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Subcutaneous daratumumab is non-inferior to the intravenous drug formulation in patients with relapsed or refractory multiple myeloma

Several studies have demonstrated the efficacy of daratumumab-based regimens in multiple myeloma (MM) across all lines of therapy. Despite the impressive efficacy of daratumumab, the long duration of the intravenous (IV) infusions are seen as a disadvantage of the agent. Results of the phase III COLUMBA study now established that the more convenient subcutaneous formulation of daratumumab is non-inferior to the IV form of the drug with similar efficacy results, a comparable safety profile and a lower rate of injection-related adverse events (AEs).


The CD38 targeting antibody daratumumab showed impressive efficacy in the treatment of both newly diagnosed and relapsed/refractory MM. One downside of a treatment with daratumumab is the IV administration route. In fact, the median duration of the first, second and subsequent IV infusions with daratumumab are 7.0, 4.3, and 3.4 hours, respectively. To overcome this issue a SC form of the drug was developed in which daratumumab is co-formulated with the recombinant human hyaluronidase PH20. In the phase Ib PAVO trial daratumumab SC at a flat dose of 1,800 mg showed comparable efficacy and safety as the IV form of the drug, with a similar pharmacokinetic profile and a lower rate of infusion-related reactions (IRR). To validate these findings, the randomized, phase III, non-inferiority COLUMBA study was designed.

In this study, patients with relapsed or refractory MM who received at least 3 prior lines of therapy were randomised (1:1) to subcutaneous daratumumab (DARA SC) (1,800mg QW in cycles 1-2, Q2W in cycles 3-6 and Q4W from cycle 7 onwards) (N=263), or the classical intravenous formulation of the drug (DARA IV) (16 mg/kg QW in cycles 1-2, Q2W in cycles 3-6 and Q4W thereafter) (N=259). The co-primary endpoints of this non-inferiority trial were objective response rate (ORR) and the maximum Ctrough level of the drug. As secondary objectives, the trial also looked at the IRR rate, the progression-free survival (PFS), the quality of the responses, the time to next therapy (TTNT), the overall survival (OS) and the safety of DARA SC vs. DARA IV.


The median age of patients in the study was 67 years, with one fifth of patients being 75 years of age or older. The median baseline body weight was 73 kg and patients received a median of 4 prior lines of therapy. In accordance to the inclusion criteria, all patients were previously treated with both a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD). Most patients were refractory to a prior systemic therapy, with 49.9% of them being refractory to both a PI and an IMiD. A slight discrepancy was seen between both study arms with respect to the proportion of patients with high-risk cytogenetics (19.8% and 13.5% for DARA SC and DARA IV, respectively).

The median duration of the treatment administration was significantly reduced with DARA SC compared to DARA IV. Whereas the administration time for DARA SC is 5 minutes, the median infusion time for DARA IV was 421, 255 and 205 minutes for the 1st, 2nd and subsequent infusion, respectively. DARA SC proved to be non-inferior to DARA IV with respect to the co-primary endpoint of ORR (37.1% with DARA IV vs 41.1% with DARA SC: RR [95% CI]: 1.11 [0.89-1.37] with a lower boundary for non-inferiority of 0.60). In addition to this, also the rates of complete and very good partial response or better were similar with both DARA formulations. The study also demonstrated non-inferiority for DARA SC with respect to the Ctrough level at the 1st day of cycle 3 (ratio DARA SC/DARA IV 107.93% (90% CI: 95.74%-121.67%, lower limit of 90% CI >80% meeting PK non-inferiority criteria). Importantly, the non-inferiority of DARA SC vs DARA IV was seen in all investigated subgroups and was maintained irrespective of the body weight of patients. Finally, the study also showed similar outcomes for PFS and OS with DARA SC and DARA IV.

With respect to safety, DARA SC was found to be associated with a significant reduction in the rate of IRR compared to DARA IV (12.7% vs 34.5%; OR [95% CI]: 0.28 [0.18-0.44]; p< 0.0001). Injection site reactions with DARA SC were seen in 6.9% of patients and were all low-grade (grade 1/2). The overall safety profile of both DARA formulations was comparable although DARA SC seemed to be associated with a slightly higher rate of grade 3/4 neutropenia (13% vs 8%). In contrast, chills (12% vs 6%) and dyspnea (11% vs 5%) were more frequent in the DARA SC arm. The overall incidence of grade 3-5 AEs was similar at 49% for DARA IV and 46% with DARA SC. Also the rate of treatment discontinuation due to AEs was similar in both treatment arms (8% with DARA IV vs 7% with DARA SC). Finally, a treatment satisfaction questionnaire revealed that DARA SC patients were generally more satisfied with their therapy than DARA IV patients.


The COLUMBA trial clearly demonstrates non-inferiority of DARA SC compared to DARA IV. The two drug formulations had comparable pharmacokinetics with similar efficacy and safety. Compared to DARA IV, DARA SC was associated with a significantly shorter administration time and a lower rate of IRR. As such, these data support the use of flat dose 1,800mg DARA SC for patients with MM.


Mateos M-V, Nahi H, Legiec W, et al. Randomized, open-label, non-inferiority, phase 3 study of subcuatenous (SC) versus intravenous (IV) daratumumab (DARA) administration in patients with relapsed or refractory multiple myeloma: COLUMBA. Presented at ASH 2019; Abstract S823.

Speaker Maria-Victoria Mateos


Maria-Victoria Mateos, MD, PhD, University Hospital of Salamanca, Salamanca, Spain


See: Keyslides


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