Subcutaneous daratumumab, a monoclonal antibody was determined to be non-inferior to FDA approved intravenous daratumumab in terms of efficacy and pharmacokinetics as treatment of patients with relapsed or refractory multiple myeloma, according to results from the phase III COLUMBA trial. The study also showed an improved safety profile with SC versus IV daratumumab.
Saad Z. Usmani, MD, FACP
Subcutaneous (SC) daratumumab (Darzalex), a monoclonal antibody was determined to be non-inferior to FDA approved intravenous (IV) daratumumab in terms of efficacy and pharmacokinetics as treatment of patients with relapsed or refractory multiple myeloma, according to results from the phase III COLUMBA trial (NT03277105). The study also showed an improved safety profile with SC versus IV daratumumab.
“The major advantages of SC daratumumab are the convenience to patients and infusion centers (saves infusion chair time, short visits with infusion in 5 minutes, low incidence of infusion reactions and comparable efficacy. This is a win-win for patients and physicians,” lead study author Saad Z. Usmani, MD, FACP, chief of the Plasma Cell Disorders, and director of Clinical Research in Hematologic Malignancies at the Levine Cancer Institute/Atrium Health, toldTargeted Oncology.
The ongoing, multicenter, open-label, non-inferiority, randomized study included patients with relapsed or refractory multiple myeloma who received at least 3 prior lines of therapy or were double refractory to both a proteasome inhibitor and immunomodulatory agent. These patients were required to have an ECOG performance status of 2 or below.
A total of 522 patients were randomized by a computer-generated randomization schedule and balanced with randomly permuted blocks to receive either SC daratumumab (n = 263) or IV daratumumab (n = 259) and were included in the efficacy analysis. These patients were administered doses based on body weight.
Responses were observed in 41% of patients in the SC arm (n = 108;, 95% CI 35.1%-47.3%) and 37% of patients in the IV arm (n = 96;, 95% CI, 31.2%-43.3%), meeting the non-inferiority standards of the study (relative risk, 1.11; 95% CI, 0.89-1.37). Responses across the bodyweight subgroups were consistent with the overall population of patients in the study with 44% of the 66 patients at the highest bodyweight having an overall response (n = 44).
A total of 295 patients were included in the pharmacokinetics analysis and of them, 149 received SC daratumumab and 146 received IV daratumumab. The mean maximum Ctroughwas 593 µg/mL (standard deviation [SD], 306) in the SC group and 522 µg/mL (SD, 226) in the IV group. The results showed the SC arm had a ratio of geometric means of 10793% (90% CI 95.74121.67), with the lower limit of the 90% confidence interval exceeding 80%, versus the IV arm, meeting the non-inferiority standards for the study. Across the bodyweight subgroups, the investigators observed notable overlap in maximum Ctrough, but the lightest weight group had about 60% higher mean maximum Ctrough, whereas the highest weight group had a 12% lower mean maximum Ctrough. The overall study population had consistently higher or comparable Ctroughvalues in the SC group compared with the IV group.
The best overall response observed in the study participants was a complete response (CR) or better, which occurred in 2% of patients in the SC arm and 3% of patients in the IV arm. Very good partial responses were observed in 17% in the SC arm and 14% in the IV arm. Thirty-nine percent of patients in the SC arm had stable disease, as did 36% of patients in the IV arm.
Disease progression occurred in an equal number of patients in both the SC and IV groups (51% each). For patients who received SC daratumumab, the median progression-free survival (PFS) was 5.6 months (95% CI, 4.7-7.6), and the median PFS was 6.1 months (95% CI, 4.7-8.3) for
those who received IV daratumumab (HR, 0.99; 95% CI, 0.78-1.26,P= .93).
Overall, both SC and IV formulations were tolerable in patients, but, SC daratumumab led to fewer infusion-related reactions (13% of 260 patients) than IV daratumumab (34% out of 258 patients). The odds ratio for this comparison was 0.28 (95% CI, 0.18-0.44;P<.0001).
Infusion-related reactions occurred most often after the first dose of daratumumab and were mainly grade 1 and 2 in severity. In the SC group, 2% of patients experienced grade 3 infusion-related reactions (n = 4), as did 5% of patients in the IV arm (n = 14). There were no grade 4 or higher cases observed in the study. Of the infusion-related reactions seen in the SC arm and IV arm, respectively, most were chills (5% vs 12%), pyrexia (5% vs 3%), or dyspnea (1% vs 7%).
For the IV arm, infusion-related reactions led to treatment interruptions in 31% of patients, a dosage decrease in 10% and 2 patients discontinued treatment. In the SC arm, there were no interruptions, dosage decreases, or discontinuations due to infusion-related reactions. The SC group did experience injection-site reactions, but these were mild and did not lead to discontinuation either.
Usmani et al concluded that these data may contribute to further FDA approval for daratumumab. Last year,a Biologics License Application was submitted to the FDA for the potential approval of the subcutaneous formulation.
Mateos MV, Nahi H, Legeic W. et al. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial [Published online March 23, 2020].Lancet Haematol. doi: 10.1016/ S2352-3026(20)30070-3.