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At December's American Society of Hematology (ASH) virtual meeting, results of the showed that the addition of ixazomib (Ninlaro) to maintenance therapy with lenalidomide and dexamethasone in patients homogeneously treated with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (together known as VRD-GEM) induction did not result in a progression-free survival (PFS) benefit.

口袋女优 has brought together three expert leaders in their field: moderator , of the University of California San Francisco, is joined by , of the University of California San Diego, and , of the University of Utah in Salt Lake City, for a virtual roundtable discussion. This second of four exclusive episodes focuses on the role of ixazomib moving forward.

Following is a transcript of their remarks:

Prasad: I'm back -- new abstract, again talking to Aaron Goodman, Manni Mohyuddin. Ixazomib plus len/dex [lenalidomide/dexamethasone] versus len/dex maintenance after auto stem cell transplant. This is the results of the Spanish study. Aaron, this is a provocative abstract out at ASH. I wonder if you might summarize, what did the authors do in this study? What was this second randomization all about?

Goodman: Yeah. So we're gonna talk about ixazomib, one of my favorite drugs, all oral proteasome inhibitors. So what they...

Prasad: That means it's better, right? If it's oral, it has to be better.

Goodman: It's oral, so it's convenient and with Rev [Revlimid] you could take all the maintenance oral, it's great. So they took transplant eligible patients who got VRD-GEM induction, and then they went to autologous stem cell transplantation, and then they randomized these patients to ixazomib+Revlimid+Dex versus Revlimid+Dex which is fair, because we are using Revlimid as our maintenance strategies in the United States and elsewhere. And what they found was, you know I usually criticize three versus two studies -- or now with four versus three. Because when you add an active drug in myeloma, ixazomib does have some activity I won't argue against that, and if your endpoint is PFS, I suspect the addition of an active drug is going to enhance the progression free survival. And other times I've mentioned that in the maintenance setting, truly the only endpoint that matters is overall survival, if you're gonna give a drug indefinitely or for a long time.

And so they did this three versus two, and I would not have been surprised if progression free survival was longer, nor would it have changed my practice. But they did the study and actually there was no increase in progression-free survival. It was the same and there was more toxicity given the ixazomib.

I just wanna point out a few other things with this drug ixazomib. So the , which looked in the relapse setting was I+Rd versus Rd in the relapse setting. And it did show progression-free survival advantage, but long term follow just published I believe in JCO [Journal of Clinical Oncology] still showed no overall survival advantage to I+Rd versus Rd. The , which looked at I+Rd versus Rd in transplant ineligible newly diagnosed patients showed no statistically significant benefit to PFS with ixazomib. And then in the , which was in the non-transplant setting, continuing ixazomib maintenance versus placebo also did not show any benefit and perhaps even a risk of increased death. So we have now a lot of data, including this most recent study showing that ixazomib does not do that much.

Prasad: That is really sobering, because I would've shared your intuition that I would've thought PFS, if anything, was a chip shot for ixazomib. Of course it was gonna do it -- but it didn't do that. Surprises me. Manni, what are your thoughts on this trial? What are your thoughts on ixazomib?

Mohyuddin: Yeah, great question. I think this should hopefully, at least in my mind be the final nail in the coffin for ixazomib. As Aaron has very eloquently pointed out, trial after trial has either been negative or has been a very marginal benefit for ixazomib. I think the consensus of all the evidence if you look at it, is that ixazomib is a weak PI. It has some activity, but that activity has probably very little clinical meaning. And I think that it should sort of make us reevaluate the trials that we are using ixazomib in.

There is an ECOG trial currently that is going on that is randomizing patients that are MRD [minimal residual disease] positive after transplant to either lenalidomide plus placebo or lenalidomide plus ixazomib. So, that for a while, but it just goes to show that ixazomib is still, they're still trying to find a niche for where it can be studied. And I think that by and large ixazomib should not be used. And if you really, really, really have to use an all oral regimen, then you should have a very frank conversation with your patient about how much incremental benefit you think ixazomib is adding. Because it does add toxicity in practice when I've given it, or when I've seen being given, it has caused significant GI issues. It's not a benign drug by that means. So I think this should be an inflection point where we look back and we're like, okay, we probably shouldn't be using a lot of ixazomib moving forward.

Goodman: There's no role, in my opinion. I mean, the , which was ixazomib versus a placebo post auto, when we know clearly that Revlimid is what we should do, showed a very modest increase in PFS. So I would never use it as a maintenance post auto. We have a better alternative with a better endpoint. And then the other positive study, the initial TOURMALINE-MM1 which was in the relapse setting with Rd, either was a fluke or again, very modest. We have much better other regimens that we would use in the relapse setting. So I see zero role and I know this argument for convenience. Well, if it's convenience, and it doesn't work and hurts you, who cares if it's convenient? It doesn't really add much.

Prasad: There's no " that's gonna save ixazomib. But here's my question for you gentlemen, a tougher question. There are other settings where we lean on proteasome and Revlimid maintenance, but we don't have robust randomized controlled trials showing that that has an improvement in overall survival. Is this an indictment of PI Revlimid maintenance in other settings, which has been taken forward without robust randomized trials showing overall survival. Manni, you're shaking your head no. You don't hold this against other proteasome inhibitors. Go on, why?

Mohyuddin: That is correct. So the closest parallel to this is , which was evaluating carfilzomib [Kyprolis]. The second randomization of the FORTE trial, which was after an auto transplant, patients were randomized to either Revlimid alone or Revlimid plus carfilzomib. In that study there was a clear PFS advantage with carfilzomib plus Revlimid versus Revlimid alone. So it's similar, there's some parallels between this study we're discussing now and the FORTE study, but obviously carfilzomib is a more effective drug. It's shown a PFS advantage in this situation. You are absolutely right that for maintenance, the onus is to show an overall survival advantage. So long term follow-up will be telling. And I hope...

Prasad: But one point about FORTE. FORTE just doesn't have the power to get you there. It's an underpowered phase II. I wouldn't hang my hat on that OS [overall survival] even if it's positive. What do you say?

Mohyuddin: So it is a phase II. It is a large phase II. So it's larger than some studies that we call phase III. I believe like the number of patients is 400 or something. It's a large phase II. And it makes me think about what sort of numbers we use to call studies phase II, cause that's smoldering myeloma trial. That's like less than 100 patients and that's called a phase III study. The one that you know was done in Europe a long time back. But you're right. I mean, I'd say that it's a decent size trial. At least it's powered for PFS. The endpoint of the second randomization was PFS. But I think time will tell. But I do think that for high risk patients, I acknowledge that there's no overall survival advantage, but on a case by case basis you can consider using carfilzomib or using Velcade plus Revlimid. But yeah, you should not be using carfilzomib in those situations.

Prasad: All right, after this discussion, you're gonna go ahead and email me the phase III study that supports Velcade. Just go ahead and send that to my email.

Mohyuddin: There is no phase III study. There is no phase III study, but we just discussed this, Velcade and carfilzomib are fairly interchangeable in my mind for newly diagnosed and for probably in the maintenance setting. But you're right...

Prasad: You're putting the transitive property to the test in my mind. Aaron, closing thoughts?

Goodman: I want to say, classic oncology: bad disease, high risk cytogenetics -- they do bad and we wanna do more. It's human nature. We wanna help these patients. As we've seen now with EPOCH and DLBCLs [diffuse large B-cell lymphomas], prophylaxis, all these things -- these things we think are helping, good chance they're not, and they're hurting. So I understand this enthusiasm to give more maintenance more intensity, but we really need the studies, especially with prolonging survival, if we're gonna take patients and make them come in every few weeks for a proteasome inhibitor indefinitely.

Prasad: Thanks for doing this, gentleman.

Watch episode 1: The 'Messy' Data on Chromosome 1 Abnormalities and Multiple Myeloma Treatment

Watch episode 3: Isatuximab Plus RVd Induction in Newly Diagnosed Multiple Myeloma

Watch episode 4: Updated MajesTEC-1 Results Continue to Show Teclistamab's Promise

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