Depth of response to daratumumab, lenalidomide, bortezomib, and dexamethasone improves over time in transplant-eligible newly diagnosed multiple myeloma
Prof Peter Voorhees - Levine Cancer Institute, Charlotte, USA
We’re going to be presenting updated data from the GRIFFIN trial. This is a randomised phase II study looking at the incorporation of daratumumab into the lenalidomide bortezomib dexamethasone, or RVD, backbone for transplant eligible multiple myeloma patients. RVD is a very important treatment strategy for newly diagnosed patients, both transplant ineligible and eligible. It’s the most commonly used induction regimen in the United States; it’s increasingly being used in other parts of the world as well. We know that adding daratumumab, the monoclonal CD38 antibody, to standard of care regimens, both in the relapsed setting as well as newly diagnosed, consistently improves depth of response and that typically is translated into meaningful improvements in progression free survival. So it only stands to reason that daratumumab could potentially do the same thing for RVD treated patients in a transplant setting.
The way that the study was designed is patients in the standard of care arm received four three-week cycles of induction RVD therapy. They then went through stem cell transplant. Upon recovery they received two cycles of post-transplant consolidation and then went on to lenalidomide maintenance therapy. For those patients in the daratumumab arm they received the exact same therapy but daratumumab was used weekly during the induction therapy for the twelve weeks of induction, they got daratumumab on day one of each consolidation cycle and then they got it once every four weeks in maintenance out to the two year mark at which point the daratumumab was stopped but patients were encouraged to remain on their lenalidomide.
We know that the RVD induction therapy in the transplant setting is associated with very long median progression free survival so we wanted to use surrogate endpoints for longitudinal outcomes to get an earlier readout. In that regard we used stringent complete response as our primary endpoint by the end of consolidation therapy but we also wanted to look at minimal residual disease, or MRD, testing as another way, a very important way, of detecting depth of response. We looked at other efficacy parameters – progression free and overall survival and, importantly, safety as well.
When we presented this at IMW back in September what we showed is that we had met our primary outcome of stringent complete response by the end of consolidation. So in the daratumumab arm the stringent complete response rate was 42.4% and in the control arm it was 32%. At that time median follow-up was 13.5 months, we now have 22.1 months of median follow-up and the stringent complete response continues to improve. At the time of this data cut the stringent complete response in the daratumumab arm was 63% in contrast to 45% for those in the control arm. When we looked at minimal residual disease, and we defined that at the 10-5 sensitivity level using the adaptive NGS platform, the MRD negative rate in the daratumumab arm was approximately 50% in contrast to about 20% for those in the control arm.
What about the safety profile? Was that consistent with your previous findings?
There were no unexpected safety signals in our study. We anticipated that we would see more hematologic toxicity and we did. So there was an increased rate of grade 3 and 4 neutropenia compared to the control arm and there was a higher rate of grade 3/4 thrombocytopenia as well. But the rates were relatively low and did not impact outcomes. We did look at infections and there was an increased rate of all grade infections in the daratumumab arm, it was actually approximately 90%, realising we have 22.1 months of follow-up at this point. It was approximately 60% for those in the control arm but when you looked at grade 3 and higher infections it was 22% and 23% respectively so really no meaningful difference.
When it comes to the actual transplant itself, we were able to successfully collect stem cells. There were no clinically significant differences in the median number of CD34 cells per kilo that we collected. We did use more plerixafor in the daratumumab arm, approximately 70% of patients received it in contrast to 55% in the control arm. Median time to platelet and neutrophil engraftment was the same in both groups.
Finally, what’s next for the study?
For those providers in resource rich areas that have access to a combination such as this, I think we’ve provided them with good evidence that there’s a clear improvement in depth of response. But the only cautionary note that I would make for the early adopters is that it’s very important that we prove that the MRD negative rates are sustained. So when we check MRD one and two years into maintenance we want to make sure that that MRD negativity persists. So that’s going to be very important.
Then we obviously want to see what the longitudinal outcomes are for these patients as well. At ASH what we’ll show is that the 24 month progression free survival in the daratumumab arm is an astounding 96%. That said, it’s also incredibly good for the control arm as well, it’s approximately 90%. So both groups of patients are doing incredibly well which is a fantastic thing for patients but we’re going to need to see how this plays out over time and whether there are meaningful differences in progression free survival.