Background
Phase 3, open-label, randomized controlled trial (ENDEAVOR). N=929 patients with relapsed or refractory multiple myeloma after 1–3 prior lines of therapy. Randomized 1:1. Key eligibility: prior bortezomib exposure allowed (but not refractory); ECOG PS ≤2; adequate organ function. A head-to-head comparison of two proteasome inhibitor-based doublets.
Interventions and follow up
Arm A (Kd56): Carfilzomib 20 mg/m² (cycle 1 days 1, 2) then 56 mg/m² IV (days 1, 2, 8, 9, 15, 16 of 28-day cycles) + dexamethasone 20 mg PO/IV (days 1, 2, 8, 9, 15, 16, 22, 23), until progression.
Arm B (Vd): Bortezomib 1.3 mg/m² IV/SC (days 1, 4, 8, 11 of 21-day cycles) + dexamethasone 20 mg PO/IV (days 1, 2, 4, 5, 8, 9, 11, 12), up to 8 cycles.
Primary endpoint: Progression-free survival
Median follow-up: 15.6 months
Arm B (Vd): Bortezomib 1.3 mg/m² IV/SC (days 1, 4, 8, 11 of 21-day cycles) + dexamethasone 20 mg PO/IV (days 1, 2, 4, 5, 8, 9, 11, 12), up to 8 cycles.
Primary endpoint: Progression-free survival
Median follow-up: 15.6 months
Results
mPFS: 18.7 vs 9.4 months, HR 0.53 (95% CI 0.44–0.65), P<.0001
mOS (updated): 47.6 vs 40.0 months, HR 0.79 (95% CI 0.65–0.96)
ORR: 77% vs 63%
≥VGPR rate: 54% vs 29%
mOS (updated): 47.6 vs 40.0 months, HR 0.79 (95% CI 0.65–0.96)
ORR: 77% vs 63%
≥VGPR rate: 54% vs 29%
Adverse events
Hematologic (Kd56 vs Vd): Grade ≥3 anemia 16% vs 10%.
Cardiovascular / pulmonary: Grade ≥3 hypertension 9% vs 3%; cardiac failure all grades 8% vs 3%; dyspnea 5% vs 2%.
Neurologic / discontinuation: Peripheral neuropathy any grade 17% vs 42% (significantly less with carfilzomib); discontinuation for AEs 17% vs 15%.
Cardiovascular / pulmonary: Grade ≥3 hypertension 9% vs 3%; cardiac failure all grades 8% vs 3%; dyspnea 5% vs 2%.
Neurologic / discontinuation: Peripheral neuropathy any grade 17% vs 42% (significantly less with carfilzomib); discontinuation for AEs 17% vs 15%.
Conclusions
Carfilzomib 56 mg/m² + dexamethasone (Kd56) significantly improved PFS compared with bortezomib + dexamethasone (Vd) in 1–3 line RRMM, doubling median PFS from 9.4 to 18.7 months, with substantially less peripheral neuropathy.
Key Limitations
The comparator was bortezomib + dexamethasone (doublet), not a contemporary triplet, limiting the ability to contextualize Kd vs modern triplet standards. Carfilzomib's cardiovascular toxicity profile (hypertension, cardiac failure) requires careful monitoring, particularly in older or comorbid patients. OS benefit was modest (HR 0.79) and shown only in updated analysis, not the primary endpoint. Vd was capped at 8 cycles while Kd was continued until progression, introducing duration asymmetry.
Clinical Context
ENDEAVOR led to FDA approval of carfilzomib + dexamethasone (Kd) in 2016, and Kd is endorsed in ASCO and ESMO relapse guidelines. Higher-dose carfilzomib (56 mg/m²) became the approved dose and is now preferred over 27 mg/m² for doublet use. Kd is commonly used in 1–3 prior line RRMM, particularly in daratumumab-naïve patients or as a backbone for triplet therapy (e.g., Kd + daratumumab per CANDOR). The reduced neuropathy profile vs bortezomib is a significant clinical advantage.