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Efficacy and Safety of Daratumumab, Bortezomib, and Dexamethasone (D-Vd) Versus Bortezomib and Dexamethasone (Vd) in First Relapse Patients: Two-Year Update of Castor

2018; Elsevier BV; Volume: 132; Issue: Supplement 1 Linguagem: Inglês

10.1182/blood-2018-99-112554

1528-0020

María‐Victoria Mateos, Pieter Sonneveld, Vânia Hungria, Ajay K. Nooka, Jane Estell, Wolney Barreto, Paolo Corradini, Chang‐Ki Min, Eva Medvedova, Katja Weisel, Christopher Chiu, Jordan M. Schecter, Himal Amin, Xiang Qin, Ming Qi, Andrew Spencer,

Multiple Myeloma Research and Treatments

Abstract Introduction : Daratumumab (DARA) is a human, CD38-targeted, IgGκ monoclonal antibody. In the CASTOR study, D-Vd reduced the risk of disease progression or death by 68% and induced higher rates of deeper responses vs Vd in relapsed/refractory (RR) MM pts (Spencer, A. ASH 2017. Abs. 3145). Overall, in phase 3 studies in RRMM and newly diagnosed MM, DARA-based regimens reduced disease progression or death risk by ≥50%, doubled complete response (CR) rates, and tripled minimal residual disease (MRD)-negative rates. While progression-free survival (PFS) benefits of D-Vd vs Vd were observed regardless of the number of prior lines (PLs) of therapy, the benefit was most pronounced in pts receiving 1 PL of therapy. Here, we examine updated (2 y after interim analysis) efficacy and safety of D-Vd vs Vd in CASTOR, with a primary focus on pts with 1 PL of therapy. Method: Pts in CASTOR were randomized to receive 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 with or without DARA (16 mg/kg, IV) given weekly for Cycles 1-3, Q3W for Cycles 4-8, and Q4W thereafter. Cytogenetic risk was evaluated centrally by next generation sequencing; high risk was defined as having t(4;14), t(14;16), and/or del17p abnormalities. MRD was assessed at the time of suspected CR and at 6 and 12 mo following the first treatment dose, and an additional MRD evaluation was required every 12 mo post-CR. MRD was evaluated using clonoSEQ® V2.0 (Adaptive Biotechnologies, Seattle, WA). Sustained MRD negativity was defined as maintenance of MRD negativity at 10-5 for ≥6 or ≥12 mo. Results: At the clinical cutoff date of January 11, 2018, 498 pts were included in the intent-to-treat (ITT) population (D-Vd, n = 251; Vd, n = 247). Pts received a median of 2 (1-10) PLs of therapy including 235 pts that received 1 PL (D-Vd, n = 122; Vd, n = 113). In the ITT population, 61% received prior ASCT, 66% V, 42% lenalidomide (R), and 32% were refractory to their last PL of therapy. Among 1 PL pts, 60% received prior ASCT, 51% V, 20% R, and 18% were refractory to their last PL of therapy. After a median follow-up of 31.3 mo, PFS was significantly prolonged with D-Vd compared with Vd in the ITT population (median: 16.7 vs 7.1 mo; HR, 0.32; 95% CI, 0.25-0.40, P <0.0001; Figure 1A). PFS benefit for D-Vd vs Vd was maintained in pts with high (median: 11.2 vs 7.2 mo; HR, 0.45; 95% CI, 0.25-0.80, P <0.01) and standard cytogenetic risk (median: 18.0 vs 7.0 mo; HR, 0.27; 95% CI, 0.19-0.38, P <0.0001). At the time of analysis, 88 deaths in D-Vd and 101 deaths in Vd were observed, and follow-up 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. Deeper responses with D-Vd translated to higher MRD-negative rates at 10-5 for the ITT population (14% vs 2%; P <0.0001) and in both cytogenetic risk groups (high risk: 18% vs 0%; P <0.01; standard risk: 15% vs 2%; P <0.0001). Among ITT pts, sustained MRD negativity was maintained in 22 (9%) D-Vd vs 3 (1%) Vd pts for ≥6 mo, and 8 (3%) D-Vd vs 0 Vd pts for ≥12 mo. Among 1 PL pts, median PFS was 27.0 vs 7.9 mo (HR, 0.23; 95% CI, 0.16-0.33, P <0.0001; Figure 1B) for D-Vd vs Vd. 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 = 0.01). For 1 PL pts, 28 vs 41 deaths were observed for D-Vd vs Vd. ORR (92% vs 74%), ≥VGPR (77% vs 42%), and ≥CR (43% vs 15%) rates were significantly higher (all P <0.001) with D-Vd vs Vd. MRD-negative rates at 10-5 were also significantly higher for D-Vd vs Vd (20% vs 3%; P <0.0001), and sustained MRD negativity was observed in 8 (7%) vs 1 (0.9%) pts at ≥6 mo cutoff and 7 (6%) vs 0 pts at ≥12 mo cutoff, respectively. The most common (≥5%) grade 3/4 treatment-emergent adverse events (TEAEs) are in Table 1. Discontinuation rates due to TEAEs were similar for D-Vd vs Vd (10% vs 9%). Second primary malignancy rates were 5% vs 2%, respectively. Updated data will be presented. Conclusions: In this 2-y update, D-Vd maintains significant PFS and ORR benefits in RRMM pts, with greater benefit in 1 PL pts. Addition of DARA to Vd allows for sustained MRD negativity. The safety profile of D-Vd remains consistent after 2 y. The data suggest that administration of D-Vd to RRMM pts after first relapse may provide the greatest clinical benefit. Disclosures Mateos: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, 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. Sonneveld:Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Hungria:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Nooka:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees. Estell:Janssen: Membership on an entity's Board of Directors or advisory committees. Corradini:Celgene: Honoraria, Other: Advisory Board & Lecturer; Janssen: Honoraria, Other: Lecturer; Roche: Honoraria, Other: Advisory Board & Lecturer; Amgen: Honoraria, Other: Advisory Board & Lecturer; Novartis: Honoraria, Other: Advisory Board & Lecturer; Sandoz: Other: Advisory Board; Abbvie: Honoraria, Other: Advisory Board & Lecturer; Sanofi: Honoraria, Other: Advisory Board & Lecturer; Takeda: Honoraria, Other: Advisory Board & Lecturer; Gilead: Honoraria, Other: Advisory Board & Lecturer. Weisel:Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria. Chiu:Janssen Research & Development, LLC: Employment. Schecter:Janssen Research & Development, LLC: Employment. Amin:Janssen Research & Development, LLC: Employment. Qin:Janssen Research & Development, LLC: Employment. Qi:Janssen: Employment. Spencer:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria.