Final Thoughts on Case Study and Treating Multiple Myeloma

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Transcript:
Joseph Mikhael, MD: I know that’s a bit of a data dump there, so I’m going to pause for a minute and turn to my colleagues in our last 10 minutes and say, what do you think of this? Do you see much of a difference, frankly, between isatuximab, carfilzomib, dexamethasone [Isa-Kd] vs daratumumab, carfilzomib, dexamethasone [DKd]? What is your sentiment? Why might you choose one over the other? I’ll start with you, Sikander.

Sikander Ailawadhi, MD: Sure. When I look at these data, the thing that stands out to me is the median follow-up. To me, that is impressive, a 44-month follow-up and results standing out with that doubling of the PFS [progression-free survival]. Of course, when we look at these trials, there will always be questions. Why did Kd [carfilzomib, dexamethasone] behave one way in one study and the other way in the other study? Those kinds of things happen, that’s why rather than making cross-trial comparisons, to me, the long follow-up is very impressive. I think that somehow stands out to me when I look at all these studies and compare all these, or look through all these data.

Joseph Mikhael, MD: How about you, Keith?

Keith Stewart, MD: I look at them and say there’s 5 months lower PFS in the CANDOR study than in the IKEMA study, so let’s add 5 months to the PFS for the daratumumab arm, and they look pretty similar to me. I don’t know, maybe I’m wrong, maybe there’s a difference, but I would say that these drugs are pretty equivalent in my head.

Joseph Mikhael, MD: That’s a good point because that’s one of our questions in the question boxes, are they pretty much interchangeable? I think there is a bit of a different target, there are differences, but I would suggest that they are very similar. We did a study where we gave isatuximab immediately after daratumumab progression, and there really was no response rate. So I think one of the important messages is, interchangeable or not, I wouldn’t think that one overcomes immediately the resistance of the other, so try not to sequence them one after the other.

I think a lot of times people’s choice is based on, right now, we can give daratumumab subcutaneously, and we have to give isatuximab IV [intravenously]. Daratumumab is given a little more intensely for the first few months, weekly for 8 weeks, whereas isatuximab is given weekly for 4 weeks. But in the long run, isatuximab is given every other week, as opposed to ultimately going down to once a month with daratumumab. So, there are some subtle differences, sometimes financial considerations, etc. But it’s hard for me to conclude that there’s a massive difference between the two. I don’t know, Elisabet, what’s your take on that?

Elisabet Manasanch, MD: I think that overall, I agree with what you all are saying. Just the caveat on the subanalysis of the IKEMA study with chromosomal abnormalities showing there’s a big benefit for these patients with isatuximab. So, with this patient with a chromosomal abnormality, I may go with isatuximab, especially also carfilzomib is given IV. It’s not so difficult, the patients already have an IV, and they have to get carfilzomib anyway. I would agree with the approach, the treatment of this patient with isatuximab. I would agree, usually a patient like this could get an IV with this regimen. But yes, I think that the choice of using one agent or the other is very setting specific and depends on several considerations, which you have mentioned very well, Joe, already.

Joseph Mikhael, MD: Thank you. That’s great.

Keith Stewart, MD: I can’t resist saying that they’re both very good, 44 months. They are both excellent.

Joseph Mikhael, MD: Yes, to go over 3 years in the relapsed setting is unprecedented, really. To think a few years ago, we were wishing for 3 years at frontline therapy, let alone at relapse, so thanks, Keith, for the caveat there. A couple more questions before we wrap up, and some other ones are coming in. someone asked an interesting question, that Sikander, I’ll ask you to answer quickly. When do you choose DRd [daratumumab, lenalidomide, dexamethasone] vs VRd [bortezomib, lenalidomide, dexamethasone] in patients not going to transplant? Do you have a strategy there?

Sikander Ailawadhi, MD: I don’t think I have a very specific strategy. I present the data to the patient, risk categories, high risk, proteasome inhibitors, those kinds of thoughts come to mind. But that is exactly the clinical trial that’s going to be starting very soon through cooperative groups, which should be hopefully going live this month. That is comparing DRd vs VRd-lite, and then the maintenance would be either DR [daratumumab, lenalidomide] or R [lenalidomide] as a single agent. Exactly trying to answer that question of which of the two is superior, because both of them have shown overall survival benefit. The caveat being that we end up using VRd-lite in those patients, and the SWOG S0777 trial’s overall survival benefit was with regular VRd. So, there are some caveats there, but hopefully, this forthcoming study will help clarify that a little better.

Joseph Mikhael, MD: I love that you used it as a commercial for the trial. Well done, certainly good. Let’s look at this patient, what if the patient hadn’t had VRd? Keith, let’s say the patient had DVRd [daratumumab, bortezomib, lenalidomide, dexamethasone]. Would your thoughts have been any different in the relapse? What if they were on DR maintenance? Or what if they were just on R maintenance? Would that have influenced your choice?

Keith Stewart, MD: If they’d had daratumumab up front, and they stopped it and progressed off of it, I would use it again. If they’re still on it, obviously, we’re not going to use that. If they’ve gone through daratumumab therapy and are now relapsing, we’re looking at a carfilzomib-based regimen, most likely I’m increasingly looking to the T-cell engagers on clinical trials for this kind of a patient at this stage.

Joseph Mikhael, MD: Excellent, really well said. I think your point is well taken, that if someone had had daratumumab but is not currently progressing on it, it may be reasonable to introduce the CD38 inhibitor, but not going from one CD38 inhibitor to another.

To close off as we come toward the end, and Keith, you just indicated, it was a perfect segue. Do we think that bispecific antibodies and CAR [chimeric antigen receptor] T-cell therapy, which are now approved much later in the disease course, Elisabet, do you feel that they’re coming earlier? Do you feel that we’re going to be doing those in early relapse in the near future?

Elisabet Manasanch, MD: I think so, I don’t know if everybody would agree. But there are certainly clinical trials being planned, being done in early relapse for bispecifics. And even for maintenance, for treatment of first relapse, from negative MRD [minimal residual disease] to positive MRD. There is a lot of research ongoing in this area; I am looking forward to seeing the results. But I do think there is an opportunity to use certain bispecifics. Even here, for example, the slide is mentioning teclistamab. But even some of the newer bispecifics that we’re seeing with newer targets, it seems plausible that those would also move forward in earlier lines of therapy.

I do have to say that some of these, and how agents are developed, depends a lot on how companies are developing these products. We don’t always have a say, when we look for example at pomalidomide, it was never in the front line. I think it depends a lot on how the companies are developing these drugs, sometimes they’ll have our help. There are other interests as well in these, so I’m just looking forward to seeing what happens with some of these agents, and which ones we can use earlier. But I do think it’s feasible and possible.

Joseph Mikhael, MD: I agree with you. I think most of us would agree, this is how myeloma has been developed. You prove it in the very heavily relapsed setting and move forward. So, as we try to wrap up things today, it’s amazing how much we could discuss further, but I would give a few takeaways as follows. First, we have more options than ever before, and you have the opportunity to tailor them to your individual patient. And each of these regimens has flexibility within themselves.

We have a few questions coming in about the dosing of carfilzomib, and I think we have options to give it either once weekly or twice weekly. I tend to favor, for example, giving it once weekly. We have the opportunity, maybe we don’t have a phase 3 trial, but we can put carfilzomib and pomalidomide together. I think understanding the cytogenetics of your patient becomes important in individualized therapy.

Someone asked, are we comfortable using venetoclax in patients with translocation 11;14? Obviously, we don’t have time to get to that today, but absolutely. It’s not yet formally FDA approved in this indication, it’s being pursued, but it does speak of a different biology. I think the key takeaways are, we have more choice than ever, and this massive distinction between transplant eligible and ineligible is less of a major distinction. I think we are trying to treat myeloma a little more aggressively in the early relapsed setting with triplet combinations, if you will, jumping on the disease relatively early, not waiting for extensive progression. Lastly, many of these newer immunotherapies, bispecifics, CAR T, with all the different targets—BCMA, GPRC5D, FcRH5—I think are going to come earlier into the disease.

Someone asked, are we on the verge of curing myeloma? Well, I’m always careful to use that term, but I think a simple way to put it is, we’re closer now than we were before, and we’re working toward improving patient’s quality of life with the disease until we absolutely have a cure.

I want to take a moment to thank our 3 extraordinary panelists today. Thank you so much for your time, your wisdom, and your efforts. It’s been great to host this event with you. I trust that we’ve gotten to just about all the questions in the audience. Sorry, there are a couple that we haven’t had a chance to get to, but we can work on that thereafter. But thanks very much for your participation today. Thanks OncLive® for putting this together, and we’ll close the show. Thank you very much and have a great rest of the day.

Transcript edited for clarity.