Endurance Trial

Background

ENDURANCE (E1A11): phase III RCT in 1087 patients with newly diagnosed standard- or intermediate-risk multiple myeloma ineligible for or not intending immediate ASCT, comparing VRd vs KRd induction.

Interventions and follow up

Arm A: VRd Q21D x C1-12, then lenalidomide maintenance
Arm B: KRd Q28D x C1-9, then lenalidomide maintenance
Primary endpoint: PFS and OS
mFollow up: 9mo (initial PFS analysis)

Results

mPFS: 34.6mo (VRd) vs 34.4mo (KRd); HR 1.04, 95% CI 0.83–1.31, P=.74
3yr OS: 84% (VRd) vs 86% (KRd); HR 0.98, 95% CI 0.71–1.36, P=.92

Adverse events

Grade ≥3 serious AE (VRd vs KRd): 22% vs 44%; composite cardiac/pulmonary/renal toxicity 5% vs 16% (mainly dyspnea, heart failure)
Other grade ≥3 (VRd vs KRd): peripheral neuropathy 8% vs <1%; dyspnea 2% vs 7%; thromboembolic events 2% vs 5%; diarrhea 5% vs 3%; fatigue 6% vs 6%; hyperglycemia 4% vs 6%

Conclusions

KRd did not improve PFS vs VRd in newly diagnosed MM without high-risk features and carried a distinct toxicity profile (less neuropathy but more cardiac/pulmonary/renal events), supporting continued use of VRd as a standard induction regimen.

Key Limitations

Excluded high-risk cytogenetics (t(14;16), t(14;20), del17p) and transplant-intended patients, limiting applicability. A subsequent subgroup analysis (ASH 2021) suggested OS but not PFS benefit with KRd in patients with 1q gain. Predates daratumumab quadruplets.

Clinical Context

Supports VRd over KRd as standard frontline induction for standard/intermediate-risk NDMM not proceeding to immediate transplant; endorsed by ESMO and ASCO. KRd may retain a role in select high-risk patients (1q gain subgroup, ASH 2021). (VRd: bortezomib 1.3 mg/m2 D1,4,8,11 q21d; KRd: carfilzomib 36 mg/m2 D1,2,8,9,15,16 q28d.)

References