Loss of CD38 and Resistance Patterns in Myeloma | Benjamin Diamond, MD | #ASH24

So. Hi, my name is Benjamin Diamond. I'm an investigator at the Sylvester Comprehensive Cancer Center, University of Miami. I do primarily genomics and also clinical trial work. And I'll be presenting, an abstract this time around on the loss of cd38, which is the cell surface target of Daratumumab and isatuximab in multiple myeloma, and trying to investigate whether the loss of this target can impact resistance patterns in multiple myeloma.

And so as we know both the CD38 antibodies, isatuximab, daratumumab, they've really revolutionized the treatment landscape of multiple myeloma. They're used in first line setting, and in relapsed refractory setting. And in general, they have, impacted and improved overall survival and also progression free survival at all settings that they’re use in.

Now the problem is that unfortunately, most patients will inevitably relapse and develop resistance. And so we really need to figure out why that's happening. Because a lot of the time patients are receiving these antibodies multiple times throughout their treatment course. And so we have no way of really guiding our treatment on a genomic level. Some previous work has shown that at least primary resistance.

In other words, people that have a hard time responding at the upfront, to either of these drugs will usually have things like genomic complexity, things that we've mentioned before, like high apobec, complex structural variants, things like that. But less is known about the patients that are having a relapse after a long response. What's driving that? So there's been previous work done by Damian Green's group.

They've shown that at relapse, such an enrichment for loss of the cd38 locus. But the technology was kind of limited. It couldn't look for the things that, that we usually look for, like single nucleotide variants, structural variants, the things that can kind of contribute to a bi allelic or a loss of both alleles of Cd38. So to accomplish this and to to kind of address this question, we worked on a very, very, very multi-institutional collaborative work team science working with Calgary University, working with Mayo Clinic, and even with Sanofi, and also with Heidelberg University to, look at samples that were collected after therapy, with anti CD38 agents with daratumumab, with isatuximab, and comparing them to patients that were newly diagnosed that had no exposure and also relapsed refractory patients that had never been exposed to these agents, in other words, cd38 naive patients. And what we found is actually similar to what Damian Green had found, about a 20% prevalence for at least a loss of one copy of Cd38.

Now, with the resolution of the next generation sequencing that we're doing, we were able to see, resolution on the alternate allele. We were able to find focal very small deletions on Cd38 that really knocked it out, that you wouldn't be able to find with other technologies. And on top of that mutations, indels, structural variants that are able to contribute to bi allelic loss.

We have an estimated 5 to 10% of patients are affected by this at relapse. After dara and Isa. And so we have a number of cases that we were able to investigate some very interesting examples of the real strong, selective pressure of these therapies, even sub clones at separate sites of extra medullary disease in the same patient have different deletions that are able to converge and form the same exact resistance mechanisms.

So really, to show you that some of the genomic instability that we see can contribute to people having, a convergence towards this kind of resistance mechanism. Now, importantly, we've found a number of these mutations that actually still let the patient express cd38 on the surface of the cell. And so we question, you know, are these truly contributing to resistance?

We don't know. So working with, Nizar Bahlis and Paola Neri and Mansoor Abraham up at Calgary University, they were able to model, these mutations, they're able to make a cell line with the mutated Cd38 and do binding assays and killing assays to see if isa and Dara could bind to these mutations that we found and induce cell death.

In most of the cases, the mutations really affected both of these drugs, and, and impacted the binding and the efficacy. But in a couple of cases, actually, on one case, we were able to distinctly see that the, binding capacity of one drug was reduced as compared to the other, in this case, the binding, the binding affinity of Daratumumab was reduced compared to isatuximab.

And on and on top of that, the cell killing was reduced with daratumumab as opposed to isatuximab. And this is a patient that had developed the mutation after being exposed to Daratumumab. So overall we're able to see that generally this is a more common than previously thought resistance mechanism. And importantly what we see is that sequencing is super important.

All right. So we really need to understand these mutations before we go ahead willy nilly and start retreating patients with cd38 antibodies, because some of the mutations that confer resistance to one drug may not give you resistance to the other. And this kind of is the rationale that we feel, there is for switching the drugs, at relapse and not using the same agent over and over throughout a patient's treatment journey.

It really also emphasizes the need for bringing extra interest, next generation sequencing into the clinic so that we can better identify these therapies, these mutations, and really personalized treatment. So there is also a question about whether, after having lost cd38, whether expression of cd38 can return, this can be a resistance mechanism that we see, but typically it's not guided by genomics.

That can be something like epigenetic or some other post translational modification that can be reversed over time. The very interesting thing about genomic loss of CD38 is that those clones are selected. The gene is genomically deleted and expression is not predicted to return. So if a patient has a bi allelic genomic loss of cd38, then trying to retreat within the CD38 antibody is often futile.