The combination of carfilzomib, lenalidomide, and dexamethasone (KRd) did not show superior efficacy in patients with newly diagnosed myeloma absent a high-risk disease prognosis, compared with the standard of care: bortezomib, lenalidomide, and dexamethasone (VRd). Data from a planned interim analysis for efficacy and toxicity in the randomized phase III ENDURANCE trial were presented in the Plenary Session of the ASCO20 Virtual Scientific Program by Shaji K. Kumar, MD, and colleagues (Abstract LBA3).
The data safety monitoring committee for the trial recommended the release of the interim data based on futility.
“There was no improvement in progression-free survival by replacing bortezomib with carfilzomib in the current standard initial treatment of patients with newly diagnosed standard- or intermediate-risk myeloma, even though we observed a higher very good partial response rate with the carfilzomib combination.”— Shaji Kumar, MD
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“There was no improvement in progression-free survival by replacing bortezomib with carfilzomib in the current standard initial treatment of patients with newly diagnosed standard- or intermediate-risk myeloma, even though we observed a higher very good partial response rate with the carfilzomib combination,” said lead investigator Dr. Kumar, of the Mayo Clinic, in a statement. “We observed more severe cardiac, pulmonary, and renal toxicities with carfilzomib, while neuropathy was more common among those receiving bortezomib.”
Study Details
VRd is the current standard initial therapy in patients with newly diagnosed multiple myeloma. Carfilzomib is a next-generation proteasome inhibitor; it is used to treat patients with relapsed or refractory multiple myeloma who have received one to three previous treatments for multiple myeloma. Carfilzomib is approved by the U.S. Food and Drug Administration for use in combination with dexamethasone or with lenalidomide plus dexamethasone.
In the ENDURANCE trial, patients with newly diagnosed multiple myeloma were randomly assigned 1:1 to receive VRd or KRd for 36 weeks (induction) and stratified based on intent for transplant at disease progression. Upon completion of induction treatment, patients were randomly assigned for a second time in a 1:1 ratio to receive indefinite lenalidomide maintenance vs 2 years.
Currently, following standard treatment, patients often receive lenalidomide as maintenance therapy until disease progression. However, the ideal duration of maintenance is presently unknown and will be addressed as part of this trial.
Among the key eligibility criteria for the ENDURANCE trial was no intent for immediate autologous stem cell transplantation (ASCT) or ineligibility for ASCT. Patients with a high-risk disease prognosis as defined by genetics [t(14;16), t(14;20), or deletion 17p on FISH; high-risk GEP70 signature] or clinically (serum lactate dehydrogenase > 2× upper limit of normal; plasma cell leukemia) were not enrolled.
The ENDURANCE study enrolled 1,087 patients between December 2013 and February 2019 at 272 centers in the United States. The median patient age was 65 years.
Results
As of the planned second interim analysis (data cutoff: January 7, 2020), there were 298 progression-free survival events (75% of 399 events at full information). Median progression-free survival was 34.4 months (95% confidence interval [CI] = 30.1 to not evaluable) for those treated with VRd compared with 34.6 months (95% CI = 28.8–37.8) for KRd; the progression-free survival treatment hazard ratio (HR = KRd/VRd) in a stratified analysis was 1.04 (95% CI = 0.83–1.31, P = .742).
Grade 3 or higher treatment-related nonhematologic toxicity rates were 41% in patients treated with VRd and 48% for KRd. Very good partial response rates were higher in the KRd arm (74% vs 65%, P = .002). At 29 months of follow-up, the 3-year overall survival probability is 0.84 for patients treated with VRd and 0.86 for KRd.
“Based on this analysis, VRd should remain the standard of care for [patients with] standard- and intermediate-risk newly diagnosed multiple myeloma who are ineligible for or will defer transplant, and it should be the backbone for adding newer therapies for those patients.”— Shaji Kumar, MD
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Dr. Kumar continued, “The ENDURANCE study highlights the importance of using data from phase III trials to drive clinical practice. Although phase II trial data suggested a better outcome with KRd, compared to historical data with VRd, this has not borne out in the phase III ENDURANCE trial. It also raises concern for toxicities, which need to be carefully monitored.”
Dr. Kumar concluded, “Based on this analysis, VRd should remain the standard of care for [patients with] standard- and intermediate-risk newly diagnosed multiple myeloma who are ineligible for or will defer transplant, and it should be the backbone for adding newer therapies for those patients.”
Disclosure: The ECOG-ACRIN Cancer Research Group designed and conducted the ENDURANCE trial with funding from the National Cancer Institute, part of the National Institutes of Health. For full disclosures of the study authors, visit coi.asco.org.
