iwHRMM 2025 | How is the definition of high-risk myeloma evolving in the era of CAR T-cell therapy?

There was a lot of focus in this meeting, as the name suggests, on high-risk and definition of high-risk and what it means to have high-risk myeloma, whether that changes based on the stage of disease, newly diagnosed myeloma, relapsed/refractory multiple myeloma, late-line relapses, or does it change based on modalities of treatment? Is what we consider as high-risk in the era of carfilzomib, bortezomib, lenalidomide, CD38 antibodies, are they still high risk in the era of CAR T-cells and bispecific antibodies? So some of the data that was presented looked at outcomes for patients who were receiving CAR T cells based on high-risk cytogenetics, the traditional cytogenetic risk factors like deletion 17p or t(14;16) translocation, other classic high-risk features. So one of the data points that was shown was, is the outcome better for these patients with CAR T-cells? And it does appear that the outcome is better compared to patients that might get other standard treatments. But in comparison to patients that do not have these high-risk features, patients that do have them, unfortunately, still tend to have a much shorter duration of response with the treatments like CAR T-cells. The other big high-risk feature, I think, for patients who are receiving CAR T-cells is the presence of extramedullary disease across multiple trials. Now, it is clear that if you have patients who have extramedullary disease, those patients tend to respond less well and also have much shorter duration of response. So these are both considered high-risk features across the board for myeloma. It appears that they remain high-risk features also for patients who are receiving CAR T-cells. The other big push, I think, would be to improve on our diagnostics to incorporate, let’s say, genomic analysis. So Francesco Maura, for instance, and his group have shown that complex genetic features that can be diagnosed pre-treatment are associated with really very suboptimal responses, including many primary refractory patients. So in addition to cytogenetics, incorporating next-generation sequencing platforms to identify these complex genomic events might help us further refine the risk. The other big question is what does this all mean? So what do we do with risk assessment? Can we tailor treatments to these risks? In other words, I think a big focus in the next two or three years is going to be perhaps targeting consolidation approaches or maintenance approaches to patients who have these high-risk features and are receiving CAR T-cells to hopefully augment and deepen the responses we’re seeing with CAR-T cells.

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