Findings from the phase III COLUMBA trial have shown 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. These results were published by Maria-Victoria Mateos, MD, and colleagues in The Lancet Haematology.

Maria-Victoria Mateos, MD

Researchers explained in the study background that intravenous daratumumab for treatment of patients with multiple myeloma involves a lengthy infusion that affects quality of life, and that infusion-related reactions are common. Subcutaneous daratumumab is easier to administer and it causes fewer administration-related reactions. In the COLUMBA study, the investigators tested the noninferiority of subcutaneous daratumumab compared with intravenous daratumumab.

Study Methods

The ongoing, multicenter, open-label, noninferiority, randomized study, conducted in 147 sites in 18 countries, recruited adult patients with confirmed relapsed or refractory multiple myeloma according to International Myeloma Working Group criteria. Patients had 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 either subcutaneously or intravenously. Randomization was stratified on the basis of baseline body weight, previous therapy lines, and myeloma type. Patients received 1,800 mg of subcutaneous daratumumab coformulated with 2,000 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 predose). The noninferiority 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 predose 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 October 2017 and 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.

Results

At a median follow-up of 7.5 months, overall response and C_trough met the predefined noninferiority 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 anemia (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 (7 [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 (two patients from sepsis, one patient from hepatitis B reactivation, and one 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.

Disclosure: The study was funded by Janssen Research & Development. For full disclosures of the study authors, visit thelancet.com.