MRD as a Composite End Point in Myeloma

Transcript: Sagar Lonial, MD, FACP: One of the points that we need to think about with MRD [minimal residual disease] as an end point for outcomes is that it’s a composite end point. It is a combination of induction, consolidation, and maintenance. When you take it out as a composite and look at it in each individual end point that’s early in the disease course, you lose the power of its ability to predict the outcome as a whole.

Nina Shah, MD: Right now none of us should be making decisions based on MRD, right?

Paul G. Richardson, MD: I agree.

Nina Shah, MD: Look at it in a clinical trial. We have good enough drugs now where we feel safe that we’ve done at least a good job up front, and patients are willing, we’re holding hands with each other to say, “OK, we’re going to look at this, and really good monitoring, but not ready for a decision MRD based.”

Amrita Y. Krishnan, MD: I would say I have concerns. I know Ola Landgren, MD, PhD, presented a proposed trial where he’s going to use this KRd [carfilzomib, lenalidomide, dexamethasone] induction, he’s going to use an MRD-negative time point to make a decision about transplant, no transplant, and this issue of delayed transplant. I think we forget that delaying transplant is not a guarantee you’re going to get a transplant.

Nina Shah, MD: Exactly.

Amrita Y. Krishnan, MD: Even in the IFM [International Myeloma Foundation] trial, 20% of people could not get a transplant because of disease progression.

Nina Shah, MD: And not everybody can collect and hold, that’s a financial reality.

Paul G. Richardson, MD: It is a financial reality and insurance. I will stress though, Amrita, in the spirit, that I was very struck by all these data because obviously the MRD rate, recognizing we’ve got to be very careful, it was very comparable to Luciano Costa, MD, PhD’s presentation with transplant, whereas Ola’s obviously was without.

I think what’s so interesting though, and to your point, Amrita, is that we also have to bear in mind what does transplant do in terms of toxicity? What does it do in terms of quality of life? I think that while the majority of patients do really well, especially with superb care from centers such as yours and from outstanding physician care, we do know that there are long-term consequences and toxicities, which I think we’re trying to make sense of, and as patients live longer, they are real. They are not huge, we know that. Nonetheless for those patients affected, they are very real. The other thing is that, I’d love your thoughts on this Amrita, being our lead discussing this section. There are quality of life data from our French partners that were interesting. Your thoughts.

Amrita Y. Krishnan, MD: Even though you’re trying to butter me up, Paul, I’m still not going to waiver on my stance on transplant. Yes, the quality of life dipped, and I know you’re going to point out it dipped below their baseline. But it’s short and it recovered, and no one is surprised when you’re neutropenic and you’re off the high dose melphalan that your quality of life is going to go down. But I would put it to you that if you are then disease-free in remission longer, your quality of life is going to be better.

Ajai Chari, MD: I want to echo that because I think we’ve heard that the FORTE study shows that for high-risk patients, transplant still likely has a role. But let’s talk about standard risk. We shouldn’t throw the baby out with the bathwater, right? We’re curing 10% of myeloma patients, though not the high risk, and how have we cured them, how did we get to here, and how has the overall survival been improving? It’s with the role of transplant. The null hypothesis should be transplant. It is the job of MRD-negativity to show us that we can get rid of it. I feel like people are switching it and assuming that MRD-negativity is the end all and be all, when the job should be even for standard risk that transplant isn’t skippable.

Sagar Lonial, MD, FACP: I think that’s an excellent point. I will reiterate though, certainly when I sit down with my patients and we talk about the process, and having done autologous transplants for myeloma for 30 years, you know it intimately. The reality…melphalan is an extraordinarily useful drug in the past. I would argue strongly that there is a future, and that future is probably what makes me feel at least anyway that 1 size doesn’t fit all. There are some of my patients who do well without necessarily that intensification. There are others who fall apart. Until we know that better and understand who benefits from what, it’s a challenging area.

Nina Shah, MD: First of all you made a good point. We don’t know who’s going to fall apart and not. It’s really hard to predict who it’s going to be, so we haven’t done a good job of that. We haven’t done a good enough job intervening not just with Zofran [ondansetron] and all these things, but with quality of life interventions, like we’re going to do this digital life coaching thing. There are ways to get around this. For a good drug, with melphalan, a lot of people can then just take LEN [lenalidomide] maintenance for a long time, and they can do well. I think it’s a really good way to put people back to, going back to work, back to their quality of life. There are toxicities, but I feel, and now I’ve been doing it for a long time, with the transplant, that most of the people do OK.

Transcript Edited for Clarity