BCMA and GPRC5D Targeted Therapy | Luciano Costa, MD, PhD | ASH 2023

So my name is Luciano Costa. I'm a multiple myeloma doctor at University of Alabama at Birmingham and I'm here at the 65th ASH annual meeting in San Diego where there's a lot, as always, a lot of new information about multiple myeloma. And I think one area of great interest is about sequencing of immunotherapy. I think we all saw over the last several years the development of several drugs or treatments that target this protein on the cancer cell called BCMA. That's the target that's used, for example, for teclistomab that is currently approved, carvicti, a CAR T cell therapy, a BCMA, CAR T cell therapy, and in the recent past, bilentumab, an antibody drug conjugate. And in general, in oncology and particularly myeloma, there is this notion that once I target a certain protein with some sort of immunotherapy, I may not have the opportunity to go after that protein again because the cell develops some mechanism where that protein is no longer expressed, the protein gets modified, there's a series of different mechanisms. So that always creates the interest of what I'm going to do next. And I think the news that are coming out of this are actually very good. For the most part, BCMA is not a target you can only use once. There's a lot of data now that if you have, for example, a CAR T cell therapy directed at a BCMA, that patient is still very, and you have a response and enjoy months long response, that patient is very likely to respond to either another CAR T cell against BCMA or a bispecific antibody like uranatumab or teclistomab directed at a BCMA. Actually, there's relatively small difference between the chance of response of those patients who already receive a BCMA CAR T cell and those who never receive any BCMA directed therapy. The other part of the good news is that there are other targets that are being further and further explored. One that has been talked a lot about is GPRC5D, which is just an abbreviation with really no great meaning. That's a protein that sits on the surface of the myeloma cell that doesn't have any known function, but makes it very targetable to immunotherapy. That has been accomplished through a TaquetaMab, that is a FDA approved T cell engager that has chances of responses as high as 75%. Interesting enough, if you take patients who never receive a BCMA directed therapy or patients who already receive a BCMA directed therapy, the chance of responding to TaquetaMab are very close. They are all north of 70%. Really proving the point that those targets operate independently and after you are done abusing one to your benefit, you still have the opportunity to go after the other and regain disease control. Another piece of information that was shared at this meeting was, for example, an update on a very interesting program with a CAR T cell directed GPRC5D. Now it's possible, for example, for patients to receive a CAR T cell against BCMA, enjoy many months, sometimes years of remission, and then receive, perhaps in the near future, a CAR T cell directed at GPRC5D and have another long remission, or the other way around. The sequence on how you go after those targets doesn't seem to matter. The other part that is way into the future, but is starting to look a lot brighter, is the possibility of going after those two targets at the same time. So there are now, in very early development, some CAR T cells that target both GPRC5D and BCMA. And we saw this meeting for the first time, the pre-clinical work of a bi-specific antibody that goes after BCMA and GPRC5D that is now entering the clinic. So think about combining, for example, TeclistaMab and ToquetaMab on one single product. So the future, of course, continues to look very, very promising, hopefully very bright.