Duffy Null: A Breakthrough for Biomarkers in AA Myeloma Patients | Paul Richardson, MD

My name is Doctor Paul Richardson, and I serve as the clinical program leader and the director of clinical research at the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute in Boston, Massachusetts.

And it's been a wonderful meeting. Lots of exciting data. You asked me just to touch a little bit on Duffy null work with determination and just wanted to first and foremost acknowledge, my colleague, Doctor Lauren Merz, who's led this effort with us, exploring the impact of Duffy null as a pathobiologic marker of different impacts of a different benefit, from autologous transplant in patients typically of African American heritage.

And it's such important work. And I want to first and foremost acknowledge Lauren's leadership in the Duffy null space. Because when we first collaborated, the working hypothesis was that West African or African ancestry, as it’s called, would be an important factor for understanding differences in treatment effect, for African American patients.

Just to remind the audience in determination, we looked at RVd followed by early transplant versus RVd, followed by delayed transplant or alternative approaches. And the most important aspects of the trial were continuous maintenance and also, for that matter, extraordinary access.

And as a result of that, we saw, 20 almost 20% participation, from African Americans, the highest number to date in our prospective randomized phase three trial. So with that strength behind us, what we saw, which was quite remarkable, was that in African American patients, the degree of progression free survival benefit was not the same as it was in white patients.

And given the fact that the economics of this were not all the medicines were provided for free. The socioeconomic aspect of this probably wasn't the explanation at all, but we know it wasn't. However, the question is what was it? And why was it that African American patients didn't appear to benefit as much as their Caucasian counterparts from high dose therapy? I should stress stress. However, there's no overall survival difference or no overall survival benefit.

So that being said, with that in mind, we would then sought to explore through comprehensive analysis what the differences might be due to, the working hypothesis was that Duffy null might be a factor. And I just to explain what Duffy null is, which I think Lauren has also explained very nicely to the meeting and to you as well.

Duffy null is a, abnormality of the red cell phenotype that in the past has been an evolutionary advantage for people who live in areas where falciparum malaria has been endemic, which, of course is why in Africans and people from the Middle East. This particular red cell phenotype has been so strongly preserved it occurs in up to 70% of people of African heritage.

The trouble with it in modern life is as a decoy receptor, its so-called the Dc receptor. It actually limits our ability to handle inflammation. So with that in mind, this inability to handle inflammation and the impact of what we call chemokines and cytokines may mean that as a person who's not able to so well tolerate the implications or impact of inflammation, this may have adverse effects on both treatment effect and also might in part explain some aspects to why myeloma, for example, is even more common in people of African heritage.

Because, as we know, myeloma is an inflammatory condition. We know that myeloma has, associations with inflammatory bowel disease, rheumatoid arthritis, lupus, autoimmune conditions generally, and it's exacerbated by inflammation. So it's a working hypothesis that there's some linkage between Duffy null, myeloma pathobiology. And then most importantly, is there some linkage with treatment effect.

So if that's all the case, how did Duffy null behave and determination. I want to especially acknowledge, Lauren and our fabulous biostatistics team led by Susanna Jacobus was in the context of dissecting this in the study population. So approximately 600 patients worth of data were analyzed for Duffy null, we established its incidence. We then looked at our Duffy null cohort for our Duffy non-null cohort.

And to cut to the chase, we're able to show that if you, Duffy null, transplants benefit early appeared relatively limited and most importantly, Duffy null’s benefit if you didn't have a transplant was quite remarkable. Conversely, if you were Duffy non-null. Actually the benefits of transplant were striking and were independent of race.

So if you are African-American and Duffy non-null, you got as much benefit from the early transplant as your white counterpart. Conversely, if you were Duffy null, transplant actually didn't really help you. And in fact, unless inflammatory, less toxic approach as exemplified by RVd alone with transplant kept in reserve, you did much better.

So the implications are really fascinating. We're going to better try and understand and dissect these, but it does mean that we have a very interesting path of biological construct for this difference to explain why some patients might benefit from transplant and others may not. And in this particular subgroup analysis, in our African-American patients, this discovery of the role of Duffy null in my opinion, is very, very important and certainly worth further better understanding and exploring. And actually, in in his own right, I think, represents quite a landmark. I think clinical research in myeloma.

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