Daratumumab's Potential as Frontline Therapy for MM

Sagar Lonial, MD, FACP: We very recently saw data presented by Dr. Mateos on behalf of her investigators in a randomized phase III trial of MPV—melphalan, prednisone, and bortezomib—versus MPV plus daratumumab. And I think that that trial is called the ALCYONE trial, which was recently published in the New England Journal of Medicine and led to the FDA approval of MPV plus daratumumab for newly diagnosed myeloma in a transplant-ineligible patient population.

I think this is a hint of more to come. We’re going to see data combining lenalidomide/dexamethasone with daratumumab. We’re going to see emerging data on VRd [bortezomib, lenalidomide, dexamethasone] plus daratumumab in randomized trials as well. And I think this gives us insight into the idea that daratumumab clearly is able to add value both to bortezomib and to MPV.

I think the real question for us in the United States is that MPV is not a regimen that we routinely use. And we will even rarely use bortezomib and dexamethasone for frail patients with a new diagnosis. And so I think how you extrapolate that data to our everyday patients in the United States remains a little bit of an issue. I’m not sure that I’m incorporating daratumumab into every [patient with] newly diagnosed myeloma at this time point. But I think if you have patients who perhaps are very frail, thinking about daratumumab-based combinations might be a gentle way to try to get them a deeper response.

I think another important area to look at is the data evolving lenalidomide/dexamethasone or carfilzomib/dexamethasone as a backbone on which to add daratumumab in the context of newly diagnosed myeloma. Again, we know from the first trial that lenalidomide/dexamethasone is clearly a great and well-tolerated treatment for these patients. Can you make it even better with the addition of daratumumab given the IMiD [immunomodulatory drug] antibody interaction? The MAIA trial will give us that data—daratumumab/lenalidomide/dexamethasone versus lenalidomide/dexamethasone in a randomized phase 3 trial. I think the readout is taking a long time, which is a good sign, meaning that the PFS [progression-free survival] is quite good for the daratumumab-containing arm. I think trying to use another backbone such as carfilzomib, sort of re-creating a CASTOR-like trial with carfilzomib instead of bortezomib in a newly diagnosed myeloma setting, is also really exciting. We have to see data on some of that before we know how to use it.

One question that comes up quite frequently is, If we use an antibody as powerful and potent as daratumumab up front, what are you going to use down the road? And the way I think about that is daratumumab, as part of these induction regimens, will likely be short-duration daratumumab. And in my mind for a lot of patients, they’ll go on to transplant, and then we’ll have a discussion about whether daratumumab gets put in the maintenance setting. Those trials are being done right now looking at daratumumab in the maintenance setting.

So I think short-duration daratumumab exposure in the context of a patient with a new diagnosis doesn’t necessarily preclude the use of daratumumab at a later date. There also are emerging data from trials looking at daratumumab re-treatment, and I think having a daratumumab-free interval helps to use daratumumab again down the road, so that would be a potential option. And there are other antibodies that we can talk about using—whether they’re antibody—drug conjugates or whether it’s elotuzumab, which targets something completely different—that we could think about in the relapsed setting as well.