Sequencing bispecific antibodies in myeloma - BCMA or GPRC5D? | Rahul Banerjee, MD | IMS 2024

Hi, everyone. My name is Rahul Banerjee. I'm an assistant professor of medicine at the Fred Hutchison Cancer Center in Seattle, Washington. I'm here live at the IMS meeting, the International Myeloma Society meeting in Rio. Yesterday, I had the pleasure of having a debate, a faux debate on the grand stage with my dear friend and colleague Dr. Celia Rodriguez from Mount Sinai, and we were debating which bispecific antibodies should be used first for patients. So just to familiarize the audience, many of you are quite familiar with this. A bispecific antibody is a two-headed antibody that with one hand grabs a T cell, an immune cell, and with the other hand grabs a myeloma scale, squishes them together and forces the T cell to recognize the myeloma cell is foreign and kill it and destroy it. We are lucky that we have many bispecific antibodies approved in the U.S. and many more are coming. So we have Teclistomab or Tecvaili, Elranatum or Elrexfeo, and soon to be Linvoseltomab will be approved late 2024 that target BCMA, B cell maturation antigen, the same antigen that's found or the same target of CAR T therapy that are commercially approved. For example, IDA cell, which is a Beckma, IDA-captogene, Viclusel or Cilta cell, which is Carvic-D, Cilta-captogene, Autolucel. So that's all BCMA. And then on the GPRC5D category, as a mouthful to say GPRC5D, we have one FDA approved agent called Talquetumab or Talve. There are many other agents on the way. For example, there are data being presented here. Actually, right now I can see it of a GPRC5D CAR T. The question is, which one do we do first? And I think historically as a field, we tend to save our newest guns for the last. Not necessarily better first, but the newest ones always come towards the end. As many of you may remember, CAR T used to be approved only in later lines and only recently as they moved to the front line or second line. There are two memab in 2015, almost 10 years ago was approved for late lines and now it's all the way up the front line. And so as a result, we often end up using BCMA first because we've had BCMA therapy for earlier. The Clistumab was the first BCMA approved, it was the first by specific that was BCMA targeting that was approved. And so historically I think many of us use BCMA. And if you look at the studies of Talquetumab of the GPRC5D one, Talve, many of them are BCMA exposed. Dr. Rodriguez took the side that we should stick to that paradigm because we know that paradigm. The Clistumab has been around for a long time. We understand it. We know how it works. Talquetumab is getting better. Why not stick with the program that we have in place? He had a reference very nice to a nice Brazilian song, La Garota de Ipanema, The Girl from Ipanema and saying the classics are the best. You stick to the way it is and figure out new strategies as we go. I took a little bit of the opposite approach and I took the opposite that look GPRC5D or Talquetumab in particular is a good team player. It can be combined with other drugs pretty well. Talquetumab does have toxicities, different toxicity. GPRC5D is found on tongue cells, skin cells, nail cells. So patients often have issues with their taste, with their nails getting thick, with rashes. We can often manage those with those reductions, but they're different. Importantly, GPRC5D bispecifics don't have that high of a risk of infection. For whatever reason, and we're still trying to figure out exactly, BCMA bispecifics have a profound risk of infections. Over half of patients often get grade three or serious infections. With GPRC5D bispecifics, more like 15 to 20 percent, probably because GPRC5D is not found on quite as many normal cells as BCMA is. So I think with Talquetumab, you actually can combine it with daratumumab. You can combine it with pomalidomide. There was data presented earlier today combining it with both. The trim II cord of Talquetumab and daratumumab and pomalidomide and infections were manageable. Patients still got them, but they weren't as high grade for quite as many. The big thing in the US, we have access to CAR-T. And Talquetumab is a very good team player with BCMA CAR-T therapy. Because again, remember, Talquetumab is targeting GPRC5D, a different protein in myeloma cells that has no bearing on BCMA on myeloma cells that can be targeted by the other bispecifics or by our currently commercially available CAR-T. And so I said that let's take our old paradigm and break it up. There's no reason that GPRC5D has to come after BCMA. I quoted one of my colleagues and mentors, Dr. Luciano Costa from University of Alabama, who often jokes, the only place that BCMA has to come before GPRC5D is the dictionary. Apart from that, choose what's best for your patients. And I've had several patients where I actually have given GPRC5D therapy before BCMA therapy, particularly with regards to CAR-T. So Talquetumab is a bispecific antibody. CAR-T therapies are all BCMA targeting. They work very well. The issue with autologous CAR-T therapies, the ones we have approved in the US right now, is it takes time to manufacture them. Those listening to this, you've heard this before, we take out some of those T cells, we genetically modify them to turn them into CAR-T cells and give them back. That process can take one month, two months. I've sometimes had it take three months sometimes for patients for different reasons. And that's hard because during that time frame, the patient's very vulnerable, right? The reason they're going to CAR-T is because that's the next best option for them. But we don't have the tools to get them there. Maybe we do. So we've had a couple of patients now where we've given Talquetumab to be ahead of time Because Talquetumab does not interfere with the efficacy of BCMA targeting or BCMA expression, it's a reasonable proposition. Because it's a short term, only a couple of months worth of Talquetumab, it doesn't seem to cause quite as many long term issues with taste and tongue issues and skin and nail issues. There is a theoretical risk of T cell exhaustion if you use a bispecific antibody right before you collect T cells for CAR-T because bispecific antibodies, they're redirecting your T cells. They're taking the T cells, the immune cells, they're supposed to be attacking something else and you're forcing them to attack the myeloma instead. And that can sometimes make them exhausted. But truly, that's the word we use, T cell exhaustion. And that's for humans, but it's a real phenomenon. You can measure it. Talquetumab can do that. But because Talquetumab, we often dose reduce or deescalate to every two weeks or every four week dosing. And because here, before CAR-T, I'm only giving a couple of doses, I don't think it exhausts the T cells that much. And I've seen some good responses with moving from Talquetumab on to BCMA-CAR-T. And indeed, at ASH this year, we'll have data looking at this much larger. This bee is very excited to hear about this as well. Much more data looking at this question of Talquetumab as holding therapy to hold the line until T-cell collection or as bridging therapy between T-cell collection and CAR-T before BCMA-CAR-T. So I think the future is bright here. And I think there is a good case to be made for GPRC5D before BCMA. I will say earlier today also, they presented data about saying, well, these two aren't enemies, maybe they can be used together. And there is a study called the Re-Direct-1 study that looked at giving both the Clistumab, which is a BCMA bispecific and Talquetumab, a GPRC5D bispecific at the exact same time for patients to kind of combo hit the myeloma from two fronts at once. They've seen some very impressive response rates. The duration of response in that study, how many patients were still after achieving a response, maintained that response at a year and a half, 18 months was over 80%. That is extraordinary. Even in patients who had pretty bad disease biology, had extramedular disease, meaning myeloma growing outside of the bones. Very impressive. I'll caution that in September 2024, that strategy is not yet FDA approved. So I don't routinely recommend the Clistumab and Talquetumab together, because again, that's not how they were. We don't have big studies of this and the FDA and insurance companies and pharmacists may have concerns about it. But obviously, research will continue in this space and I can't wait to see it.