Among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, daratumumab combined with bortezomib, melphalan, and prednisone resulted in a lower risk of disease progression or death than the same regimen without daratumumab. The daratumumab-containing regimen was associated with more grade 3 or 4 infections. (Funded by Janssen Research and Development; ALCYONE ClinicalTrials.gov number, NCT02195479 .).

No abstract

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Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. The addition of DARA to standard-of-care regimens in phase 3 studies reduced the risk of disease progression or death by ≥44%, nearly doubled the rate of complete response or better, and induced a ≥3-fold increase in minimal residual disease (MRD)-negativity rates versus standard of care alone in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) and relapsed/refractory multiple myeloma. In the primary analysis of the phase 3 ALCYONE study (median follow-up: 16.5 months), a significant progression-free survival (PFS) benefit (median not reached vs 18.1 months; hazard ratio [HR], 0.50; P <0.001) was observed with the addition of DARA to bortezomib/melphalan/prednisone (D-VMP) in patients with transplant-ineligible NDMM, without an increase in overall toxicity (Mateos MV, et al. N Engl J Med. 2018;378[6]:518-528). D-VMP continued to demonstrate a significant PFS benefit versus VMP alone after 1 year of additional follow-up, including in patients ≥75 years of age (Dimopoulos MA, et al. Blood. 2018;132[Suppl 1]:156). After a median follow-up of 27.8 months, D-VMP reduced the risk of disease progression or death by 57% versus VMP alone, with a 24-month PFS rate of 63% in the D-VMP group and 36% in the VMP group. This PFS benefit was observed regardless of patient age and was maintained during the subsequent line of therapy in patients with transplant-ineligible NDMM. Here, we present >36 months of follow-up from ALCYONE, including analysis of overall survival (OS) from a prespecified interim analysis. Methods: Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplantation due to age (≥65 years) or comorbidities were randomized 1:1 to receive up to nine 6-week cycles of VMP (bortezomib 1.3 mg/m2 subcutaneously on Days 1, 4, 8, 11, 22, 25, 29, and 32 of Cycle 1 and Days 1, 8, 22, and 29 of Cycles 2-9; melphalan 9 mg/m2 orally and prednisone 60 mg/m2 orally on Days 1-4 of Cycles 1-9) with or without DARA (16 mg/kg intravenously once weekly for Cycle 1, once every 3 weeks for Cycles 2-9, and once every 4 weeks for Cycles 10+ until disease progression). The primary endpoint was PFS. Secondary endpoints included overall response rate, rate of complete response or better, rate of very good partial response or better, MRD-negativity rate (10-5 threshold), PFS on subsequent line of therapy (PFS2), OS, and safety. Results: A total of 706 patients were enrolled in this study (D-VMP: n = 350; VMP: n = 356). Patient baseline characteristics were well balanced between treatment arms. The median (range) age was 71 (40-93) years, and 29.9% of patients were ≥75 years of age. 518 (84.1%) and 98 (15.9%) of 616 patients evaluated had standard and high (del17p, t[14;16], and/or t[4;14] positive) cytogenetic risk, respectively, as assessed via local fluorescence in-situ hybridization/karyotyping. Median PFS was 36.4 months with D-VMP versus 19.3 months with VMP after a median follow-up of 40.08 months (HR, 0.42; 95% confidence interval [CI], 0.34-0.51; P <0.0001; Figure A). Median PFS2 was not reached with D-VMP versus 42.3 months with VMP (HR, 0.55; 95% CI, 0.43-0.71; P <0.0001). The estimated 36-month OS rate was 78% with D-VMP versus 68% with VMP, with a significant benefit for OS observed for D-VMP versus VMP alone (HR, 0.60; 95% CI, 0.46-0.80; P = 0.0003; Figure B); median OS was not reached in either group and follow-up is ongoing. Additional efficacy data, including MRD negativity, and updated safety data will be presented at the meeting. Conclusions: For the first time, we demonstrate that the addition of DARA to VMP prolongs OS in patients with transplant-ineligible NDMM, with a 40% reduction in the risk of death versus VMP alone after a median follow-up of 40 months. D-VMP continued to demonstrate a significant PFS benefit, which was also maintained during the subsequent line of therapy. These findings, together with the phase 3 MAIA study (DARA plus lenalidomide/dexamethasone vs lenalidomide/dexamethasone), continue to support the addition of DARA to frontline treatment regimens in patients with transplant-ineligible NDMM. Disclosures Mateos: Abbvie: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; 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; Amgen: 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; Adaptive: Honoraria. Cavo:Janssen, Celgene, Amgen, Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Amgen, BMS, Abbvie, Takeda: Honoraria; Janssen, Celgene: Other: Travel Accommodations; Janssen, Celgene: Speakers Bureau. Bladé:Irctures: Honoraria; Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Sanofi Oncology: Research Funding. Suzuki:Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapeutics: 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; Juno: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: 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; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Knop:Janssen, AMGEN, Bristol-Myers Squibb, Celgene: Consultancy, Honoraria. Lucio:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Nagy:Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Cook:Celgene, Jannsen-Cilag, Takeda: Honoraria, Research Funding; Amgen, Bristol-Myers Squibb, GlycoMimetics, Seattle Genetics and Sanofi: Honoraria. Liberati:Janssen: Honoraria; Bristol & Mayer: Honoraria; Celgene: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Campbell:Janssen: Honoraria, Research Funding, Speakers Bureau. Garg:Novartis, Janssen: Research Funding; Janssen, Takeda, Novartis: Other: Travel expenses; Janssen: Honoraria. Krevvata:Janssen: Employment. Wang:Janssen: Employment. Kudva:Janssen: Employment, Equity Ownership. Ukropec:Janssen: Employment, Equity Ownership. Wroblewski:Janssen: Employment, Equity Ownership. Kobos:Janssen: Employment. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria.

Introduction Daratumumab (DARA) is a human IgGκ anti-CD38 monoclonal antibody with a direct on-tumor and immunomodulatory mechanism of action. In combination with standard of care (SOC) regimens, DARA has consistently demonstrated a doubling of complete response (CR) rates, tripling of minimal residual disease (MRD)-negative rates, and reduction in the risk of progression or death by ≥50% vs SOC alone in relapsed/refractory MM and NDMM pts. In the prespecified interim analysis of ALCYONE, a phase 3 study of D-VMP versus VMP in transplant ineligible NDMM (Mateos MV, N Engl J Med 2018. 378[6]:518-528), significant progression-free survival (PFS) benefit (median not reached [NR] vs 18.1 mo; hazard ratio [HR], 0.50; P <0.001) and a higher rate of MRD negativity (10-5 threshold: 22% vs 6%; P <0.001) were observed without increased overall toxicity for D-VMP versus VMP after a median follow-up of 16.5 months. This report provides updated efficacy and safety findings from ALCYONE after 1 year of additional follow-up. Methods Pts were ≥65 years of age or ineligible for high-dose chemotherapy with autologous stem cell transplantation. Pts were randomized 1:1 to receive up to nine 6-week cycles of VMP (V 1.3 mg/m2 SC on Days 1, 4, 8, 11, 22, 25, 29, 32 [Cycle 1] and Days 1, 8, 22, and 29 [Cycles 2-9]; M 9 mg/m2 PO and P 60 mg/m2 PO on Days 1-4 [Cycles 1-9]) with or without DARA (16 mg/kg IV QW for Cycle 1, Q3W for Cycles 2-9, and Q4W for Cycles 10+ until disease progression). PFS was the primary endpoint. PFS on the subsequent line of therapy (PFS2), overall response rate (ORR), CR or better rate, very good partial response (VGPR) or better rate, MRD-negative rate (10-5 threshold: clonoSEQ® V2.0, Adaptive), overall survival (OS), and safety were secondary endpoints. PFS2 was defined as the duration from randomization to progression on the next line of subsequent antimyeloma therapy or death, whichever occurred first. Results A total of 706 pts were randomized (350 D-VMP; 356 VMP). Median (range) age was 71 (40-93) years, with 29.9% being ≥75 years of age. Of the 616 pts evaluable for cytogenetic risk assessment via fluorescence in-situ hybridization/karyotyping, 84.1% had standard-risk and 15.9% had high-risk (del17p, t[14;16], and/or t[4;14] positive) disease. At the updated clinical cutoff date (June 12, 2018), all pts in both arms had either completed or discontinued from 9 treatment cycles of VMP, with 194 (56%) pts in the D-VMP arm remaining on the study to receive DARA monotherapy in Cycles 10+. After median follow-up of 27.8 months, median PFS was NR for D-VMP vs 19.1 months for VMP (HR, 0.43; 95% confidence interval [CI], 0.35-0.54; P <0.0001; Figure). All prespecified subgroups showed a PFS benefit of D-VMP vs VMP, including pts ≥75 years of age (median: 32.2 mo vs 20.1 mo; HR, 0.51; 95% CI, 0.34-0.75). Significantly higher ORR and rates of deeper responses were observed for D-VMP vs VMP (Table). Median duration of response among responders was NR for D-VMP vs 21.1 months for VMP. Median PFS2 was NR in either arm (unstratified HR, 0.59; 95% CI, 0.43-0.82; P = 0.0013); 24-month PFS2 rates were 84.1% vs 78.5%, respectively. Updated MRD results will be presented. Grade 3/4 treatment-emergent adverse events (TEAEs; D-VMP/VMP) occurring in ≥10% of pts were neutropenia (39.9%/39.0%), thrombocytopenia (34.7%/37.9%), anemia (17.1%/19.8%), and pneumonia (12.4%/4.0%); grade 3/4 infection rates were 25.1% vs 14.7%, respectively. Among D-VMP pts who received D monotherapy (Cycles 10+; n = 278), 66 (23.7%) pts reported grade 3/4 TEAEs; the most common were anemia (3.6%), pneumonia (2.5%), neutropenia (1.8%), and thrombocytopenia (1.4%). Two pts in the D-VMP arm and 1 pt in the VMP arm discontinued treatment due to pneumonia, and treatment discontinuations due to infection occurred in 1.4% vs 1.7% for D-VMP vs VMP. Conclusions With 1 year of additional follow-up, the combination of DARA and VMP in transplant ineligible NDMM pts continues to demonstrate a significant PFS benefit, including in pts ≥75 years of age, and allows for maintenance of PFS benefit during the subsequent line of therapy. Improvements in duration and depth of response continue to be observed with D-VMP with longer follow-up. No new safety signals emerged following the addition of DARA to VMP, and grade 3/4 infections continue to be manageable with no notable increase in rates. These results continue to support the use of D-VMP in the first line of treatment in transplant ineligible NDMM. Disclosures Dimopoulos: Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Mateos:GSK: 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; GSK: 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; 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavo:Adaptive Biotechnologies: 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, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: 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; AbbVie: 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; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Suzuki:Sanofi Aventis: Consultancy, Honoraria; Ono: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; SRL.Inc: Employment. Jakubowiak:Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Knop:Takeda: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Doyen:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lucio:Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Cook:Chugai: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz: Honoraria; YAkeda: Honoraria; Amgem: Honoraria. Grosicki:Affimed: Research Funding. Garg:Novartis: Other: travel support, Research Funding; Janssen: Honoraria; Takeda: Other: Travel Grant; Amgen: Honoraria, Other: Travel Support. Chiu:Janssen Research & Development, LLC: Employment. Wang:Janssen Research & Development, LLC: Employment. Kudva:Janssen Research & Development: Employment. Kobos:Janssen Research & Development: Employment. Wroblewski:Janssen Research & Development: Employment. Qi:Janssen Research & Development, LLC: Employment. San-Miguel:Celgene: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; BMS: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Roche: Honoraria. Bladé:Janssen: Honoraria.

No abstract

Background In the phase III ALCYONE trial, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) significantly improved overall response rate and progression-free status compared with VMP alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) from ALCYONE. Methods The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaire were administered at baseline, every 3 months (year 1) and every 6 months (until progression). Treatment effects were assessed using a repeated-measures, mixed-effects model. Results Compliance with PRO assessments was comparable at baseline (> 90%) and throughout study (> 76%) for both treatment groups. Improvements from baseline were observed in both groups for EORTC QLQ-C30 Global Health Status (GHS), most functional scales, symptom scales and EQ-5D-5L visual analog scale (VAS). Between-group differences were significant for GHS (p = 0.0240) and VAS (p = 0.0160) at month 3. Improvements in pain were clinically meaningful in both groups at all assessment time points. Cognitive function declined in both groups, but the magnitude of the decline was not clinically meaningful. Conclusions Patients with transplant-ineligible NDMM demonstrated early and continuous improvements in health-related quality of life, including improvements in functioning and symptoms, following treatment with D-VMP or VMP. Trial registration ClinicalTrials.gov identifier NCT02195479, registered September 21, 2014

ObjectiveFollicular and mantle cell lymphoma are low-grade B-cell malignancies that lack good responses to chemoimmunotherapy. This study aimed to assess retrospectively clinicopathological features and to determine independent prognostic factors for follicular and mantle cell lymphoma patients treated at two Brazilian medical centers: the Hematology and Hemotherapy Center of the Universidade Estadual de Campinas (Unicamp), a public university hospital, and AC. Camargo Cancer Center, a specialized cancer center.MethodsTwo hundred and twenty-seven follicular and 112 mantle cell lymphoma cases were diagnosed between 1999 and 2016. Archived paraffin blocks were retrieved and reviewed. Corresponding demographics and clinical data were recovered from medical charts. Outcome analyses considered both overall and event-free survival.ResultsFor follicular lymphoma treated with the R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone) and R-CVP (rituximab, cyclophosphamide, vincristine sulfate, prednisone) regimens, both B-symptoms (p-value < 0.01 for overall and event-free survival) and high-risk Follicular Lymphoma International Prognostic Index (p-value < 0.01 for overall survival) were independently associated to worse prognosis. Maintenance with rituximab improved the prognosis (p-value < 0.01 for overall survival). For mantle cell lymphoma, B-symptoms (p-value = 0.03 for overall survival and event-free survival) and bone marrow infiltration (p-value = 0.01 for overall survival) independently predicted reduced survival, and rituximab at induction increased both event-free and overall survival (p-value < 0.01 in both analyses). Combinations of these deleterious features could identify extremely poor prognostic subgroups. The administration of rituximab was more frequent in the AC. Camargo Cancer Center, which was the institution associated with better overall survival for both neoplasias.ConclusionThis study represents the largest cohort of follicular and mantle cell lymphoma in South America thus far. Some easily assessable clinical variables were able to predict prognosis and should be considered in low-income centers. In addition, the underuse of rituximab in the Brazilian public health system should be reconsidered in future health policies.