Oxford Myeloma Workshop 2025 | Phase II study of Dara-based response-adapted therapy for older adults with newly diagnosed myeloma

What’s cool is there’s two abstracts at ASH that we put in. One was the clinical part, which is a Phase II looking at response-adapted therapy, and then this abstract was more of the kind of the, I call it correlative science around that. And so I’ll kind of put the two together if you don’t mind. 

But essentially what we said is, again, to the point of personalized therapy and myeloma, we all need to figure out how to do this, is that we put together a clinical trial led by Rachid Baz at our institution where we said, you know, if you’re older and frail, you know, the world of myeloma says you need more drugs to help you respond. And what our study has kind of said is, well, maybe let’s take a look. Let’s say if you’re frail, maybe not all these drugs are important. We can induce remission, not just take care of frailty, right? 

And so we used this response-adapted approach where we said, let’s give them Darzalex or Daratumumab up front for two cycles. Okay, give them a chance to respond to that. And if they don’t respond, we’ll add either bortezomib or lenalidomide based on, you know, clinical choice as well as some ex vivo testing we’ve done and using other models we have. 

And essentially what we showed is that, one, it’s a very viable model. Okay, so one, overall 97% response rates, only 37% of patients that had just daratumumab by itself responded, had a PR at least by two cycles and did very well, still ongoing in terms of response. So we just saved over a third of patients that are average age around 80, 81, the need for three drugs or even two drugs – they had Darzalex or daratumumab. So I think it’s a win from that perspective. 

We know without question, you know, the PFS so far in the follow-up isn’t quite what MAIA would be, another three-drug combination, but essentially you’re leading that way. But we also reduce the risks, the side effects, the AEs by using this kind of approach. So I think from a clinical perspective, it’s a really novel way of thinking about ideas for patients that are maybe not as fit and really can’t handle the three or four-drug triplet or quad therapy. So from a clinical perspective, I think check without question. 

Then the correlatives, I think, were really interesting because it gave us an opportunity to say by itself, what are the predictors of response, what things are associated with response to daratumumab by itself. You don’t have many trials where it’s given by itself in the newly diagnosed homogeneous setting. 

And so what we learned there is there’s really critical aspects of what makes you a responder is one, you have to have antigen expression, more CD38, more cells then you’re going to respond. So CD38 is the target of daratumumab so that kind of makes sense, right? 

We also learned that there are very specific tumor effects. Like, believe it or not, within myeloma, there are patients that, even though it’s a disease of plasma cells, certain patients their plasma cells aren’t as plasma cell-like. So they express different things, more like an earlier B-cell, they don’t respond as well. So these are all things I think are really kind of novel ideas that we think about how to identify patients that may respond or not respond as well. 

And I think really another cool part about it was we looked at the tumor microenvironment. So using single-cell RNA sequencing on a patient-to-patient basis, we can also get the different cell types within the tumor microenvironment. And we showed that really, you know, for patients that respond well, they have increased NK cells. They have increased neutrophils. They have increased T-effector cells. They have lower levels of certain kinds of myelosuppressive cells, specifically looking at some kind of trafficking classical monocytes, as well as decreased levels of things called inducible Tregs or peripheral Tregs, so they have a [unintelligebile] phenotype. So really kind of finding out what’s going on with a response. 

The other really nice part about this is it allowed us to track this response over time. So we took marrows and identified these things both before we started therapy, 60 days after therapy, and then at relapsed. And we learned that really when you start responding, you have multiple clones in a patient. And these clones can have, again, these same phenotypes. And again, we’re selecting for the resistant ones even early on, even within 60 days, you’re seeing clones that might not be as responsive becoming more predominant. And that was really novel to us, it has the same biology as those that were resistant at the beginning. And then what became really interesting is that if you look at relapse, the biology is the same. So the same people that were resistant up here, these biological effects are still the same biology we see out here at relapse, but they come from clones you barely saw at diagnosis. Like clones that were less than 1% or 3% of the cells at the beginning become the dominant clones, and they carry all these resistant mechanisms. So it’s kind of a really novel way of matching and watching the evolution of daratumumab resistance over time. So those are the things I think would be the highlights of those two abstracts put together.

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