The findings from an ongoing, multicentre, open-label, non-inferiority, randomised, phase III trial show that subcutaneous daratumumab is not inferior to intravenous daratumumab in terms of efficacy and pharmacokinetics and had an improved safety profile in patients with relapsed or refractory multiple myeloma. The results from the COLUMBIA study are published on 23 March 2020 in The Lancet Haematology.
Prof. Saad Z Usmani of the Levine Cancer Institute-Atrium Health in Charlotte, US and COLUMBIA researchers wrote in the study background that 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 easier to administer and it causes fewer administration-related reactions. In the COLUMBIA study, the investigators tested the non-inferiority of subcutaneous daratumumab to intravenous daratumumab.
The study, conducted in 147 sites in 18 countries, recruited adult patients if they had confirmed relapsed or refractory multiple myeloma according to International Myeloma Working Group criteria. It was required that the patients 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 to receive daratumumab subcutaneously or intravenously. Randomisation was stratified on the basis of baseline bodyweight, previous therapy lines, and myeloma type. 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 (C trough; 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% confidence interval (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.
In total 655 patients were screened between 31 October 2017 and 27 December 2018. Of those 522 patients were recruited and randomly assigned: 263 in the subcutaneous group and 259 in the intravenous group. 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, overall response and C trough met the predefined non-inferiority criteria. An overall response was seen in 108 (41%) patients in the subcutaneous group and 96 (37%) in the intravenous group (relative risk 1.11, 95% CI 0.89–1.37). The geometric means ratio for C trough was 107.93% (90% CI 95.74–121.67), and the maximum C trough was 593 μg/mL in the subcutaneous group and 522 μg/mL 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 (2 patients from sepsis, 1 patient from hepatitis B reactivation, and 1 patient from Pneumocystis jirovecii pneumonia).
The study team concluded that data from their study could contribute to the approval of the subcutaneous daratumumab formulation by regulatory bodies.
The study was funded by Janssen Research & Development.
Mateos M-V, Nahi H, Legiec W, et al. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBIA): a multicenter, open-label, non-inferiority, randomised, phase 3 trial. The Lancet Haematology; Published online 23 March 2020. DOI: https://doi.org/10.1016/S2352-3026(20)30070-3