Subcutaneous Daratumumab is Noninferior to IV Administration in Relapsed/Refractory Myeloma

Subcutaneous daratumumab was found to be noninferior to intravenous (IV) daratumumab in patients with relapsed or refractory multiple myeloma (MM), according to results from the phase III COLUMBA trial.

The investigators also found that subcutaneous daratumumab may be perceived as more convenient by patients. “The subcutaneous formulation of daratumumab shows similar efficacy while increasing the convenience for patients and oncology infusion centers,” said lead study author Saad Usmani, MD, of the Levine Cancer Institute–Atrium Health in Charlotte, North Carolina. “This formulation will likely become the preferred way of administering daratumumab based on these attributes.”

The trial enrolled adults from 18 countries who had confirmed relapsed or refractory MM and had received ≥3 prior lines of therapy (e.g., proteasome inhibitor and immunomodulatory drug) or were double refractory to a proteasome inhibitor and immunomodulatory drug and had evidence of response to ≥1 previous therapeutic regimen. All patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2.

Randomization was stratified by body weight at baseline, prior therapy lines, and type of myeloma. Patients were randomized to either:

  • subcutaneous daratumumab 1,800 mg coformulated with 2,000 U/mL recombinant human hyaluronidase PH20 (n=263)
  • IV daratumumab 16 mg/kg (n=259)

Treatments were administered once weekly for cycles 1 and 2, every 2 weeks for cycles 3 to 6, and every 4 weeks thereafter for 28-day cycles until either progressive disease or toxicity.

Overall clinical response rate and a pharmacokinetic parameter, maximum trough concentration (Ctrough) of daratumumab, comprised the co-primary endpoints. The intention-to-treat population was used for the response rate efficacy analyses, whereas the pharmacokinetic analyses were performed in patients treated with all 8 weekly doses of daratumumab in cycles 1 and 2 who provided a predose pharmacokinetics blood sample on day 1 of cycle 3. The safety of daratumumab was assessed in patients treated with ≥1 dose of the therapy during the study period.

The treatment groups were balanced in terms of sex, age, race and ethnicity, and weight at baseline. More patients in the subcutaneous daratumumab group, however, had an ECOG score of 1 (58% vs. 51%) and 2 (18% vs. 15%). Patients in the subcutaneous group also had more high-risk cytogenetic abnormalities, including del(17p) (16% vs. 11%), t(4;14) (11% vs. 7%), and t(14;16) (4% vs. 2%).

“The subcutaneous formulation shows similar efficacy while increasing the convenience for patients and oncology infusion centers.”

—Saad Usmani, MD

Up to 13% of patients in the subcutaneous group and 14% of patients in the IV group experienced grade 3 or 4 anemia. Other grade 3 and 4 adverse events (AEs) included neutropenia in 13% of patients in the subcutaneous group and 8% of patients in the IV group as well as thrombocytopenia in 14% of patients in the subcutaneous group and 13% of patients in the IV group. The only serious AE was pneumonia, which was observed in 3% of patients in the subcutaneous group and 5% of patients in the IV group.

One death associated with a treatment-related AE (febrile neutropenia) was observed in the subcutaneous daratumumab group, whereas 4 deaths associated with treatment-related AEs were observed in the IV group (sepsis [n=2], hepatitis B reactivation [n=1], and Pneumocystis jirovecii pneumonia [n=1]).

The overall response and Ctrough met the predefined noninferiority criteria at a median follow-up of 7.5 months (interquartile range 6.5–9.3). Approximately 41% of patients who received subcutaneous daratumumab and 37% of patients who received IV daratumumab experienced an overall response during the study (relative risk=1.11; 95% CI 0.89–1.37). The maximum Ctrough values for the subcutaneous and IV groups were 593 μg/mL and 522 μg/mL, respectively, and the geometric means ratio for Ctrough was 107.9% (90% CI 95.74–121.67).

Researchers also used the 16-item patient-reported modified Cancer Therapy Satisfaction Questionnaire (CTSQ) to assess patient therapy satisfaction based on efficacy, tolerability, and convenience. More than 88% of the overall study population completed the self-reported outcome measure. Patients in the subcutaneous daratumumab arm had consistently high mean scores for the “satisfaction with therapy” domain compared with patients in the IV arm. In addition, patients treated with subcutaneous daratumumab tended to respond more positively to individual components of the “satisfied with form of cancer therapy (IV/subcutaneous),” “taking cancer therapy as difficult as expected,” and “were side effects as expected?” domains.

Limitations of the COLUMBA trial include the lack of patient and physician blinding to the assigned treatments and the imbalances between the two groups in baseline ECOG scores and cytogenetic risk profiles.

Several study authors report relationships with Janssen, which sponsored the trial.

Reference

Mateos MV, Nahi H, Legiec 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. Lancet Haematol. 2020;7:e370-e380.