Maria-Victoria Mateos1, Hareth Nahi2, Wojciech Legiec3, Sebastian Grosicki4, Vladimir Vorobyev5, Ivan Spicka6, Vania Hungria7, Sibirina Korenkova8, Nizar Bahlis9, Max Flogegard10, Joan Bladé11, Philippe Moreau12, Martin Kaiser13, Shinsuke Iida14, Jacob Laubach15, Hila Magen16, Michele Cavo17, Cyrille Hulin18, Darrell White19, Valerio De Stefano20, Pamela L Clemens21, Tara Masterson21, Kristen Lantz21, Lisa O'Rourke21, Christoph Heuck21, Xiang Qin22, Dolly A Parasrampuria21, Zhilong Yuan22, Steven Xu23, Ming Qi21, Saad Z Usmani24. 1. Cancer Research Unit, University Hospital of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Institute of Cancer Molecular and Cellular Biology (USAL-CSIC), Centre for Cancer Research (IBMCC), Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain. 2. Unit of Hematology, Department of Medicine, Karolinska University Hospital at Huddinge, Karolinska Institutet, Stockholm, Sweden. 3. Department of Hemato-Oncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Poland. 4. Department of Hematology and Cancer Prevention, School of Public Health in Bytom, Medical University of Silesia in Katowice, Katowice, Poland. 5. S P Botkin City Clinical Hospital, Moscow, Russia. 6. 1st Department of Medicine, Department of Hematology, First Faculty of Medicine, Charles University, Prague, Czech Republic; General University Hospital in Prague, Charles University, Prague, Czech Republic. 7. Clinica São Germano, São Paulo, Brazil. 8. Kiev Bone Marrow Transplantation Center, Kiev, Ukraine. 9. Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada. 10. Department of Internal Medicine, Falun General Hospital, Falun, Sweden. 11. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain. 12. University Hospital of Nantes, Nantes, France. 13. Department of Haemato-Oncology, Royal Marsden Hospital, London, UK; Division of Molecular Pathology, Institute of Cancer Research, London, UK. 14. Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. 15. Department of Hematology and Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. 16. Department of Hematology Chaim Sheba Medical Center, Ramat-Gan, Sackler Faculty of Medicine, Tel Aviv, Israel. 17. Diagnostic and Specialty Medicine Department, Seràgnoli Institute of Hematology, University of Bologna, Bologna, Italy. 18. Centre Hospitalier Universitaire Bordeaux, Pessac, France. 19. Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax, NS, Canada. 20. 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. 21. Janssen Research & Development, Spring House, PA, USA. 22. Janssen Research & Development, Raritan, NJ, USA. 23. Janssen Research & Development, Spring House, PA, USA; Genmab US, Princeton, NJ, USA. 24. Levine Cancer Institute-Atrium Health, Charlotte, NC, USA. Electronic address: saad.usmani@atriumhealth.org.
Abstract
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.
RCT Entities:
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 humanhyaluronidase 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.
Authors: Marie A Printz; Barry J Sugarman; Rudolph D Paladini; Michael C Jorge; Yan Wang; David W Kang; Daniel C Maneval; Michael J LaBarre Journal: AAPS J Date: 2022-10-20 Impact factor: 3.603
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