CAR-T Meeting 2024 | Moving CAR-T into earlier lines of therapy in multiple myeloma
In this video, Hermann Einsele, MD, FRCP, University of Würzburg, Würzburg, Germany, highlights the need for moving CAR T-cell therapy into earlier lines of treatment in patients with multiple myeloma (MM). Earlier in the disease course, fewer mutations are present, and T-cells have been found to exhibit greater fitness, which is associated with improved outcomes following CAR-T. Due to the attrition rate seen in myeloma treatment, only 15% of patients make it to fourth-line therapy where CAR-T is available to them, despite trials such as CARTITUDE-4 (NCT04181827) indicating encouraging safety and efficacy of CAR-T in earlier lines. This interview took place at the EBMT-EHA 6th European CAR T-cell Meeting in Valencia, Spain.
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Transcript (edited for clarity)
What we learned in the last few years is that we have to use CAR T-cells earlier in the course of the disease for several reasons. First of all, we’re aiming to get fitter T-cells, and there have been very interesting studies showing that if we take T-cells from patients not as heavily pretreated as, for example, in the KarMMa and the CARTITUDE-1 trial, we can see that these T-cells are definitely fitter, we have a higher percentage of early memory T-cells, we have T-cells with better proliferative activity, a better CD4:CD8 ratio...
What we learned in the last few years is that we have to use CAR T-cells earlier in the course of the disease for several reasons. First of all, we’re aiming to get fitter T-cells, and there have been very interesting studies showing that if we take T-cells from patients not as heavily pretreated as, for example, in the KarMMa and the CARTITUDE-1 trial, we can see that these T-cells are definitely fitter, we have a higher percentage of early memory T-cells, we have T-cells with better proliferative activity, a better CD4:CD8 ratio. And this is clearly a prerequisite for an effective CAR T-cell therapy.
On the other hand, if we treat patients that are at a late line of their disease, we often see an increase in mutations, and we have shown that some mutations like KRAS mutation and TP53 mutation have an impact on the expression of the surface antigens like BCMA, and therefore might also lead to a decrease in the efficacy of CAR T-cells.
And finally, and I think that has been nicely shown, especially by the UK groups, is that there is an attrition rate. So, with each treatment line, we get fewer patients to the next line. And actually looking at a current UK data analysis, only 15% of patients make it to the fourth line of therapy and that’s the line where we’re currently offering CAR T-cells, which would mean that 85% of our patients will never make it to CAR T-cell therapy.
So a lot of reasons to do it earlier, and I think CARTITUDE-4 and also KarMMa-3 have nicely shown that with earlier treatment you can be even more effective and in CARTITUDE-4 it was actually 99.4% of patients responding to CAR T-cells and 86% achieving a complete remission. I think that’s a response quality and response rate we have never seen before in myeloma. So, my personal belief clearly is in myeloma CAR T-cells are changing the treatment algorithm, and they’re going to be already used in early lines -maybe second, maybe even first-line therapy is currently being tested in the CARTITUDE-6 trial, CARTITUDE-5, and also in the KarMMa-9 trial.
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Disclosures
Honoraria: GlaxoSmithKline, Sanofi, Takeda, Amgen, Novartis, Janssen, Bristol Myers Squibb/Celgene; Consulting or advisory role: GlaxoSmithKline, Sanofi, Takeda, Amgen, Novartis, Janssen, Bristol Myers Squibb/Celgene; Travel support: GlaxoSmithKline, Sanofi, Takeda, Amgen, Novartis, Janssen, Bristol Myers Squibb/Celgene; Research Funding: GlaxoSmithKline, Sanofi, Takeda, Amgen, Novartis, Janssen, Bristol Myers Squibb/Celgene.
