As reported in The Lancet Oncology by Shaji K. Kumar, MD, of the Division of Hematology, Mayo Clinic, Rochester, and colleagues,1 the phase III ENDURANCE trial has shown no improvement in progression-free survival with carfilzomib plus lenalidomide/dexamethasone (KRd) vs bortezomib plus lenalidomide/dexamethasone (VRd) in patients with newly diagnosed multiple myeloma with no planned immediate autologous stem cell transplant.

Shaji K. Kumar, MD

Study Details

In the open-label multicenter trial, 1,087 patients from U.S. sites were randomly assigned between December 2013 and February 2019 to receive KRd (n = 545) or VRd (n = 542) for a total of 36 weeks. For 12 cycles of 3 weeks, patients in the VRd group received 1.3 mg/m² of bortezomib subcutaneously or intravenously (IV) on days 1, 4, 8, and 11 of cycles 1 to 8 and days 1 and 8 of cycles 9 to 12; 25 mg of lenalidomide on days 1 to 14; and 20 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. For nine cycles of 4 weeks, patients in the KRd group received 36 mg/m² of IV carfilzomib on days 1, 2, 8, 9, 15, and 16; 25 mg of lenalidomide on days 1 to 21; and 40 mg of oral dexamethasone on days 1, 8, 15, and 22.

Patients who completed induction therapy were randomly assigned to indefinite maintenance or 2 years of maintenance with lenalidomide. The co-primary endpoints were progression-free survival in the induction phase and overall survival in the maintenance phase in the intention-to-treat population.

Efficacy Outcomes

At a second planned interim analysis, median progression-free survival was 34.6 months (95% confidence interval [CI] = 28.8–37.8 months) in the KRd group vs 34.4 months (95% CI = 30.1 months to not estimable) in the VRd group (hazard ratio [HR] = 1.04, 95% CI = 0.83–1.31; P = .74). Since the hazard ratio was over 1, the data safety and monitoring committee recommended the release of data on the basis of futility. Median time to disease progression was 44.6 months in the VRd group vs 36.3 months in the KRd group (HR = 0.97; P = .79).

For the VRd vs KRd groups, 84% vs 87% of patients achieved a partial response or better during induction therapy (P = .26), 65% vs 74% achieved a very good partial response or better (P = .0015), and 15% vs 18% achieved a complete response or better (P = .13). Undetectable minimal residual disease was observed in 7% vs 10% of patients (P = .079).

A total of 516 patients were randomly assigned in the maintenance phase to receive indefinite lenalidomide (n = 260; 110 in VRd group and 150 in KRd group) or 2 years of lenalidomide (n = 256; 108 in VRd group and 148 in KRd group). Follow-up of the maintenance phase is ongoing.

Median follow-up for overall survival was 26 months. At the time of the analysis (not prespecified), 14% of patients in each group had died. The Kaplan-Meier estimate for overall survival at 3 years was 84% in the VRd group vs 86% in the KRd group (HR = 0.98, 95% CI = 0.71–1.36; P = .92).

Adverse Events

The most common grade 3 or 4 treatment-related nonhematologic adverse events included fatigue (6% of VRd group vs 6% of KRd group), hyperglycemia (4% vs 6%), diarrhea (5% vs 3%), peripheral neuropathy (8% vs < 1%), dyspnea (2% vs 7%), and thromboembolic events (2% vs 5%). Grade ≥ 3 serious adverse events occurred in 22% of the VRd group vs 44% of the KRd group (P < .0001).

Adverse events led to treatment discontinuation in 17% of the VRd group vs 10% of the KRd group. Treatment-related deaths occurred in 2 patients (< 1%) in the VRd group (due to cardiotoxicity and secondary cancer) and in 11 patients (2%) in the KRd group (due to cardiotoxicity in 4, acute kidney failure in 2, respiratory failure in 2, liver toxicity in 1, thromboembolic event in 1, and sudden death in 1).

The investigators concluded: “The KRd regimen did not improve progression-free survival compared with the VRd regimen in patients with newly diagnosed multiple myeloma and had more toxicity. The VRd triplet regimen remains the standard of care for induction therapy for patients with standard-risk and intermediate-risk newly diagnosed multiple myeloma and is a suitable treatment backbone for the development of combinations of four drugs.” 

Disclosure: The study was funded by the National Institutes of Health, National Cancer Institute, and Amgen. For full disclosures of the study authors, visit thelancet.com.

REFERENCE

1. Kumar SK, Jacobus SJ, Cohen AD, et al: Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): A multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol 21:1317-1330, 2020.