乌鸦传媒

Discontinuing maintenance therapy in multiple myeloma based on multimodal measurable residual disease (MRD)-negativity was associated with a high rate of sustained MRD-negativity without disease progression in the prospective MRD2STOP study, data presented at the American Society of Clinical Oncology (ASCO) annual meeting showed.

乌鸦传媒 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 whether MRD status can help guide treatment deescalation in multiple myeloma.

Click here to watch more videos from this roundtable series.

Following is a transcript of their remarks:

Mikhael: Well, I wonder if we can shift our focus a little bit now as we have this discussion here at ASCO about abstracts to an area that is clearly a hot topic. I mean, if there were three letters that are included in every single myeloma meeting in the year 2024, and I'm going to suggest 2025, it's the letters MRD, right? Minimal residual disease, or some who like to have now adjusted to be measurable residual disease. So whether you're a minimal or a measurable, whatever, two parties you're part of, let's come together and have this discussion. And I say it a little bit tongue in cheek, but it really is remarkable. We've had a recent ODAC [Oncologic Drugs Advisory Committee] review of whether or not MRD can be used as a clinical trial endpoint that we hope will facilitate and clearly speed up drug development. And the ODAC voted 12-0 in favor of this concept.

Obviously, that's a recommendation to the FDA. The FDA is not bound by that. I don't necessarily want to focus as much about the clinical trial endpoint, but really about the value of MRD. And we have a really important abstract here at ASCO, which is building on the history of the trial. The MASTER trial was giving D-KRd [daratumumab (Darzalex), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone] to patients in an ongoing fashion, incorporating a transplant, but trying to deescalate patients based on their MRD or what they call the MRD-SURE status, that you become MRD twice, MRD negative on at least two occasions, 3 months apart. Then we can start deescalating therapy. And here we have the study, which Ben Derman also from Chicago -- got a bit of a Chicago flavor -- from the University of Chicago, has presented this great platform and opportunity. And I think it's heralding to us multiple trials that are trying to do this.

I mean, almost like we said with the #downwithdex, right? Patients would love us to deescalate therapy, and I always say my favorite drug is nada, nothing. If I can give nada, then every insurance company covers it. Every patient is 100% compliant. I mean, again, I say it a bit tongue in cheek, but it's true, right? Sometimes we say to our patients in myeloma, you're going to get treated forever. Is there a way to deescalate? So my question to both of you, based on this study and other studies that are still ongoing in myeloma, is it really all about MRD? And of course I'm leading the witness, your honor. It's not all about that. But maybe start with you Amrita. Do you think MRD testing and the presence of MRD negativity -- whether it's once or more than once, and I'd like your thought on that -- do you think that at least is going to factor into how we deescalate patients in their treatment in particular maybe after transplants or maybe after relapse when they're in a more ongoing treatment phase?

Krishnan: So I totally agree with you. I always say the biggest unmet need in myeloma is stopping therapy. Having said that, of course, the other problem with myeloma is nothing is straightforward and simple, right? So two things I mean by that. Number one is obviously MRD is a marrow-based test, so you still need to account for other sites of myeloma. So really you need to take your decisions in terms of abrogating therapy in context also of imaging.

The second part of that is the idea of when you measure MRD and how do you sort of make a decision in terms of either escalating therapy or deescalating therapy. I think we really have very little data in terms of escalating. The data in terms of deescalating, I would be interested to hear both your viewpoints. I think what we can clearly say is deescalating and stopping therapy in high-risk myeloma, even those who become MRD negative, unfortunately [is] not a sustainable path. In those patients we need to continue treatment.

So really the group of patients we're talking about is low-risk patients who achieve MRD negativity. And again, you can argue did they become MRD negative because they were low-risk or because of the intervention you did? But nonetheless, that is the group to act upon. And certainly data from , the trial looking at dara-len [daratumumab-lenalidomide] versus len suggests you can deescalate. Waiting for the , which goes even a step further, right? And patients who have MRD negative at 2 years randomized to stopping therapy or continuing therapy. So I think those will be important trials and certainly as PERSEUS reads out further. So I do agree with this concept of stopping therapy, but again, it's not a one-size-fits-all.

Mikhael: Well, beautifully said, Amrita. Of course, I agree with you. But Tulio, I'd be interested in your thoughts as well about this incorporation of MRD into our decision making.

Rodriguez: Well, very controversial concept, and the reason is because the intention is correct. The tools that we have today are not perfect. Of course, we want to offer this patient the opportunity of being without therapy, keeping in mind that multiple myeloma remains an incurable disease. And what we're talking about is a window without treatment rather than permanent discontinuation of therapy.

And then as Amrita mentioned, you have to do a bone marrow biopsy to determine the MRD. Perhaps in the future we will have circulating plasma cells that might be a better indicator of minimal residual disease because the concept is there. However, the tools that we have today might not be the best to make those determinations. I 100% agree that stopping therapy in someone with high-risk multiple myeloma might not be the most practical approach. That being said, Dr. Derman, in his study, he screened a fairly good number of patients and he found that half of them were eligible for discontinuation after following them for a certain period of time. And many of them remain MRD negative for a significant period of time as well. But I'm not so sure that that can be applied to everybody with multiple myeloma that we see in our office today.

Mikhael: And I think both of you hit the nail on the head in your sort of one-size-doesn't-fit-all. I think we just have to realize the limitations of MRD. On the other hand, we want to appreciate the value of it that there are a lot of patients whose marrow really does reflect their disease, especially those that are standard risk and maybe some who historically been thought of as at least somewhat high risk. I think that's what we learned from the MASTER study. Those patients that had one cytogenetic abnormality seem to, if you will, behave much like those with no high-risk cytogenetic abnormality.

So I think there is hope for a significant number of patients that we can, especially with prospective studies as you've mentioned, where we randomize people, not just say, OK, let's stop and see what happens. Let's actually randomize them to continuing versus discontinuing therapy that we may be able to do that.

Following your food theme today, I sometimes think of it as a really big thick Oreo cookie with the two edges on the side and a double or triple stuff in the middle. Ironically, the patients with the highest-risk myeloma and the lowest-risk myeloma are the ones where MRD testing may be less valuable because in that highest-risk myeloma, the biology of the disease is just such that they can get into that deepest response, but then immediately bounce back.

And paradoxically, we do not have an insignificant number of low, low-risk patients, as it were. They're typically hyperdiploid, maybe translocation (11;14) patients that never get that really deep response, but actually do very, very well. And so I think we have to be careful on that end that we don't look to the patient say, "You better get into MRD negativity," and we overtreat them because yes, deescalation is a goal, but also we don't want to overtreat them as well. But thankfully, there's quite a few patients in the middle who may benefit from these strategies.

And lastly, I completely agree with your point about the technology getting better. You know, antigen, this is part of the work that we're doing in Jon Keats' lab, , we're working to try and see if we can capture those circulating plasma cells down to the tiny amounts of them. Because if I say to a patient, "Look, we're going to do this protocol and we're going to be checking your MRD status every 3 months, and it requires a bone marrow each time," they're going to say, "Really, Dr. Joe, can you not put so many needles in my backside?" Whereas if we could do it blood-based, which we're exploring with the circulating plasma cells, at least for a fraction of patients, that may help reduce that because above all do no harm, right? We try to do less and less.

So I think the bottom line here is that MRD testing is a powerful tool in myeloma, but it's not the ultimate tool. And we're still learning how to use it, but I do think we'll be using it a little bit more with time.

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