Case 2: Overcoming High Risk in Myeloma

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Ola Landgren, MD, PhD:A thought I also have is, can prognosis be determined at baseline, or do you need to give a few cycles of therapy and see what happens? MRD [minimal residual disease] has been found to be a very strong prognostic marker. Of course, there are outliers. You can reach MRD, and you can bounce back again. But if you reach MRD, that tells you that the disease is also responding to treatment. What do you think about that?

Ajai Chari, MD:This is another very important point. There are 2 topics I’d like to mention. One is that it’s not just the depth of response. It’s durability. High-risk patients can get deep responses. It’s the sustaining and the durability that’s important. And I think 1 of the challenges of MRD testing is that in clinical trials it’s been very reproducible and helpful, but in the real world, when is the last time you had a community physician who did a serum immunofixation test? If you don’t do that and it’s positive, this patient, whatever the marrow shows, is not in a stringent complete remission, MRD negative, right? So I think there are some caveats that we should put on that. High-risk patients maintain MRD negativity, but if they don’t sustain it, that’s the problem.

I think the other challenge to talk about with risk, and this isn’t true of myeloma alone, is we have to distinguish between therapies that are improving high risk and those that are overcoming high risk. I think a lot of agents…we’ve had so many drug approvals in the last decade in myeloma. Every drug has improved high risk, but none of them has overcome high risk. And so I think that’s the real challenge—for both physicians in the community as well as patients, to talk about what to expect for high-risk patients with these endpoints.

Nina Shah, MD:Actually, that’s a really important point you make. Just in our previous discussion about if we were going to use quads or add daratumumab…and I think the 1 place where I’m not seeing daratumumab really push the envelope is high risk. I know that all these have been subgroup analyses. Maybe in the ALCYONE trial there was a better subgroup outcome for high-risk patients? But in MAIA, there wasn’t. In some of the earlier data that are coming out of these quad trials, we don’t know that high risk is being overcome. And so that might be a situation where if you were really thinking about it, if you had KRd [carfilzomib, lenalidomide, dexamethasone] versus daratumumab—VTd [bortezomib, thalidomide, dexamethasone], something like that, you might choose KRd over that. That’s completely hand-waving and not evidence based.

Ajai Chari, MD:I’m going to challenge that, because if you look at every study in phase III, first of all, people want to talk about risk and drugs in phase II studies, which is not appropriate. You need all 4 groups represented. You need standard risk and high risk with both novel and conventional therapy. You need all 4 of those Kaplan-Meier curves in the same graph to determine what’s going on. And the problem with carfilzomib in the ENDEAVOR study is that it did not do any better. Those high-risk patients still did worse.

One of the challenges with daratumumab is that we look at these forest plots that may look like high risk but don’t do as well. That’s different from the Kaplan-Meier curves. These patients with high-risk disease are still doing better with the addition of daratumumab. They may not be doing as well as standard-risk patients, which is definitely true. But I think that’s a misinterpretation of the data. No one is being harmed with daratumumab. They’re just not being overcome.

Nina Shah, MD:No, I don’t think they are being harmed. Should you choose something else? Is there another study where…

Ajai Chari, MD:Well, CAR T [chimeric antigen receptor T-cell therapy]. That would be a great. But with our current arsenal, no drug has overcome high risk.

Nina Shah, MD:No, I don’t think there’s any drug. Maybe a combination if you believe this University of Chicago data of getting equal outcomes for high-risk patients. But it’s smaller numbers. I don’t know.

Ola Landgren, MD, PhD:I agree with you, Ajai, that in the true high-risk case, none of the drugs has been able to overcome that. But I think there is some evidence of improvement. If you look at the number of patients who fare poorly clinically, we all agree that these markers are not optimal. If I think about my clinic, say 10 years ago, and how many patients had a poor outcome, I would think it’s maybe 30%, 40% of patients. But today, with the newer combinations, including the quads, or if you use KRd [carfilzomib, lenalidomide, dexamethasone] or KRd [carfilzomib, lenalidomide, dexamethasone]—daratumumab on trials, I think you might see a group of patients who have a poor outcome as a shrinking species. So I think there is some improvement that we are overcoming. I’m not really sure where to put the finger, but something is happening in the right direction.

Ajai Chari, MD:Well, we’re improving, not overcoming. Those patients are still doing worse than standard-risk patients.

Ola Landgren, MD, PhD:But the ones who still fare poorly on the best drugs we have today compared with the best we had a few years ago, those patients really do poorly. We’re kind of starting to enrich the group of patients who have a very aggressive biology.

Ajai Chari, MD:But the fact is, those patients may not even have been alive in the past, right?

Nina Shah, MD:It’s plausible.

Ajai Chari, MD:We never had flat OS [overall survival] curves.

Nina Shah, MD:No, of course not. That’s why there’s always something to be developed in myeloma.

Transcript edited for clarity.