Frontline Therapy's Impact on Later Treatment in MM

Amrita Krishnan, MD, FACP: Our treatment in myeloma has evolved, and we started out with this treatment-like, parsimonious idea of “Oh, we don’t want to use all our best drugs up front, because what will we do later for relapse?” At least my thinking, and I think many of my colleagues’ thinking, has evolved to say, “In fact, you want to use your best drugs up front, because once you get that deep response, that’s what’s going to sustain the patient.” And we’ve seen that. For example, the SWOG 777 trial that used lenalidomide/bortezomib/dexamethasone compared with lenalidomide/dexamethasone showed deep responses, and it also showed an overall survival benefit to using 3 drugs versus 2. So, if you think back, we used to be scared of using 3 drugs—“Oh, we don’t want to use lenalidomide/bortezomib/dexamethasone; let’s just do 2, and then save the other one.” So, clearly, now we know that 3 is better than 2. And ultimately, I think we’re going to see that adding an antibody on top of that—so, 4 is better than 3—is likely going to be our future paradigm.

One of the questions that people struggle with is this idea of, if you use all your good drugs up front, what happens next? And as we see the antibodies moved earlier and earlier, really—ultimately into the up-front setting—what will happen when patients relapse? Daratumumab was approved, really, in the third-line setting initially, then it moved to the first relapsed setting in combination. And now if we use it in the frontline setting, what will we give patients when they relapse? Part of that, I think, will stem from, first of all, our understanding of mechanisms of resistance to daratumumab, which will evolve.

It may be, in fact, that just because you progress on daratumumab plus one regimen, it doesn’t mean that you can’t use daratumumab in combination with a different agent—for example, still use daratumumab plus pomalidomide. Because it’s not just the daratumumab effects on the plasma cell per se but other mechanisms in the immune environment that also are beneficial to the activity of daratumumab. So, I think just because you use daratumumab up front doesn’t mean that you’re restricted from using it at time of relapse. And if you look at the Rituxan (rituximab) analogy from my lymphoma colleagues, just because you got R-CHOP up front, that doesn’t necessarily mean that you don’t give R plus something else at relapse. And their landscape changed as they got other antibodies, and that probably will happen in myeloma, too. There are other anti-CD38 antibodies that are being studied, phase II and in phase III—such as isatuximab, for example—and I think that will become a very interesting question. Can you use isatuximab after you progress on daratumumab? And, obviously, there are other bispecific antibodies, different targets, many of them focusing on BCMA and antibody-drug conjugates. So, there are options for patients after you progress on daratumumab, not the least of which is reusing daratumumab in a different fashion.