Impact of MRD Assessment on Myeloma Treatment



A. Keith Stewart, MB, ChB: Are you using MRD in your practice, Christina?

Cristina Gasparetto, MD: Well, yes and no. Yes, after transplant in some patients, particularly the younger patients; all the data are pointing to an improvement of at least progression-free survival if you reach the MRD. So, it becomes an anxiety for a lot of patients and for us to achieve that goal. If I have a young patient with high-risk disease, I do transplant and can use a more cumbersome maintenance with elotuzumab/lenalidomide or a proteasome inhibitor to get there and faster. So, I use it as a guide.

A. Keith Stewart, MB, ChB: Bob, are you using MRD in your clinical practice?

Robert Orlowski, MD, PhD: I am. We mentioned earlier about the notion of early transplant versus delayed transplant. There are also studies being designed looking at, for example, in the maintenance setting, if you achieve MRD negativity, can you maybe either reduce the intensity or even stop maintenance altogether versus continuing maintenance? So, those would be interesting.

A. Keith Stewart, MB, ChB: And so, would you stop it? I’m going to come back to that because that’s…

Robert Orlowski, MD, PhD: I don’t think we know yet, but one of the interesting abstracts here at ASH was an update from the IFM, the Dana-Farber study, where they looked at MRD and outcomes. And because the MRD data track so well with PFS and OS, their, actually, conclusion was that you should use MRD negativity as an endpoint for drug registration. I don’t think the FDA is quite there yet, but those discussions are ongoing.

A. Keith Stewart, MB, ChB: This is a very important point because we have to wait so long now for the outcomes of clinical trials. If we can use a surrogate marker, that would be a big advance in myeloma, but our first point about how the technology hasn’t been standardized yet is probably what’s limiting that. Hari, you very cleverly talked about something called post-MRD positivity stress disorder, which is what do you do when your patient is MRD-positive after transplant. Do you chase it? Do you keep treating and try and get it negative? Do you just live with it like Noopur seems to be doing? What’s your take on that?

Parameswaran Hari, MD, MRCP, MS: It’s a source of anxiety for the treating physician and, of course, for the patient and their family, if they really understand MRD. And that’s the black box of MRD, and that’s where I don’t think anybody can come up with an answer. So, these are patients who are either on a clinical trial or have read about MRD or heard about experts speaking about MRD and they want to get to that MRD 0 level. And if they are even minimally positive after intense treatment, including double transplants, further consolidation, and a year of maintenance, some people just cannot achieve that goal. And the question becomes, is it biology of disease that some people cannot get to MRD negativity and they are going to be OK or that everyone has to get to MRD negativity?

Noopur Suresh Raje, MD: I think I just want to push back. I don’t like to live with MRD positivity. But the issue is people can become MRD-negative over time. All of us are doing continuous therapy. In the high-risk patient population, we are already doing a doublet for maintenance, and you can achieve MRD negativity even way down, 18 months into your treatment, and that’s something people need to appreciate.

Parameswaran Hari, MD, MRCP, MS: But there are 2 strategies. You can actually pile on more treatment and try to get to MRD negativity, but then what do you do if you still don’t get there? You’ve actually exposed the patient now to 5 different drugs.

A. Keith Stewart, MB, ChB: This is where I find like you’re chasing it and you keep adding. Are you switching to daratumumab and it’s still coming back positive? And at a certain point, you say enough is enough. My understanding from the literature, and I may be off with the numbers, but even with something like VRd and transplant, maybe only one-third to half of the patients we treat get into MRD-negative states. That seems to me like we’re going to cause a lot of anxiety in the patients who don’t get there, a lot of anxiety for the treating physician that somehow they haven’t been able to get their patient to that state. Bob, how do you use it if it comes back positive? Maybe after 1 year of transplant? And you’ve had them on Revlimid (lenalidomide) and Velcade (bortezomib) maintenance, and it’s still positive? What do you do? Do you ignore it, keep going with what you’re doing, or change therapy? What’s your advice?

Robert Orlowski, MD, PhD: I think these kinds of scenarios provide a rationale for testing at multiple time points because if you just look at one number, it’s tough to know what to do. But if you’re MRD-positive at one time point but the level is lower than where you were, let’s say, 6 months or a year ago, that gives you some rationale to continue on with what you’re doing because there seems to be something working. Whereas I think we would all probably argue that if you’ve got an increasing level of MRD positivity, that’s a higher-risk patient. When we would change something, or add something, is still up for debate but probably not continuing the same thing.

A. Keith Stewart, MB, ChB: Do you need a log scale change to be positive or if it goes from 100 to 500? Do you have any sense of that?

Robert Orlowski, MD, PhD: Well, I think a log scale change, we don’t have data, but I would certainly do something with a log scale increase. A smaller increase, I think it depends. If you’re going from 5 cells to 6 cells, I wouldn’t worry about it, obviously.

A. Keith Stewart, MB, ChB: Christina, are you making decisions based on MRD? Let me ask you the other question. If it comes back negative twice after being on maintenance for a year, are you happy to stop maintenance or do you keep going?

Cristina Gasparetto, MD: Well, I think that’s something that we will need to investigate further. I think I like the idea of doing sequential, and I attempted in a few patients. And actually what I’m struggling with the most is negative, negative, and then positive. We know evidence of progression. What do I do in that situation? And I found myself recently with 2 patients in that situation. They were all very upset and clearly hyperventilating a little bit about what we do next, both in maintenance…

A. Keith Stewart, MB, ChB: We call it MRD hyperventilation syndrome.

Transcript Edited for Clarity

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