Where should CAR-T cell therapy be positioned in the RRMM?

When should CAR T-cell therapy be positioned and relapsed in refractory myeloma? Where we are today with CAR T-cells is we have two approved CAR T-cell products. Both of them target the BCMA on the myeloma cell. One is siltacell or carvicti and the other one is idacell or abeckma. They are both approved for use in patients who have relapsed myeloma who have had four prior lines of therapy. And that's where we are currently using them. That's where they are approved and as everyone knows these are very expensive. So we really must get insurance approval. Insurance approval really requires there to be four prior lines of therapy. So that's where they are currently used and currently approved. On April 5th, 2024, the FDA approved new indications for both carvicti and abeckma. The FDA approved carvicti for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent and who are refractory to lenalidomide. The FDA approved abeckma for the treatment of adult patients with relapsed or refractory multiple myeloma after two or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent and an anti CD 38 monoclonal antibody. And just like we saw almost with every drug that's been approved in myeloma, it gets approved in the relapsed refractory setting and then we learn more about the drug and we bring it earlier and earlier. And I predict that the best place for a CAR T cell is not going to be after four prior lines of therapy. It's going to be much earlier. And that's for a variety of reasons, particularly the immune system that we need, a healthy immune system, healthy T cells that we need to make the CAR T cells are going to be better earlier in the course of the disease. And we now have one randomized trial that looks earlier, looks in patients who've had two to four prior lines of therapy. And this is a Beckmore IDA cell and compared against what was considered to be the standard. And in this scenario, the CAR T cell was better than what the standard care that was available. That's the first randomized trial that confirms that. There's also a very similar study with car victor, so to sell that is looking trying to answer the same question. And I predict that the more we learn about CAR T cells, the earlier that will bring it up into therapy. A single silta cell infusion significantly improved progression free survival versus standard of care and lenalidomide refractory patients with one to three prior lines of therapy with a favorable risk benefit profile across patient populations. And there are current studies now designed to look at CAR T cell as consolidation, similar to how we do high dose chemotherapy and transplant as consolidation in first remission. And I'm not suggesting that we're able to replace transplant today, but I think that's the question that we all have as myeloma investigators and treaters and as patients. The other question that comes up is where does CAR T cell fit versus by specifics? There's currently one by specific antibody approved to Clistamab. And again, it's approved in that patients who've had four prior lines of therapy. Talvi and Orexvio received FDA approval in August 2023 for myeloma patients who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti CD38 monoclonal antibody. And when we're in a large part, the patients that we're thinking about for Tclistamab today are somewhat different than the patients we're thinking about for CAR T cell. At least this is our approach for CAR T cell. We need a patient whose disease is not progressing rapidly because it takes time. We have to build time to do the T cell collection. And then after the T cell collection, there's a manufacturing process and that whole process can take six to 10 weeks. And so if a patient has really rapidly progressive disease, they can't wait 10 weeks for what would be more definitive therapy. And so the more rapidly progressing patients are those are the patients that we're choosing to use the bispecific to Clistamab at this time and patients who are progressing slowly. And we can see they're progressing, but it's not fast. And if we didn't give their therapy for 10 weeks, they wouldn't be harmed. So that's where we are today. And just like I mentioned, the CAR T cells are going to be moving earlier. We're also starting to have studies of the bispecifics moving earlier, whether it's part of maintenance therapy or consolidation after transplant or as second line, third line therapy. All of these are under discussion and currently in investigation. And in addition, we're also looking at using combinations of therapy with to Clistamab and other bispecific antibodies to increase the response rate and the lengthen the time of response. So I think CAR T cell therapy is, as many of you may know, is somewhat different from all the other treatments we have available for cancer therapies, including myeloma. So the basic idea is patients have T cells in their body. These are immune cells. We all have them. The idea is to take these T cells out from the patient, genetically modify to be able to recognize cancer cells, in our case, myeloma cells. And then these engineered T cells are put back into the patient's body after some preparative chemotherapy, low doses to help go after myeloma. So in some ways, this is a fairly new clinical concept. The very first patient to get a CAR T cell for any cancer was less than 20 years back. This was for leukemia, a different kind of blood cancer. And then over the last 20 years, there's been a lot of progress in this treatment for many different diseases, including myeloma, starting with the very first clinical trial for patients with the lab refractory myeloma, about 2014. And since then, as you all know now, there's two different CAR T cells that are US FDA approved for the treatment of relapsed and refractory myeloma. One is IDA cell. The other one is a CILTA cell. So where do we think about integrating these treatments for our patients? So I guess a few things to keep in mind about both. They're very active. The response rates in patients who have had three or more lines of treatment is somewhere between 74 to 98 percent. That is a very high proportion of patients respond. If you look at complete response, that's not just responding, but having disease go back to undetectable levels. That's seen in approximately 35 to 82 percent of patients. So again, a pretty high number. And lastly, if you look at how long these responses last, that is again measured in the order of 12 to 34, 35 months at this point for both of these products. And keep in mind that these are patients who've already received most of the available standard treatments. So in that setting, seeing these kinds of responses with a one time treatment is quite impressive and unprecedented. So the approval from the US FDA is for patients who've had a triple class refractory myeloma and patients have had at least four lines of treatment. So this is fairly advanced patient population, and that's where we currently have access for commercial CAR T cells. It is expected based on some of the data that's emerging that in the near future, this will start to move up to earlier lines. There are two large randomized studies that have just been completed. One has been reported already a second that's expected to be reported in the coming weeks, both for IDA cell and CILTA cells, suggesting that you could potentially use these treatments earlier on, say, after one or two or three lines of treatments waiting for advanced four lines of therapy. If that happens, we will see more patients benefiting from these treatments and earlier in their disease course. The results of the CARMA 3 study and CARTITUDE 4 study lead to new indications for both abeckma and carvacti. On April 5th, 2024, the FDA approved new indications for both carvacti and abeckma. The FDA approved carvacti for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent and who are refractory to lenalidomide. The FDA approved abeckma for the treatment of adult patients with relapsed or refractory multiple myeloma after two or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent and an anti-CD38 monoclonal antibody. To learn more about CAR-T cell therapy, visit the link in the description.