Background
Phase 3, open-label, randomized controlled trial (ASPIRE). N=792 patients with relapsed or refractory multiple myeloma after 1–3 prior lines of therapy. Randomized 1:1. Key eligibility: measurable disease, ECOG PS ≤2; prior lenalidomide allowed if responsive and discontinued ≥6 months prior.
Interventions and follow up
Arm A (KRd): Carfilzomib 20 mg/m² (day 1, cycle 1), then 27 mg/m² IV (days 1, 2, 8, 9, 15, 16 of 28-day cycles 1–12, then days 1, 2, 15, 16 thereafter) + lenalidomide 25 mg PO (days 1–21) + dexamethasone 40 mg PO/IV (days 1, 8, 15, 22), until progression.
Arm B (Rd): Lenalidomide 25 mg PO (days 1–21) + dexamethasone 40 mg PO/IV (days 1, 8, 15, 22), until progression.
Primary endpoint: Progression-free survival
Median follow-up: 32.3 months
Arm B (Rd): Lenalidomide 25 mg PO (days 1–21) + dexamethasone 40 mg PO/IV (days 1, 8, 15, 22), until progression.
Primary endpoint: Progression-free survival
Median follow-up: 32.3 months
Results
mPFS: 26.3 vs 17.6 months, HR 0.69 (95% CI 0.57–0.83), P<.001
mOS: 48.3 vs 40.4 months, HR 0.79 (95% CI 0.67–0.95), P=.0045 (updated analysis)
ORR: 87.1% vs 66.7%
≥CR rate: 31.8% vs 9.3%
mOS: 48.3 vs 40.4 months, HR 0.79 (95% CI 0.67–0.95), P=.0045 (updated analysis)
ORR: 87.1% vs 66.7%
≥CR rate: 31.8% vs 9.3%
Adverse events
Hematologic (KRd vs Rd): Grade ≥3 anemia 17.4% vs 17.8%; grade ≥3 thrombocytopenia 16.8% vs 12.7%.
Cardiovascular: Hypertension any grade 14.3% vs 6.9%; cardiac failure all grades 6.4% vs 4.3%.
Discontinuation: For toxicity 14.5% vs 15.4%.
Cardiovascular: Hypertension any grade 14.3% vs 6.9%; cardiac failure all grades 6.4% vs 4.3%.
Discontinuation: For toxicity 14.5% vs 15.4%.
Conclusions
Carfilzomib added to Rd (KRd) significantly improved PFS by 8.7 months and demonstrated OS benefit in 1–3 line RRMM, establishing KRd as an effective triplet regimen for relapsed myeloma. The OS benefit (HR 0.79) was notable at the time.
Key Limitations
Prior lenalidomide exposure was limited (must be lenalidomide-naïve or -responsive), restricting generalizability to the current era where most patients have received prior lenalidomide. The carfilzomib dose (27 mg/m²) was lower than the later-approved and commonly used 56 mg/m² dose (studied in ENDEAVOR). The cardiac toxicity signal (cardiac failure 6.4%) requires attention, particularly in older patients. OS benefit was shown in an updated analysis rather than the primary endpoint.
Clinical Context
KRd was FDA-approved in 2015 and established carfilzomib as a key agent in RRMM; ASCO and ESMO guidelines include KRd as a recommended relapse option. In the current era with widespread prior lenalidomide use, KRd is less commonly used as a planned regimen but remains relevant in lenalidomide-sensitive relapse. Higher-dose carfilzomib combinations (e.g., KPd) and anti-CD38 triplets have largely supplanted KRd in lenalidomide-refractory patients.