The combination of carfilzomib with lenalidomide and dexamethasone (KRd) as induction therapy has failed to improve outcomes in newly diagnosed multiple myeloma compared with bortezomib, lenalidomide, and dexamethasone (VRd).
Data from the phase 3 ENDURANCE trial presented at the ASCO20 Virtual Scientific Program showed comparable progression-free survival (PFS) between the 2 regimens despite previous data suggesting higher efficacy with KRd.
Although KRd was associated with a higher rate of very good partial responses, reflecting a better depth of response, the carfilzomib-containing regimen also had increased cardiopulmonary and renal toxicity. Investigators found no difference in overall survival between study arms with the current follow-up.
“Based on these data, the combination of bortezomib, lenalidomide, and dexamethasone should remain the standard of care for initial therapy of newly diagnosed symptomatic multiple myeloma,” said Shaji Kumar, MD, professor of medicine at the Mayo Clinic in Minnesota. “VRd should also be considered the backbone for adding new drugs, such as monoclonal antibodies in the development of normal regimens for myeloma induction therapy.”
Initial therapy of myeloma has changed dramatically over the past decade with the introduction of several new drugs and drug combinations. Currently, the combination of the proteasome inhibitor bortezomib, the immunomodulatory drug lenalidomide, and dexamethasone is considered standard of care in the frontline setting for newly diagnosed, symptomatic disease.
Carfilzomib is a next-generation proteasome inhibitor that was shown in a phase 3 trial to be more effective than bortezomib in the relapsed setting of myeloma. Dr Kumar and colleagues designed the ENDURANCE trial to examine whether replacing bortezomib with carfilzomib in the triplet combination would improve the efficacy of initial therapy for patients with newly diagnosed disease with no intent for an immediate up-front stem cell transplant.
Comparable Survival, Increased Toxicity
As Dr Kumar reported, the median PFS was 34.4 months for VRd compared with 34.6 months for KRd. Subgroup analysis of PFS also showed comparable performance in the majority of subgroups, although there was a trend toward improved PFS for KRd in patients with abnormal cytogenetics. In patients 70 years or older, however, the median PFS was 37 months for VRd and 28 months for KRd.
“Almost 85% of patients achieved a partial response or better across the study, and the overall response rate was comparable between the VRd and the KRd groups,” said Dr Kumar. “However, when you look at the deeper responses, a significantly higher proportion of patients in the KRd arm achieved a very good partial response or better compared with patients in the VRd arm.”
At a median follow-up of 29 months, overall survival appears to be identical between VRd and KRd arms at approximately 85%. However, data also revealed differences in treatment-related adverse events. Grade 3 or higher nonhematologic toxicity was significantly higher in the KRd arm compared with the VRd arm. Specifically, dyspnea, hypertension, heart failure, and acute kidney injury were more frequent in the KRd group, whereas neurotoxicity and peripheral neuropathy were significantly higher in patients receiving VRd.
Grade 3 or higher cardiac, pulmonary, and renal toxicity was also significantly higher in the KRd arm versus VRd, Dr Kumar reported.
Discussant of the abstract, Jesus G. Berdeja, MD, director of myeloma research, Sarah Cannon Research Institute, Nashville, TN, said that based on these data, VRd and KRd appear to be equivalent options for frontline treatment of newly diagnosed multiple myeloma without high-risk features.
“Comorbidities and toxicity profiles should guide the choice between the 2 regimens in any individual patient,” said Dr Berdeja. “For example, patients with renal insufficiency should favor the bortezomib arm, while patients with baseline peripheral neuropathy should consider treatment with the carfilzomib triplet.
“It’s also worth noting that VRd is less costly than KRd, and it remains an excellent backbone for continued evaluation of additional agents,” Dr Berdeja concluded.
