ASH 2025 | The impact of functionally high-risk disease in patients with R/R myeloma receiving late-line CAR-T

So, we know that CAR T-cell therapy has revolutionized outcomes for relapsed/refractory myeloma. Previously, it was approved with four prior lines of therapy. More recently, it’s got an approval for one prior line of therapy. We also know that there’s a subset of myeloma patients who, despite having a standard cytogenetic profile, will relapse within 12 to 24 months of their frontline therapy, and we define them as functionally high-risk multiple myeloma. We actually also know, based on CARTITUDE-4 data, that patients who have functionally high-risk disease, when they receive CAR-T, can have outcomes as good as patients without functionally high-risk disease. In other words, CAR-T does overcome the negative prognostic impact of functionally high-risk disease when it’s given in the earlier lines of therapy. Having said that, what we do not know is whether CAR-T would also overcome the negative prognostic impact of functionally high-risk disease in late-line therapies. And that’s the question that we investigated with this particular study. 

We had about 220 patients. Half of these patients had functionally high-risk disease. All of these patients received CAR-T as late-line therapy with a median of five prior lines of therapy. And what we determined is that patients with functionally high-risk disease tend to have more extramedullary disease, higher disease burden, as well as a shorter time from transplant to CAR T-cell therapy. And when we looked at the outcomes in these patients with CAR-T, patients who were late-line relapses, who received CAR T-cell therapy, we learned that the response rates and progression-free survival may be similar between the high-risk and non-high-risk patients, but when you look at overall survival, it was significantly inferior in patients who were functionally high-risk compared to those who were not. 

We again performed a very cautious multivariable analysis to study the impact of functionally high-risk disease, and what we learned is that extramedullary disease and high disease burden within this group of patient populations were actually big determinants of inferior outcomes. So what we concluded from our study is that if patients have functionally high-risk disease and they receive CAR-T as late-line, it’s actually not able to overcome the negative prognostic impact. And we do recommend that any patients who have functionally high-risk disease where they’re progressing within 24 months of their frontline therapy should be considered for CAR-T at the time of their first relapse.

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