Integrating MRD in Myeloma: Guidance for Therapy Escalation and De-escalation

At the American Society of Hematology annual meeting, a roundtable discussion highlighted the evolving role of minimal residual disease (MRD) as a treatment endpoint in multiple myeloma, exploring its implications for therapy escalation, de-escalation, and discontinuation.

MedPage Today 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. This final episode focuses on the potential of MRD to guide personalized treatment strategies in multiple myeloma.

Watch other videos from this roundtable series here.

Following is a transcript of their remarks:

Mikhael: So let’s chat about our final topic, which is that you can’t go to any myeloma talk about anywhere on the planet and not hear the three letters MRD, right? Minimal residual disease. It is hard to put our arms entirely around it, but we’re seeing MRD now, especially since the ODAC [Oncologic Drugs Advisory Committee meeting]. It’s being placed in design for the primary endpoint of clinical trials. We’re seeing it evaluated, in just about every trial people are reporting it.

But maybe the one angle I thought would be interesting to talk about, Tulio, is MRD guidance of therapy, which could be to deescalate, if not even stop therapy, or possibly to escalate therapy when someone is MRD positive. And I know we want to be careful not to land in an overly simplistic response of saying, “Oh yeah, as soon as my patient’s MRD negative, I stop all treatment.” I think we saw some good data that that’s not the case, but we also saw some studies looking at it being at least part of the decision tool to potentially stop therapy. So what do you think about all this, and how are you using MRD?

Rodriguez: I think that the data is really strong now, and initially we all saw MRD as a deeper response. And with caution, because in relapse refractory myeloma, sometimes response is not necessarily translating to progression-free survival, prolonged prevention-free survival, now we’re seeing our MRD actually translate into a prolonged disease-free survival.

That being said, there were data out there that support the fact of continuing therapy because it depends also on the therapy that we have available. And right now, I think that will be too premature to stop therapy because your MRD became negative. There’s some studies where even on patient with MRD negativity, you see an improvement in long-term outcomes when you maintain the treatment.

So at this point, I think that we go slowly, cautiously. I know that MRD is a good endpoint now for our patients, and I feel more comfortable pursuing MRD than interrupting therapy because I achieve that MRD.

Krishnan: Oh, you’re preaching to the choir here, Tulio, because a couple things. Number one, I am the chair for the DRAMMATIC study, the SWOG S1803 trial, which is an over 1,400 patient trial, which we’re almost towards the end of accrual. And the fact that we accrued so robustly speaks to the question [that] needs to be answered. And then in that trial, patients are randomized to stopping or continuing maintenance if they are MRD negative. So to get it done in a phase III fashion, I think is very important.

We have AURIGA, certainly in terms of deescalating therapy as sort of our first signal. The data the Greeks presented today, albeit was a small study, was very intriguing and I think reflects what some of us are doing in clinical practice, i.e., sustained MRD. In that trial, it was obviously sustained MRD at three time points and negative imaging. So it was quite a stringent criteria, but I was struck by that the level in terms of the majority of patients stayed in remission stopping that.

Mikhael: Absolutely. Boy, you captured that so nicely. I completely agree. I mean, I think you have to respect the biology of myeloma. And I think of MRD as being one feature to the disease. And in the majority of patients, it will ultimately likely lead to our ability to deescalate therapy. But we’ve seen some very high risk patients that even achieving MRD negativity isn’t sufficient. So adding risk status, adding someone’s inherent immune status and, as you’ve said, the treatment they’re on, those are three other variables that we sort of work on with MRD. And now we’re doing the prospective studies, and that’s I think what we need to wait for.

We’re seeing, and some of them are presented here, where they’re building MRD status into the design of the study, meaning once someone achieves MRD negativity, then they’re randomized to a second therapy or to whatever was designed within the study. And I think that will be helpful to us. Because as a clinician today, I wouldn’t want people to say, “Oh, my patient’s MRD negative, I stop. My patient’s MRD positive, I have to quickly change therapy.” Because paradoxically, there’s some people who are MRD positive who are actually going to do very well in the long run.

Rodriguez: Right. And yes, at this point, MRD as I said, is a good endpoint, but we need to be careful because the technology that we have available today is still getting improved. And we are seeing even deeper response as you go from -5 to -6, and you still see that you are capable of detecting even deeper responses with the MRD technology that we have today.

Mikhael: Absolutely. Yeah. The technology is not done, that’s for sure.

Rodriguez: It’s not done yet. So I’ll be really concerned of just relying on what we have right now. We do know, as I said, that our patient(s) are going to do better if we achieve an MRD. We don’t know what’s going to happen if we discontinued therapy because of that marker.

Mikhael: Absolutely. Thank you so much for joining me today. Thank you everyone for being a part of this program, and we’re just delighted that you were able to join us for this MedPage Today roundtable on multiple myeloma at the American Society of Hematology annual meeting 2024.

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