Daratumumab, a CD38 human monoclonal antibody, demonstrated significant clinical activity in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in the primary analysis of CASTOR, a phase 3 study in relapsed and/or refractory multiple myeloma. A post hoc analysis based on treatment history and longer follow up is presented. After 19.4 (range: 0–27.7) months of median follow up, daratumumab plus bortezomib and dexamethasone prolonged progression-free survival (median: 16.7 versus 7.1 months; hazard ratio, 0.31; 95% confidence interval, 0.24-0.39; P<0.0001) and improved the overall response rate (83.8% versus 63.2%; P<0.0001) compared with bortezomib and dexamethasone alone. The progression-free survival benefit of daratumumab plus bortezomib and dexamethasone was most apparent in patients with 1 prior line of therapy (median: not reached versus 7.9 months; hazard ratio, 0.19; 95% confidence interval, 0.12-0.29; P<0.0001). Daratumumab plus bortezomib and dexamethasone was also superior to bortezomib and dexamethasone alone in subgroups based on prior treatment exposure (bortezomib, thalidomide, or lenalidomide), lenalidomide-refractory status, time since last therapy (≤12, >12, ≤6, or >6 months), or cytogenetic risk. Minimal residual disease–negative rates were >2.5-fold higher with daratumumab across subgroups. The safety profile of daratumumab plus bortezomib and dexamethasone remained consistent with longer follow up. Daratumumab plus bortezomib and dexamethasone demonstrated significant clinical activity across clinically relevant subgroups and provided the greatest benefit to patients treated at first relapse. Trial registration: clinicaltrials.gov identifier: 02136134.

CASTOR showed the significant clinical benefit of daratumumab plus bortezomib and dexamethasone for patients with previously treated multiple myeloma. With w3 years median follow-up, this regimen continues to demonstrate significantly improved progression-free survival with higher minimal residual diseaseenegativity rates and consistent safety, with the greatest benefit observed when used earlier in the treatment of relapsed/ refractory multiple myeloma. Background: In the phase III CASTOR study in relapsed or refractory multiple myeloma, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone. Outcomes after 40.0 months of median follow-up are discussed. Patients and Methods: Eligible patients had received ! 1 line of treatment and were administered bortezomib (1.3 mg/m 2 ) and dexamethasone (20 mg) for 8 cycles with or without daratumumab (16 mg/kg) until disease progression. Results: Of 498 patients in the intent-to-treat (ITT) population (D-Vd, n ¼ 251; Vd, n ¼ 247), 47% had 1 prior line of treatment (1PL; D-Vd, n ¼ 122; Vd, n ¼ 113). Median progression-free survival (PFS) was significantly prolonged with D-Vd versus Vd in the ITT population (16.7 vs. 7.1 months; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.25-0.40; P < .0001) and the 1PL subgroup (27.0 vs. 7.9 months; HR, 0.22; 95% CI, 0.15-0.32; P < .0001). In lenalidomide-refractory patients, the median PFS was 7.8 versus 4.9 months (HR, 0.44; 95% CI, 0.28-0.68; P ¼ .0002) for D-Vd (n ¼ 60) versus Vd (n ¼ 81). Minimal residual disease (MRD)enegativity rates (10 À5 ) were greater with D-Vd versus Vd (ITT: 14% vs. 2%; 1PL: 20% vs. 3%; both P < .0001). PFS2 was significantly prolonged with D-Vd versus Vd (ITT: HR, 0.48; 95% CI, 0.38-0.61; 1PL: HR, 0.35; 95% CI, 0.24-0.51; P < .0001). No new safety concerns were observed. Conclusion: After 3 years, D-Vd maintained significant benefits in patients with relapsed or refractory multiple myeloma with a consistent safety profile. D-Vd provided the greatest benefit at first relapse and increased MRD-negativity rates.

Background Multiple myeloma (MM) patients with high cytogenetic risk have poor outcomes. In CASTOR, daratumumab plus bortezomib/dexamethasone (D-Vd) prolonged progression-free survival (PFS) versus bortezomib/dexamethasone (Vd) alone and exhibited tolerability in patients with relapsed or refractory MM (RRMM). Methods This subgroup analysis evaluated D-Vd versus Vd in CASTOR based on cytogenetic risk, determined using fluorescence in situ hybridization and/or karyotype testing performed locally. High-risk patients had t(4;14), t(14;16), and/or del17p abnormalities. Minimal residual disease (MRD; 10−5 sensitivity threshold) was assessed via the clonoSEQ® assay V2.0. Of the 498 patients randomized, 40 (16%) in the D-Vd group and 35 (14%) in the Vd group were categorized as high risk. Results After a median follow-up of 40.0 months, D-Vd prolonged median PFS versus Vd in patients with standard (16.6 vs 6.6 months; HR, 0.26; 95% CI, 0.19-0.37; P < 0.0001) and high (12.6 vs 6.2 months; HR, 0.41; 95% CI, 0.21–0.83; P = 0.0106) cytogenetic risk. D-Vd achieved deep responses, including higher rates of MRD negativity and sustained MRD negativity versus Vd, regardless of cytogenetic risk. The safety profile was consistent with the overall population of CASTOR. Conclusion These updated data reinforce the effectiveness and tolerability of daratumumab-based regimens for RRMM, regardless of cytogenetic risk status. Trial registration ClinicalTrials.gov, NCT02136134. Registered 12 May 2014

Introduction: 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.