CAR-T Meeting 2025 | CAR-T in multiple myeloma: optimizing bridging therapy & moving CAR-T into earlier lines of therapy

Welcome from Strasbourg from the European CAR T-cell meeting, which is co-organized by the EBMT and the EHA, which is a meeting that started about exactly seven years ago. I was actually one of the initiators of this meeting, the first meeting that took place in Paris. And it’s great to see how CAR T-cell therapy is moving ahead and that we are seeing more and more new indications and more and more new constructs and so also new strategies. 

Now also in myeloma, the field of cellular therapy has improved and moved very much into the right direction. The right direction is better responses and lower toxicities. So when we started using cellular therapy in multiple myeloma, we addressed mainly the unmet medical need. These were triple-class exposed, triple-class refractory patients that normally have an overall response rate of about 30%, the median progression-free survival of only about four months. So these patients were really patients for whom we needed better treatment options, and these were the patients that were also the first ones in which CAR T-cell therapy was tested on. In the KarMMa trial and later on in the CARTITUDE-1 trial, two BCMA-directed CAR T-cell products were actually tested. One of them in the KarMMa study was the Abecma, the ide-cel product. And in patients that had a median of six lines of prior therapy, 84% triple-class refractory and a lot of patients, I think 39% of patients, with extramedullary disease. In this patient cohort, 80% of patients responded, 35% achieved a complete remission and the median progression-free survival was about 11.3 months. We could already see that patients that achieved a complete remission did specifically well with a duration of response of nearly two years. 

Then the second CAR T-cell product came that was also approved, both are approved now in Europe for patients after three lines of prior therapy being exposed to PI-IMiD and an anti-CD38 antibody and progressing under the last treatment. And cilta-cel in the CARTITUDE-1 trial showed an overall response rate in these really heavily pre-treated patients of 97.9%, more than 80% achieved a complete remission and about three-year median progression-free survival. And actually some follow-up data show that even after five years, quite a significant proportion of patients is still in ongoing remission, indicating that maybe even in this very late-line therapy, we can actually achieve long-term remission in some patients using CAR T-cell therapies. 

Then there were the two randomized trials, the KarMMa-3 and the CARTITUDE-4, and in both it was shown that BCMA-directed CAR T-cells were really significantly better when compared to any standard of care treatment. And so, again, this changed the approval in Europe for BCMA-directed CAR T-cells. Now, cilta-cel is approved for second-line patients that are exposed to an IMiD and a PI and lenalidomide refractory, and ide-cel is approved for third and fourth and further lines of therapy if the patients have actually also been exposed to a PI and IMiD and an anti-CD38 antibody. 

So how can we further improve? And this was a big discussion also at the CAR T-cell meeting in Strasbourg. So especially for the patients that receive CAR T-cells in later lines of therapy, it’s increasingly clear that we need good bridging therapies. And there have been studies with ide-cel and also with cilta-cel clearly showing that patients that showed a response to bridging therapy have a much better response rate also to the consecutive CAR T-cells. So, for example, in the KarMMa-3 trial, patients responding to bridging therapy had an overall response rate of 97% and a complete remission rate of 56% with a median progression-free survival of 20.7 months. Whereas for patients that progressed during bridging therapy, the overall response rate was only 56%, only about 30% achieved a complete remission, and the median progression survival was not 20.7, but 6.9 months, so much shorter. And at the same time, effective bridging therapy also reduced the toxicity. So in patients that responded to bridging therapy, there was no grade three CRS or grade three neurotoxicity when compared to a higher percentage in patients that had an increasing tumor load during bridging therapy. 

So bridging therapy is important. And a big question also in Strasbourg, a discussion was, what is the optimal bridging therapy? And it’s very surprising data now that you can use a bispecific antibody also for bridging therapy. You shouldn’t use it before you do the leukapheresis because prior exposure to a bispecific can actually reduce the efficacy of leukapheresis and the CAR T-cell production from these harvested lymphocytes, but you can use it after the leukapheresis. And there have been nice studies showing that, especially if you use a bispecific antibody targeting a different surface antigen when compared to the consecutive CAR T-cell therapy. So, for example, giving talquetamab before a BCMA-directed CAR T-cell therapy, that this can be very efficient. And it was shown that bispecific antibody, during bridging therapy, have a 100% response rate, which is much higher than for chemotherapy, in which it’s around 50%, and actually, about 20% of patients achieve already a complete remission prior to CAR T-cell therapy. 

The other big question in Strasbourg about the application of CAR T-cell therapy was the best time of CAR T-cell therapy, and we know that T-cells, when we take them at an earlier time point, so if the patient is less heavily pre-treated, we have fitter T-cells, these T-cells have more memory markers, they have a better CD4:CD8 ratio, and a better proliferative capacity. Which means that the T-cells we take earlier from a patient also make fitter CAR T-cells. At the same time, less pretreatment means that we increase the immunogenicity of the tumor cells. So it was nicely shown that if you give the patient long pretreatment before you actually put the patient on CAR T-cells, there is an increase in mutations, and these mutations, especially KRAS and p53 mutations, have an impact on the expression of BCMA on the target for CAR T-cells and therefore patients who have an increased mutation load probably have a higher likelihood to respond to CAR T-cells – another argument to use CAR T-cells earlier in patients with multiple myeloma. 

So with these theoretical considerations it was also interesting to see a comparison between CARTITUDE-4 and CARTITUDE-1, which means patients that have been exposed to a median of six lines or a median of one to three prior lines of therapy, and it could be clealry shown that earlier application of CAR T-cells induces a higher PFS, a better OS, clearly again supporting earlier use of CAR T-cell therapy for multiple myeloma. And actually in the CARTITUDE-4 trial it was shown that patients with one to three prior lines of therapy that achieved sustained MRD negativity had a likelihood of 93% to remain in remission 13 months post-CAR T-cell therapy. At the same time, again, concerning what we already know about the bridging therapy approaches that, if we use CAR T-cell therapy earlier we have less toxicity, also because of better bridging options, a lower severity of CRS and ICANS, late neurotoxicity and also cytopenias. And now, and that’s the strategy that was also discussed in Strasbourg, we are moving CAR T-cell therapy to first line, and first data already showed, from the KarMMa-2 trial, that CAR T-cells are very effective, even in functionally high-risk myeloma patients, in improving the overall response rate and also the CR rate in patients that have a suboptimal response after autologous stem cell transplantation, and you can improve these responses dramatically by giving another CAR T-cell product, and we have a very impressive PFS in these patients. And so we are all very eager to see data from the actual first line therapy now, the KarMMa-9, the CARTITUDE-6, and the CARTITUDE-5 trial, in which CAR T-cells are tested in first line, and in, for example the CARTITUDE-6 trial, actually challenging autologous stem cell transplantation as a consolidation strategy in first line. 

So clearly what we learned at this congress in Strasbourg is to improve the management of patients receiving CAR-T, optimizing side effect management, optimize bridging therapy, and clearly, in the future, move CAR T-cells to first or second line therapy.

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