Francesco Maura:
Good morning. We are here in New York with my friend Holly Lee from the University of Calgary and Karlo Perica from Memorial Sloan Kettering. I’m Francesco Maura, Memorial Sloan Kettering as well, and today we are talking a little bit about GPRC5D as a target for multiple myeloma. So, Karlo, why don’t you introduce why GPRC5D is important biologically and as a target?

Karlo Perica:
That’s actually a very good question because I don’t think we fully know. So it emerged, I think, in the interest as a target for myeloma and what it’s most famous for from some early studies that came out of many places, including Sloan Kettering. And we still don’t fully appreciate the biological role of exactly how it contributes to myeloma tumorigenesis, if it does, which I think is an interesting thing to consider when we consider targeting it and escape and resistance mechanisms, as I’m sure we’ll discuss. But it is an antigen that we think is widely expressed, relatively universally expressed, and relatively highly expressed on many patients who have myeloma, which has prompted interest in targeting it with a variety of cell therapy and non-cell therapy-based approaches.

Francesco Maura:
Holly, you work a lot in the lab with the modeling on this gene. Do you have anything to add about or something that you think GPRC5D may be involved in the myeloma?

Holly Lee:
Yeah, I think as I mentioned, right now we don’t know very well what the exact role is in terms of plasma cell biology, but we know it’s a seven transmembrane protein. We know that it has certain extracellular domains that are also targetable by these different agents. And another thing that’s different from BCMA is that obviously it’s differently regulated, so it’s not shed from the cell surface, which is another advantage of why we can target it so well.

Francesco Maura:
Yeah, that’s another important topic that maybe, Holly, you can expand a little bit. What’s the difference between GPRC5D and BCMA? Like why we have two different targets and why some patients respond to one or the other? Of course, we don’t know, but we can kind of, knowing the biology and the data that you also published, a little bit more about the difference between the two?

Holly Lee:
Yeah, so I mean as we know BCMA is a very prime target in myeloma and there’s lots of agents that target it, but what we’re learning from the biology is that BCMA is prone to getting lost or deleted or mutated in the process of these immune selective treatments, and that’s where GPRC5D really comes out because it’s completely independently regulated from how BCMA is regulated. Again, it’s expressed adequately on these cells that are potentially BCMA-negative or that have cells that have undergone BCMA antigen escape, and that’s why it’s such a viable target. And again, as I mentioned, it’s not shed from the surface of the cells; it has those seven transmembrane domains that allow it to be really secured on the cell membrane surface. So for all those reasons, I think it’s a very potent target.

Francesco Maura:
So, Karlo, how does GPRC5D distribute in expression across normal tissue and in plasma cells? Like, is there… we know BCMA is very specific for plasma cells because basically, it’s what makes plasma cells, plasma cells—one of those genes that without it, plasma cells cannot develop properly. So GPRC5D, is there like any cells that express it as well, and that might kind of be something we need to know for our treatment approaches?

Karlo Perica:
Sure. So in many ways, I would say that GPRC5D has very favorable expression properties. It is, we think, and this is ongoing work, abundantly expressed on most patients with myeloma. We think a lot about the quantity of expression, and we think it has sufficient quantity of expression for detection and killing by cell therapy-based approaches. It’s probably more highly expressed on most myeloma patients than plasma cells, although that’s going to vary by patient and by tumor. And then when you look at off-target expression, the things that we’re most concerned about and that we see in the clinic include expression in the skin and nails, which does manifest in our patients. And then probably an area of most significant concern, but which is still not completely well understood, is this concern for cerebellar toxicity. And one of the original manuscripts by Sham Mailankody that was published recently did point to the potential for low-level expression in the inferior olivary nucleus, which is connected to the cerebellum. Now, that’s based off publicly available transcriptomic data. It’s still very early. It needs to be studied more, but it certainly is provocative to think how some of these toxicities that we’re seeing in our patients could be due to on-target, off-tumor antigen expression.

Francesco Maura:
So regarding this point, do you think that there is a difference between bispecifics and CAR-T in this type of toxicity?

Karlo Perica:
I think that is the million-billion-dollar question, and I think it is something that we will be learning about over the course of the next year. My feeling is that yes, we will see differences between engagers and cell therapies. We think, in part, based off of sensitivity to antigen expression, but it’s very much an emerging topic and very much a topic where the data will show itself over the next year or two.

Francesco Maura:
So, Holly, you published last year—now two years ago—a seminal paper on mechanisms of resistance on GPRC5D CAR-T and bispecific therapies. So, you want to expand a bit more and tell us how multiple myeloma, unfortunately, relapses even in patients that have a very good response to these anti-GPRC5D therapies.

Holly Lee:
Yeah, so what we’ve seen in our experience is that patients undergo treatment with talquetamab, prior to therapy, their plasma cells express GPRC5D, and they have both copies of the gene most of the time. However, at the time of relapse, they can either undergo biallelic deletion of the GPRC5D gene itself or large deletions in the chromosome 12p, where the GPRC5D gene is located. Or they can have one copy number loss of the GPRC5D gene coupled with different mutations on the gene itself. We also know from other reports that epigenetic silencing is another mechanism by which these genes are silenced. So really, the plasma cells are so dynamic; they know how to clonally take advantage and expand under these immune selective pressures. And I guess we know at baseline already, 15% of the patients have one copy deletion of the gene, even without any prior T-cell engagement or CAR-T exposure. So really, I think there’s a lot to learn about how these genes are regulated in plasma cells but also how they actively undergo change and mutation with treatment.

Francesco Maura:
So, what’s the proportion of patients at relapse with the loss of GPRC5D in your study and also in other studies that have been published so far?

Holly Lee:
Yeah, so it seems to be quite prevalent. So after bispecifics, it’s really in the majority. Now, we had a cohort of—currently, we have a cohort of about 14 patients. And again, more than half of those patients have some form of GPRC5D structural variations or SNVs. In the setting of CAR-T, I know from reports that it seems again to be more than the majority. About six out of 10 patients post-GPRC5D CAR-T had loss of GPRC5D protein expression by IHC, and one confirmed case of biallelic deletion, confirmed by whole exome sequencing. So really, again, we’re learning a lot, but it seems to be quite a frequent event.

Francesco Maura:
And, you know, for the general audience, when you say biallelic loss of mutation, it means that GPRC5D protein is not expressed anymore, so the drug doesn’t work anymore, and the myeloma can expand again. And the idea is that these require smarter strategies. Of course, we think we’re very smart, but myeloma often outsmarts us. So, Karlo, you are pioneering a lot of new CARs, you have a Nature paper just published focused on how we can maximize our logistics, manufacturing, and efficacy of CAR-T. So, what’s your take about how we can be a little bit smarter and maybe outsmart myeloma?

Karlo Perica:
Right. So, on this topic of antigen expression, I think what you’ll see entering the clinic over the next several years are combinatorial targeting approaches that attempt to target BCMA and GPRC5D and/or other antigens expressed on myeloma. And again, here the big question is whether co-targeting is going to actually change the nature of some of these resistance mechanisms. Whether if we simultaneously target both antigens, we’re still going to see these high rates of GPRC5D loss. There are, of course, also very practical questions of how to design these studies, particularly as more and more patients are exposed to GPRC5D and don’t have GPRC5D at the time of enrollment on the trials. So it’s something that we’re thinking a lot about. What is the optimal co-targeting strategy? Which combination of myeloma antigens should we use? I would characterize the myeloma antigenic landscape as more abundant, certainly, than solid tumors, but none of the antigens are perfect. So, how do we do a combination of antigens to really get at myeloma, and will that selective pressure prevent resistance?

Francesco Maura:
And that, of course, includes also identifying new antigens that might not be for every myeloma patient, but maybe just for some subgroups, as you said. Some myeloma don’t express a lot of GPRC5D at baseline; others lose BCMA, and so we need to find something also for these patients. So, I guess that was a very intriguing conversation. We have a lot of work to do in the lab and in the clinic, but it’s good that we have this target. We have drugs that are effective in patients after BCMA or even before in some, and that, of course, brings a lot of opportunities for our patients and clinical practice, but there is still a lot of work to do, and I guess we will do it. Thank you for your time.

Karlo Perica:
Absolutely.

Holly Lee:
Thank you.

Saad Usmani:
Hello everyone, my name is Saad Usmani. I’m the Chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center, and we are here to discuss how targeting GPRC5D is helping our patients in day-to-day clinics, and we want to share this data with you and help you manage your patients out in the community. So I’m joined by a wonderful group of colleagues. I’m going to ask them to introduce themselves starting with Dr Hashmi.

Hamza Hashmi:
I’m Hamza Hashmi. I’m one of the myeloma and cell therapy physicians at Memorial Sloan Kettering.

Shonali Midha:
Hi, I’m Shonali Midha. I’m one of the myeloma physicians at Dana-Farber Cancer Institute in Boston.

Susan Bal:
Hi, and I’m Susan Bal. I’m a myeloma and cell therapy physician at the University of Alabama in Birmingham.

Saad Usmani:
All right. Thank you so much, guys, for joining this meeting. And there are so many discussions that are ongoing about GPRC5D as a target. One of the things that is striking to me is despite the fact that we have some therapeutics targeting this, there’s not a lot of data—hardly 170, 180 citations on PubMed with GPRC5D. But it appears to be a pretty lucrative target with very specific high expression in malignant plasma cells. Susan, you’ve led now some trials targeting this with CAR-T constructs and have reported this out there in the public domain, although they might not be ready for prime time. But can you tell us a little bit more about that experience?

Susan Bal:
Absolutely. Thank you for having me. GPRC5D as a target has been a really exciting avenue for myeloma therapeutics. It was led in its discovery by Dr Smith. And what we’ve seen in its relatively young life is that it appears to be promising. We traditionally think of GPRC5D as a post-BCMA therapy, at least currently, but early data from the Phase I arlocabtagene autoleucel study suggests that patients can respond both with or without BCMA exposure. So I think that’s something that’s been really exciting. In the Phase I study, we now have over 80 patients that have been treated based on the data that was presented at this ASH 2024 meeting. These patients do very well; at the recommended Phase II dose of 150 million, we see a response rate as high as 91%, so the vast majority of patients responding. We see complete responses as high as 53% in the overall population. And the duration of response, as well as the median progression-free survival, is about 18 months in this very heavily pretreated population. And as I mentioned, these responses and this PFS data appear similar for patients who are BCMA exposed and BCMA naive. So I think this is a very exciting target. In terms of safety, certainly, you know, we need to understand the safety factor a little bit better. Hematologic toxicities, just like other CAR T-cells in myeloma, are common. But we see a lower rate of infections, we see a lower rate of on-target off-tumor toxicities that affect the hard keratinized tissues. And we see this sort of cerebellar toxicity, or what is now being called other select neurotoxicity, that has been seen in about 12% of the cases, which I think we need to understand better to further delineate and understand who are the patients that are more likely to get it so we can hopefully mitigate that, and as that remains a risk that needs to be better understood. But overall, a very promising approach for our patients.

Saad Usmani:
Are we getting to a point where we are entering the dose expansion Phase IIs? What do you think about the regulatory path?

Susan Bal:
So the Phase I study was a large proportion. We had a small dose expansion in that, but the registrational Phase II QUINTESSENTIAL study is currently ongoing. We also have the QUINTESSENTIAL-2 trial that’s a Phase III study in earlier disease lines that’s actually ongoing. So we hope that this agent will soon enter the market.

Saad Usmani:
All right, that’s great. And I think it will be good to have this kind of option in a post-BCMA exposed population specifically. But we also have bispecifics and other therapies that are kind of already in the clinic, but then also emerging. So Shonali, you want to take a stab at sharing with us some of the data and what’s really exciting about it, especially in the context of what’s been presented at ASH?

Shonali Midha:
Absolutely. So we have talquetamab, which is an FDA-approved GPRC5D bispecific antibody. As opposed to CAR-T, this is an off-the-shelf product. So it does open options for patients that may not have the luxury of waiting for CAR-T or access to CAR-T locally. We see very promising high levels of response—70% overall response rate, with the majority of that being very good partial response or better, 55 or more, depending on the dose cohorts. Conversely, compared to CAR-T therapy, you do see decreased response rates in patients that have gotten prior T-cell redirecting therapy. And I think that’s something we have to keep in mind as we think about sequencing in the future, because we do have BCMA-targeting CAR and bispecific options on the market and available. But again, a very promising target moving forward. That being said, there is also now more data coming out on GPRC5D bispecific antibodies in combination with other myeloma medications, those that are standard of care, or even novel. And I think that’s a very exciting area of research to try to rescue the response, especially in those populations that are hard to treat and that we see in studies with talquetamab and forimtamig of decreased responses in those with high-risk cytogenetics or extramedullary disease that may not be paramedullary or bone-associated extramedullary disease, to try to rescue those responses.

Saad Usmani:
Got it. And Hamza, I want to ask you, so with both the bispecifics and CARs, there are off-tumor, on-target effects that we’re concerned about. What’s your impression about the differences or similarities between what we know about the CAR strategy versus the bispecific?

Hamza Hashmi:
Yeah, so I think what we have seen with the toxicity profile, especially the real-world studies, is that patients who are receiving the bispecific antibodies do end up experiencing skin-related, oral GI-related… toxicities more commonly, more frequently. Oftentimes, these toxicities occur early, and they can persist even despite dose modifications frequency changes with the bispecific antibodies, and it can persist once the bispecific antibody has been discontinued. On the other hand, what we have learned from the trials with CAR-Ts is that these therapies are given as a single one-time infusion may lead to these toxicities not as frequently and, very importantly, not as persistently.

Saad Usmani:
Okay, so you know, kind of that quote-unquote “one and done” kind of an approach might be, you know, just a one-shot but if you’re continuing to have sustained antigen engagement, that becomes an issue especially. And then there is also interesting information about the presence of GPRC5D expression, you know, within the nervous tissue. So, you know, what are your thoughts around some of the data that’s recently been shown?

Susan Bal:
I think that’s something that’s of interest. You know, when we essentially looked at normal tissue expression, it was not noted. But once the initial MCARH109 study was onboarding, the dose-limiting toxicity at the highest dose level was the cerebellar toxicity at that point, I think the team went on to further characterize why this toxicity occurred. And at that point, we noted that there was expression of GPRC5D in the inferior olivary nucleus. It was not substantially higher, but it was increased compared to other areas, such as, you know, Caudate or Putamen, as we see for BCMA. And so this may be driving some of the toxicities. I do believe that based on the clinical data that we’ve seen, it makes sense because, you know, even in talquetamab, we see these toxicities. They’re less well described, but I think if you look at the package insert, you know, you’ll see neurotoxicity that’s as high as 10 or 15 percent. And certainly, in the real world, we have seen ataxia really mimicking what we’ve seen with the CAR T-cells. So I do think that this is an on-target off-tumor toxicity. I think figuring out what are some of the risk factors with why people get it. On the arlo-cel study, I know that all of the analyses that we’ve done has not clearly shown what seems to be, whether there are demographic factors or other patient or disease-related factors that stand out. But I think that’s something that we need to understand both for the bispecifics as well as CAR-Ts. How can we anticipate these and how can we mitigate these?

Saad Usmani:
I think one thing that, Hamza, you brought up is changing the schedule and the dose. I think we only have one commercial bispecific targeting GPRC5D that’s currently approved. Can you share with us, you know, what you know we’re doing at MSK, you know, and as a team, and then I’d love to get feedback from both Shonali and Susan about their approaches at Dana-Farber and UAB.

Hamza Hashmi:
Yes, absolutely. So we have at MSK looked at bispecific antibodies, toxicity profiles, and dose modification where we will change the frequency of administration based on its toxicity profile. We have done that for BCMA, and now we have also done that for GPRC5D antibodies, talquetamab, where when patients are experiencing skin, GI, oral weight loss, really toxicities, we would either reduce the dose or we would actually have the frequency decrease from every week to every two weeks, from every two weeks to every four weeks. And what we have noticed is that patients who have had a dose modification, either a decrease in the dose or a decrease in the frequency, actually experience a better recovery from those side effects, including oral toxicities and weight loss. Very interestingly, what we have also learned is that despite having those modifications—which means that either they have a decrease in the dose or decrease in the frequency—the response persists or actually improves, and very few patients will actually have disease progression despite the change in the frequency. I think so, an area of untapped potential when decreasing the frequency or dose may actually help mitigate these toxicities at the same time to preserve the response.

Saad Usmani:
Yeah, I think then the rationale was that, you know, you’re getting to first response in most patients within a cycle, and then by two or three cycles, you’re getting to that response plateau. So then, you know, if in a responding patient, if they’re having side effects, why don’t you just space things out a little bit? And one thing that’s, you know, again, speaking to community colleagues—you know, the FDA approved dosing might be a 0.4 weekly or 0.8 Q2 weekly—but there’s no reason why you can’t reduce the dose to mitigate some of those side effects. So thoughts?

Shonali Midha:
I absolutely agree, and we’ve done the same at our institution. In patients, especially because the median time to response is within a month, time to best response within about two months, that we try to back off on dose frequency as quickly as we can, especially if it’s not well tolerated. And that is something that you see more frequently with the bispecific antibodies than with CAR-T, obviously. So in those instances, we have similarly backed off from weekly to Q2-week dosing, or Q2-week to Q4-week dosing as tolerated, and similarly have not seen a negative effect on efficacy or increased chance of progression in those patients.

Saad Usmani:
And then Susan, in addition to sharing, you know, the UAB experience, are you noticing any differences in different patient demographics, ethnicities, racial backgrounds? Because we all deal with diverse patients, but geographically, I think Alabama has a very different demographic. So what do you think?

Susan Bal:
So certainly, we completely agree with all of my colleagues. I think we need to understand if we can dose these in a fixed duration and also start to de-escalate the dosing as soon as possible. From the recent publication in Lancet Hematology, we’ve seen that patients who have these toxicities are also the responders. So I think that’s a unique opportunity where de-escalation can definitely assist. We at UAB also use MRD to guide our decisions, especially when it comes to cessation of therapy. So we do de-escalate as soon as patients respond, usually after cycle two, going to every four-week format as early as cycle six, and then using MRD to decide on the duration of therapy. A good question. I think that different patient populations do experience toxicities differently. We’ve seen that both in the immunomodulatory space where we’ve seen increased dermatologic toxicity with immunomodulatory agents. Similarly, we see a higher incidence of peripheral neuropathy, for example, with bortezomib. And similarly, I think some of these oral and skin toxicities, at least in my anecdotal experience, appear to be higher in our African-American colleagues. And I think it’s important to keep that in mind and closely monitor these toxicities, de-escalate as able.

Saad Usmani:
All right, that’s great. Now, this has been a wonderful discussion. One thing that I want to share with our community colleagues—we’re here as a resource. These therapies are coming out at a rapid pace. GPRC5D may be a new target, but there are other therapies that are coming out. There are going to be combination therapies. There are going to be antibody-drug conjugates that are being evaluated in clinical trials. So use us as a resource to help in any way. At the end of the day, it’s you guys who are taking care of these patients for the most part in the community. Academicians are there just as a resource. So please leverage our expertise, and we’re here to help. Thank you to my colleagues for joining me. Truly appreciate all your wonderful comments.

Hamza Hashmi:
Thanks.

Shonali Midha, Susan Bal:
Thank you for having us.

Sham Mailankody:
Hello, my name is Sham Mailankody. I’m a multiple myeloma and cell therapy physician at MSKCC in New York. And I have my friends and colleagues here.

Rahul Banerjee:
Thank you for having me. My name is Rahul Banerjee. I’m an assistant professor of medicine at the Fred Hutchinson Cancer Center in Seattle, also specializing in myeloma and CAR-T therapies.

Joshua Richter:
My name is Joshua Richter. I’m an associate professor of medicine at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, and like my esteemed colleagues, I specialize in multiple myeloma.

Binod Dhakal:
Hello, my name is Binod Dhakal. I’m an associate professor of medicine at the Medical College of Wisconsin, and I also specialize in multiple myeloma.

Sham Mailankody:
So thank you all for joining. I guess I wanted to start this off by focusing on some of the toxicities we are seeing with GPRC5D-directed therapies. Rahul, which ones kind of stand out to you as a distinguishing factor from other T-cell redirecting therapies?

Rahul Banerjee:
Absolutely. So I think, as you alluded to, T-cell redirecting therapies come with the risk of cytokine release syndrome (CRS) or ICANS, neurotoxicity. Separately from that, because of where GPRC5D is found off-tumor, there are on-target toxicities. So skin, nail, and tongue come to mind. I’ll be very high-level because I would love to hear from all of us here. So many of our patients, for example, maybe perhaps as many as half of patients receiving talquetamab will have some form of dysgeusia, some form of tongue or taste disturbances. Lower but significant proportions may have issues with their skin, often palms and soles, or nails.

Sham Mailankody:
Josh, anything else that you have noticed? And particularly when you think about different modalities of targeting GPRC5D—CAR-T, bispecific—are they made similar in terms of toxicities? Are there differences?

Joshua Richter:
So I think it’s a great question. So I think we see more of the oral toxicities with the bispecific as opposed to the CAR-T. And one thing I’ll add, which is really coming to light now that we’re having this discussion under the very hot lights, is salivary involvement. So one of the things is not having the same type of salivary flow when you get the GPRC5D bispecific. So it’s something to tell our patients because in the setting of a really dry mouth, you not only have to worry about xerostomia, but does this lead to things like fungal infections or other problems in the mouth as well?

Sham Mailankody:
Binod, how about infections? Again, with the BCMA treatments, we worry a lot about infections. Is there a similar level of concern for infections and immune compromise with GPRC5D, or are there some differences?

Binod Dhakal:
So if you look at the data, the pivotal trial that looked at this, both the BCMA and the GPRC5D, the infection rates are actually much lower. Especially if you look at grade 3-4 infections, it’s almost half. So GPRC5D is probably about 17-18%. But it’s almost double in BCMA bispecific. The risk is lower, but it’s still there. So I think if you ask me, in the real world, do we do anything differently or less than BCMA bispecific? I don’t do it. I do the same thing as BCMA bispecific for these patients as well because 70% is still a pretty big number. And more importantly, they are using the T-cell, which is the common target for both BCMA and GPRC5D, which probably is the main reason why the infections happen. So I think the risk is lower than BCMA, but in terms of management, probably you do the same thing in the clinic.

Sham Mailankody:
So in general, it seems like the theme is quite apart from the CRS and ICANS neurologic toxicities, which are common for these treatments. With GPRC5D, perhaps a lower risk of infections but higher rates of GI, dysgeusia, skin changes, etc., are somewhat higher. Rahul, are these on-target off-tumor toxicities reversible? What happens when patients stop these treatments or discontinue them for whatever reason?

Rahul Banerjee:
Great question. So I’ll add just to say that we’ve talked about everything. So I think maybe the other ones, correct me if you disagree, so I think tumor flare can sometimes happen. Just we’ve talked through everything. So sometimes patients, especially with plasmacytomas, I’ve seen them get worse before they get better. And I think we’ll probably talk about this later. There is some expression of GPRC5D in the cerebellum. And so we will talk about it, I’m sure, about some of those potential side effects. To your question, those are much less common. So I think in terms of skin, nail, and tongue, generally speaking, I will say that they get better for almost all of my patients, particularly with the bispecifics, well, both of them, because with the bispecifics, you can hold or de-escalate the frequency of the drug. And with CAR-T therapy, the kinetics of these toxicities are often lower because it’s a one-time infusion as opposed to continually redirecting the T-cells every couple of weeks. I will say that the ones that I think are the toughest, in my personal experience, I think nails often take a little bit longer to recover, just by definition. Rashes, I found, often resolve the quickest. Dysgeusia and the weight loss that can sometimes happen to my patients can take time. It’s tough; it’s a lot of retraining, how you eat, how you drink, and everything. Even with optimal support, even with a dose hold, I think it’s taken me time. I don’t know what all of you would say.

Joshua Richter:
So the one thing I would add, with all the T-cell redirection, which to me was a big kind of switch from drugs like Revlimid, is that the answer is not necessarily lowering the milligram dosage, but extending the interval. So I think we’re all used to, “Hey, you come in neutropenic on Rev, let’s go from 25 to 15.” But with these drugs, BCMA and GPRC5D, it seems more, “Let’s extend out the dosing to Q2 or Q4 weekly.”

Sham Mailankody:
So that brings a good point, which is, I guess, what are some of the practical, so this drug was studied and approved with a single dose, with a schedule, but now that we’ve used drugs of this kind for quite a while in clinics, I guess what are some of the practical, was it all the kind that you said, spacing out dosing, stopping maybe, when to stop, how to space, what do you do in your practice for GPRC5D?

Joshua Richter:
Yeah, so I think we rush to get to Q2 or Q4 weekly dosing as quickly as possible. To me, there’s a kind of dichotomy. Most patients are in VGPR before they leave the hospital, before they finish the step-up. So I think if you’re in that group that achieves a very deep response very quickly, we move quickly to Q2 and then to Q4-week dosing. The people that are a little more delayed, I kind of stick with it a little bit longer, for right or wrong. The one thing I would add in terms of supportive care: we give IVIg as primary prophylaxis for BCMA redirection therapy. GPRC5D is interesting because you still preserve the CD19-positive B-cells. And some of these patients can actually recover immunoglobulins later on. So it’s not just IVIg for all – I spend a little more time focusing on what the IGg levels are doing over time.

Sham Mailankody:
And last question to wrap up these toxicity discussions, I guess, Binod, this was alluded to—the cerebellar or other neurologic toxicities that we sometimes see with GPRC5D-targeted treatments. Are there any special considerations about the timing of when these toxicities might occur and/or management of these toxicities when they develop with both CAR T-cells and bispecifics?

Binod Dhakal:
You know, that’s very interesting. This is an evolving situation right now because we, in the clinic, you know, at least in the pivotal studies, they were not reported that extensively and as compared to GPRC5D CAR-T, but we are seeing that now slowly in the clinic. So what is the actual rate and what is the mechanism, especially with the bispecific, and what are the risk factors to develop that, is really still something we need to know more about. So I think the timing is probably, you know, probably after a certain period of time once they are in a really good dose of this treatment, probably after a month or two, as is the same with the CAR-T—you see it after a month. But again, this is something that we really need to know a little bit more about and wait for more patient events to happen.

Sham Mailankody:
So switching gears a little bit, I think about one of the big questions is we have these very effective treatments, multiple classes of them—is sequencing. So, again, there are two main targets in this context for the relapsed/refractory multiple myeloma. There’s BCMA-directed treatments, there’s GPRC5D-directed treatments, there’s CAR T-cells, bispecifics, and antibody-drug conjugates for each of these modalities. So when you see patients, and presuming you have access readily for your patient, and they’re able to get any of these treatments, are there specific things you use to decide which way to go, which target, which modality, and how do you make those decisions?

Rahul Banerjee:
That’s a great question. So all of us have debated both sides of this topic—BCMA or GPRC5D first, or CAR-T or bispecifics first. And I’ll say this is being filmed in March 2025. I’m sure a year from now, it could be totally different. I think… I think if a patient can get CAR-T therapy, I do sort of generally recommend CAR-T therapy as their first T-cell redirection. We could talk about this for hours, but very briefly, there are randomized trials of CAR-T versus standard treatments—not bispecifics per se—but showing that patients not just have better responses but much better quality of life. And I think that one-time infusion nature of CAR-T therapy, for most patients, is the first time ever that they’ve been truly off treatment for more than six months at a time, and I think that’s really encouraging. In terms of BCMA first versus GPRC5D first in that metric, because there are GPRC5D CAR-T clinical trials that many of you are leading, I am agnostic there. I will say that, in general, I do, because we have commercially available BCMA CAR-T therapies, I do lean towards them first. GPRC5D—the story’s still being written about how best to manage these toxicities we’ve alluded to, both with bispecifics and with CAR-T. So I often historically have gone for BCMA first before GPRC5D. My colleague down at the University of Alabama, Birmingham, Dr Costa, as you know, Luciana Costa often says, “That being said, the only place where BCMA has to come before GPRC5D is in a dictionary.” You know, so there are—and this is his quote, not mine—and there are scenarios where GPRC5D first may be helpful. I don’t want to steal Dr Dhakal’s thunder here, but Binod’s led some work there for patients who otherwise would not be able to get to BCMA CAR-T, using GPRC5D bispecific strategically beforehand. And I think it’s a really intriguing idea that I’ve used several times with great results.

Sham Mailankody:
And then I guess looking forward a little bit, Josh, I guess, how do you think about targeting both of them at the same time? So, do we need to pick, can we target both BCMA and GPRC5D? Should we target both of them together?

Joshua Richter:
So, you know, I think that this really brings up the concept that right now—you know, I like to joke with our lymphoma colleagues—they have 100 diseases; one treatment, because they all get R-CHOP. We have one disease, 100 treatments. And we need to start thinking in the lymphoma world of who has the CLL-like myeloma and who has the Burkitt’s-like myeloma. I think there are clearly patients that we need to give both. And the most clear-cut, at least for me, comes out of the RedirecTT data that was published in the New England Journal , Yael Cohen, first author. Extramedullary disease seems to not do well with almost everything we do. And they had some really great responses there. That being said, when you start combining all the toxicities of BCMA and GPRC5D, it’s hard to continue that long-term. So, you know, I think it’s right for some people, but not all.

Sham Mailankody:
No, I guess a lot of the development of these treatments has happened in academic, large-volume centers in the early part, but as these treatments are showing very promising efficacy, there’s obviously a need and certainly an interest to expand the access to practices and areas where they may not be as adapted. Using bispecific antibodies with some of their unique side-effect profiles, what are some of the pearls that you have for your community practice oncologists that you work with in terms of what’s the best way to do the initial treatments? Do you do them at your site and then send them back, or when do they need to come back to you, maybe with side effects or other issues? How do you manage?

Binod Dhakal:
That’s a great question. The reason I say bispecifics are game-changers is because they’re community-friendly when compared to CAR-T. Right? It’s a very active drug for both BCMA and GPRC5D, and it can be used in the community. We have some community centers already started doing that in their practice, but not all community centers are ready for that, purely because of this side effect profile. But if you ask what is the major side effect concern, it’s mainly the initial acute toxicities of CRS and ICANS. And that’s why we always—you know, plan to—whenever the community site wants to start, or at least do the subsequent doses—we always have very good interaction and communication with the providers and provide them the guidelines on what are the potential side effects, what are the main risks. You know, like infection is a major risk we talked about. Similarly, for GPRC5D, this is the quality-of-life-impacting side effects. So it’s constant communication—be available to them, provide the guidelines of how to manage that, how to be aware of them, because a lot of times they are not even aware of these side effects. So I think being there for that, educating them about this, and having that close collaboration—you know, at least see those patients time and again from your site as well—and that’s what we have done in our state, and that has worked out well. And still, there is inertia, I would say, in some centers not to start it because of fear of these toxicities. But, to be honest, I mean, we have managed all of them in the clinic, and we can confidently say that this can be managed in the community. It’s not something that needs more expertise at the academic level.

Sham Mailankody:
Yeah. If I may add that, I think into the practical nuts and bolts—I agree. These drugs need to come to the community because our patients need them, and driving or flying to one of these big cities is not always practical. I would love to hear all of our words of wisdom. I would also tell my community colleagues: one, for these bispecifics, you can always give more dex. I normally hate dexamethasone. A lot of my research is trying to down dex. Here, I would say a lot of them are nervous about cytokine release syndrome (CRS), but like—you can treat it. And these patients are getting dex anyway as a pre-medication. It’s okay to treat the CRS. I think that’s one part. It’s not CAR-T-level scariness. And two, we talked about this. I agree – I think most of us will focus on the CRS and ICANS in that first week or two is all that we’re worried about. But often, the dysgeusia with GPRC5D bispecifics, like talquetamab, can happen like within the first cycle. So I think the biggest lesson that I’ve learned is we actually at Fred Hutch have the nutritionist meet with our patients like cycle one day eight or 15 after that first CRS, just to remind them. Even if they’re having zero side effects, reminding them that, hey, the side effects may come—tell us if you’re having side effects, think about changing your taste, think about different strategies, think about dexamethasone mouthwash. Because if you wait for the patient to come to you as a community doctor saying, “I can’t taste anything,” you’ve waited too long. I don’t know what you would all say.

Binod Dhakal:
I think I would add one more thing. The bispecifics are also widely being used—or going to be approved—in other cancers as well. So we’ve already started using them for lymphoma and solid tumors. So I think it’s just a matter of time. I think it will definitely happen that it will be community friendly. It’s just a matter of time.

Sham Mailankody:
So I guess one last question to wrap this up would be—as you said, we are using more bispecifics in myeloma, more CAR T-cells in myeloma, but also other cancers. And one of the challenges we’re all facing is, I guess, resources for those initial admissions and inpatient-outpatient follow-up and care. How are each of your centers handling, let’s say, outpatient, entirely outpatient treatments, outpatient monitoring, prophylactic strategies to minimize anything? You’re doing differently or new in the last year or so to adapt to this increased need for these kinds of treatments for outpatients?

Rahul Banerjee:
This is great. You’re looking at me, so I’m happy to go first. We have three different answers here, which is great. I mean, there’s no right answer. The biggest thing I would say is flexibility. Like, it is not illegal to still move your patient inpatient for a step-up if you’re worried about them—if they have a high risk of CRS, etc. I won’t say prophylactic tocilizumab in case one of you says it, so we don’t all say the same thing. I would say that, again, I am all about done with dex except here. So we have sent our patients home with “pocket dex”, so dexamethasone to take.. grade one CRS, they will call us—I think if someone’s destined to get high-grade CRS, one dose that’s 10 milligrams will not prevent that, but I think it just buys you time. You’re not as worried about that patient getting super sick while waiting in the emergency department. So I think just letting go and letting Dex take the reins—I think has helped. I don’t know what the rest of you would say.

Joshua Richter:
So I’m going to have to throw a little bit out for prophylactic tocilizumab. So as of about a month or so ago, the NCCN does have it listed, but specifically only for teclistamab. So unclear how that’s going to evolve over time. The reason I like tocilizumab, I call this the Ender’s Game of Myeloma and CRS. For those of you who remember Ender’s Game —it’s all about if you win today’s fight really, really well, you prevent the fights later on. Toci has a very long half-life, so it doesn’t just prevent CRS now—it prevents it later. The other two things: number one, flexibility. Inpatient to outpatient, outpatient to inpatient. You can start in and go out, you can start out and go in. And I think the most important thing Binod said—which is great communication with our community colleagues—that if right now they’re concerned about that initial step-up, hey, we used to do this with Darzalex when it was a 10-hour IV, we started and sent it back to the community.

So the ongoing communication is critical.

Rahul Banerjee:
Very quickly, I just thought, where and when for the toci? Step-up dose number one, beforehand, or treatment dose, or between them?

Joshua Richter:
So the way that I’m currently doing it is, we’re admitting our patients – we’re giving the first dose outpatient and then admitting them that day directly. And then we have an early release program, so once they’re in the hospital, I like to give the toci then because you don’t have to worry about the outpatient administration, it gets kind of sucked up in the DRG, it’s a little more free-flowing. But over time, I think in order to get everyone on board, we’re going to have to figure out kind of like the Emory group, I think has led a lot of this, you know, giving everything outpatient.

Binod Dhakal:
Yeah, so at our place, we have a 24-hour clinic, and we do all commercial CAR-T and all this stuff outpatient—so it is easy for us because you have resources in place. But when you talk about this prophylactic toci, I think this would be probably important for when people in the community want to start outpatient step-up dosing, right? Even if they don’t have a lot of resources. So I think that will be critical to use that and see how that impacts that. I think the number two thing is the rate of recurrent CRS is very, very minimal once we cross over that step-up dosing. So I think that will be critical to make the community aware that if they are not willing to start the step-up dosing, at least they should be willing to start the subsequent doses because the rate of CRS goes down to less than 3% in both tec and elran and even like talquetamab. So I think that is encouraging. Now, to combine the toci prophylaxis, and I think that might be a kind of solution for them to start them, you know, the program with the community.

Rahul Banerjee:
One thing I will add—and it’s MSK that has helped fix this—but I will say, because I’ve had the package insert for talquetamab—all of them said, ” if it’s been more than 28 days, consider re-stepping them up” And I would say like, no. Like, if they stopped it for a toxicity and they’ve had a good response, the risk of CRS in my mind is zero. So –

Joshua Richter:
By the time I’m ready to start, the numbers are creeping up. I get a little touchy about that.

I think that’s the key point, yeah.

[Overlapping chatter]

Binod Dhakal:
Because if the patient’s disease is in a good response, you can even give them without step-up after three months. I have done that, you know, and patients have done well.

Sham Mailankody:
And we’ve just recently started doing toci prophylaxis for our outpatients. We treat some patients entirely outpatient in that setting to avoid readmissions, etc. We’re trying to do toci, and we do it about an hour before dose number one.

Rahul Banerjee:
Thank you. That’s helpful.

Sham Mailankody:
And so far, it’s very early days.

Binod Dhakal:
Yeah, I mean, at least there is no grade 3 toxicity in the studies. There is still the grade 1. So I think people have to be aware of that—the fact that it doesn’t completely resolve the CRS.

Sham Mailankody:
I guess we can go on and on, but we’ll wrap up here. Thank you so much, everybody.