Sagar Lonial, MD, FACP: I think it’s important to think about, What are you going to use for most of the patients you see in the context of fitter myeloma? And so I think VRd [bortezomib, lenalidomide, dexamethasone] has become a standard for those patients across the board based on several randomized phase 3 trials. I think that there are compelling phase 2 data on KRd [carfilzomib, lenalidomide, dexamethasone] in that same situation, but we don’t have phase 3 data supporting KRd over another regimen. That’s actually being done in the context of an ECOG [Eastern Cooperative Oncology Group] trial, and that’s a really important clinical trial for us to get results and to see enrollment from.
I think that there are also emerging data from the European colleagues looking at VTd [bortezomib, thalidomide, dexamethasone] because lenalidomide is not easily available in Europe. And then again, IRd—the use of ixazomib in combination with lenalidomide/dexamethasone—I think does have some emerging data as well.
One of the challenges that is often brought up by community physicians regarding the use of carfilzomib is some of the cardiac or pulmonary issues that are associated with its use. And I think it’s important to recognize that these are relatively rare events. Even when they occur to a point where patients have to have changes in therapy because of the acute development of heart failure, that is still a relatively uncommon event. I think that understanding a patient’s cardiac comorbidities prior to initiation of therapy is really important. Getting a baseline echocardiogram, I think, is also important. And then following their symptoms very closely through that first and second cycle is also very important to help mitigate symptoms or adverse effects. And we partner very closely with a cardio-oncologist to help us to try to maximize cardiac and pulmonary function in the context of carfilzomib-based therapy.
I think we’ve become used to using 3 drugs now pretty standardly for newly diagnosed myeloma, and with the availability of monoclonal antibodies, we’ve now pushed that to 4 drugs. And so there are a number of trials looking at daratumumab in combination with RVd, which looks very, very encouraging and promising. There’s actually a randomized phase 2 trial, RVd plus or minus daratumumab for patients with newly diagnosed myeloma, in conjunction with high-dose therapy in a transplant. Those, I think, are really exciting and compelling data. The early data look really strong, with patients’ achieving not just complete remissions but MRD [minimal residual disease]—negative remissions at 10-6, so about as sensitive as we can measure.
At the same time, we have data on KRd looking at once-a-week dosing of carfilzomib in combination with daratumumab as well. Those are data that are being presented both at ASH [the American Society of Hematology Annual Meeting] and at ASCO [the American Society of Clinical Oncology Annual Meeting] and look really, really exciting. Again, a high proportion of patients achieving CR [complete response] and a high proportion of patients achieving VGPR [very good partial response] as well. These, to me, need to be validated in phase 3 trials because we know that we can achieve deep responses with KRd and VRd. And the question is, What’s the real value added of daratumumab in that early treatment approach? And I suspect it’s going to be there, but I think we need that data to know it.
When we think specifically about frail or transplant-ineligible patients, again, I think it’s important to realize that’s not an age determination as most large clinical trials define it. It really is a performance status definition. And so for most patients, even if they’re over the age of 65, RVd would continue to be a standard for us, as defined by the SWOG 777 trial, which was a randomized phase 3 trial of RVd versus Rd [lenalidomide, dexamethasone] in patients across the board without a transplant. Some were younger, some were older, and clearly there was a benefit in PFS [progression-free survival] and OS [overall survival] favoring RVd in that situation.
There are also emerging data from the group at Massachusetts General Hospital looking at RVd-lite, which I think is a little bit easier for truly frail patients. And then again, the first trial has given us very compelling data on lenalidomide/dexamethasone in this patient population as well.