BACKGROUND: Intravenous daratumumab for treatment of patients with multiple myeloma involves a lengthy infusion that affects quality of life, and infusion-related reactions are common. Subcutaneous daratumumab is thought to be easier to administer and to cause fewer administration-related reactions. In this study (COLUMBA), we tested the non-inferiority of subcutaneous daratumumab to intravenous daratumumab. METHODS: In this ongoing, multicentre (147 sites in 18 countries), open-label, non-inferiority, randomised, phase 3 trial, we recruited adult patients (age ≥18 years) if they had confirmed relapsed or refractory multiple myeloma according to International Myeloma Working Group criteria; received at least three previous lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or were double refractory to both a proteasome inhibitor and immunomodulatory drug; and had an Eastern Cooperative Oncology Group performance status score of 2 or lower. Patients were randomly assigned (1:1) by a computer-generated randomisation schedule and balanced using randomly permuted blocks to receive daratumumab subcutaneously (subcutaneous group) or intravenously (intravenous group). Randomisation was stratified on the basis of baseline bodyweight (≤65 kg, 66-85 kg, >85 kg), previous therapy lines (≤four vs >four), and myeloma type (IgG vs non-IgG). Patients received 1800 mg of subcutaneous daratumumab co-formulated with 2000 U/mL recombinant human hyaluronidase PH20 or 16 mg/kg of intravenous daratumumab once weekly (cycles 1-2), every 2 weeks (cycles 3-6), and every 4 weeks thereafter (28-day cycles) until progressive disease or toxicity. The co-primary endpoints were overall response and maximum trough concentration (Ctrough; cycle 3, day 1 pre-dose). The non-inferiority margin for overall response was defined using a 60% retention of the lower bound (20·8%) of the 95% CI of the SIRIUS trial. Efficacy analyses were done by intention-to-treat population. The pharmacokinetic-evaluable population included all patients who received all eight weekly daratumumab doses in cycles 1 and 2 and provided a pre-dose pharmacokinetics blood sample on day 1 of cycle 3. The safety population included all patients who received at least one daratumumab dose. This trial is registered with ClinicalTrials.gov, NCT03277105. FINDINGS: Between Oct 31, 2017, and Dec 27, 2018, 655 patients were screened, of whom 522 were recruited and randomly assigned (subcutaneous group n=263; intravenous group n=259). Three patients in the subcutaneous group and one in the intravenous group did not receive treatment and were not evaluable for safety. At a median follow-up of 7·5 months (IQR 6·5-9·3), overall response and Ctrough met the predefined non-inferiority criteria. An overall response was seen in 108 (41%) of 263 patients in the subcutaneous group and 96 (37%) of 259 in the intravenous group (relative risk 1·11, 95% CI 0·89-1·37). The geometric means ratio for Ctrough was 107·93% (90% CI 95·74-121·67), and the maximum Ctrough was 593 μg/mL (SD 306) in the subcutaneous group and 522 μg/mL (226) in the intravenous group. The most common grade 3 and 4 adverse events were anaemia (34 [13%] of 260 patients evaluable for safety in the subcutaneous group and 36 [14%] of 258 patients in the intravenous group), neutropenia (34 [13%] and 20 [8%]), and thrombocytopenia (36 [14%] and 35 [14%]). Pneumonia was the only serious adverse event in more than 2% of patients (seven [3%] in the subcutaneous group and 11 [4%] in the intravenous group). There was one death resulting from a treatment-related adverse event in the subcutaneous daratumumab group (febrile neutropenia) and four in the intravenous group (sepsis [n=2], hepatitis B reactivation [n=1], and Pneumocystis jirovecii pneumonia [n=1]). INTERPRETATION: Subcutaneous daratumumab was non-inferior to intravenous daratumumab in terms of efficacy and pharmacokinetics and had an improved safety profile in patients with relapsed or refractory multiple myeloma. These data could contribute to the approval of the subcutaneous daratumumab formulation by regulatory bodies. FUNDING: Janssen Research & Development.

1st Department of Medicine Department of Hematology 1st Faculty of Medicine Charles University Prague Czech Republic; General University Hospital Prague Charles University Prague Czech Republic

Arnie Charbonneau Cancer Institute University of Calgary Calgary AB Canada

Cancer Research Unit University Hospital of Salamanca Instituto de Investigación Biomédica de Salamanca Salamanca Spain

Centre Hospitalier Universitaire Bordeaux Pessac France

Clinica São Germano São Paulo Brazil

Department of Haemato Oncology Royal Marsden Hospital London UK; Division of Molecular Pathology Institute of Cancer Research London UK

Department of Hemato Oncology and Bone Marrow Transplantation Medical University of Lublin Lublin Poland

Department of Hematology and Cancer Prevention School of Public Health in Bytom Medical University of Silesia in Katowice Katowice Poland

Department of Hematology and Oncology Dana Farber Cancer Institute Harvard Medical School Boston MA USA

Department of Hematology and Oncology Nagoya City University Graduate School of Medical Sciences Nagoya Japan

Department of Hematology Chaim Sheba Medical Center Ramat Gan Sackler Faculty of Medicine Tel Aviv Israel

Department of Internal Medicine Falun General Hospital Falun Sweden

Diagnostic and Specialty Medicine Department Seràgnoli Institute of Hematology University of Bologna Bologna Italy

Institut d'Investigacions Biomèdiques August Pi i Sunyer Hospital Clínic de Barcelona University of Barcelona Barcelona Spain

Institute of Hematology Università Cattolica del Sacro Cuore Rome Italy; Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico Università Cattolica del Sacro Cuore Rome Italy

Janssen Research and Development Raritan NJ USA

Janssen Research and Development Spring House PA USA

Janssen Research and Development Spring House PA USA; Genmab US Princeton NJ USA

Kiev Bone Marrow Transplantation Center Kiev Ukraine

Levine Cancer Institute Atrium Health Charlotte NC USA

Queen Elizabeth 2 Health Sciences Centre Dalhousie University Halifax NS Canada

S P Botkin City Clinical Hospital Moscow Russia

Unit of Hematology Department of Medicine Karolinska University Hospital at Huddinge Karolinska Institutet Stockholm Sweden

University Hospital of Nantes Nantes France

Komentář v

Lancet Haematol. 2020 Aug;7(8):e558. doi: 10.1016/S2352-3026(20)30125-3. PubMed

Komentář v

Lancet Haematol. 2020 Aug;7(8):e559. doi: 10.1016/S2352-3026(20)30188-5. PubMed

Erratum v

Lancet Haematol. 2020 Oct;7(10):e710. doi: 10.1016/S2352-3026(20)30296-9. PubMed

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ClinicalTrials.gov
NCT03277105