IMS 2025 | The impact of the Duffy null phenotype on outcomes of induction therapy in multiple myeloma

This is data actually led by my colleague Dr Lauren Merz, who actually couldn’t be here in person, so asked me as her senior investigator and mentor to present her data for her as part of a poster session. And what Lauren and our whole investigative team have been evaluating is the impact of the so-called Duffy null phenotype amongst patients on a clinical outcome to induction remission therapy, including transplant or deferring it. And this was all data derived from the determination trial, where we had the largest participation of African Americans to date in a randomized upfront Phase III study. This approached 20%. And what this allowed us to do was better understand how treatments might benefit this particularly important group of patients and do so in a way that hasn’t actually been done before. What we’re able to show, because fortunately, with determination, with our pharma partners, we were able to provide therapy essentially free of charge. As a result of that, socioeconomic and social factors were really not at play in terms of outcome. We were able to show that for reasons that took us by surprise, high-dose chemotherapy followed by autologous stem cell transplant was beneficial to African-American patients. We saw that actually if you deferred that approach and just use triplet therapy alone, patients of African-American heritage did remarkably well with keeping transplant in reserve. So this prompted us to look deeper and understand better what was going on. And because obviously race is often a social construct and people identify according to various preferences that they may have, we sought to look at a pathobiological correlate, so-called Duffy null. And when we looked at this, we found remarkably that it amplified the benefit of keeping transplant in reserve. And at the same time, whilst we showed that transplant was beneficial to patients of Duffy null status, if they were Duffy null and didn’t get transplant, they did substantially better. And we thought to ourselves, well, why would this be? And in fact, we thought perhaps it was related to so-called African leukopenia, which is an association of Duffy null to low white count. And we found to our surprise, that was not the case. So we dug deeper. And just to explain to our audience what Duffy null is. Duffy null is a red cell phenotype that makes the red cell hardened for the penetration of falciparum malaria. So in patients who have it, from an evolutionary point of view, it’s there because it was such a survival advantage over the millennia in the past. Now, this, of course, is very important if you hail from Africa or the equatorial countries or the Middle East. Obviously, in modern life, this hardening of the red cell becomes a little more challenging for various reasons. Why? Because red cells are actually an incredibly important sink in our body for inflammation. In other words, when you have inflammatory cytokines and inflammatory chemokines, your red cell acts as a sink to absorb these inflammatory factors. If you are Duffy null, your ability to do that may be quite different. And so because of that, we’ve seen other situations where inflammatory conditions are more magnified in patients who have Duffy Null. And we’ve seen in other cancers that the cancers may have different behavior. For example, in breast cancer, patients who are Duffy Null or of African-American heritage have different patterns of pathobiology than those who do not, who are so-called Duffy Non-Null or Caucasian. Well, interestingly, in the myeloma setting, this ability to analyze Duffy Null and identify Duffy Null and Duffy Non-Null patients has become very important, not only from the point of view of understanding the issue of the low white counts, which in our particular study weren’t seemingly important, but to understand therapeutic outcome. And what we were struck by is in the presentation that I gave on behalf of Lauren at the meeting here at IMS, was that if you kept transplant in reserve and you were Duffy null, your ability to benefit from just triplet therapy alone was remarkable. It was significantly higher than those patients who were Duffy non-null who received just triplet therapy. And most importantly, if you were also Duffy Null, the benefit of transplant early was not nearly as great as it was if you kept it in reserve. In fact, the hazard ratio was a striking 0.21 in Duffy Null patients for keeping transplant in reserve. Now, we have to be careful because this was a subset analysis that was designed to be hypothesis generating. And I think it warrants the question, we need to analyze this further and understand better what this means. But our working hypothesis is that in patients who are Duffy null, there may be merit to keeping intensive pro-inflammatory treatment modalities in reserve. And transplantation with high-dose melphalan, stem cell support is exactly that. It’s highly pro-inflammatory. And it may be that in these patients, that approach from a pathobiological point of view is less favorable than being less intensive with your treatment, more biologically driven and derived, therefore, better outcomes. So very interesting preliminary work, fascinating observations, but the hazard ratios in favor of keeping transplant in reserve stand to statistical analysis and are real with this hazard ratio of 0.21 clearly being important and therefore exactly what we were hoping to see in terms of hypothesis generation and leading us to do further studies to better understand exactly why this might be.

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