Medical Roundtable: New Multiple Myeloma Treatments
We now have data from the Phase III Study of Lenalidomide and Dexamethasone with or Without Elotuzumab to Treat Newly Diagnosed, Previously Untreated Multiple Myeloma (ELOQUENT–2), which looked at elotuzumab len/dex versus len/dex.2 We have data from the Panobinostat or Placebo with Bortezomib and Dexamethasone in Patients with Relapsed Multiple Myeloma (PANORAMA) trial, which looked at panobinostat in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone.3 We have two additional trials that are coming in the near future looking at triplets versus doublets. What we need is longer follow-up on those to see what the survival looks like. My sense is going to be that early relapse is going to start to look like newly diagnosed.
It's going to be the new newly diagnosed in the sense that we're going to want to treat patients aggressively in early relapse—try and put them into a major response, and then try and let that duration of remission last as long as it can. Just as we do for newly diagnosed myeloma patients as well. I don't think we have all the data to make that clear-cut recommendation right now. I think that's a direction that the field is going to be moving in, if we have the supportive data from large randomized trials.
Dr. Kalaycio: It's so difficult to find evidence of an overall survival benefit starting with three drugs versus two. It's going to be harder perhaps, in the relapse setting, to make the case from a survival standpoint because the variables are so many and these patients get treated in so many ways. Getting a randomized trial in a relapse setting for patients who have been treated so many different ways upfront makes it very difficult to—in my mind—create a trial that's clean enough to answer that question definitively. Do you think that overall survival is the marker that we should be analyzing, or should we be looking more at duration of remission, quality of life, things like that?
Dr. Lonial: Well, I think if you're trying to compare the two versus three, the addition of the new drug, I think progression-free survival (PFS) is the right end point. That's what the U.S. Food and Drug Administration (FDA) has identified as the primary endpoint for most relapsed myeloma trials. I think that the question—Is a triplet better than a doublet?—will require putting together many different phase III trials and trying to analyze that kind of a question. Just to give you a hint of an example, the ASPIRE trial, which looked at carfilzomib len/dex versus len/dex, at least at the early look, suggests there is an improvement in survival for the three drug combination. The ELOQUENT-2 trial, which looked at elotuzumab len/dex versus len/dex, also looks very early like there's a difference in overall survival. PANORAMA does not look like there's a difference in overall survival right now. There are other trials coming that, if you put them in aggregate, you may be able to see that difference you need that may be able to wash across differences in how patients were treated in their frontline approach.
Dr. Kalaycio: There's a smorgasbord of available options that makes it fascinating in trying to read these studies, and trying to make sense out of them. I feel for the clinician in the community trying to figure this out and pick what's best for their particular patient. There are lots of potential options. The most recent one approved by the FDA is the addition of panobinostat to our armamentarium.3,4 We are not clear where it fits in our treatment algorithms and I'm wondering if you've thought about that, and where you think it might fit best.
Dr. Lonial: Yes. I think you're struggling with what I think a lot of people are struggling with, which is, as the data get more mature, we're starting to identify that there are subsets of patients that really may seem to gain benefit from the use of a histone deacetylase inhibitor. There were a couple of analyses presented at the Congress of European Hematology Association (EHA) and at ASCO this year that I think are beginning to clarify some of that for us.5 If you look at the PANORAMA-1 trial (which was the randomized phase III trial of panobinostat in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone) what I think we're starting to see is that in the patients who were exposed to both lenalidomide and bortezomib, that the incremental benefit in PFS for the addition of panobinostat is actually much higher. It's close to 7.8 months now. That's because those are patients who are not gaining as much benefit from retreatment with a PI, and have already been exposed to—or maybe even resistant to—an IMiD in that situation.
