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.
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
PURPOSELimited information is available on multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL) management in Latin America. The primary objective of the Hemato-Oncology Latin America (HOLA) study was to describe patient characteristics and treatment patterns of Latin American patients with MM, CLL, and NHL.METHODSThis study was a multicenter, retrospective, medical chart review of patients with MM, CLL, and NHL in Latin America identified between January 1, 2006, and December 31, 2015. Included were adults with at least 1 year of follow-up (except in cases of death within 1 year of diagnosis) treated at 30 oncology hospitals (Argentina, 5; Brazil, 9; Chile, 1; Colombia, 5; Mexico, 6; Panama/Guatemala, 4).RESULTSOf 5,140 patients, 2,967 (57.7%) had NHL, 1,518 (29.5%) MM, and 655 (12.7%) CLL. Median follow-up was 2.2 years for MM, 3.0 years for CLL, and 2.2 years for NHL, and approximately 26% died during the study observation period. Most patients had at least one comorbidity at diagnosis. The most frequent induction regimen was thalidomide-based chemotherapy for MM and chlorambucil with or without prednisone for CLL. Most patients with NHL had diffuse large B-cell lymphoma (DLBCL; 49.1%) or follicular lymphoma (FL; 19.5%). The majority of patients with DLBCL or FL received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.CONCLUSIONThe HOLA study generated an unprecedented level of high-quality, real-world evidence on characteristics and treatment patterns of patients with hematologic malignancies. Regional disparities in patient characteristics may reflect differences in ethnoracial identity and level of access to care. These data provide needed real-world evidence to understand the disease landscape in Latin America and may be used to inform clinical and health policy decision making.
Introduction: The use of lenalidomide (len) in the treatment of newly diagnosed multiple myeloma (NDMM) as induction and/or maintenance therapy is increasing. The majority of patients (pts) progress and require further treatment, highlighting a need for effective regimens for these len-exposed and len-refractory RRMM pts. Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. In three phase 3 studies, the addition of DARA to standard of care (SOC) regimens has doubled complete response (CR) rates, tripled minimal residual disease (MRD)-negative rates, and reduced the risk of progression or death by ≥50% vs SOC alone in RRMM and NDMM 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). To evaluate the efficacy of DARA plus SOC regimens in RRMM pts previously exposed or refractory to len, we evaluated data from relevant subpopulations of patients in the phase 3 CASTOR and POLLUX studies and the phase 1 MMY1001 study. Methods: CASTOR and POLLUX are both open-label, randomized, phase 3 studies of DARA plus bortezomib/dexamethasone (D-Vd) or lenalidomide/dexamethasone (D-Rd), respectively, vs SOC alone in RRMM pts with ≥1 prior line of therapy. Len-refractory pts were ineligible for POLLUX. Within MMY1001, a multi-arm phase 1b study, RRMM pts treated with DARA plus carfilzomib/dexamethasone (D-Kd) or pomalidomide/dexamethasone (D-Pd) were included in this analysis. In the phase 3 studies, progression-free survival (PFS) was assessed in the intent-to-treat (ITT) population and were compared using a stratified log-rank test. Responses were assessed in an evaluable population defined as pts with measurable disease at baseline and ≥1 post-baseline disease assessment. Minimal residual disease (MRD) was evaluated in the ITT population using clonoSEQ® V2.0 (Adaptive Biotechnologies, Seattle, WA). Results: Median (range) number of prior lines received was 2 (1-10) in CASTOR, 1 (1-11) in POLLUX, 2 (1-4) in the MMY1001 D-Kd cohort, and 4 (1-13) in the MMY1001 D-Pd cohort. A total of 493 pts (323 pts treated with DARA) received prior len across the 3 DARA studies. Among len-exposed pts in CASTOR (D-Vd, n = 89; Vd, n = 120), median PFS was 9.5 vs 6.1 months (hazard ratio [HR] 0.40; 95% confidence interval [CI], 0.28-0.58; P <0.0001) after median follow up of 31.3 months. A similar PFS HR was reported for len-exposed pts in POLLUX (D-Rd, n = 50; Rd, n = 50) after median follow up of 39.5 months, in which D-Rd treated pts demonstrated significantly longer PFS vs Rd treated pts (median: 38.9 mo vs 18.6 mo; HR 0.39; 95% CI, 0.22-0.70; P = 0.0010). In both the CASTOR and POLLUX studies, rates of deeper responses and MRD-negative rates at 10-5 sensitivity threshold were all significantly higher (P <0.05 for all comparisons) for DARA-containing regimens vs SOC alone (Table). A total of 284 pts (203 pts treated with DARA) were len-refractory across CASTOR and MMY1001. Among 60 D-Vd and 81 Vd len-refractory pts in CASTOR, median PFS was 7.8 vs 4.9 months (HR 0.44; 95% CI, 0.28-0.68; P = 0.0002). Significantly higher response and MRD-negative rates at 10-5 were observed for D-Vd vs Vd in len-refractory pts (Table). In MMY1001, nearly all pts treated with D-Kd (n = 81/85) or D-Pd (n = 103/103) were exposed to len, and the majority of pts treated with D-Kd (n = 51/85) or D-Pd (n = 92/103) were len-refractory. Among all pts, median PFS was not reached for D-Kd after median follow-up of 12 months (12-mo PFS rate: 62%), and median PFS was 9.9 months for D-Pd after median follow-up of 28.1 months. Among the 51 len-refractory pts treated with D-Kd, median PFS was 14.1 months. In all-treated pts, ORR was 66% for D-Pd and 84% for D-Kd (79% for the len-refractory subgroup). Updated data from all 3 studies will be presented at the meeting. Conclusion: In len-exposed or -refractory patients, DARA enabled deep responses and prolonged PFS irrespective of the SOC combination partner and number of prior lines of treatment. DARA-based regimens were more effective in less heavily pretreated len-exposed or len-refractory pts, suggesting earlier use (eg, after first relapse) would provide a greater benefit. Disclosures Usmani: Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Mateos:Takeda: 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; 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; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lentzsch:Caelum Biosciences: Consultancy, Other: Dr. Lentzsch recused herself as an investigator from the Phase 1a/b trial testing CAEL-101 in 11/2017., Patents & Royalties: Shareholder for Caelum Biosiences; BMS: Consultancy; Janssen: Consultancy; Bayer: Consultancy. Quach:Celgene: Consultancy, Research Funding; Janssen Cilag: Consultancy; Sanofi Genzyme: Research Funding; Amgen: Consultancy, Research Funding. Capra:Janssen: Research Funding, Speakers Bureau; Roche: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Research Funding; Sanofi: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Sonneveld:Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Qi:Janssen Research & Development, LLC: Employment. Amin:Janssen Research & Development, LLC: Employment. Wang:Janssen Research & Development, LLC: Employment. Qin:Janssen Research & Development, LLC: Employment. Okonkwo:Janssen Research & Development, LLC: Employment. Ukropec:Janssen Scientific Affairs, LLC: Employment. Trivedi:Janssen Research & Development, LLC: Employment. Suzuki:Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Ono: Consultancy, Honoraria; Sanofi Aventis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; SRL.Inc: Employment. Dimopoulos:Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Cavo:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: 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; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nooka:Adaptive technologies: 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; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Amgen: 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. Chari:Array Biopharma: Research Funding; The Binding Site: Consultancy; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.
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