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At December's American Society of Hematology (ASH) annual meeting, results from the showed that minimal residual disease (MRD) rates were superior when isatuximab (Sarclisa) was added to lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) as induction therapy compared with RVd alone in patients with newly diagnosed transplant-eligible multiple myeloma.

口袋女优 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 third of four exclusive episodes focuses on these data and how they might change practice.

Following is a transcript of their remarks:

Prasad: I'm back. Aaron Goodman, UCSD; Manni Mohyuddin, Utah. There's a new abstract out in ASH. It's the talk of the town in myeloma. It's the addition of isatuximab to RVd as induction therapy for newly diagnosed transplant-eligible multiple myeloma patients. It's a very provocative abstract. Manni, would you tell us about this abstract?

Mohyuddin: Totally. Before I delve into this abstract, I just want to state two facts about MRD based on the literature that we have. So, MRD is, without a doubt, prognostic, in the sense that patients who achieve MRD negativity tend to do better than patients who do not achieve MRD negativity. I don't think that there's any controversy left in that.

Fact number two, historically in the past, additional interventions to deepen responses in myeloma -- deepen responses, get more MRD negativity -- have not always translated to an improved survival if that intervention is given later. So, case in point is auto transplant, right?

So, the -- RVd plus auto versus just RVd. If you look at the long-term overall survival, as long as people got auto later, long-term overall survival was similar. I think it's not fair to assume that just because you're doing an additional intervention and you'll increase MRD negativity, you're going to get additional survival.

So, with those two facts, let's move on to this trial. This trial is looking at RVd versus the addition of isatuximab to RVd. It is a trial for newly diagnosed patients. It's a phase III trial with 662 patients with a primary endpoint of MRD negativity, NGF [next-generation flow], cutoff 1 × 10^-5, which is basically looked at at the end of induction. And induction in this particular study is basically 18 weeks of induction, so three long 6-week cycles.

So, after 18 weeks of induction, patients who got RVd, the MRD negativity is 35%, whereas for the patients receiving isa-RVd, it was about 50%. So, yes, the trial has met its primary endpoint of a single timepoint of MRD negativity, which is what we expected. Isatuximab has shown that it's effective in the relapsed/refractory setting. So, I guess, yes, it is a positive trial. It is a phase III trial. It is actually, for a change, powered to look for MRD. Because previously you've had studies that have looked at SCR [stringent complete response] and then made strong conclusions about MRD. But is it the right question to ask?

Prasad: That's the key. Let's ask Aaron, your thoughts. You have a new option. It's a four-drug option. It has a higher rate of MRD negativity. What more do you need to change your practice, Aaron? Change it tomorrow. Change it today.

Goodman: I mean, it's going to be hard. I'm just thinking about me and how I'm going to discuss this with my patients in the clinic. We have a study, and it did show more MRD negativity at one timepoint. And I suspect with longer follow-up, there will be a progression-free survival [PFS] advantage with the addition of CD38 monoclonal antibodies to induction. So, there is maybe something to this first remission. I do it with auto already, I usually give auto in first remission.

I do think there's something to say about a long first remission, a deeper response. But I think I'm not immediately ready to change practice, but I think I will discuss with the patients and show, yeah, this is likely to prolong your first remission. It's going to add some toxicity. It's another drug. And we won't know. And we may never know the true answer that we want, whether giving you this drug early with induction is going to prolong the amount of time that the patient is alive. I know it's not going to make them feel better. That's the other thing I care about. And I just think, unfortunately, that's just how it's going to be. I'm not running these myeloma studies and designing them. I just have to be a consumer of what's given to me. And that's why I'm going to use the data.

Prasad: Manni, let me ask you this. If you're going on a long hike in the wilderness, you pack a breakfast, lunch, dinner, and a snack. And you go out there, 1 hour on the trail and you just eat all those four things together, it's going to be a longer time until you're hungry. But when you are hungry, you're going to have nothing to eat in your bag. So, what do you think about that when it comes to myeloma drugs? We're forever obsessed with the first PFS, the time until you get hungry, but what do we have left if we use all of our drugs upfront? Is that really the right question? What do you think, Manni?

Mohyuddin: Yeah, so I guess for your analogy, what I would say is that we're waiting for a helicopter to deliver us, like, some fancy food. And those who say that the helicopter is going to deliver fancy food, there is some wish to that because there is promise in some of the early-phase studies that are coming out with some of our newer agents -- bispecifics, the CAR-Ts.

So, there is that argument, yes, that you give your best treatment upfront. You get a really long PFS and you have other options available when a relapse happens. But I will tell you, Vinay, that I'm philosophically on the same wavelength that you and Aaron are, that what I want to answer is, is this curing more people?

And MRD negativity of a single timepoint is not cure. That's been shown from other studies that have MRD negativity of a single timepoint, it's fickle. It can go away; in a few months they may not even hold. So is this curing more people? Is this making people live longer? And I don't know the answer to those questions.

But the problem is, and I will admit to you that ASH 2021 has sort of put me into this, like, I've gone into this existential crisis about, am I going to get the studies that I want in the newly diagnosed setting? And I don't think I will, because even if the FDA doesn't approve of MRD as a surrogate for OS [overall survival], I think the field has moved on. The field doesn't care. The field is already making MRD a primary endpoint in itself.

So, we're not even going to get studies in the future that look at PFS for newly diagnosed myeloma, let alone overall survival. So, like, if we wait for PFS too, or if you wait for OS, we're gonna be waiting a really, really, really long time to get our answers on whether four drugs is better than three drugs.

Prasad: Well, if we wait for a trial that tests the right strategy of giving all the drugs upfront versus optimal sequence of drugs, we'll be "Waiting for Godot," we'll be waiting forever. But back to your helicopter analogy, I would say that if you didn't eat all the meals at once and you used them in a row, that helicopter can still land in the afternoon and give you a lovely dinner from UberEats.

Aaron, this is a philosophical question we're talking about. And that question is, what is the threshold to take all your drugs and use them all upfront? I mean, I concede the responses will be deeper. MRD will be deeper. PFS will be longer.

My question is always, is the global health-related quality of life for your cancer journey, is that better or is your survival better? And I think I agree with Manni, that we're not going to see those trials in our lifetime, because it has been hijacked, I think, by the industry and by KOLs and that they have their own agenda. They're in love with MRD. So, I guess I think it puts us in a tough space when we counsel our patients, Aaron. And I wonder what you think about this? How do you reconcile that?

Goodman: Well, I always go back to this when I explain to fellows and anyone about escalating therapy, at some point whether it's five drugs, six drugs, seven drugs, at some point that toxicity:benefit ratio is going to tip and we will start hurting survival. And without asking these good questions of who's living longer, we'll never know that. We add five, six drugs, we're going to deepen responses and have more MRD negativity. But at some point the scales are going to tip in favor of it not helping patients.

And the other thing that I look into, what are we adding? So, we're adding a monoclonal. I haven't given isatuximab-RVd, I have given daratumumab [Darzalex]-RVd. It's not a huge amount of additional toxicity. So that's another thing when we're adding more, I take into account, what are we adding? You know, it's not like we're adding selinexor [Xpovio] to this regimen. It's something that we can, and we're comfortable with monoclonals. But it's tough, and those are things that I think about.

Prasad: Yeah. Well, one last thing about . I do think we have evidence that CD38 antibody inhibition is not going to be like trastuzumab in breast cancer, giving it always and forever. It may not be the right strategy. There might be an optimal saturation point to CD38 inhibition. Manni, closing thoughts. Are you sold that we're going to be [giving] CD38 antibody from induction until final courses of treatment? Or do you want to see more data?

Mohyuddin: Yeah, so we are hopefully going to see more data, at least on the duration of CD38 therapy, but based on CASSIOPEIA, if I use quad induction after transplant, I do not use anti-CD38 maintenance. So, I would go straight to Revlimid maintenance. And I will use CASSIOPEIA, which is the closest analogy that we have, to guide my answers.

At least with that argument, you're not giving month after month, year after year, of an expensive treatment that predisposes people to infections. And you can argue that at least if, when they progress, they probably would still be sensitive to CD38 therapy. Because you didn't give it continuously month after month, year after year. But, yeah, it does make me sad on the state of affairs, as far as endpoints are concerned, and as far as the design of our trials are concerned.

Prasad: I was so sad I wrote a book about it. . So, thank you both for this discussion.

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

Watch episode 2: Any Role for Maintenance Ixazomib in Multiple Myeloma?

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

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