Which Proteasome Inhibitor for Upfront Treatment of Myeloma?

Transcript:Sagar Lonial, MD: There are a lot of data for bortezomib; there are a lot of data now emerging on carfilzomib and there are data on ixazomib.

Keith Stewart, MB, CHB: Let’s talk about that because there are some abstracts about that at this 2016 ASH meeting. Tell us what you’ve learned about using carfilzomib in the newly-diagnosed patient at this meeting that’s been updated?

Sagar Lonial, MD: I think it’s clear from Ola’s series that he’s published previously, as well as Andrzej Jakubowiak’s series—both with and without transplant—that the KRd regimen is clearly very active, with less neurotoxicity than we see with bortezomib, and probably better efficacy, at least from what we can tell, than what we know at least with the oral ixazomib on the surface of things right now. There aren’t really any head-to-head data helping us to understand what it looks like. It’s an apples-to-apples comparison, but it certainly looks very encouraging.

Keith Stewart, MB, CHB: Now, the French had an abstract here where their experience with KRd up front was reported. Are you familiar with that one, Saad? Do you want to comment on that?

Saad Usmani, MD: I think in terms of efficacy with that KRd induction transplant—KRd consolidation followed by lenalidomide maintenance strategy that the French have employed in the phase II study—the efficacy appears to be okay. But, they appear to have a safety signal with some toxicities relevant to the cardiovascular events that we have observed with carfilzomib in the relapsed space. We have to look at that data a little carefully, and try to tease out why that’s happening.

Keith Stewart, MB, CHB: I’ve heard that, but I was looking at the abstract just before we came in this morning. When you parse right through it, there were no deaths on the KRd arm. There was mostly thrombosis and hypertension.

Saad Usmani, MD: I think there was just one cardiac event, and that was, if I remember correctly, in the posttransplant setting.

Keith Stewart, MB, CHB: Nevertheless, this is something that we need to pay attention to. There is a randomized phase III trial in the United States going on, is that right?

Amrita Krishnan, MD: That’s right, of KRd versus RVD. I think it will very much answer for us the efficacy question, and probably, more importantly, the safety question.

Keith Stewart, MB, CHB: Now, it’s not been presented at this meeting, but we did see a press release in one randomized trial where carfilzomib was compared to bortezomib with melphalan/prednisone, the CLARION. Is it the CLARION studies?

Saad Usmani, MD: Yes.

Keith Stewart, MB, CHB: The press release suggests that there was no advantage to using carfilzomib, as I recall, but we don’t know much about that study yet, Paul.

Paul Richardson, MD: What I understand from the investigators involved is that there’s no evidence of clinical benefit, one versus the other. Having said that, this is an elderly population, and obviously, the carfilzomib dosing is at 27 mg/m2. Perhaps that partnership with alkylators in that setting may be more challenging. I do think it touches on, though—from talking to Dr. Philippe Moreau, who’s one of the principle investigators—the fact that this issue of vascular toxicity in the older population does appear to be real. And, I think, that hypertension we touched on, Keith, is real. I think the other thing that we’ve realized is this vascular toxicity could be endothelial based. I would switch it and say, “Well, let’s look at strategies to minimize that, because if we can, perhaps we can preserve efficacy and, at the same time, get around some of these toxicities.”

Keith Stewart, MB, CHB: We’ll probably come back to this question in the relapsed section as well, where we have a lot of choices in what we choose. I think it would be fair to summarize the carfilzomib story as it’s clearly highly efficacious. We don’t know yet if it’s going to be any better than bortezomib, and we need the results of the trial. And we have to balance that neuropathy versus this vascular signal, and with a little bit more evidence. I know many of my colleagues at this meeting are telling me they’ve already been employing this carfilzomib/lenalidomide/dexamethasone regimen even before trial results. But, whether that’s the right thing to do or not, time will tell. We talked about 4-drug regimens. They’re not really reality yet, but you mentioned daratumumab. Saad, what’s your feeling? Where are we heading in newly-diagnosed patients with upfront therapy?

Saad Usmani, MD: I think with the PI/IMiD-based induction combination therapies, we are getting a significant number of patients to good levels of response, but not everyone. So, adding an agent that improves the efficacy without adding toxicities would be ideal. And monoclonal antibodies may be the way to go there. I think we’re going to see more data with different combinations of triplets. The other advantage is that there’s a population of transplant-ineligible folks who are older, the patient population that we were referring to earlier. We mentioned that toxicity with carfilzomib may be a concern for the frailer, elderly patients. That patient population may also benefit from getting a drug that is efficacious without causing side effects, so monoclonals may be helpful there.

Paul Richardson, MD: I’d echo what Amrita talked about it earlier: we’re all participating in studies of RVD plus elotuzumab, RVD plus daratumumab, and now of course, there are carfilzomib-based platforms with the antibodies coming forward. I think that truly is the wave of the future. We’re looking probably at R-CHOP/Rituxan equivalents in our disease now, certainly under study. I certainly know of community colleagues who felt comfortable trying to use that up front and off protocol in the high-risk setting. I think we need to wait for more data, but at the same time, there’s such impressive evidence from the antibodies that it does seem reasonable to me to be moving them up front as soon as we reasonably can.

Keith Stewart, MB, CHB: And that’s probably where we’re heading as trials emerge.

Transcript Edited for Clarity