Importance of MRD Negativity in Changing Relapse Patterns

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C. Ola Landgren, MD, PhD: Youmention that Rafael has published on that. Rafael, I know you have used a lot of the Mayo Clinic data and you have worked with your colleagues up in Rochester, [Minnesota]. I have myself looked at how long the duration of therapy lasts, with every line showing beautifully with these retrospective databases that it gets shorter and shorter. You also have published on the importance of driving the disease down, and I know you are a strong believer in MRD [minimal residual disease] testing, and I am too. Do you think, Rafael, in the near future, maybe in 2021, that MRD negativity [testing] could be something that we see more and more in the first line? Even in the first relapse, second relapse, and that’s going to change these patterns? Or is that wrong?

Rafael Fonseca, MD: I think you’re absolutely right, Ola. I declare myself as a believer that MRD will define the 2 boundaries of therapy. One is the depth of the response; we need to go deep to make as many patients as possible become MRD negative. But I think it would also play a role in the duration of disease therapy.

That’s what I call the 2 boundaries, the depth and the duration, to be defined by MRD.As you stated, we’ve looked at the data; the reality is that most patients cannot see all the lines of therapy that we would hope we have available, not because we hope for long treatment. But the reality is right now a lot of the patients need to face a subsequent line of therapy.

We’ve looked at these data, and we’ve complemented the Mayo Clinic data with real-world analysis, and have found that if you look, for instance, just at the known transplant candidates, and this is done with databases with thousands and thousands of patients, you have an attrition rate of 50% per line of therapy.

When we start thinking about the totality of care for a person who’s diagnosed with myeloma, if you take the real-world intent-to-treat analysis, you have to account for that [attrition rate] because patients just don’t make it. Of course, we all have patients who do great, who will have 8 lines of therapy, but those are more the exception than the rule. When you see real-world data sets, the treatment will get shorter and shorter, and as Luciano was saying, with less depth in that response as well.

Now your point is a critical one. I think we’re all ready to go if we’re MRD negative up front, but for the first relapse, that’s a second chance, right? I think we shouldn’t flip our mentality immediately and think, “Boy, we should just give up.” In fact, we can see great ability to control the disease in that setting.

C. Ola Landgren, MD, PhD: Ajai, you and I, and all of us have all been in these debates back and forth [about MRD testing]. I know we have at least on stage debated, where I’ve been debating pro-MRD testing, and you have been debatingthe cons.Do you think MRD is going to change the management? Are these remissions going to be longer for patients who are MRD negative for every line? What do you think?

Ajai Chari, MD: Well, we always tell medical students, if you’re going to do a test, you should be prepared to answer the patient who asks, “How will my management change with the results of this test?” What we’re getting at with MRD is the important distinction between prognostic and predictive value. Prognostic value has been shown in study after study. The deeper the remission, the longer the remission; it’s a great surrogate. Particularly in clinical trials, there’s no question in newly diagnosed or maintenance settings where the standard end points of overall survival are impractical. PFS [progression-free survival] is even impractical, because if your PFS is now approaching 5 years, how long are you going to wait for these studies to read out? In that setting, MRD is definitely a good surrogate. But do we need MRD in heavily treated patients? I would argue no. Even in CAR T [chimeric antigen receptor T-cell therapy] studies that are showing MRD negativity, [patients] are still relapsing. When you have PFS as a reasonable surrogate, you don’t need the MRD.

But when you leave these pristine clinical trials, then you get back to that patient question. What are you going to do with the test? Unfortunately, we have a dearth of risk-adapted therapies in myeloma. This isn’t true just of MRD, but broadly speaking, everybody gets everything forever. But is that needed? Can somebody stop therapy, and perhaps low-risk patients who have 2 sustained MRD-negative time points, is that a reasonable person to stop therapy? That’s one setting outside of the clinical trial where I would say potentially somebody, especially if they’re having tolerance problems, I would feel more comfortable [stopping therapy]. Then at the other extreme it might be somebody who is very high risk and you haven’t obtained MRD negativity, again, we don’t have data, but I think many of us would feel that they’re not happy, they really want to do more for this patient.

The reality is we don’t have evidence-based data to support any of these things because you could even argue, people who do better, do better. Meaning, several studies have shown that if you are responding to therapy, discontinuing may not be valuable. I think patient experience is really ultimate in making these decisions.