Shaji Kumar, MD, Mayo Clinic, Rochester, Minnesota, discusses results from the phase 3 ENDURANCE trial, comparing carfilzomib, lenalidomide, and dexamethasone (KRd) with bortezomib, lenalidomide, and dexamethasone (VRd) in patients with newly diagnosed multiple myeloma (MM). The results of this trial were presented at the 2020 Virtual ASCO Annual Meeting.
Transcript
Hi. I am Shaji Kumar, I'm a Professor of Medicine at Mayo Clinic in Rochester, Minnesota.
We presented the results of the E1A11 ENDURANCE trial, which is a phase 3 randomized trial that compared two triplet regimens for the treatment of newly diagnosed multiple myeloma.
The combination of bortezomib, lenalidomide, and dexamethasone has been the standard initial treatment for patients with newly diagnosed myeloma, often irrespective of whether they are going to a stem cell transplant or not.
This is based on the SWOG S0777 trial that showed that VRd improved not only the progression-free survival, but also overall survival compared to lenalidomide and dexamethasone.
In phase 2 trials, the combination of carfilzomib, lenalidomide, and dexamethasone has been shown to be quite effective with high rates of deep responses, like very good partial response as well as higher rates of minimal residual disease negativity. In the relapse setting, carfilzomib has been studied compared to bortezomib, and has been shown to be more effective in the end of the trial.
Given this data, we designed this phase III trial to ask whether KRd would be a better triplet regimen compared to VRd for the initial treatment of newly diagnosed multiple myeloma.
We also wanted to ask a second question in this clinical trial, which is the ideal duration of therapy for a patient with newly diagnosed myeloma. The current standard is often to continue therapy until disease progression, and we wanted to see if that would be better compared to limiting the maintenance treatment for about 2 years.
The trial was designed to include only patients with standard-risk multiple myeloma. The reason for doing this was because there was a parallel trial called the S1211 that was focused on patients with high-risk multiple myeloma.
Essentially, we enrolled 1087 patients with newly diagnosed myeloma, who either were transplant-ineligible or were planning on deferring the stem cell transplant until disease progression, who did not have any high-risk features like translocation (14;16), (14;20) deletion 17p, high LDH, or plasma cell leukemia.
We did allow patients with translocation (4;14) into the study as that was considered to be an intermediate risk finding.
The trial assign patients to initial therapy with either bortezomib, lenalidomide, and dexamethasone giving us 3-week cycles for a total of 12 cycles or carfilzomib, lenalidomide, and dexamethasone as 4-week cycles given for a total of 9 cycles.
Patients who completed the induction therapy were then randomized a second time to receive lenalidomide maintenance either for 2 years or indefinitely till disease progression.
What we found in the clinical trial was that the progression-free survival from the time of the first randomization, which was the primary end point, was identical for both bortezomib, lenalidomide, dexamethasone, and carfilzomib, lenalidomide, dexamethasone.
We also looked at the background progression-free survival in a variety of different subgroups including the older patients as well as patients with ISS stage III versus remaining, and so forth. We really did not find a significant difference in PFS between the 2 arms in any of the subgroups that we studied.
Even though there was a trend towards better PFS with carfilzomib, lenalidomide, dexamethasone in patients with abnormal metaphase cytogenetics which constituted about 30% of the patients. There was also a trend towards better PFS with the bortezomib combination in patients who were older than 70.
We also looked at the responses. The overall response rates were comparable between the 2 arms. However, the proportion of patients with a VGPR or better was higher in the carfilzomib arm.
The overall survival at the time of the current follow-up appeared to be fairly similar. The 3-year survival was approximately 85% in both arms.
We also looked at the side effect profile. The peripheral neuropathy was significantly higher in the bortezomib, lenalidomide, dexamethasone arm with about 8% having grade three or higher peripheral neuropathy.
The carfilzomib arm had higher proportion of patients with cardiac, renal, or pulmonary toxicity, and also a higher proportion of patients with serious adverse events. We believe that the toxicity probably offset the advantages associated with the deep responses that we saw with the carfilzomib, lenalidomide, and dexamethasone.
We also examined the quality of life metrics in these patients, and we did not see any significant difference between the 2 groups, except in the neurotoxicity-related scores which favored the carfilzomib arm, as expected, given the neuropathy associated with bortezomib.
Overall, the results of our clinical trial demonstrates that the combination carfilzomib, lenalidomide, dexamethasone does not provide any advantage over the current standard of bortezomib, lenalidomide, and dexamethasone.
In patients with newly diagnosed myeloma who do not have high-risk FISH features of other high-risk characteristics, and those patients who intend to go to an early autologous stem cell transplant.
We believe the combination of bortezomib, lenalidomide, dexamethasone should remain the standard PI plus IMiD combination for newly diagnosed myeloma. We also believe it forms the best backbone for combining with other new therapeutics, like monoclonal antibodies, as we pursue quadruplet combinations in this disease.
