ASH 2020: GRIFFIN Study Assesses Quadruplet Therapy with Daratumumab, Lenalidomide, Bortezomib, and Dexamethasone for Multiple Myeloma

Peter M. Voorhees, MD, of the Levine Cancer Institute, Atrium Health in Charlotte, NC, discusses outcomes from the phase II GRIFFIN, presented at the ASH Annual Meeting & Exposition, that assessed the combination of daratumumab plus lenalidomide, bortezomib, and dexamethasone in transplant-eligible newly diagnosed patients with multiple myeloma.

DocWire News: Can you give an overview of the study design of the phase II GRIFFIN study and highlight the updated findings?

Dr. Voorhees: GRIFFIN was a clinical trial, a phase II clinical trial where we assessed the efficacy and safety of the addition of daratumumab into the lenalidomide, bortezomib, and dexamethasone, or RVd, backbone for patients with newly diagnosed multiple myeloma who were transplant-eligible. There were two components of the study that we’ll be providing updates at the American Society of Hematology meeting. There was a 16-patient safety run-in, that we now have very long follow-up on. Then that was followed by a randomized, phase II trial. With regards to the safety run-in phase of this study, we wanted to be absolutely sure that the incorporation of daratumumab into the RVd backbone was going to be safe. In particular, we were very interested in determining whether the addition of daratumumab into the RVd backbone would have any impact on stem cell mobilization and time to engraftment.

We took 16 patients, and they were treated with four induction chemotherapy cycles consisting of daratumumab given on a weekly basis with RVd. Those patients then went on to stem cell collection utilizing granulocyte colony-stimulating factor (GCSF) with or without the addition of plerixafor for stem cell mobilization, melphalan 200 mg/m² stem cell transplant, and at the time that they recovered from transplant, they then received two cycles of consolidation therapy consisting of daratumumab and RVd followed by two years of daratumumab and lenalidomide maintenance therapy. For those patients completing a study maintenance, those patients were encouraged to remain on lenalidomide monotherapy as maintenance until disease progression or the emergence of unacceptable side effects.

I’m happy to report that the addition of daratumumab into the RVd backbone was very well tolerated in the safety run-in phase. All 16 patients completed induction therapy, stem cell mobilization, transplant consolidation, and entered maintenance therapy. There were only two out of the 16 patients who had to discontinue therapy during maintenance—one due to an adverse event and the other one due to progression of disease. The majority of the patients who were enrolled in the safety run-in had International Staging System (ISS) stage I disease (75%), but high-risk cytogenetics were well represented with 25% of the patients in the safety run-in and having a del(17p). Importantly, when we looked at stem cell yields in this particular part of the study, the median CD34-positive stem cell yield was 8.1, with a range of 3.5 to 17.6. About half of the patients, a little over half of the patients, received plerixafor in addition to the GCSF for the stem cell mobilization. No patients required chemotherapy, specifically cyclophosphamide for mobilization, and median time to neutrophil and platelet engraftment were 14 and 13.5 days, respectively.

This would indicate, at least in the early run of things, that there was not a clinically significant impact on stem cell mobilization or engraftment with the addition of daratumumab into the RVd backbone. As far as the other adverse events, I think I’ll save that for when I discuss the randomized, phase II portion of the trial.

When we look at the efficacy of this particular regimen and the safety run-in patients, by the end of induction therapy, the complete response rate was 13%—that swelled to 50% by the end of transplant. And then by the end of the two cycles of daratumumab-RVd consolidation therapy, 70% of patients were in a complete response, with 56% of patients being in stringent complete response. Overall response rate was 100%.

Interestingly, when we get into the maintenance portion of this trial, you’ll see that the depth of response continues to improve. The complete response rate actually swells to 94% after 12 months of daratumumab-lenalidomide maintenance therapy, and it remains at 94% after two years of maintenance therapy. Essentially 15 out of 16 patients achieved a stringent complete response, and we’re holding on to that after two years of maintenance therapy. When we look at minimal residual disease (MRD) negativity at 10^-5 level of sensitivity, this is using Adaptive’s next-generation sequencing platform, at the end of induction, we have a 19% MRD negativity rate that goes up to 50% by the end of post-transplant consolidation treatment. After one year of maintenance therapy, that increases further to 75%. Then by the end of two years of maintenance therapy, we’re at 81%. So 81% of the patients on the safety run-in achieved MRD negativity over the course of therapy.

Progression-free survival at the 36-month mark in the safety run-in is a respectable 78.1%, which mirrors the randomized, phase II portion of the trial quite nicely. The 36-month overall survival is 93.8%, which is really quite remarkable and also mirrors the experience from the randomized, phase II portion of the study as well.

The other thing that I’ll mention is that only three of the 16 patients that were on the safety run-in experienced dose-limiting toxicities. These dose-limiting toxicities did not prevent them from continuing on therapy, so generally speaking, based on that experience, we felt that the regimen was very safe for moving forward in a randomized trial.

Basically, in the randomized portion of the trial, the standard of care arm received four cycles of RVd induction therapy, followed by transplant, two cycles of post-transplant RVd consolidation, and then two years of lenalidomide maintenance therapy. In the experimental arm patients received four cycles of induction daratumumab-RVd therapy, followed by transplant, two cycles of post-transplant consolidation with daratumumab-RVd, and then two years’ worth of daratumumab-lenalidomide maintenance therapy. After completion of protocol maintenance, patients were encouraged to stay on lenalidomide maintenance until disease progression or the emergence of unacceptable side effects.

The primary endpoint of the study was stringent complete response rate by the end of consolidation, with important secondary endpoints including rates of MRD negativity, overall response, depth of response, progression-free and overall survival, as well as safety. With regard to the baseline characteristics of the patients on the randomized portion of the trial, they were well balanced with regard to ISS stage—the majority of patients having ISS stage I disease going into therapy; approximately 15% of patients in both arms of the trial had high-risk cytogenetics. But generally speaking, the baseline demographic and disease characteristics were well balanced between the two arms of the study.

Importantly, the depth of response improved over the course of time in both arms of the trial, but the depth of response favored the daratumumab arm at every step of the game. Just focusing on the end of consolidation, and this is data that we’ve reported previously, we met our primary endpoint of showing superiority of stringent complete response by the end of consolidation. This has been published in Blood at this point. The stringent complete response rate by the end of consolidation in the daratumumab arm was 42.4%, relative to 32% for those that were on the control arm. Importantly, this improved dramatically over the course of the first year of the maintenance therapy, which is the focus of this ASH presentation.

By the end of 12 months of maintenance therapy, the overall complete response rate in the daratumumab arm increased to 81.8%, relative to 60.8% for those in the control arm. And if you look specifically at stringent complete response at the end of one year of maintenance, 63.6% versus 47.4%—a very clear and highly statistically significant difference in overall complete response rate, as well as stringent complete response, with the addition of daratumumab into the induction, consolidation, and maintenance portions of the therapy. When we again look at MRD-negative rates at the 10^-5 level of sensitivity, if we’re looking specifically at the MRD-evaluable patient population, MRD-negative rates at the 12 months of maintenance therapy cutoff was 78.3% for those in the daratumumab arm versus 39.4% for those on the control arm—very clearly a dramatic difference in MRD negativity that increases further as you go into maintenance therapy, favoring the daratumumab arm.

We also looked at sustained MRD negativity, and we looked at both six months or longer as well as 12 months or longer. If we’re looking just at six months or longer, close to 40% of patients in the daratumumab arm have sustained MRD negativity in contrast to just 7.8% for those in the control arm. And if we’re looking at sustained MRD negativity lasting at least 12 months, about 30% in the daratumumab arm versus 3% in the control arm. Not only are we seeing an improvement in MRD negativity, but we’re seeing a very clear improvement in sustained MRD negativity, which is likely even more important. This was highly statistically significant.

As far as progression-free survival is concerned, at 24 months progression-free survival is 94.5% in the daratumumab arm versus 90.8% the control arm—a numerical difference that has not reached statistical significance at this point. The 24-month overall survival is very good in both arms at 94.7% and 93.3%. As far as side effects are concerned, we did see a higher rate of hematologic toxicity, particularly neutropenia, with the addition of daratumumab. If we’re looking at grade 3 or higher neutropenia, 43% versus 24% in the daratumumab arm. If we’re looking at thrombocytopenia grade 3 and 4, 15% in the daratumumab arm versus 9% in the control arm. If we’re looking at infections, there was a higher rate of infections overall in the daratumumab arm. But when you look at grade 3 and higher infections, there was not a significant difference between the two arms of the trial.

DocWire News: What are important take-aways from the study about the quadruplet therapy daratumumab plus lenalidomide, bortezomib, and dexamethasone?

Dr. Voorhees: I would say that the take-home points are that it’s safe—as far as side effects are concerned, a higher rate of neutropenia and thrombocytopenia, but a manageable difference. There also is an increased risk of infection. When you look at serious infections of grade 3 or higher, there’s no difference. That’s one important point. Also, with regard to safety, while there may be a slightly increased need to use plerixafor in addition to GCSF for stem cell mobilization, stem cell mobilization is not clinically impacted with the addition of daratumumab into induction therapy. Similarly, time to engraftment is not impacted by the use of daratumumab either. I think we’ve demonstrated very clearly in a randomized trial that adding daratumumab into induction, consolidation, and maintenance therapy in transplant-eligible myeloma patients clearly improves depth of response.

That signal of improved depth of response, whether you’re looking at stringent complete response or MRD negativity, continues to improve over the course of time, including one year into maintenance therapy. We’re going to need longer follow-up to determine whether that translates into a difference in progression-free or overall survival.

DocWire News: Is there any future research planned for this regimen in multiple myeloma?

Dr. Voorhees: The primary purpose of the GRIFFIN trial was to support the incorporation of daratumumab into the RVd backbone here in the United States. This study was specifically powered on stringent complete response by the end of consolidation; it was not powered to look at a difference in progression-free survival. However, after this particular trial was written and launched, very critical data from the SWOG Group, the S0777 trial, showed in a non-transplant setting that the addition of bortezomib into the lenalidomide-dexamethasone backbone in newly diagnosed myeloma patients not only improved progression-free survival but overall survival as well. That actually did lead to regulatory approvals of the use of RVd in other countries in the world.

For that reason, the phase III PERSEUS study was launched, which is very similar in design to the GRIFFIN trial but is a larger study that is powered on progression-free survival. We will see definitively with that particular trial whether this very clear improvement in depth of response with the addition of daratumumab into the RVd backbone does improve progression-free survival or not.