Episode 50: The MajesTEC-3 Trial in Myeloma

Dr. Vincent Rajkumar of the Mayo Clinic joins the Healthcare Unfiltered EXPRESS to highlight a major study recently published in the NEJM concerning patients with R/R multiple myeloma. This study is arguably changing the standard of care for relapsed disease. We discussed the study, its rationale, its implications, and limitations.

Here is a link to the actual publication: https://www.nejm.org/doi/full/10.1056/NEJMoa2514663

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Transcript

SPEAKER_01 0:01

Welcome to the Healthcare Unfiltered Express, where I conduct short video interviews packed with relevant and timely information that you cannot miss. So sit back and enjoy the show. Well, Healthcare Unfiltered Express. Vincent, welcome back to the show. But it's the Express version, so I won't have a lot of time with you. We're gonna focus only on the Majestic trial and real life refractory disease. How are you doing?

SPEAKER_00 0:31

I'm doing great, uh Chadie. Thanks for having me.

SPEAKER_01 0:35

So lots of buzz on the Majestic trial that was presented at Ash and then subsequently published in the New England Journey of Mass. And what was the trial and why was it uh so important?

SPEAKER_00 0:46

So it's the Majestic 3 trial. I mean, they have a whole series of trials. Uh, and this trial looked at uh patients with relapsed myeloma, one to three prior lines of therapy, uh, randomized close to about 600 patients. And the real question was in this early relapse, do patients benefit from an immunotherapy approach with a bi-specific plus an anti-CD38 antibody or a standard triplet like a DPD, DVD type of thing that we've always been using. Um, the reason the trial created so much buzz is because, number one, it had unprecedented improvement in progression-free survival. Like, you know, 83% progression-free at three years with the Tech DARA immunotherapy combination versus only like 26% with the triplet. And similarly, a huge difference in overall survival as well. And so, an 83% overall survival at three years, which for a relapse population was quite striking. Um, so it caught everyone's eye because it heralded a paradigm shift that we may want to use immunotherapy early in the treatment of uh relapse disease. And secondly, the side effects were managed quite effectively by using IVIG monthly, and that reduced the risk of side effects. There was an increase in the risk of early infections, but then after the trial, as the trial went on by year two and three and later, there there was no major difference between the two arms for infection risk. So here's a regimen that can be given safely. It combines an anti-CD-38 monoclonal antibody with a bi-specific tachlistomab and delivers very impressive results in the relapsed setting.

SPEAKER_01 2:38

Before the majestic three trial, let's take us before this was presented. What were you doing for relapse refractory disease?

SPEAKER_00 2:47

So one to three prior relapses, prior lines of therapy, the standard was a triplet. The triplet would be based on whether patients are lenolidomide, refractory, lenolidomide sensitive. So we have Dera RD, DERA POMDEX, DERA Botesimib DEX, Carfilzimib Lendex, Carfilzamib POMDEX, ELOPOMDEX, and so on. We were doing a standard triplet. This trial comes in and uh potentially changes the paradigm by introducing a bispecific plus an anti-CD38 molecule antibody, tech DARA, an immunotherapy option instead of the triplet, and shows in a head-to-head randomized trial a significant difference in overall survival and a really uh incredible difference in progression tree survival. So that's the main take-home message. Uh the other option that has been approved for first relapse immunotherapy option is silta cell, but people have, you know, as you know, CART T uptake has been low, and particularly in the first relapse. So really what we were doing was a triplet for most patients, and now potentially that might change.

SPEAKER_01 3:57

Why wouldn't it change? I mean, does this represent a new standard of care? So in relapse disease, one to three lines of therapy. And by the way, does it mine, does it matter if it's one, two, or three in your decision making whether you would use this new regimen versus the triplet?

SPEAKER_00 4:14

Why I like coming on this podcast. You know exactly the questions to ask. So yeah, it does matter because of the uh regulatory situation and things like that, so as well as what data is available. So in the first relapse, right now I would say that the three options would be uh tech dera, and hopefully that'll be approved. The techlist map plus dera to mumap, that's the majestic three. Silta cell, which is already approved for that indication, and a standard triplet. And we have to evaluate patients to choose between these three options. Okay. And uh hopefully, if techdera is approved, all three would be approved options that we choose from. Why wouldn't it become standard? Because there's always a concern whether you can actually pull off what was done in the trial in the real world. There is a high risk of infection, so you have to be willing to give IVIG monthly. You have to have the ability to give tech data safely, particularly the first stand star uh you know, startup doses, uh step-up doses. Uh, you have to make sure that patients are told about CAR T as an alternative because that's a one and done. Uh, and some patients may prefer that. And so all those discussions have to take place. And I'll I think in a year we'll get clarity on that. When you talk second and later relapse, in addition to these three options, there's also the other CAR T that's approved, IDACL, and then the antibody drug conjugate that was recently approved, Bellantomab. So in the second or later relapse, you're dealing with, you know, is it a triplet? Is it going to be the tech dero or other bi-specifics? Is it going to be uh balantomab or is it going to be uh CAR T cell therapy? The other wrinkle is by the time people get to second relapse, they're most of the time already dera-refractory. So tech dera may not be the option, but maybe tech alone or other bi-specifics. We have L-rin atomab, we have Lenboctimab, we have talketamab. So those things all come into play by second or later relapse. So that'll be the difference.

SPEAKER_01 6:20

Just a quick question. In the Majestic 3 trial, uh, they had one to three prior lines of therapy. What percent of patients have received prior CAR T, or maybe the trial was incepted before CAR T was being given? Or were there some patients in the Majestic 3 who have had actually CAR T and they still responded to the tech uh uh regimen?

SPEAKER_00 6:42

No. Uh tech Tech DERA Majestic 3 didn't have prior CAR T. And in fact, only 5% of patients had prior uh DARA. So this is a DARA-naive population. I think if somebody had a DARA as part of induction alone, I think even though that population was not represented in tech three, I think the data probably applies to them also. But I don't think the data apply to patients who are refractory to DARA.

SPEAKER_01 7:11

Yeah, that was my other question in addition to the CART, was the DARA, because you guys are using DARA as part of induction routine, at least in the US.

SPEAKER_00 7:19

Correct.

SPEAKER_01 7:20

Right? Um, so and how would you find refractory versus relapse to DARA? Like refractory would be somebody, yeah.

SPEAKER_00 7:27

Yeah, yeah. So most of the time DARA is given as part of the induction, then patients get some maintenance, and that maintenance may or may not have DARA. So there was a history of exposure to DARA years prior. Then I think the tech three data still apply, the majestic three trial data still apply. Because they're probably all data-sensitive still. On the other hand, data refractory are defined as patients who are progressing while taking Dara to moment.

SPEAKER_01 7:56

Yeah, yeah. Well, I mean, this is really an excellent paper and excellent data. And how long did it take for this to enroll? I mean, how how when did you guys start thinking with the trial and how long did it take?

SPEAKER_00 8:09

I'm not sure. I think uh the accrual overall, as in other phase three trials, most of the accrual was from overseas. I think they had more US patients on this trial than others, like 10% or 15%. But um, the trial accrued quite fast. I'm not sure how fast they accrued. Uh, well, let's see here, two years.

SPEAKER_01 8:31

That's actually pretty fast. That is very fast. Well, congratulations to the myeloma community. You guys continue just to push uh things forward.

SPEAKER_00 8:38

And uh what I think you need to congratulate these investigators, this is like uh and the and the company. Um, Dr. Mateos was the chair of the study. She had an amazing presentation at the Late Breaker at Ash. Dr. Costa, Luciana Costa. Um, a lot of top investigators were involved in the study who had um led the way in in bi-specifics. I I have to admit, I am not an investigator on the uh tech three trial. I was very uh impressed with the results, and so you're getting a very um neutral opinion on the trial.

SPEAKER_01 9:13

Yeah, and I look forward to hopefully speaking with Dr. Mateos. Um, last question, Vincent, before I let you go, is what is the current major study that is ongoing in real life refractory disease that the myeloma community is anticipating, or is there such a trial that is ongoing?

SPEAKER_00 9:30

Well, there's a trial that just released results that the Majestic 9 trial, um, that was just uh single-agent tech cluster map versus uh standard triplets, and that uh those results are expected to be presented soon. We haven't, I haven't seen the data, I've just seen the press release. Um, then there are, of course, other uh bi-specifics which are doing the same thing, trying to combine it with other anti-CD38 antibodies so that we have some choice in in what regimen we use. Uh, I think many of us are trying to still figure out when you have a relapse patient for whom you want to give immunotherapy, is it better to give CAR T first and then bi-specific or bispecific first and then CART? Those trials, I don't know when they'll read out and uh when we'll have clear data. So mostly what I'm looking for are real-world studies, uh, large-scale real-world studies that shed light on that question.

unknown 10:36

Dr.

SPEAKER_01 10:36

Vincent Rashkumar of the Mayo Clinic, thank you so much for highlighting the Majestic 3 trial in Readlands Reflectory, my mom. Thanks, Charlie. Thanks for having me. Thank you for listening to this edition of the Healthcare Unfiltered Express. Until next time, take care.