New Subcutaneous Daratumumab Formulation Overcomes Infusion Barrier for Patients

Daratumumab-based regimens have shown efficacy across all lines of therapy in multiple myeloma (MM), but the agent requires a long intravenous infusion time, lasting from three to seven hours. To lessen the treatment burden on patients, investigators have developed a new subcutaneous formulation of daratumumab that shortens the treatment time from hours to minutes, while maintaining the original formulation’s efficacy and tolerability, according to results reported at the 2019 American Society of Clinical Oncology annual meeting.

“Subcutaneous daratumumab had a similar safety profile … and a reduced treatment burden, due to considerably shorter administration duration,” lead author María-Victoria Mateos, MD, PhD, from the University Hospital of Salamanca in Spain, noted during her presentation.

The phase III COLUMBA trial evaluated the efficacy, pharmacokinetics, and safety of daratumumab administered subcutaneously or via intravenous infusion. All participants had relapsed/refractory MM and had received at least three prior lines of therapy (including an immunomodulatory drug and a proteasome inhibitor).

In the intravenous group, 259 patients received daratumumab 16 mg/kg weekly for cycles 1 and 2, every two weeks for cycles 3 through 6, and every four weeks thereafter until disease progression.

In the subcutaneous group, 263 patients received daratumumab 1,800 mg that was coformulated with recombinant human hyaluronidase PH20 (rHuPH20) 2,000 U/mL,
following the same treatment schema. Daratumumab 15 mL was given over three to five minutes, alternating between left and right abdominal sites.

Patient characteristics at baseline were similar between the intravenous and subcutaneous groups: Median ages were 68 years and 65 years, respectively, and median body weight was 73 kg and 72.4 kg. However, it appeared that more patients in the subcutaneous group had high-risk cytogenetics (83% and 74%; p value not reported).

After a median follow-up of 7.5 months (range = 0.03-13.9 months), safety was evaluable in 258 patients in the intravenous group and 260 in the subcutaneous group. Fifty-seven patients in each arm had discontinued treatment, mostly due to progressive disease (44 and 43 patients, respectively).

Dr. Mateos reported that “the median durations of treatment, as well as the median number of cycles, were comparable in both arms” but highlighted the substantially shorter duration of injection in the subcutaneous group. In the intravenous group, administration time ranged from 7.0 hours for the first infusion to 3.4 hours for subsequent infusions, but “subcutaneous daratumumab was delivered in only five minutes.”

In the efficacy analysis, overall response rates (co–primary endpoint) were 41% in the subcutaneous arm and 37% in the intravenous arm (relative risk = 1.11; 95% CI 0.89-1.37; p<0.001), meeting the significance for noninferiority of the new formulation. Rates of very good partial response (VGPR) and complete response (CR) also were similar between the two groups (VGPR: 17.1% and 14.3%, respectively; CR: 1.9% and 2.7%; p values for comparisons not reported).

“The responses were sustained across different subgroups … and regardless of patients’ body weight,” she added.

Each treatment formulation had similar pharmacokinetics, as well (measured as maximum Ctrough concentration at cycle 3). The ratio of Ctrough with subcutaneous daratumumab over intravenous daratumumab was 108%, again meeting the noninferiority criterion.

Dr. Mateos also shared results for secondary efficacy endpoints, noting that each administration type appeared to have similar overall survival (OS) and progression-free survival (PFS) outcomes:

  • 6-month OS rate: 87.5% for intravenous vs. 83% for subcutaneous (p=0.6)
  • median PFS: 6.1 months vs. 5.6 months (p=0.9)

Importantly, the subcutaneous route of administration was associated with a significantly lower rate of injection-related reactions (12.7% vs. 34.5%; p<0.001), suggesting that the new formulation avoids some of the toxicity seen with standard intravenous administration. Dr. Mateos added that injection-related reactions were generally mild, with no grade 4 events, and typically occurred at the first administration in each group.

Subcutaneous daratumumab also appeared to be better tolerated by patients, with more patients in the subcutaneous arm than the intravenous arm reporting that they were satisfied with their treatment.

The study results support the use of flat-dose, subcutaneous daratumumab, but the findings are potentially limited by the short duration of follow-up.

The authors report relationships with Janssen, which sponsored the study.

Reference

Mateos MV, Nahi H, Legiec W, et al. Efficacy and safety of the randomized, open-label, non-inferiority, phase 3 study of subcutaneous (SC) versus intravenous (IV) daratumumab (DARA) administration in patients (pts) with relapsed or refractory multiple myeloma (RRMM): COLUMBA. Abstract #8005. Presented at the 2019 ASCO Annual Meeting, June 2, 2019; Chicago, IL.

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