CARFILZOMIB AND DEXAMETHASONE IMPROVES PROGRESSIONFREE SURVIVAL AND RESPONSE RATES VS BORTEZOMIB AND DEXAMETHASONE IN PATIENTS (PTS) WITH RELAPSED MULTIPLE MYELOMA (RMM): THE PHASE 3 STUDY ENDEAVOR

Konference: 2015 20th Congress of the European Hematology Association - účast ČR

Kategorie: Mnohočetný myelom

Téma: Late Breaking Abstracts 2

Číslo abstraktu: LB2071

Autoři: Meletios Athanasios Dimopoulos, MD; Prof. MD Philippe Moreau; MD Antonio P. Palumbo; Douglas E. Joshua; Doc.MUDr. Luděk Pour, Ph.D.; prof. MUDr. Roman Hájek, CSc.; MD Thierry Facon; Prof. MD Heinz Ludwig; M.D. Albert Oriol; Prof. Dr. med. Hartmut Goldschmidt; MD Laura Rosiñol, PhD; MUDr. Jan Straub; M.D. Alexander Suvorov; MD Carla Araujo; Elena Rimashevskaya; MUDr. Tomáš Pika; MD Gianluca Gaidano, PhD; MD Katja C. Weisel; MD Vesselina Goranova-Marinova, PhD; prof. MUDr. Anthony Schwarer; Dr. Leonard Minuk; MD Tamas Masszi, PhD; Ievgenii Karamanesht; M.D. Massimo Offidani; Vânia Tietsche de Moraes Hungria; MD Andrew Spencer; Heidi H. Gillenwater; Nehal Mohamed; Shibao Feng; Wee Joo Chng

 Background
Bortezomib and dexamethasone (Vd) is a standard-of-care regimen for RMM. Carfilzomib (20/27 mg/m2; 2–10 min intravenous [IV] infusion) is approved in Argentina, Israel, Mexico, and the United States for relapsed and refractory multiple myeloma and significantly improved progression-free survival (PFS) when given with lenalidomide and dexamethasone for RMM in the phase 3 study ASPIRE (NCT01080391; Stewart et al, N Engl J Med, 2015). In study PX-171-007 (NCT00531284), carfilzomib (20/56 mg/m2; 30-minute infusion) and dexamethasone (Kd) had promising activity in pts with RMM (Papadopoulos et al, J Clin Oncol, 2015).

Aims
ENDEAVOR (NCT01568866) compares Kd with Vd in pts with RMM. Results from a prespecified interim analysis are presented.

Methods
Adults with RMM (1─3 prior treatments) were eligible. Pts were randomized 1:1 and stratified by prior K or V (yes vs no), prior lines of treatment (1 vs 2–3), International Staging System stage (1 vs 2–3), and intended route of V (IV vs subcutaneous [SC]). The Kd arm received K (30-min IV infusion) on days (D) 1, 2, 8, 9, 15, 16 (20 mg/m2 on D1, 2 [cycle 1]; 56 mg/m2 thereafter) and dexamethasone (20 mg) on D1, 2, 8, 9, 15, 16, 22, 23 of a 28-day cycle. The Vd arm received V (1.3 mg/m2; IV or SC) on D1, 4, 8, 11 and dexamethasone (20 mg) on D1, 2, 4, 5, 8, 9, 11, 12 of a 21-day cycle. Cycles were repeated until disease progression or unacceptable toxicity. The primary end point was PFS assessed by an independent review committee. Secondary end points include overall survival (OS), overall response rate (ORR), duration of response (DOR), rate of peripheral neuropathy (PN), and safety.

Results
In total, 929 pts (Kd: 464; Vd: 465) were randomized. In the Vd arm, 83.6% of pts received SC bortezomib. Median treatment exposure was 39.9 weeks (Kd) and 26.8 weeks (Vd). Kd led to a 47% decrease in the risk of progression or death (hazard ratio, 0.53; 95% confidence interval [CI], 0.44–0.65; P<.0001), with a median PFS of 18.7 months (95% CI, 15.6–not estimable) in the Kd arm vs 9.4 months (95% CI, 8.4–10.4) in the Vd arm. OS data were immature (deaths: Kd=75; Vd=88); pts continue to be followed. Best overall responses are presented in the table. The median DOR was 21.3 months (Kd) and 10.4 months (Vd). Treatment discontinuation due to an adverse event (AE) occurred in 14.0% (Kd) and 15.7% (Vd) of pts. An AE led to dose reductions of K or V in 22.9% and 47.8% of pts, respectively; 61.9% of dose reductions in the Vd arm were due to neuropathy-related AEs vs 6.6% in the Kd arm. Rates of grade ≥2 PN (grouped term) were 6.0% in the Kd arm vs 32.0% in the Vd arm (P<.0001). The most common hematologic AEs (preferred terms; all grades) in the Kd and Vd arms, respectively, included anemia (39.3% vs 27.0%) and thrombocytopenia (20.5% vs 17.1%); the most common nonhematologic AEs (preferred terms; all grades) included diarrhea (30.9% vs 38.4%), fatigue (29.4% vs 28.5%), and dyspnea (28.5% vs 13.2%). Grade ≥3 AEs of interest in the Kd and Vd arms, respectively, included hypertension (preferred term; 8.9% vs 2.6%), dyspnea (preferred term; 5.4% vs 2.2%), cardiac failure (grouped term; 4.8% vs 1.8%), and acute renal failure (grouped term; 4.1% vs 2.6%). A total of 3.9% of pts in the Kd arm and 3.4% of pts in the Vd arm died on study owing to AEs.

Summary
Carfilzomib and dexamethasone demonstrated statistically significant and clinically meaningful superiority over bortezomib and dexamethasone in RMM, with a 2-fold improvement in median PFS and a favorable benefit–risk profile. These data suggest that carfilzomib could be a best-in-class agent for RMM.

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Datum přednesení příspěvku: 14. 6. 2015