ASH 2025 | Impact of Duffy status on PFS in newly diagnosed multiple myeloma treated with RVd ± autoSCT

This is actually a very specific subgroup analysis of the DETERMINATION study. It’s the first time that DETERMINATION is being presented as an oral session to the society and reflects the fact, obviously, that the original primary data was presented as an ASCO plenary session a few years ago and then published in the New England Journal. And since then, there have been poster presentations of subgroup by high risk here at the ASH meeting. This one, however, is being led by my colleague and mentee, Dr Lauren Merz, and she’s done remarkable work looking at the impact of Duffy as a pathobiological marker of differential treatment benefit according to treatment type used. And let me explain the background to this. Duffy-null is expressed in up to 70% of people of African American heritage. And it’s there as a specific genotypic, phenotypic difference to the Duffy-null population because it confers survival advantage in the setting of falciparum malaria. And what this means is that the red cells concerned are highly resistant to the penetration of the parasite. This means actually that the receptor that normally sits on this red cell is gone. It’s the so-called Duffy receptor. The Duffy receptor is, however, still expressed on the endothelium and in also neurological tissue. But by not being expressed on the red cells, it actually prevents the complications of malaria. But unfortunately, it provides profound resistance to chemokine and cytokine stress through this very important reservoir that is the red cell phenotype or the red cell membrane and the red cell as a whole. So if you’re Duffy-null, you are actually highly resistant to inflammatory stress. This is a very important point. And it means that in the context of treatment for myeloma, for example, there may be a difference. And what we observed originally in DETERMINATION was a striking progression-free survival benefit for RVD followed by early transplant compared to delayed transplant. But what we also showed was absolutely no survival benefit to that early approach. And what was even more striking in DETERMINATION is actually only 28% of the patients in the delayed transplant arm actually underwent transplant. And so with the absence of survival benefit, it was very clear there must be some element of competing risk. And there are lots of various reasons for that. But when we looked hard at the PFS differences, we saw that African-Americans did not derive the same PFS benefit as their Caucasian counterparts. So we took a deeper dive on this to look at Duffy. And interestingly, we found no evidence that it was related to African leukopenia. That was not the entity that was at play. However, that led us to question perhaps it was the pathobiology of Duffy-null itself and this relative impact on the so-called inflammasome. And what we showed is that the hazard ratio for patients who are Duffy-null, regardless of race, was actually 0.41 in favor of keeping transplant in reserve. If you were Duffy non-null, if you were Caucasian or African who was Duffy non-null, the benefit of transplant early was preserved in PFS at least, if not survival. So this is a very important observation because it suggests that it’s not whether you’re African-American, it’s whether you’re Duffy-null as to whether a transplant will benefit you early or not. So this is a very important observation. It’s preliminary, it’s hypothesis generating, but it meets all the parameters of statistical significance and hazard ratios of the past muster because fortunately in DETERMINATION we were able to enroll up to 20% of our patients were African-American. So that gave us the sort of number of patients to be able to make at least some sense of what we were observing and have some degree of confidence around the findings we found. So I want to stress that hypothesis generating, they’re going to generate future studies, but they’re strong enough to say there’s something real going on here. And it’s a privilege actually to work with Lauren in this world and she’ll be presenting this as an oral abstract this afternoon.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.