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Using quadruplet regimens with anti-CD38 monoclonal antibodies, such as daratumumab (Darzalex) or isatuximab (Sarclisa), has significantly advanced frontline therapy for both transplant-eligible and transplant-ineligible patients with newly diagnosed multiple myeloma, according to data presented at the American Society of Hematology (ASH) annual meeting.

番茄社区app brought together three expert leaders in the field: Moderator Joseph Mikhael, MD, is joined by Amrita Krishnan, MD, and Tulio Rodriguez, MD, all of City of Hope, for a roundtable discussion. This second of four exclusive episodes focuses on frontline therapy advancements in multiple myeloma, including the evolving role of quadruplet therapies and tailored approaches for specific patient populations.

You can watch part 1 here.

Following is a transcript of their remarks:

Mikhael: So let's talk about the second major area of interest. Although there were 50 major areas of interest in myeloma, but we have to only choose a few. But let's choose frontline therapy with multiple myeloma. I mean, we've had two remarkable FDA approvals in the year of 2024 where we now could use daratumumab, bortezomib [Velcade], lenalidomide [Revlimid], and dexamethasone [dex] for patients going to transplant and isatuximab, bortezomib, lenalidomide, dexamethasone for patients not going to transplant.

And here at ASH, we saw a lot of data furthering our understanding and belief in these quadruplet therapies. And maybe one way for me to ask you the question is, do you really think it's pretty much quads for all now? Are you leaving ASH thinking that the vast majority of frontline patients should be given a quadruplet?

Rodriguez: Absolutely. And I have to admit that I was not one of the believers initially. The data that came up continues to be so strong now that it's hard to ignore. So I think that quadruple for transplant-eligible as well as for transplant-non-eligible is the way to go.

The responses that you see that translate even into MRD [minimal residual disease] negativity are really outstanding. And not only that, it was demonstrated on this ASH that the MRD translates into progression-free survival [PFS]. And that maintenance with some of these anti-C38 antibodies can take someone who is positive at the end of the induction and convert them into negative MRD as well, which in the same way, translates into a longer progression-free survival. So I think the data was fascinating.

Krishnan: For transplant eligible, I would say the data is solid and yes, I mean obviously you have to understand access issues in ex-U.S. So while it's nice to say, the practicalities of that still remain harder to implement. In regards to the transplant-ineligible population, do I think that's a little bit more of a nuanced discussion because only went up to age 80, about 25% of those patients were frail, while they still benefited quad versus non-quad -- obviously their PFS was shorter than the non-frail -- and there was a higher mortality signal in the quad versus the non-quad arm. I believe it was about 11% versus 5%.

Now, the argument was a lot of that was COVID-related, yes, and also that those patients were on therapy longer, so they had more time to also develop infections. True, but I think I personally, for a frail patient, would still not be comfortable with a quad. I don't know about you.

Mikhael: On that notion of frailty, I was also fascinated by the presented by Salomon Manier where they designed giving daratumumab, lenalidomide, and dexamethasone, the sort of historical MAIA approach, but actually only giving the dexamethasone for 2 months -- the "downwithdex" movement, as I call it. And I've written a little bit about this -- it's coming out soon, so I won't be a spoiler alert -- but what are your thoughts about not having to give everybody dexamethasone every week for the rest of their treatment?

Rodriguez: Absolutely. Very provocative data. And we have tried in the past modulating our steroid, especially for frail patients. You probably remember that in patients who are 70 years old or older, some of our trials, we decided to go for 20 mg instead of 40. And this time we're going into just the length of exposure. And I think that is absolutely a way to go and explore. And as I said, long-term follow-up will give us more information, but at this point, I certainly believe that it is data that needs to be observed because it can benefit our patients, especially the frail ones.

Mikhael: Yeah, I completely agree. I mean, I think we've just overdone dexamethasone. I mean, it has a boosting effect. It even has anti-infusional reaction, anti-nausea, anti-pain. But it has such an impact on the quality of life of patients and their sleep patterns and blood pressure and blood sugar. We really need to modulate that.

Rodriguez: And I don't know if you, I'm sure you might remember that several years ago, perhaps 14 years ago, when we compare high-dose dexamethasone with low-dose dexamethasone, and even we were very impressed by the response rate, ended being a problem with survival, our survival was lower.

Mikhael: Absolutely.

Rodriguez: So I'm always concerned about, of using too much. The response data that we see with this.

Mikhael: The way I think of it is we went from high-dose dex to low-dose dex, and now we need to go to optimal-dose dex. I think we have a little ways to go.

Rodriguez: Yes.

Mikhael: And maybe just to round out the frontline therapy, I'll just comment that I was quite impressed with novel approaches in frontline. Obviously we have to wait more for the trials of bringing CAR-T in frontline, but we saw some really interesting data of incorporating bispecific antibodies like teclistamab [Tecvayli], for example, in frontline therapy.

So I think the jury's out on that. It's a little bit early, but to just tell our crowd and share with our crowd that these things are being explored. Because we know if we have great therapies that work later in the disease course, it's worth trying to bring them frontline.

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