ASH 2025 | Earlier use of cilta-cel is associated with better immune fitness in multiple myeloma: CARTITUDE-4

I presented on the earlier use of cilta-cel and its correlation with better immune fitness from correlative data presented from the CARTITUDE-4 study. And just to set the stage, CARTITUDE-4 is a clinical trial where patients were randomized to either standard of care or CAR-T after receiving one to three lines of therapy. And they needed to be lenalidomide refractory at that stage. About 80% of the patients had gotten an autologous transplant. And in contrast, CARTITUDE-1 is a study for later lines of treatment where patients had at least three or more lines of treatment and were both refractory to proteasome inhibitors and Revlimid. The outcomes of both trials have been some of the most exciting results of the year. The long-term follow-up of CARTITUDE-1 has actually shown a third of the patients are relapse-free and treatment-free more than five years, which is really exciting for this population. Similarly, CARTITUDE-4 has shown that treatment in earlier lines of therapy with CAR-T results in durable outcomes and in fact outperforms standard of care both in progression-free survival as well as overall survival. The new data that I presented showed that we now have follow-up indicating that treatment in one or two lines of treatment is even better than treatment in three or more lines. As an example, the progression-free survival was significantly better in patients that got three or more lines versus exactly three lines. It was 50 months versus 34 months. And in the patients that had one to three lines, they haven’t even reached the median progression-free survival. Overall survival, similarly, even in patients that received similar prior treatment, had similar disease burden, age, and other clinical characteristics, was better in one to two lines versus more than three lines. And this raised the hypothesis that the patients in earlier lines may have a better immune fitness that supports CAR-T durability. So to test this, we took bone marrows from prior to treatment, day 28 and at six months, and also looked at BCR sequencing and gene expression from these studies. We also looked by flow cytometry at pre-treatment peripheral blood, and both of these showed a striking pattern. The bone marrow showed that there was robust anti-tumor myeloid cell activation. For example, M1 macrophages and neutrophils were degranulating as CAR-T expanded and killed the tumor. There was across the board T-cell activation and better antigen presentation when patients were treated in earlier lines of treatment. And perhaps the most important evidence was higher CD4-naive cells, which have been shown to be associated with durable responses in patients that have received anti-BCMA CAR-Ts of different types. So the patients that had higher CD4-naive cells actually did better in terms of progression-free survival, as well as they were numerically higher in patients that had prior lines of therapy with either one or two lines as compared to three or more. Overall, this suggests that prior lines of treating patients with CAR-T in earlier lines of therapy is associated with better immune fitness and better progression-free survival and overall survival. And this is, I think, going to change the paradigm where we now counsel patients regularly but the message has to go out to the primary practitioners that see these patients in the local communities that CAR-T is indeed a superior option for these patients relapsing after one or two treatments and they should try to offer it to them.

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