IMS 2025 | MRD dynamics and early immunotherapy interception in multiple myeloma

Nowadays, MRD assessment is not only, I would say, a critical component of each clinical trial, but also the number of MRD tests has become much higher than in the past. And obviously under the expectation that the more you test, the better you can predict. But I think it is important to actually show that with so many assessments you can define dynamics, kinetics of MRD, and these are clearly more prognostic than a single or two or three assessments because at the end of the day you are relying on multiple bone marrow aspirates and so many bone marrow aspirates will have a negative impact on patients’ quality of life. Well, in this study, we did show that MRD kinetics based on three or more assessments are very, very prognostic, definitely much more prognostic than a single assessment and probably the most relevant prognostic factor. So it is worthy to perform so many assessments. And then we, surprisingly, we saw that among MRD-positive patients based on the kinetics, you can clearly define a subgroup with a dismal outcome and another group that, despite being MRD-positive, the levels are relatively stable and PFS is only slightly inferior compared to MRD-negative, and in fact, no differences in overall survival. And this led us to interrogate the biology of persistent MRD to try to understand dynamics associated with a durable persistent MRD or, by contrast, an imminent relapse. And we did find some interesting findings in terms of genomics, also transcriptomes associated with evolving complexity from diagnosis to MRD to relapse, also associated with signals coming from inflammation and eventually immune suppression in the microenvironment. And because of that, we hypothesized that intervening at the time of MRD instead of waiting for clinical relapse could produce better outcomes. Obviously, this has to be interrogated in clinical trials. We didn’t initiate a clinical trial, but we asked the question in those clinical trials that we can conduct using the experimental models developed by my colleague José Ángel Martínez Climent, also from our university in Pamplona. And in those models, we did show that early treatment at the stage of MRD with CAR-T therapy, for example, produces better outcomes when compared to treatment with the same strategy at the time of clinical progression.

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