosing because the continued dosing is actually pretty easy. The same here with in our practice, we have a very large practice and we have I think about 35 different clinics, but some are actually quite rural and some of them they may have one or two doctors and some do not even have a doctor.

They do a lot of remote because our goal is to try and get the therapies to the patients. We still do the step up dosing of all the bispecific antibodies, including talquetamab in three of our locations that are set up to do so. Then with the goal that then the patient then goes back to their home clinic. All those docs are, are REM certified, the staff is as well to continue dosing. I think it is just that communication and then looking at studies. 

Are we going to be able to do what we are doing BCMA where maybe prophylaxis, tocilizumab will reduce the risk of cytokine release syndrome to such levels that maybe this can all be done as an outpatient and be done in local clinics? I think it is possible. I think it is a little bit further behind than BCMA, but I am curious, are you giving it all as outpatient or are you still admitting patients for observation?

Dr. Krishnan: We are doing it all as outpatient, except for patients who have significant comorbidities or a very high tumour burden. I just recently had two 80 something year olds doing it as an outpatient.

Dr. Berdeja: Are you giving prophylactic tocilizumab?

Dr. Krishnan: Yes. We are giving prophylactic toci everyone.

Dr. Berdeja: You do the same thing for talquetamab as you would with the BCMA bispecifics.

Dr. Krishnan: Yes. Correct.

Dr. Berdeja: I think that is all the time we have. Dr. Krishnan is always a pleasure doing this with you and thank you for your insights.

Dr. Krishnan: Thank you Dr. Berdeja. I always enjoy chatting with you. It certainly has somewhat aligned views, but then we have some interesting differences in certain points. I think it is we learn from each other, so thank you.

Outro: 

Thank you, Drs. Berdeja and Krishnan, and many thanks to you, our listeners, for joining us. As a reminder, to view the full program “GPRC5D-Directed Bispecific Antibody Therapy in RRMM: Clinical Evidence and Practice Implications” please click the link in the show notes. And be sure to check back regularly for more episodes on important Oncology topics!