In an interview with <em>Targeted Oncology </em>during the 2018 ASH Annual Meeting<em>, </em>Peter Voorhees, MD, discussed the safety and efficacy findings from the safety run-in cohort and the next steps for the Griffin study.
Peter Voorhees, MD
According to updated findings from a safety run-in cohort from the randomized phase II Griffin trial, the addition of daratumumab (Darzalex) to bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (Dara-RVd) was effective and generally well-tolerated in patients with newly diagnosed multiple myeloma eligible for stem cell transplantation.
At the end of induction therapy, 94% of the 16 patients in the safety run-in cohort had responded to treatment, with 56% of the patients achieving at least a very good partial response, said Peter Voorhees, MD. While 6% of patients had achieved complete response at the end of induction, the overall response rate was 100% at the end of consolidation.
Additionally, there were no new or unexpected adverse events (AEs) observed in this safety run-in, said Voorhees.
The investigators also looked at the impact of adding daratumumab on stem cell mobilization and engraftment. Their findings demonstrated that the addition of daratumumab to frontline therapy did not have a negative impact on these areas.
In an interview withTargeted Oncologyduring the 2018 ASH Annual Meeting,Voorhees, investigator, department of hematologic oncology & blood disorders, Levine Cancer Institute/Atrium Health, discussed the safety and efficacy findings from the safety run-in and the next steps for the Griffin study.
TARGETED ONCOLOGY:Can you give some background on this study?
Voorhees:What we did is we presented an updated safety analysis and efficacy from the safety run-in cohort of the Griffin trial. This is a randomized phase II trial incorporating daratumumab into the lenalidomide/bortezomib/dexamethasone backbone for newly diagnosed myeloma patients that are eligible for stem cell transplant.
As far as background is concerned, we know that treatment outcomes have clearly improved for patients with newly diagnosed disease. We also know that the lenalidomide/bortezomib/dexamethasone induction regimen has performed very well, not only for patients with transplant eligible disease but transplant ineligible patients as well. The IFM 2009 trial as well, which looked at the RVd induction therapy followed by transplant, RVd consolidation and 1 year of lenalidomide maintenance, demonstrated a complete response (CR) rate of 60% and a median progression-free survival (PFS) of 50 months. While that is very good, we are certainly very interested in improving outcomes even further. With that in mind, we were very interested in incorporating daratumumab into that central backbone.
Daratumumab is a monoclonal antibody directed against CD38 and obviously has been shown to be quite active as a stand-alone therapy for patients with heavily pretreated relapsed/refractory multiple myeloma. It has also performed very well in combination with backbone therapies for multiple myeloma in the relapsed setting as well as newly diagnosed disease, so the addition of daratumumab typically increases the overall response rate (ORR), increases depth of response, and that typically has translated into improved PFS. Again, we were very interested in looking to see whether the addition of daratumumab into the RVd backbone would not only be safe but active.
TARGETED ONCOLOGY:How was this trial designed?
Voorhees:The first thing we did is we enrolled 16 patients into what we call a safety run-in. The goal of that was to make sure there wasn’t any severe toxicity with the first cycle of therapy. We reported some of that information at ASH last year, and we only saw 3 dose-limiting toxicities out of the 16 patients. They were grade 3 in severity and thankfully all patients were able to resume treatment and continue on the study. That allowed us to move forward with the randomized phase II portion of the trial, but the focus of the presentation this year is to give an updated assessment on the safety of the regimen, as well as efficacy data for the first time.
TARGETED ONCOLOGY: What were these findings?
Voorhees:As far as the 16 patients are concerned, we had a high representation of patients with International Staging System (ISS) stage 1 disease, three-quarters of the patients had ISS stage 1 disease, but 5 out of the 16 patients had deletion 17p so high-risk cytogenetics was well represented. The way that it worked was patients received 4 cycles of daratumumab with RVd induction. They then went on to stem cell transplantation. When they recovered, they got 2 cycles of daratumumab with RVd consolidation, and then they went on daratumumab/lenalidomide maintenance therapy for 2 years, and were allowed to continue lenalidomide until disease progression after those 2 years of a 2-drug therapy were over.
As far as side effects were concerned, they were largely what you would expect when you add daratumumab to RVd, so we did see neutropenia in 75% of the patients and we did see grade 3 neutropenia, but importantly we saw no grade 4 neutropenia. We saw thrombocytopenia in half of the patients, 25% of the patients had grade 3 or 4 thrombocytopenia, but only 2 out of the 16 patients had experienced febrile neutropenia.
As far as the non-hematologic toxicities are concerned, they were what you would expect with daratumumab, so we did see some fevers, probably related to infusion reactions, then a lot of the other side effects were what you expect with RVd. We saw gastrointestinal side effects, so constipation, diarrhea, nausea, we did see some constitutional side effects of fatigue, we saw some of the steroid-related side effects [such as] edema, insomnia, some electrolyte imbalance, but the vast majority of those non-hematologic side effects were low-grade and readily manageable.
There’s a lot of interest in infection rates when incorporating daratumumab into these kinds of regimens for a couple of reasons. We know that previous phase III studies when you add daratumumab to immunomodulatory (IMiD)-based therapies that the rates of neutropenia increase. There also appeared to be a signal of hypogammaglobulinemia for patients on CD38-directed therapy which is daratumumab, so we were clearly interested in what the infection rate was.
The follow-up for these patients was relatively long, so all of the patients at the time that we presented this are already well into maintenance therapy. With that in mind, 81% of the patients did experience infection at some point over the continuum of their therapy. Most of it was respiratory tract infections. We saw 6 patients who experienced upper respiratory tract infections. We saw 4 patients who did experience pneumonia at some point. All of it was grade 3 in severity, nothing worse than that. We did see a couple episodes of acute bronchitis as well, but again, generally speaking, [it was] reasonably well tolerated. [However] we were most excited about the efficacy data.
TARGETED ONCOLOGY:Can you discuss that data with us?
Voorhees:At the end of induction therapy, 94% of the patients had responded to treatment, and 56% of patients had at least a very good partial response. We only had 6% CRs at the end of induction, but when you go to the end of consolidation, the ORR goes up to 100%. Everybody was in a very good partial response, and 63% were in a CR or stringent CR. When we go into the maintenance portion of the trial, again everybody is in a very good partial response. Fifteen out of 16 patients had either a CR or stringent response, and 63% of those patients actually had stringent CRs. We are very excited about that.
There’s also interest in whether adding daratumumab in frontline therapy negatively impacts the stem cell mobilization and engraftment at the time of transplant. We did look at this. The median number of cells collected was 8 x 106CD34 cells per kilogram. The median time to neutrophil engraftment was 13 days, and the median time until platelet engraftment was 13.5 days, so it did not appear that adding daratumumab into the frontline therapy had any kind of negative impact on stem cell mobilization, or time to neutrophil or platelet engraftment.
I think what this tells us is that this is a very potentially promising regimen. I do want to emphasize the fact that this is only 16 patients, and again three-quarters of these patients had stage I disease. We also have to be a bit cautious about the infection signal. I would certainly encourage people not to use this as their standard of care at this point, but what I will tell you and what we are excited about, is that the randomized phase II portion of the trial actually finished enrollment earlier this year. We are hopeful that we will be able to provide data from that study in 2019.
TARGETED ONCOLOGY:What is the main takeaway from this?