Produção Nacional
Revisado por pares
Efficacy and Safety of Daratumumab, Bortezomib, and Dexamethasone (D-Vd) Versus Bortezomib and Dexamethasone (Vd) in First Relapse Patients (pts) with Multiple Myeloma (MM): Four-Year Update of Castor
2019; Elsevier BV; Volume: 134; Issue: Supplement_1 Linguagem: Inglês
10.1182/blood-2019-123527
ISSN1528-0020
AutoresKatja Weisel, Pieter Sonneveld, María‐Victoria Mateos, Vânia Hungria, Andrew Spencer, Jane Estell, Wolney Barreto, Paolo Corradini, Chang‐Ki Min, Eva Medvedova, Maria Krevvata, Sonali Trivedi, Xiang Qin, Huiling Pei, Jon Ukropec, Rachel Kobos, Ming Qi, Ajay K. Nooka,
Tópico(s)Cancer Mechanisms and Therapy
ResumoIntroduction: Daratumumab (DARA), a human, IgGκ monoclonal antibody targeting CD38, is approved either as a single agent or in combination with anti-myeloma regimens for newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM). In phase 3 studies, DARA-based regimens reduced the disease progression or death risk by ≥44%, nearly doubled the rates of complete response (CR) or better, and tripled minimal residual disease (MRD)-negativity rates (10-5 sensitivity threshold) in NDMM or RRMM pts (Palumbo A, et al. N Engl J Med 2016. 375[8]:754-766; Dimopoulos MA, et al. N Engl J Med 2016. 375[14]:1319-1331; Mateos MV, et al. N Engl J Med 2018. 378[6]:518-528; Facon T, et al. N Engl J Med 2019. 380[22]2104-2015). In the phase 3 CASTOR study (median follow-up 40.0 mo), D-Vd reduced the risk of disease progression or death by 69% and induced higher rates of deeper responses vs Vd in RRMM pts. Pts who received 1 prior line (PL) of therapy achieved the greatest benefit with D-Vd. Here, we examine updated (47.0 mo median follow-up) efficacy and safety of D-Vd vs Vd in CASTOR, with a focus on pts with 1 PL of therapy. Methods: In CASTOR, pts were randomized to 8 cycles (21 d/cycle) of V (1.3 mg/m2, SC) on Days 1, 4, 8, and 11 and dexamethasone (20 mg, PO or IV) on Days 1, 2, 4, 5, 8, 9, 11, and 12 ± DARA (16 mg/kg, IV) given weekly for Cycles 1-3, Q3W for Cycles 4-8, and Q4W thereafter. Cytogenetic risk was evaluated by local fluorescence in situ hybridization or karyotyping; high risk was defined as the presence of t(4;14), t(14;16), or del17p abnormalities. Results: A total of 498 pts were randomized (D-Vd, n = 251; Vd, n = 247) and included in the intent-to-treat (ITT) population. A total of 235 pts had 1 PL of therapy (D-Vd, n = 122; Vd, n = 113). After a median follow-up of 47.0 mo, progression-free survival (PFS) was significantly prolonged with D-Vd vs Vd in the ITT population (median: 16.7 vs 7.1 mo; HR, 0.31; 95% CI, 0.25-0.39, P <0.0001). The PFS benefit for D-Vd vs Vd was maintained in pts with prior V (median: 12.1 vs 6.7 mo; HR, 0.34; 95% CI, 0.26-0.46, P <0.0001), with prior R (median: 9.5 vs 6.1 mo; HR, 0.40; 95% CI, 0.28-0.58, P <0.0001), and high (median: 12.6 vs 6.2 mo; HR, 0.41; 95% CI, 0.21-0.83, P = 0.0106) and standard cytogenetic risk (median: 16.6 vs 6.6 mo; HR, 0.26; 95% CI, 0.18-0.36, P <0.0001). D-Vd significantly prolonged PFS on the subsequent line of therapy (PFS2) vs Vd (median: 34.6 vs 20.7 mo; HR, 0.47, 95% CI, 0.37-0.59; P <0.0001; Figure 1A). At the time of analysis, 114 deaths with D-Vd and 132 deaths with Vd were observed with 3-yr overall survival (OS) rates of 61% vs 51%, respectively; follow-up for OS is ongoing. The overall response rate (ORR; 85% vs 63%), ≥very good partial response (VGPR) rate (63% vs 29%) and ≥CR rate (30% vs 10%) were all significantly higher (all P <0.0001) with D-Vd vs Vd. Among 1 PL pts, median PFS was 27.0 vs 7.9 mo (HR, 0.21; 95% CI, 0.15-0.31, P <0.0001) for D-Vd vs Vd. The PFS benefit for D-Vd vs Vd was maintained among 1 PL pts previously exposed to V (median: 20.4 vs 8.0 mo; HR, 0.22; 95% CI, 0.13-0.37; P <0.0001) or R (median: 21.2 vs 7.0 mo; HR, 0.30; 95% CI, 0.11-0.82; P = 0.0140). PFS2 was also significantly prolonged with D-Vd vs Vd in 1 PL pts (median: not reached vs 23.4 mo; HR, 0.34, 95% CI, 0.24-0.49; P <0.0001; Figure 1B); 42-mo PFS2 rates were 58% vs 19%, respectively. For 1 PL pts, 39 vs 56 deaths were observed with D-Vd vs Vd, with 3-yr OS rates of 76% vs 57%, respectively. ORR (92% vs 74%; P = 0.0007) and rates of ≥VGPR (77% vs 42%; P <0.0001) and ≥CR (43% vs 15%; P <0.0001) were all significantly higher with D-Vd vs Vd. Additional data including MRD analyses will be presented. The most common (≥5%) grade 3/4 treatment-emergent adverse events (TEAEs) with D-Vd vs Vd included thrombocytopenia (46% vs 33%), anemia (16% vs 16%), neutropenia (14% vs 5%), pneumonia (10% vs 10%), lymphopenia (10% vs 3%), hypertension (7% vs 1%), and peripheral sensory neuropathy (5% vs 7%). Discontinuation rates due to TEAEs were similar for D-Vd vs Vd (10% vs 9%). The rate of invasive second primary malignancy rates were 4.9% in the D-Vd group vs 1.7% in the Vd group. Conclusions : In this updated analysis of CASTOR, D-Vd maintains significant PFS and ORR benefits in RRMM, with the greatest benefit achieved by pts who received 1 PL of therapy. The safety profile of D-Vd remains consistent with longer follow-up, with no new safety concerns reported. These data continue to suggest that administration of D-Vd to RRMM pts after first relapse may provide the greatest clinical benefit. Disclosures Weisel: Juno: Consultancy; Adaptive Biotech: Consultancy, Honoraria; GSK: Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Sonneveld:SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BMS: Honoraria. Mateos:Adaptive: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees. Hungria:BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Spencer:Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Specialised Therapeutics Australia: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Estell:Janssen/ Celgene: Membership on an entity's Board of Directors or advisory committees. Barreto:Hemocentro, USP-Ribeira; Preto-SP: Employment. Corradini:Gilead: Honoraria, Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Amgen: Honoraria; Celgene: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; BMS: Other: Travel Costs; Takeda: Honoraria, Other: Travel Costs; Servier: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; KiowaKirin: Honoraria; Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria. Krevvata:Janssen: Employment. Trivedi:Janssen: Employment, Equity Ownership. Qin:Janssen: Employment, Equity Ownership. Pei:Janssen: Employment, Equity Ownership. Ukropec:Janssen: Employment, Equity Ownership. Kobos:Janssen: Employment. Qi:Janssen: Employment. Nooka:Amgen: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; Takeda: Honoraria, Other: advisory board participation; GSK: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation.
Referência(s)