Sham Mailankody:

Hello, my name is Sham Mailankody and I’m a cell therapy physician at MSK. I’m here with Dr. Jonathan Keats from the TGen Institute in the City of Hope. We’re here at the International Workshop of GPRC5D Therapies in New York City. This is the second annual meeting. Jonathan, what do you think so far of the meeting?

Jonathan Keats:
This first session was really good because we talked about things that are actually missing in most of the clinics around the country and around the world on how to assess which patients might benefit the most from one of these therapies. And as we’re starting to appreciate more and more how often patients who do get exposed, particularly more to talquetamab at the time, because that’s the lead agent in the field, how many patients have lost that target antigen. And as we move forward and need to decide who gets what when, being able to assess which patients are viable and is going to be really essential to optimize care outside of clinical trials.

Sham Mailankody:

And that brings up an interesting point, which I think is in the last five or so years, the clinical applications of our technologies and our preclinical science sometimes has outpaced or at least kept as much with pace with the research, which by that I mean, we now have a plethora of treatment choices. We have CAR T-cells, we have antibody drug conjugates, we have bispecific and maybe trispecific antibodies soon, and we have different targets as well, BCMA and GPRC5D. So an important question in the clinic is sequencing and which drugs to use first or which target to go after, which modality to go after. And I think you very presciently, more than almost nearly 20 years back, talked about sequencing before all of these drugs were available and genomic evolution, the context of sequencing. So how do you see diagnostic testing helping us decide which drug or modality to use and how to sequence these therapies best?

Jonathan Keats:
Yeah, I think it’s going to change how we view in the frontline setting as I think all of us acknowledge most of these agents are going to get approved in the frontline or at least in first progressions kind of scenarios. So being able to assess our targets available in those patients, in most patients they are, but that’ll be really essential even at baseline. And then as patients progress, where now, as you mentioned, the research on how the drugs work and mechanisms of resistance has, in the immune therapy space, been amazing compared to all the other therapies that we did. We really understand what leads to a patient no longer responding. And bringing that from the genetics to cell surface protein expression, I think the last one that’s gonna really help clinicians like yourself make those decisions is now also gonna be assessing the immune system to know is this patient a good candidate for a CAR-T versus a T-cell engager versus an ADC because the immune system’s not going to be there to assist? And how you’ll cycle them at those different times will really change. I’d imagine your clinic, you have those patients that you’re sitting there scratching your head and going, okay, you’ve seen A, B, and C, and D. What is the right thing for my patient today? And a lot of times we’re just acting on best, most likely statistics, not that patient’s actual profile. Because even advanced MSK, City of Hope, we don’t always have access to these diagnostics today.

Sham Mailankody:
And I think the panel discussion, several speakers, including yourself, I think brought up important concepts about how these testing might influence sequencing. So for instance, I think an important problem that we’ll face in now and in the near future, given that I think second line and third line, almost all patients will now be treated with BCMA, or many patients will be treated with BCMA therapies. With the new approvals that have come in the last year, we have bispecific antibodies, CAR T-cells and ADCs are all now approved for patients with early relapse. And so that means then, unfortunately, that when patients get these treatments and eventually relapse off of a BCMA treatment, a critical question will be, can we give them more BCMA treatment, i.e. if they’ve progressed after cilta-cel or ide-cel or BCMA CAR T-cell, can we re-treat them or re-treat them bispecific antibody or ADC? Or should we be switching targets to GPRC5D? And I think that’s a question that many of us will increasingly face with the availability of all these different agents. How do you think diagnostic testing will help us resolve this? In other words, can we re-target the same target or should we change the target?

Jonathan Keats:
I think it will fundamentally change our basic tenets of the clinic, right? Classic basic tenet was if a patient’s been exposed to that agent and they progressed, you don’t go back. And I think now, as we understand, especially from the immune therapies, the target is no longer on the tumor cell, well, you can’t go back. Or it is there, now you have to make a decision of the modalities. Because even most of these targets, we have in clinical trials for all of them, we have CAR-Ts, we have T-cell engagers, and we have ADCs that, again, give you, if the target’s present, now you have to pick which of those three pillars is gonna give you the best response, that’s one parameter, but also which one’s gonna work for that patient because it might not be, the one that works for the best for everyone may not work for that patient. We will work towards those ways of defining that. I think that’s the one of immune assessment. I think target assessment is something. It’s just a matter of making reagents commonly available, standardizing how people interpret those things across clinics to then decide who’s the right patient for the right agent.

Sham Mailankody:
The other dogma in the field for the last several years has been all other things being equal, if you want to go after a target, let’s say BCMA or GPRC5D, that a CAR T-cell provides more advantages over a bispecific antibody. However, in the last few months, we have data now from MajesTEC-3, for instance, which was a trial, albeit in BCMA, with Dara and Teclistamab compared to standard of care, and then CARTITUDE-4, where cilta-cel was compared to the same standard of care. These are now cross-trial comparisons, but many people were quite struck by how impressive the data for dara-tec looked like, perhaps arguably reaching similar levels of responses and efficacy as cilta-cel does, which raises a question then, are we really certain that the efficacy of CAR T-cells are superior to bispecifics, or are they more comparable to each other? Which then leads to the next sequencing question, which you alluded to as well, which is which modality to go after? And do you think it would be different for different patients or can we come up with kind of a more uniform rubric for saying everybody gets a CAR if they can get a CAR or are there patients who would benefit from an alternate modality more? All of the things being equal.

Jonathan Keats:

I think those things, I hope, will resolve some of those. Again, like a lot of people, seeing those early data from CARTITUDE-1 showing 30% of patients being disease-free at five years adds to those arguments that we had as CARs came into the field that a CAR is potential for curative. I would, from the genomic sidepoint, we see so much more tumor acquired resistance in the T-cell engagers which I guess thinking more of like how we measure microbial resistance to different antibiotics. Usually the better the drug, the more you start to see genetic resistance. So I almost think at some levels, the fact that we see such aggressive resistance coming out in T-cell engagers might argue that they’re better. I think the clinical data for some of those early studies to see that final endpoint, obviously we know they don’t have the same overall response rate at the front end, but now when we’re seeing things like the trispecifics and combinations, like you said, with daratumumab or combinations of two T-cell engagers, I think it will be really interesting to see how it spells out. I’d love to say we’re gonna be able to find, I think, and we didn’t talk about it in this meeting, but understanding whose immune system is best for those different therapies because there’s, inevitably, I think that’ll be one of those things that dichotomizes who gets it. I think that’s still a little bit more advanced research than they need to do.

Sham Mailankody:

And I think you mentioned that the pace at which we’ve kept up genomic characterization of tumor antigen expression on the research side has been pretty impressive for these therapies compared to historical. But I do think we’re maybe slightly lagging in defining immune fitness or immune health in a way that’s clinically actionable. And that is probably the next frontier of challenges in terms of translationally understanding what T-cell fitness means. Is there such a thing as T-cell exhaustion? And if so, how do we measure it in a clinically actionable way? I think it’s gonna be the challenge for diagnostics in the coming years.

Jonathan Keats:

No, and I think, well, again, a lot of times we talk about AI, and I think these are the kind of scenarios where AI-like tools will have a better opportunity because they can see patterns that we as basic, rudimentary, statistically-oriented scientists will not see. That being said, I think one of the talks we did have was about how microbiome can influence the immune system. And I think where that type of approach has struggled to get into the clinic is because it’s so diverse and inconsistent by study, inconsistent by center. And that’s where the immune system part, like I do worry that’s going to be a really hard lift. Like when we’re doing something, we sequence, do DNA sequencing. Is gene present or absent? It’s a yes, no. It’s a really clear diagnostic. It helps when I give you a report. Yes, no. Now I know what to do. Versus if I say it’s 63% probability. I’m like, well, I just don’t want to give that patient a CAR-T because’s

[overlapping conversation] 63%. Yeah, I get 95% response rate, so I don’t care about your 63%.

Sham Mailankody:

I think the other challenge we’re kind of addressing in the clinic now is, particularly in the context of CAR-T cell, is the fact that they’re not readily off the shelf. So there’s patient selection, there’s apheresis and bridging considerations. So often if I see a patient today in clinic, it’s not as if I could give them a CAR T-cell tomorrow. By the time they get a CAR T-cell, it’s about six, eight weeks from now. And one of the approaches that a lot of people are now adopting, and we have some clinical data for this as well, of bridging is to use a GPRC5D agent as bridging and for six weeks or eight weeks leading up to a BCMA CAR T cell. From a genomic perspective, what does brief duration of GPRC5D targeting as a preamble to a BCMA CAR T cell, what do you make of that strategy for bridging? And do you have concerns? Do you think it makes sense?

Jonathan Keats:

So we actually covered this in one of our recent meetings. From my side, my view, so again, a lot of things are multifactorial, but for BCMA, one of the things we think about is soluble BCMA inhibiting T-cell engagers or CAR-T from being able to recognize the tumor. So one thing that, we’ve talked about this because we use talquetamab a lot in bridging to CAR-T is that it provides an opportunity to also do a little bit of effect, quite effective tumor reduction over that month, but that also brings down that soluble BCMA level, making more tumor that’s remaining visible to that CAR-T or even another T-cell engager or a trispecific. So I do think that kind of approach, there’s biological rationale. The debulking actually does help that next line therapy, particularly when it’s a BCMA-based therapy that can be affected by soluble BCMA.

Sham Mailankody:
And so this is also kind of interesting. I think the field has kind of gone on an evolution of thinking given some of the toxicities we see with patients with high burdens of disease getting CAR T-cells. When I first started doing CAR T-cells, there was an idea that off-the-shelf CAR T cells would be great, no bridging needed. Now we’ve come a full circle to say, well, we actually do need bridging to debulk patients appropriately, as you said, start with lower tumor burden, which potentially helps with efficacy, but also there’s an increasing understanding, I guess, that also improves the safety of CAR T-cells such that in many of our practices, now it’s quite routine to try to give effective bridging therapy leading up to CAR T-cells, whether that’s talquetamab or chemotherapy or other agents that not only are aimed at just buying some time, but debulking so that patients don’t go in with very, very rapidly proliferative, very high levels of disease. And so therefore, I think some of the delays that are inherent to autologous CAR T-cells may not necessarily be as much of a disadvantage as one’s thought.

Jonathan Keats:
Yeah, and I think this is very much for the BCMA side, and that really plays into the count.

Sham Mailankody:
And then last thoughts, I guess, in terms of practical considerations would be, is there an optimal washout period from these treatments? In other words, if I were to use talquetamab for bridging, since it’s an antibody, long half-life, do I need to be worried about giving CAR T-cells in soon in soon close proximity within a week after stopping talquetamab or treatments like talquetamab? Or would I be waiting for two, three weeks to allow for clearance of the drug? On the clinical side, I’ll say we’ve not seen a big difference. We usually try to give a washout period of about one to two weeks, two weeks ideally, but sometimes if clinical situation dictates then one week. And we’ve not really seen an additive toxicity or lack of efficacy from doing so but any thoughts or perspectives on how you think about washout periods for these treatments, biologic agents particularly?

Jonathan Keats:
I guess the only example case I can say because I was involved in counseling a family with a situation like this where we’d done whole genome sequencing on them and actually knew that BCMA was lost, but we really had ran out of options for that patient. And they had been on talquetamab for a while and had started to progress on it. And in talking with the family, they’re asking like, well, should we really try the CAR-T? And we’re like, well, there’s clonal divergence, there’s all these other issues. But one potential is that we are giving those patients a very active population of T-cells that we know pretty rapidly can expand. And if you have those T-cells now also having the opportunity to have some remnant T-cell engager there, you are doubling up, bringing that target, not just recognizing BCMA, but those cells that are activated also have an opportunity to bind CD3 and activate. So from my side, again, not the clinician, but if you felt it was safe, you could see the biological argument that you actually could get additional benefit. And to be honest, most CAR-T effectiveness is happening that first week to month of the treatment. So that little window where both are still present, I think you have the opportunity for an extra benefit.

Sham Mailankody:

And then to close out, I was gonna say, I think, you know, there’s a lot of new modalities of both diagnostics and treatments that are coming. We’re hearing allogeneic CAR T-cells, in vivo CAR T-cells, trispecific antibodies, other ways of engaging immune system, for which some of which we’re already starting to see some very early clinical data. And similarly, I think diagnostics is improving as well. What are one or two things that you’re most excited for the field, whether it’s GPRC5D or more broadly in the coming two or three years that you think may have an immediate clinical impact on how we treat these patients?

Jonathan Keats:
Again for more specifically things that I’m working on I think it is that relapsed/refractory subset where a lot of patients have been exposed to many of these agents and using technology that we’re moving into the clinic and making available with say like in our case our case, it’s the whole genome sequencing, we have a good opportunity to assess which patients are viable for some of these follow-on drugs that are targeting the same events. Obviously, we had here talking a little bit more about more classic pathology, some IHC and flow cytometry tests that also really will make it broadly available for people to start assessing in that late-stage phase, which agents are right for those patients. And I think in the future, when we move everything to the frontline, we’ll be assessing all those features and then asking the question of, for this patient, which of these combinations or which of these individual drugs is the best for that patient, as opposed to just setting a standard field where it’s drug A, then B, then C. It’ll be a bit more personalized to that patient’s tumors because we definitely see diversity of things like you have 1q, your GPRC5D expression is a little bit higher than if you don’t have 1q. So there’s some little subtle things that do have influence on the potential for therapeutic effectiveness.

Sham Mailankody:
Thank you, Jonathan. This was interesting and hopefully we’ll have a good rest of the meeting. We have one more day of interesting talks. So thank you so much.

Jonathan Keats:
Yeah, first session was awesome.

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Charlotte Pawlyn:
Hi, my name is Charlotte Pawlyn. I’m a hematologist from the Royal Marsden Hospital and the Institute of Cancer Research in London, and I’m here at the iwGPRC5D meeting in New York. I’m joined by two colleagues who I’ll let introduce themselves.

Sridevi Rajeeve:
Yes. Hi, my name is Sridevii Rajeeve. I’m part of the Multiple Myeloma and Cell Therapy team at Memorial Sloan Kettering Cancer Center right here in New York, where this iwGPRC5D conference is being held for the second time, and we are having great discussions, which we hope to continue in this session.

Omar Nadeem:
And hi, I’m Omar Nadeem. I’m from the Dana-Farber Cancer Institute Myeloma Program in Boston, Massachusetts. Glad to be here.

Charlotte Pawlyn:
Great, thank you. So perhaps you could summarize what some of the discussions we’ve been having so far around GPRC5D-directed therapy in terms of what we’re seeing in terms of responses and duration of responses with some of these new approaches to treatment.

Sridevi Rajeeve:
Absolutely. I think, you know, since Omar recently just gave a talk on that, you know, I can maybe summarize what happened yesterday in our session. So yesterday, there was a lot of focus regarding basic science and translational science with a specific emphasis on diagnostics. So what tools do we have in our armament to really go after GPRC5D? Because GPRC5D testing is not really that available or yet scalable. And therefore, for many institutions, it’s really hard to really determine if a patient has had a GPRC5D-exposed agent before, do they have retained expression? And if there is retained expression, is there a mutation present? And all this helps in sequencing. So there was a very robust discussion regarding methods of detection, how they can be scaled. And I think that has a lot of practical implications, not just academia, but how we can make it available to the community within the U.S. and ex-U.S., and hopefully more. So I think that was a great start to the conference. And again, you know, just pivoting to the clinical perspective where we have multiple modalities that are now directed against GPRC5D. We have CAR-T products, which are single or dual-antigen targeting. We have antibodies, which are GPRC5D-directed, mono, bispecific, and now tri-specific. And now we have ADCs, which Omar just recently talked about, which is in clinical development. So there’s a lot of data that is coming in with, you know, really good PFS and overall survival data is still yet not mature, but, you know, we are seeing decent PFS that is really following along the tail of BCMA-directed therapies. You know, I think it’s getting there, but it’s really amazing that we have a separate target we can go after. When we have exhausted probably BCMA-directed therapy. So that’s just a summary. And feel free to add on, please.

Omar Nadeem:
Yeah. And I think the responses, you know, have been phenomenal. You know, you see the data already with talquetamab, which we’re using in clinic. You know, you see about two-thirds, about 70% of patients respond to talquetamab. And the duration of response can be several years for some patients that are doing well on that drug. And then it was really exciting to see the data from arlo-cel, which is our GPRC5D CAR T-cell product. In that phase one trial, about half the patients had prior BCMA therapy. And we tend to see no detriment to response in a very similar PFS in that cohort as we do with the non-BCMA-exposed patients. So I think it’s just giving us some clues that these are therapies that we can potentially sequence because it is a different target as most patients now have had prior BCMA exposure.

Sridevi Rajeeve:
And regarding at least publicly available data regarding the combination of teclistamab and talquetamab in the Redirec-TT trial and also the tri-specific antibodies, again, we are seeing robust responses. For specific cases, the NCCA now allows the use of teclistamab and talquetamab for patients with bulky disease, including extramedullary disease, and they have a really overall response rate close to 80% and no real increase or additive increase in toxicity despite the combination of BCMA and GPRC5D. And that is something that we have started using in our own clinics. We’re not getting significant pushback from insurance because it is in the guidelines. So again, excellent responses and safety signals with this target.

Charlotte Pawlyn:
Great. Perhaps you could tell us a little bit about what some of the side effects are that patients experience, and maybe a little bit about how that should impact how we understand those toxicities. What measures can we use to find out from patients what they’re experiencing in terms of toxicity?

Omar Nadeem:
Yeah, so when this target was first discovered, you know, we learned that, you know, it is universally expressed for the most part on plasma cells, but there are some other areas of the body where it has expression, which can impact, you know, some of the toxicities. So this was particularly noted with talquetamab as our data was first coming out, these, you know, so-called on-target off-tumor effects where patients started reporting some dysgeusia, dysphagia, and some of these, you know, symptoms that do have some quality of life implications where they lose their taste and they’re having some weight loss as a result and not able to eat. And then over the years, I think we have, you know, acknowledged this side effect, but also have now tried to mitigate it. So, you know, kind of using some dose modifications and adjustments in patients that experience some of these toxicities and our dosing for talquetamab, for example, can be relatively infrequent now for patients that have had some of these symptoms that you can dose reduce and give it, you know, perhaps monthly and not necessarily lose a response, but certainly allow them to tolerate this a bit better. So every CAR-T or ADC or anything that targets GPRC5D that’s now in development, we’re always looking for these similar toxicities. And there is a kind of a class effect there for sure with this antigen. But there are differences, I think, between the different modalities. So in the CAR-T program so far with arlo-cel, we’re not seeing that to be as much prevalent as much, and especially not in higher grades, and it’s definitely more transient. But we are seeing some other signals of these other select neurotoxicities that are reported in that CAR-T cell trial so far that manifests with either dizziness, ataxia, balance issues, and things like that, again, in a small fraction of patients, and probably dose dependent based on some of the data that we’ve seen at this meeting and other meetings, but something to monitor going forward. So I think there are some unique toxicities associated with this antigen, and they can certainly have quality of life implications, but I think we’re learning a bit more about how to mitigate it and hopefully how to prevent it in the future.

Sridevi Rajeeve:
A practical point that, as practicing clinicians, we can all do is to try to involve your oncology pharmacist early in the treatment paradigm. Again, you know, they have been an integral part of whenever we have any patient on talquetamab, and we prophylactically give them saliva substitutes for mucositis, you know, emollients and bland creams for protection of skin. And again, you know, there are certain interventions you can do for taste changes as well, because they are very significant, leading to weight loss as well, which is often a big reason why we stop these medications. So, you know, involving a pharmacist, identifying the side effects right at the onset and then acting on it immediately can try to really help.

Charlotte Pawlyn:
Yeah, I think you raise a good point. There are lots of people to kind of in there around who work around us who can perhaps help dietitians, pharmacists, other people who can contribute to the patient care. Okay, so perhaps we could switch tack slightly and talk a little bit about mechanisms of resistance to these drugs. So we’ve heard some fantastic talks over the last two days from various different people reporting their findings on this. So perhaps you could maybe revisit some of the most common mechanisms that have been identified and some of the ways in which people have been talking about how we can identify those in patients.

Sridevi Rajeeve:
Absolutely. So, you know, there’s a lot of work that has been coming out in the last two years. But just to summarize, and we had a fantastic talk by Dr. Bahlis this morning about ongoing work in his lab and collaborating across the continent of the U.S., I believe. You know, there’s always the issue of antigen loss that has been a part for whichever target that we are targeting. And Dr. Bahlis also demonstrated that it’s not just necessary that the antigen loss can be after exposure to a drug, you know, it can happen right at the onset as well. And there was an elegant experiment that showed both antigen loss of BCMA and GPRC in treatment-naive patients, as well as for patients who received the treatment. So antigen loss or losing the target, either from the beginning or after exposure to a drug, is a significant resistance mechanism. And other mechanisms, obviously, again, mutations that are acquired along the way that renders… So you have the presence of the gene, but then it’s rendered inefficient, they can’t really translate into the required proteins because of mutations, so that is also another resistance mechanism that we are seeing. Again, there is loss of expression of antigen on the surface and many other mechanisms that we are finding out. But again, how do we get past them clinically? And these are going to be part of clinical trials that are going to be designed in the future, as well as translational studies.

Charlotte Pawlyn:
And we heard, Omar, a little bit about, I guess, by the end of yesterday, I wanted to be able to do flow cytometry for GPRC5D, IHC for GPRC5D, but also in-depth mutation analysis. How far away are we, I guess, from having some of those accessible to us in the clinic?

Omar Nadeem:
Yeah, I think the technology’s there. It’s really more about just standardizing it and trying to understand how that impacts potential decision-making and response to therapy. I think that area is not yet clear. So IHC is reported as kind of weakly positive all the way to strongly positive, which has some interpretation naturally there. And then flow cytometry, again, the assays, they look pretty reliable. But again, at what point do you use these? Do you use these at the time of diagnosis to kind of identify who has this present or not? Or do you do it at a biopsy at at a time of relapse, biopsy an extramedullary site when you’re making treatment decisions and then which of these modalities you’ll use i think is still a work in progress but hopefully over time we’ll have all this data available to us because we have so many of these therapies many times targeting you know very similar antigens and it’d be really important to kind of get more of a real time analysis or an update as to kind of how these things look. And then going back to the resistance you know, very similar antigens. And it’d be really important to kind of get more of a real time analysis or an update as to kind of how these things look. And then going back to the resistance, you know, question, it was interesting to see that you tend to see more GPRC5D loss than you do, you know, BCMA, which I think is really critical because ultimately, you know, we may be able to cycle perhaps more BCMA therapies, but we may not be able to cycle as many GPRC5D therapies. So it’s really critical to kind of choose which one you will for the patient if we have a few of these available in the clinic and they all have some of their differences as we just talked about. And the final point there is T-cells, right? I mean, we’re so focused on the antigen, but many of these therapies are using the same exact T-cells to attack myeloma, just using a different antigen. And T-cell exhaustion is always a big topic, whether that’s more impacted by bispecifics or CAR-T or whatever. And we still don’t really have the best tools in the clinic for me to be able to say, OK, your T-cells are at 50% or 80%. It’s just more that I hope that over time we have something that gives us that kind of information.

Sridevi Rajeeve:
I think just pivoting back to the question you asked, I’m curious in your institutions, where are you guys with GPRC5D diagnostics? You know, I can share at MSK, you know, initially for the last two years, we had to email our pathologist to say, can you please add on GPRC5D? It was not part of the standard protocol. We’ve had BCMA reporting in all BMAs for maybe the past two and a half years, and GPRC used to be at request. However, with the concerted effort of Dr. Malakori, we have now had more GPRC5D reporting without us requesting for it. And I know that’s not something that’s easily available. For patients who come for second opinions, we often get requests from local oncologists and collaborative oncology colleagues to do the BMA here so that we can have BCMA and GPRC5D expression information from MSK. So, you know, we’re slowly scaling up, but I’m very cognizant that this is not something available. So I’m just curious to see how things are.

Charlotte Pawlyn:
And you’re doing this by flow cytometry or on bone marrow IHC?

Sridevi Rajeeve:
IHC now. And Dr. Dogen is, I believe, you know, very close to formalizing and finalizing the flow cytometry as well. But so far it’s IHC and it’s reported as, again, weak plus or two plus, which is helpful for us. Again, we don’t actively look into, again, mutation status, but at least it’s helpful to know… And because we’ve had surprises where GPRC right at the onset is very weak. So that’s in a way guiding us as to what therapy to choose. But again, lots of way to go. So I often wonder of how it’s done at other places as well.

Omar Nadeem:
Yeah, I think we’re just getting kind of started, you know, kind of standardizing this reporting as well, just like you are. So kind of incorporating it into the biopsies, both the BCMA and GPRC5D, but up until this point, it hasn’t been universally done on those samples. But again, over time, hopefully that’ll be standard because it is going to impact our choice of therapy.

Charlotte Pawlyn:
Yeah, I think we have a similar kind of in development time scale at the moment and partly driven by the fact that in the UK, we’ve had access to talquetamab clinically probably for less time than you have here. And so obviously the need for diagnostics comes after you have clinical access to make decisions based on them. But I think also from the talks we had today, it’s important that expression could be there, but that could be a mutation and/or you could have loss without a mutation. So you could have epigenetic loss of expression. So I guess what we really need is all of, in order to make kind of confident clinical decisions, we need to combine the modalities to be able to see all of those aspects. Okay, and then if we are thinking about overcoming the resistance once it’s generated, we talked a bit in the last session about should we be targeting two different antigens simultaneously? Should we be doing that with two separate bispecifics or in a tri-specific format? Or should we be sequencing these agents one after another? So perhaps you could give us your thoughts, especially as you now have access in some cases to the combination of targeting both antigens simultaneously. How do you think about that clinically?

Omar Nadeem:
I think the preliminary data so far that we have with the tri-specific antibodies and even some of the dual-targeting CAR T-cell therapies looks really good. I mean, you see very high robust responses, deep responses, MRD-negative disease, even in heavily pre pre-treated patients so that gives me hope that the combination effect right from the get-go is gonna be the way to go. Now how durable is that gonna be what that’s gonna do at the time of relapse from some of these agents? I think that’s really the critical question because right now you may be able to kind of go from one to the other because they’re you know different enough but here you know like we’ve done in the past with all myeloma therapies, most of the time when you combine some of these targets right off the bat, you tend to have way better outcomes and much more durable responses. And then at that point, there’s newer strategies, you know, usually available, which is historically what’s happened in the last 10 to 15 years. So I’m in the camp that I think giving, you know, two of them simultaneously, whether it’s in the same construct or just two different agents at the same time.

Sridevi Rajeeve:
And we’re doing some translational studies. We have all these dual-exposed patients at MSK. So we’re doing translational studies to really understand, to quantify the antigen loss with respect to monotherapies in multiple modalities. So we should have answers in the next couple of years, but I think it’s still evolving and sequencing will remain a big challenge.

Charlotte Pawlyn:
Great. Well, perhaps we’ll leave it there on that forward-looking note. And thank you very much for joining me today.

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Francesco Maura:
Good afternoon. I’m very pleased to be here today with my colleagues at the iwGPRC5D conference. It’s a second edition and we’re spending two days here in New York to discuss about new evidence and how we can improve our use of these very effective drugs targeting GPRC5D. So maybe we can start with you introduce yourself guys. I’m Francesco Mauro from Memorial Sloan Kettering.

Carlyn Tan:
I’m Carlyn Tan, I’m also at Memorial Sloan Kettering.

Andrew Yee:
Hi, I’m Andrew Yee from Mass General Brigham Cancer Institute.

Joshua Richter:
Josh Richter from Mount Sinai Hospital.

Fran:
All right, so maybe we can start with Carlyn, like a little bit of a summary of where are we with the GPRC5D, in particular after the clinical trial. What are, you know, the real life confirming the efficacy or is worse or maybe better?

Carlyn Tan:
So there have been multiple large real-world studies. Most of them are still pretty short median follow-up time and so the response rates are pretty comparable to what we see with MonumenTAL-1 between 60 to 70 percent although the median PFS has been a little bit shorter potentially due to the shorter follow-up time although these patients could be more frail in the real-world setting and have had multiple prior T-cell engaging therapies or T-cell redirecting therapies as well as BCMA-targeted agents.

Fran:
So it seems that there are a couple of factors that seem to influence the outcome particularly. One, of course, is toxicity, but another one is more like disease presentation, like extramedullary disease. Is this confirmed? There are some patients that we know will not respond a lot, so maybe we should postpone the therapy to a better time?

Carlyn:
Yes, or we could use combination treatments that are coming down the pike with the tec-tal from RedirecTT-1 There was a real world study of patients that had extramedullary disease being treated with talquetamab and the response rates were surprisingly like in the 70% range. Although the PFS, we will need to see how long that they actually have.

Fran:
So overall, if the patients without EMD comes tomorrow to your ambulatory and ask how, what are the chances to be remission at one year? Of course, you will not tell it, but like, what would be the range according to the study? 30, 40%?

Carlyn:

Probably. Okay. I mean, with Tec-tal, it would be much better.

Fran:
Yeah. So before we go to the new therapies and combination, one of the aspects that patients complain always about these medications, at least a fraction of them, is toxicity, in particular at the beginning, where we didn’t know that some strange toxicity would occur. So Joshua, I know you are an expert on that.

Joshua Richter:

Yeah. So I was lucky enough to be at Mount Sinai when Ajai Chari was heading up MonumenTAL-1. So we saw almost half of the patients accrued globally. So got a lot of experience. And really what we see is data that ultimately comes from Memorial and now Boston. So bringing everything together from Eric Smith’s data about where GPRC5D is expressed. And we see a fair amount of on-target, off-tumor effects of the drug. Most notably, we know that GPRC5D, besides being expressed on malignant plasma cells, is expressed on keratinizing epithelium of the hands and feet, so getting a desquamating rash is pretty common and reminds me a lot of the Xeloda days when we used to use capecitabine. Well, again, as a heme malignancy doc, I never used capecitabine in the last decade, but I still remember being a fellow. You get this desquamating rash. We use a lot of emollients, lac-hydrin to help with that. We know that it’s expressed in the oropharynx pretty extensively. So dysgeusia and dry mouth are really big issues. We really don’t know the optimal way to manage this. I think with a lot of the toxicities for T-cell redirecting therapy, we’re noticing that bringing down the numeric dose is not necessarily the answer, but extending out the interval dosing. And more recently, you know, I think we’ve begun to understand mostly from work being done outside of the bispecific world, but in the CAR-T world with arlo-cel, the expression of GPRC5D in the olivary nucleus causing the cerebellar toxicities and ataxia. And I think the more we go back to some of our patients with talquetamab, some of these toxicities can be really hard to tease out in multi-relapse patients. What’s fatigue? What’s dizziness? What’s lightheadedness? What is drug related? So I still think we’re filling our way through the weeds with some of the newer side effects.

Fran:

So for like patients that are watching, when we give them like all the instructions about, you know, a lot of Aquaphor on the hands, all the mouthwash. Like, I think, you know, in your experience, are these making a difference? And also after when you start to do biweekly and then monthly, do you feel any improvements in these symptoms? Because we all, you know, for patients that stay long time, we can say the beginning is worse and then later it gets better.

Joshua:
Yeah. So, you know, I think prophylaxis is really important or being up front of this you know an ounce of prevention is worth a pound of cure so yeah we tell them to have a lot of emollients on hand sour candies things to help with saliva production I think is really important vitamin e lotions for the nails although I don’t know that that helps all that much. In terms of the taste you know one of the things that we’ve seen anecdotally is help with MSG so for more savory foods including MSG and the cooking process may actually help some of the taste although I don’t know if that’s gonna go great on ice cream, that’s not my call. In terms of what happens when we space it out yeah to get better. But again, it’s a little hard to know if this is truly a biologic phenomenon or a bias that the patients that have made it all the way to cycle six and cycle 12 had less of that initially.

Fran:
So it seems that we are learning a lot of things moving forward on early toxicity, how to handle them and late toxicity, how to kind of manage but it’s also seem at least to me that we are not using this therapy at the best yet because we still have to learn how to combine with other therapy or to move in earlier line ,sso maybe Andrew you can provide some overview on where the field is going?

Andrew Yee:
right so you know with these drugs I think the first order of business is to, you know, get the drugs approved. And now that they’re approved, we have more experience in using them. And how do we use them more effectively to improve patient outcomes? So just as a reminder, you know, talquetamab is approved for four prior lines of therapy. And, you know, the toxicity profile is there. But I think when you see these responses in patients who are really just, are some of the most challenging to treat patients, it’s very gratified. And the patients are really happy to have those responses. And I think now that we’re getting to using them, as Dr. Richter is saying, we have all these better strategies for managing the toxicities. But I think the key part when we partner with our patients is to be kind of laid all out there as to what to expect so that when the change in taste happens, that they’re ready to expect it and they’re not surprised when that happens. So now that the drug has received accelerated approval, in myeloma therapy, you know, there are very few things that we just do as just one drug. And I think we, you know, everything, it’s like going to a meal. You’re not just going to have one item. You’re going to have it paired with a certain wine or some other, you know, certain different food items paired together. And so I think with these myeloma therapies, to think about what combines best with talquetamab or other drugs for that matter so there are ongoing clinical trials looking at these different combinations and the hope is that these can you know maximize response, give you more durable responses and also allow you know more opportunities to say space out the dosing so that you can help minimize these adverse events. So some of the combinations involve combinations with established drugs that are already in use. So for example, there’s an ongoing clinical trial, MonumenTAL-3, that’s taking the combination of talquetamab with daratumumab and pomalidomide, and it’s randomized against the well-established of daratumumab, pomalidomide, and dexamethasone, and then daratumumab-talquetamab is the third arm. So these are ongoing studies, and this is in one prior line of therapy, and I think it’ll be really useful to see what are the gains in efficacy that you can see, as already we’re seeing significant gains with other combinations in myeloma. And I think ultimately this will help us achieve you know getting closer and closer to a cure potentially.

Fran:
So Carlyn, this brings to another aspect that we haven’t covered which is something a lot of doctors are doing even if in trial is not like developed which is bridging using talquetamab, in particular anti-GPRC5D bispecific antibody as a bridging towards something can be more sustained or effective. Do you want to comment on that?

Carlyn:
Yes, there was a large study that was headed by Dr Dhakal that involved the US MMIC and then two German centers looking at 134 patients that receive talquetamab bridging. The majority of patients did end up getting their BCMA CAR-T. The response rates for talc itself was pretty high and then continued to deepen once patients received CAR-T. There seemed to have been less incidence of ICANS or high-grade ICANS in the patients that got the talquetamab bridging, possibly because they had debulked the disease by the time they got the BCMA CAR-T. So it looks like it’s safe, feasible, and very promising to get patients that have been very difficult to treat to a BCMA CAR T cell therapy.

Fran:
I guess we all agree that the CAR is just once and you have to use it at the right time and with the right condition. Often it’s hard to get those, but this type of approaches can bring us almost there. And as a final, both on Andrew and Joshua, we are having now not necessarily a combination of two drugs like tec-tal, or talquetamab plus pomalidomide and dexamethasone, but we have a single drug with two binders. So maybe, Andrew, you can comment on the efficacy and Joshua can follow up on the toxicity that seems to be promising.

Andrew Yee:
So yeah, I think you referred to like the trispecifics. So there are several trispecifics in development against different targets, but one of the trispecifics that’s gained a lot of attention and that’s currently in clinical trials is a trispecific that binds to GPRC5D, BCMA, and CD3 as one drug. And so it goes along the lines of combination. You can do a combination in an easy, logistically convenient format that’s potentially a big advantage. So the trispecifics could be the next frontier. We have bispecifics, but I think the trispecific can be the next frontier. And some of the responses that we’re seeing are really quite remarkable and almost could rival CAR-T even. And one of the trials that is ongoing with this trispecific romantamig – I’m not sure if I’m pronouncing it correctly, but the schedule is very convenient and it’s for a fixed duration. And if you’re able to generate the efficacy that was seen in some preliminary studies, I think that could be, it could be transformational. And it does go along with the fact that once you have a good target, if you can have multiple targets and you can effectively engage both, you can really maximize outcomes.

Fran:
And because there is a fixed duration and there are different types of binding, I guess the toxicity might be also different for patients, in particular for the long responders.

Joshua:

Yeah, so I mean, I think when we all saw the data that was presented by Rakesh Popaot showing 100% overall response rate of recommended phase 2 dose, you know, anytime in the oncology world you see 100%, everyone takes a step back. But yeah, what are the side effects? And at least so far, it does seem to be muted, at least in terms of some of the on-target, off-tumor toxicities of GPRC5D, which is potentially a very good thing. The question is, what’s that trade-off? Because now maybe the response rates are as good, let’s say, for patients with extramedullary disease, where we’ve already seen in RedrecTT-1 that giving TEC and TAL is highly effective. I don’t know if we know that that’s going to be true with a trispecific. But I will actually throw a shout out to this meeting where Omar Nadeem brought up a really great factor about the toxicity profile of romantamig as compared to the bispecifics. And one of them is the flexibility of holding one or the other. So if you’re giving a tec-tal combo and you have a toxicity that you attribute to one of the drugs, you can hold that and proceed with therapy. But he brought up the wonderful fact that once you start having a trispecific, it’s all or none.

Fran:
And one aspect about toxicity that comes to the talquetamab, both as a bridging, as a different compared to other antibodies, is the infection risk. So every time we have anti-BCMA patients going home after a step-up dose, we always say, be careful on infection, right? That’s your worst enemy. If you have fever, cold. For the rest, don’t worry. And so, for talquetamab, it seems to be a little bit different, right? The risk is lower, and there are some data that have been discussed today from Thomas Jelinek group, for example. So, I don’t know who wants to comment on that.

Joshua:
I’ll throw it on that one. I mean, I think one of the things that we’ve seen is that, you know, at least from the BCMA world, we know that it’s actually expressed on more than just malignant plasma cells and some later B cells. But there’s been some wonderful work done by Jelinek and done by Nazar Bahlis showing the lack of expression of GPRC5D on CD19 positive B-cells. So the hypogammaglobulinemia, always the toughest word to say, is not universal in everyone. And in many of the patients with talquetamab, they’ll actually recover not only B-cell function, but immunoglobulin function. So yes, the infection profile definitely seems to be better with this agent.

Fran:
Well, I guess we discuss a lot of interesting things, but the most interesting thing is that it’s still an open field. So even if these drugs, we know unfortunately more than half of the patients don’t have deep response for more than a year, we still have a big room for optimizing them by combining with other drugs or to develop new drugs targeting, as you said, a good target, reducing toxicity but also increasing the efficacy so I think it’s an exciting time to for us as a doctor but also I guess for patients suffering it’s – you know there is a lot of hope and a lot of margin in the next year to further improve your care.

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