Transcript: Sagar Lonial, MD, FACP: Let me ask you this then because I think if it looks like the high risk are getting benefit, and I didn’t see the forest plot of that in that presentation, but that would certainly be encouraging because it’s one of the few in the relapsed setting where we clearly see that. That would be good. The reason we use POM/DARA [pomalidomide, daratumumab] so much is because if you look at single agent activity, 1 of the most potent drugs in 17p deletion is actually [pomalidomide]. I’m curious how in your POM/ISA [pomalidomide, isatuximab] phase III trial, where did the high risk fall out on that?

Paul Richardson, MD: Sagar, I’m very grateful because it was a perfect segue, because I think this to me is a fascinating concept. Obviously, having been with everyone on the panel and part of the development of daratumumab, we’ve been very pleased, however, with the performance of isatuximab. In the ICARIA-MM trial, isatuximab in the high-risk group—and there’s a very nice abstract from Simon Harrison MBBS, PhD, at IMW [the International Myeloma Workshop] on the high-risk group—clearly did well. And this was striking. It’s interesting because, Ajai, you’ve been the pioneer of DARA/POM/DEX [daratumumab, pomalidomide, dexamethasone], but it’s a phase II trial, isn’t it?

Ajai Chari, MD: Yes.

Paul Richardson, MD: Correct me if I’m wrong, but in that high-risk population that was part of that study, how did they fare?

Ajai Chari, MD: They did slightly worse than the standard risk.

Sagar Lonial, MD, FACP: But that was 5 lines of therapy.

Ajai Chari, MD: Right, exactly.

Paul Richardson, MD: We’re going to have to see the randomized comparisons before we conclude. But anyway, in the context or ICARIA, which obviously was phase III and randomized, we’re able to see that signal. We had several presentations at this meeting that included, actually what was very interesting to me, an elderly subgroup, which really did well. And this gets to our points in earlier discussion about the frailty of those patients and how we might benefit them. That was another positive for isatuximab.

I think the other studies we did, one was we looked at biomarkers. What was fascinating was that we saw no relationship between the levels of CD38 and even cellular markers in response, which is intriguing. That brings me to an interesting point about isatuximab. It binds to a different epitope. It has a powerful effect through the adenosine pathway, which means that it actually is more pro-apoptotic. This may be an interesting mechanism because it may be subtly different from daratumumab. My only real point of sharing that is because perhaps we’ll see, as we know with the isatuximab approval platform looks set for next year, certainly by April, perhaps we’ll see an opportunity for our CD38 platform to expand to allow us to think daratumumab, then when daratumumab fails, perhaps re-treatment, perhaps yes. But also, we may have a different choice.

Amrita Krishnan, MD: If I may say, to be honest, that’s the 2 questions you’re really trying to understand, mechanism of CD38 resistance and how do you overcome that. Is it just adding an IMiD immunomodulatory drug, for example, pomalidomide, in terms of immunomodulatory effects overcoming some of that? We presented data on TAK-079, another anti-CD38 antibody, which is subcutaneous, no significant infusion toxicity, quick injection. We are expanding to look specifically at daratumumab refractory, so really to try to answer that in a more codified setting, because I think the real question is going to become, what do you do in terms of your CD38 re-treatment strategy?

Paul Richardson, MD: Right, exactly. I think in the same context, if daratumumab fails a patient, meeting it with monotherapy with isatuximab doesn’t make any sense. And we have preliminary data from a small trial in France that suggested that that was not successful. But a different construct for combinations, to your point, and how you build on that. The way I think of it is in lymphoma we do Rituxan-CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], we do RICE [rituximab, ifosfamide, carboplatin, etoposide], we do R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, hydroxydaunorubicin]. I’m wondering if this will not be the case in myeloma; myeloma is too cloudy for that.

Ajai Chari, MD: One other point to make on the re-treatment is there are pharmacokinetic issues. Are you on weekly daratumumab or monthly daratumumab? There are pharmacodynamic issues. Have you lost your T-cell expansion? There’s single agent versus combination therapy at the time of progression, and is it a clinical or biochemical relapse? I don’t think we can just put all of those into 1 basket, and re-treatment studies likely would need to be stratified by some of those to answer that question. A biochemical progression on single-agent daratumumab monthly is very different than....

Paul Richardson, MD: Quite.

Amrita Krishnan, MD: The way you are talking it makes it sounds like lymphoma is so much easier because you get progression….

Nina Shah, MD: And also as daratumumab moves to the front, if people do what Sagar is saying, RVd/DARA [lenalidomide, bortezomib, dexamethasone, daratumumab] up front, transplant, and then just REV [Revlimid] maintenance, now they’re not daratumumab refractory, they’re daratumumab exposed. So that’s another population that’s different.

Paul Richardson, MD: Yes, I agree.

Transcript Edited for Clarity