Treatment Options for Lenalidomide-Refractory Myeloma

Jan 29, 2020

Transcript: Paul Richardson, MD: That’s a perfect segue for this next thing we wanted to discuss, which was best strategies for lenalidomide-refractory disease. I would welcome everyone’s input on this. As a result of the OPTIMISMM trial, we’ve got some very high level evidence of the benefit of pomalidomide-based strategies in that setting. Certainly we use, because we’re looking for a real-world experience, pomalidomide, bortezomib, and DEX [dexamethasone] in that setting. Sagar, if I may, I would imagine you embrace the pomalidomide idea. What do you typically use after LEN [lenalidomide] failure?

Sagar Lonial, MD, FACP: Our go-to first relapse regimen is POM/DARA/DEX [pomalidomide, daratumumab, dexamethasone]. In our own retrospective analysis, it looks like the median PFS [progression-free survival] is somewhere between 40 and 44 months. It’s pretty good for pomalidomide, daratumumab, dexamethasone. I think you get that synergy between an IMiD [immunomodulatory drug] and a proteasome inhibitor [PI]. If you think about it, we’ve got 3 backbones, right? We’ve got a CD38 backbone, we’ve got a PI backbone, and we’ve got an IMiD backbone. The question I think at first relapse is which of those 3 has to be in that first relapse backbone. I think if a patient has not seen a CD38 up front, that becomes the primary driver, and it’s what do you partner it with. I’m sure we’ve got lots to discuss about optimal partners for daratumumab in that situation.

Paul Richardson, MD: In that spirit, obviously, Ken, when you think about this, do you think of a proteasome inhibitor plus pomalidomide plus daratumumab? Do you do that?

Kenneth H. Shain, MD, PhD: For the most part, I follow what Sagar’s point has been, that daratumumab, pomalidomide, dexamethasone has been what I’ve thought about or we’ve thought primarily. I think really it tells us that really daratumumab and a PI would be a fantastic way to think about these refractory patients or maintenance refractory patients when you’re seeing some fantastic data where you are getting great responses with a PI and a monoclonal antibody.

Paul Richardson, MD: Yes, I agree.

Kenneth H. Shain, MD, PhD: Although we all embrace IMiDs forever, it’s not always true for a patient when you have data like that. You have to recognize that really it’s daratumumab-based now, maybe the IMiD we can hold for another line of therapy when we have this great combination. That’s what that does in terms of changing how I look at a patient, how am going to decide which one am I going to do at this point.

Paul Richardson, MD: Nina, when you think of carfilzomib, pomalidomide, dexamethasone, now you already touched on KRd [carfilzomib, lenalidomide, dexamethasone] earlier, do you do KPd [carfilzomib, pomalidomide, dexamethasone] and keep the daratumumab in reserve, or do you bring your CD38 early?

Nina Shah, MD: It really depends.

Paul G. Richardson, MD: Yes.

Nina Shah, MD: If the patient has cardiac issues, I’m going to go with the daratumumab. I agree with Sagar that bringing something new is good for myeloma patients, new mechanisms of actions. I think we’ve been moving more toward daratumumab in the first relapse if the patient has not had daratumumab originally. As you know, Saad Usmani, MD, presented the CANDOR study with [daratumumab, carfilzomib, dexamethasone], or he would say carfilzomib, [daratumumab, dexamethasone]. Anyway, the point is that this is in 1 to 3 prior lines, and they showed that the median PFS met its end point, not reached yet, versus about 16.9 months in the control group.

Really interesting in this is that although those data are outstanding, and I think now we have another regimen that we can use there, that’s great. But there was a significant amount of more toxicities. They spent a lot of time in the slides going through that because they didn’t want to minimize that. These included infections, and I would say double the amount of treatment emergent adverse events that lead to death. It was 5% versus 10%, but it’s there. They talked about what caused these, and part of it was pneumonias, as you would expect. The other part was that patients stayed on study longer if they were in the treatment arm, so that’s one of the things. Age also was a factor. If you know these are risks, again, now we know all these things from studies, you can try to mitigate them up front.

One thing that stuck out to me from this study was a little bit better for high risk in the subgroup analysis. It just was heading in to the bar, but on a forest plot it’s the best that I’ve seen so far when you take these high-risk groups out, RISS-3 [Revised International Staging System, stage III], and high-risk cytogenetics. It’s not like you can use that for sure, but I think it did better probably because of the carfilzomib. So that’s something, you have a high-risk patient, they’ve already gotten RVd [lenalidomide, bortezomib, dexamethasone], they progress, I think DKd [daratumumab, carfilzomib, dexamethasone] is okay.

Paul Richardson, MD: Amrita, when you think about your patients in whom lenalidomide is failing them and you’ve moved your pomalidomide platforms, you think about these strategies especially in the context of the data you’ve heard at the meeting. How is your strategy for these people?

Amrita Y. Krishnan, MD: It’s probably going to be changing now because of the daratumumab, carfilzomib, dexamethasone data. Actually, I was going to ask Ken when he mentioned that point because I always struggle sometimes, am I going to use the CASTOR data and use daratumumab, Velcade or am I going to use daratumumab, pomalidomide, dexamethasone at that first relapse setting? I think it depends on the things we’ve talked about, prior toxicities, patient preference to some extent. I think we need to obviously take that into account a lot, so the combination of both. My question really would be more, we’re going to obviously be using more and more daratumumab up front, daratumumab re-treatment. I went back and read probably the only paper there right now, which is from Sagar’s institution, on daratumumab re-treatment, and it’s very hard to make sense of it, to be honest.

Sagar Lonial, MD, FACP: You didn’t like the way we wrote it? I think when you talk about daratumumab re-treatment, it’s a lot about interval between when you last saw it. The patients who re-responded in the double resistant group, so the group that’s resistant to pomalidomide and to daratumumab, was about 30%. Median PFS was somewhere around 3 months as well. We may not be in that same ballpark because if they got daratumumab up front, they probably didn’t seem pomalidomide. You may be in that middle group where the PFS was longer. I think you need to have an interval where you’re away from daratumumab to sort of maximize the likelihood of....

Ajai Chari, MD: I just wanted to go back to again the cross-trial comparisons because it’s important to remember that the only PI, daratumumab phase III studies we’ve had have all been with fixed-duration PI. So the CASTOR and ALCYONE trials are fixed duration and that’s because of the regulatory bodies. That’s how it was done. I think that’s what distinct about this because people always want to say daratumumab plus IMiD is better than daratumumab plus PI, but you’ve never been given a PI till progression. This is why I think CANDOR is so important. I think that’s why you’re seeing the high-risk doing better because daratumumab is the same, but you’re giving a PI till progression.

Another brief point I wanted to make is I think this was with carfilzomib 56 mg twice weekly, which I think is again going to be challenging to do till progression in the real world. And we had previously done the weekly 70 mg, it can be given safely with daratumumab. I think that’s more deliverable in the real world, but I think the issues of the toxicity, we always have to look at not just the adverse total event, not just the absolute reporting rate but the per unit time, as Nina alluded to. Any time we see people on therapy longer, we’re going to see more infections because we know that daratumumab does that because of the hypogammaglobulinemia, presumably. I think we really need to adjust for the time on therapy, and I think the high risk to me is very compelling because to date, no study has shown if you look at all the daratumumab-based studies, those high-risk patients are always crossing the forest plot 1 line. I think that’s very interesting.

Amrita Y. Krishnan, MD: You bring up a good question because are you going to use 56 mg twice weekly of carfilzomib?

Ajai Chari, MD: I think I would do 70 mg weekly.

Transcript Edited for Clarity

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