Peter Voorhees, MD, Levine Cancer Institute, Atrium Health, Charlotte, North Carolina, presents updated efficacy and safety results from the GRIFFIN study, following 12 months of maintenance therapy with lenalidomide or daratumumab plus lenalidomide, bortezomib, and dexamethasone (VRd) for patients with newly diagnosed multiple myeloma (MM).
This updated analysis was presented at the virtual 62nd Annual American Society of Hematology (ASH) Annual Meeting and Exposition.
Transcript
My name is Peter Voorhees, and I'm a myeloma specialist and clinical investigator at Levine Cancer Institute in Charlotte, North Carolina.
As we know, the CD38 antibody, daratumumab plays a very important role in the treatment of multiple myeloma. We initially established that with its single-agent activity that led to its initial regulatory approvals.
Study after randomized study, since then—both in the relapse setting as well as in the newly diagnosed space—have shown that when you add daratumumab to a standard of care backbone in multiple myeloma, you see not only an improvement in overall response rates as well as depth of response, but that typically has translated into improvement in progression-free survival and, in some instances, overall survival at this point as well.
The CASSIOPEIA Trial was a very important study adding daratumumab into the backbone of bortezomib, thalidomide, and dexamethasone for newly diagnosed, transplant-eligible multiple myeloma patients.
That study not only showed an improvement in depth of response with the additional of daratumumab into the VTd backbone, but it also showed an improvement in progression-free survival with the incorporation of daratumumab.
However, in the United States and increasingly in other countries around the world, the lenalidomide/bortezomib/dexamethasone, or RVd backbone, is being used more and more frequently over the VTd backbone for transplant-eligible, newly diagnosed myeloma patients.
We wanted to see what impact daratumumab would have on the efficacy and safety of the RVd backbone in transplant-eligible patients.
We initially had a 16-patient safety run-in. We wanted to be absolutely sure that the addition of daratumumab into a triplet combination was going to be safe.
In particular, since we already know that lenalidomide has some impact on stem cell mobilization, we wanted to be absolutely sure that the addition of daratumumab into the RVd backbone did not compromise, not only stem cell mobilization, but time to neutrophil and platelet engraftment.
We have an update on the safety run-in with very long follow-up that we're presenting in a poster presentation at ASH. We followed that up with a randomized phase 2 study looking at the addition of daratumumab into the RVd backbone for patients with newly diagnosed, transplant-eligible multiple myeloma.
That is a study that we actually presented at ASH last year, and the manuscript describing the primary findings of that study have been published in Blood earlier this year. I'm happy to report that patients on the randomized portion of the GRIFFIN trial have all completed at least 1 year of maintenance therapy at this point.
At ASH, as and oral presentation given by my colleague, Dr. Jonathan Kaufman, we update the experience with the addition of daratumumab into the RVd backbone for transplant-eligible myeloma patients.
With regards to the safety run-in, we've reported this data before, but suffice it to say, there were only three patients experiencing dose-limiting toxicities. Those dose-limiting toxicities did not preclude them from resuming therapy on protocol.
In fact, all of the patients in the safety run-in received induction therapy. They went through stem cell collection, they got transplanted, they got their post-transplant consolidation therapy, and then they went onto a maintenance therapy.
Only 2 of the 16 patients had to discontinue therapy at any point during the study treatment continuum. One came off study because of disease progression, and another one came off because of an adverse event.
When we looked at stem cell yields, the median CD34-positive stem cell yield in the safety run-in was 8.1, with a range of 3.5 to 17.6. 56% of patients did require the addition of plerixafor into the GCSF backbone for stem cell mobilization, and median time to neutrophil and platelet engraftment was 14 and 13.5 days, respectively.
I think it's safe to say, at least in the initial 16-patient safety run-in, stem cell yield and time to engraftment was not significantly impacted in a clinically meaningful way. When we look at depth of response, by the end of dara-RVd consolidation post-transplant, the complete response rate was 69%, and the stringent complete response was 56%.
This actually improved over the first year of maintenance therapy quite dramatically, and this'll be important when I discuss the follow-up data from the randomized phase 2 portion of the trial. That stringent CR rate went from 56% to 94% after 1 year of maintenance therapy.
Essentially, 15 out of 16 patients in this trial achieved stringent complete response after 1 year of maintenance therapy. Then when we look at 24 months after maintenance, that stringent CR rate is still 94%.
When we look at MRD negativity at 10-5 level of sensitivity, by the end of dara-RVd consolidation in the safety run-in, the MRD-negative rate was 50%. That increased to 75% after one year of dara-len maintenance therapy, and then further to 81% after 24 months of therapy. Depth of response continues to improve over the course of time.
Then when we look at 36-month progression-free and overall survival, that was a respectable 78.1% and 93.8% in the safety run-in. This very nicely mirrors the data that we've seen in the randomized portion of the trial.
Speaking of the randomized portion of the trial, again, this is data that we presented before and published, but we want to see what happens to depth of response as patients go into maintenance therapy.
As I mentioned earlier, the patients in the randomized phase 2 portion of the trial have all completed at least 1 year of maintenance therapy at this point. We thought that that would be a good time to take a new look at the data.
Just to outline how patients were treated in the randomized phase 2 portion of the trial, in the experimental arm, it was designed in the exact same way as the safety run-in. Patients received 4 cycles of daratumumab-RVd induction therapy.
They then went onto stem cell collection with GCSF, with or without the assistance of plerixafor. They received melphalan autologous stem cell transplant. Upon recovery, they got 2 cycles of daratumumab-RVd consolidation therapy, followed by 2 years of subsequent daratumumab-lenalidomide maintenance therapy.
The control arm was essentially the same, with one notable exception, that daratumumab was not part of the regimen. After completing 2 years of study maintenance therapy, patients were encouraged to remain on lenalidomide maintenance until disease progression or the emergence of unacceptable side effects.
The primary endpoint of the study, which we've already reported and published, was a stringent CR by the end of consolidation. We showed that there was an improvement in that benchmark in the daratumumab arm.
We also wanted to look at MRD negativity, progression-free and overall survival, as well as safety. As far as responses are concerned, as we reported before, the stringent CR rate in the daratumumab arm by the end of consolidation was 42.4%, in contrast to 32% in the control arm.
That was statistically significant, but when we look at the 12 months of maintenance cutoff, the stringent CR rate increases to 63.6% in the dara arm, in contrast to 47.4% in the control arm. That was highly statistically significant.
If we look at MRD negativity again at 10-5 level of sensitivity, in the intent to treat group, again, with longer follow-up, MRD negativity rate in the dara arm is 62.5%, in contrast to just 27.2% in the RVd arm. That was obviously highly statistically significant.
If we just look at those patients who are MRD-evaluable, specifically those with an appropriate and evaluable baseline and follow-up sample, MRD-negative rates were 78.3% in the dara arm, in contrast to 39.4% in the RVd arm.
Clearly, with longer follow-up, a very important difference in depth of response with the addition of daratumumab into the backbone of RVd. We know that MRD negativity at one snapshot in time isn't the end-all.
Sustained MRD negativity is clearly very important, so we looked at MRD negativity sustained for at least 6 months and 12 months. Again, whether you look at either metric, the addition of daratumumab improved sustained MRD negativity.
MRD negativity, for at least 6 months, was 37.5% in the dara arm versus 7.8% in the RVd arm. If we're looking at MRD negativity, sustained for at least 12 months, 28.8% versus 2.9%. This was very statistically significant.
As far as median progression-free and overall survival are concerned, we have not hit either of those benchmarks yet. Both groups of patients continue to do very well. When we look at the 24-month mark, progression-free survival in the dara arm is 94.5%, versus 90.8% in the RVd arm.
A numerical difference, but that does not reach statistical significance at this point. The 24-month overall survival in both groups is phenomenal, at 94.7% and 93.3%. As far as side effects are concerned, the addition of daratumumab does increase the rate of hematologic toxicity, particularly neutropenia.
Grade 3 or higher neutropenia occurred in 43% of patients on the dara arm, in contrast to 24% on the RVd arm. There was also a slightly higher rate of thrombocytopenia in the daratumumab arm as well.
We did also see an overall increased incidence of infection in the dara arm, relative to the RVd arm. If you look at grade three or higher infections, they were very similar in both arms of the trial. Overall, increased incidence of infection but no difference in more significant infections.
To summarize, the safety run-in cohort clearly showed that the addition of daratumumab into the RVd backbone is safe, not only from a dose-limiting toxicity perspective, but as well as stem cell mobilization and engraftment in the transplant setting as well.
The preliminary, very promising efficacy signal we saw with regards to depth of response in the safety run-in was clearly seen in the phase 2 randomized portion of the trial. I think that we've clearly demonstrated that the addition of daratumumab into the RVd backbone improves depth of response, not only measured by stringent CR but MRD negativity as well with an acceptable safety profile.
I think it's going to be important that we see how this data translates into longitudinal outcomes of progression-free and overall survival. I think do think that the daratumumab-RVd backbone should be considered an important standard of care for newly diagnosed, transplant-eligible myeloma patients.
I'll just quickly give a shout-out to the PERSEUS trial, which is a phase 3 randomized study, which is very similar in design to the GRIFFIN trial, but a larger sample size, that will be powered on progression-free survival as the primary endpoint.
I think the dara-RVd backbone is going to increasingly become an important standard of care, not just in the United States, but hopefully throughout the world. The question is how to improve upon that. I do have concerns about the addition of a fifth agent into a quadruplet regimen.
If we're going to do something like that, we would certainly want to target a patient at very high risk of adverse outcomes because of bad disease biology. For example, high-risk cytogenetics. I think what we'll see going forward is that the dara-RVd backbone is going to be used as the initial induction in a number of different new treatment strategies going forward.
As we start looking at CAR-T cell therapies earlier in the course of treatment or bispecific antibodies as consolidation therapy, I think you'll see a lot of studies using the dara-RVd backbone as the initial induction with a number of different studies looking at novel ways of consolidating that initial response.
Whether it's CAR-T cell therapy, stem cell transplant followed by a CAR-T cell therapy, bispecific antibodies to see if we can improve durability of response, particularly in the higher-risk patients. Again, I think we've clearly established and improvement in depth of response with the addition of daratumumab into the RVd backbone.
I think that there still remains some level of controversy as to whether or not MRD negativity can be used as a surrogate measure for overall survival. I think that the studies that are out there have clearly established that achievement of MRD negativity does lead to improvement in not just progression-free but overall survival.
I think that the challenge that we have is what is the best time to measure MRD negativity? I think, as the GRIFFIN data evolves, to me, it seems like one year into maintenance therapy is a very nice time point to look and see what the MRD-negative rate is.
I say that, because, while we did show an important improvement in stringent CR and MR-negative rate by the end of consolidation therapy, that difference improved dramatically over that first year of maintenance therapy, and it was highly statistically significant.
If we're going to try and improve on this backbone and use MRD negativity as a surrogate marker for longitudinal outcomes, I think looking at the 1-year mark into maintenance therapy makes a lot of sense.
