Subcutaneous Daratumumab in Myeloma Does Not Require Dose Individualization Based on Body Weight

The overall response rates (ORRs) with subcutaneous (SC) daratumumab (Darzalex Faspro) proved to be similar to that of the intravenous (IV) formulation of the drug irrespective of body weight, according to findings from a subgroup analysis of the phase 3 COLUMBA trial (NCT03277105) presented during the 2020 European Society for Blood and Marrow Transplantation Annual Meeting.¹

Results showed that the ORR with SC daratumumab in the intent-to-treat population was 41% versus 37% with the IV formulation. The ORRs reported with both formulations across the body weight subgroups analyzed proved to be consistent with the ITT population.

In the subgroup of patients with a body weight of 65 kg or less, the ORRs with the SC and IV formulations was 44% and 38%, respectively. For the subgroup of those who weighed between 65 kg and 85 kg, the ORRs were 37% versus 39%, respectively. In the last subgroup, those who weighed more than 85 kg, the ORRs with the SC and IV formulations were 44% versus 33%, respectively.

“In this subgroup analysis, ORRs in all body weight subgroups were consistent with the overall study population for the respective treatment groups, and ORRs were similar across body weight groups for subcutaneous daratumumab versus [the] IV [formulation],” Maria-Victoria Mateos, MD, PhD, director of the Myeloma Unit at University Hospital of Salamanca-IBSA, and colleagues wrote.

In the open-label, active-controlled, multicenter phase 3 COLUMBA trial, investigators set out to examine the efficacy, pharmacokinetic profile, and safety of SC daratumumab versus IV daratumumab monotherapy in heavily pretreated patients with relapsed/refractory multiple myeloma.

To be eligible for participation, patients had to be 18 years of age or older, have a multiple myeloma diagnosis per International Myeloma Working Group criteria with measurable disease at the time of screening, shown evidence of response to 1 or more prior lines of treatment, had an ECOG performance status score of 0 to 2, and acceptable bone marrow and organ function. Patients also had to have relapsed/refractory disease, have received 3 or more previous lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or have been refractory to both a PI and and IMiD. If they received prior treatment with daratumumab or other anti-CD38 therapies, they were not permitted to enroll.

A total of 522 patients were randomized 1:1 to receive daratumumab via IV administration (n = 259) or SC (n = 263). Patients were stratified based on baseline body weight into 3 groups: ≤65 kg, >65-85 kg, >85 kg; they were also stratified based on the number of prior lines of therapy they received (≤4 prior lines vs >4 prior lines), and the type of disease they had (IgG vs non-IgG).

Participants in the SC group received the agent at a flat dose of 1800 mg in a 15 mL solution, while those in the IV group received the drug at a dose of 16 mg/kg. In both arms, patients received daratumumab treatment weekly in the first 2 cycles followed by every 2 weeks for cycles 3 through 6 and every 4 weeks from cycle 7 until progressive disease.

Pre- and post-infusion medications encompassed acetaminophen, diphenhydramine, montelukast, methylprednisolone, and control agents for those who were at high risk of developing respiratory complications.

The primary end points of the trial were ORR and maximum C_trough, while key secondary end points included infusion-related reactions (IRRs), progression-free survival, rates of very good partial response or better and complete remission or better, time to next therapy, overall survival, and patient-reported outcomes.

Patient disease characteristics at baseline proved to be comparable between the treatment arms, with some variation with regard to cytogenetic risk levels. More patients in the SC group had high-risk cytogenetics (26%) versus those in the IV group (17%). The median age was 67 years and the median weight was 73 kg. Participants had received a median of 4 previous lines of treatment. All received previous treatment with both a PI and an IMiD and just under half, or 49% were refractory to both a PI and an IMiD.

Previous results from COLUMBA were presented during the 2019 ASCO Annual Meeting and showed that SC daratumumab elicited an ORR of 41.1% versus 37.1% with the IV formulation; this met the criteria for noninferiority (relative risk, 1.1; 95% CI, 0.89-1.37; P <.0001). Moreover, pharmacokinetic analyses also reached noninferiority for C_trough, and the median duration per infusion was reduced from 3 hours/infusion in the IV arm to just 5 minutes in the SC arm.²

Additional results from the subgroup analysis showed that the flat dose of SC daratumumab achieved acceptable exposure for all body weight subgroups. The maximum C_trough (cycle 3, day 1 pre-dose) surpassed the 236 µg/ml threshold that had been established in prior studies with IV daratumumab as necessary for 99% target saturation.

Moreover, maximum C_trough in both arms were found to have considerable overlap across each body weight subgroup, although mean concentrations of the drug were 60% higher for those who weighed 65 kg or less and 12% lower for those who weighed over 85 kg who received treatment with the subcutaneous formulation compared with the intravenous formulation.

For subcutaneous daratumumab, the range of C_trough across body weights was found to be within the previously observed range of 36-1,764 µg/ml for cycle 3 day 1 C_trough for the approved IV 16 mg/kg formulation, according to the study authors.

With regard to safety, higher rates of treatment-emergent adverse effects (TEAEs) were observed as body weight decreased with SC daratumumab, while rates of any-grade TEAEs were comparable across all body weight subgroups with the IV formulation.

Notably, high-grade neutropenia was observed at a higher rate in the group of patients receiving SC daratumumab who weighed 65 kg or less versus all other SC and IV body weight groups (range, 12%-17%). A similar trend was noted for grade 3/4 neutropenia in the SC body weight groups, at 20% for the ≤65-kg group, 10% for the >65-85–kg group, and 8% for the >85-kg group, and the IV groups, at 9%, 9%, and 5%, respectively.

However, across all groups, this toxicity was rarely considered to be serious; only 1 patient in the IV arm who fell into the >65-85–kg group had serious neutropenia. Investigators noted that the higher incidence of neutropenia reported in those who received SC daratumumab and fell into the ≤65-kg group did not lead to a higher incidence of infections. The incidences of infections that were grade 3/4 in severity were determined to be comparable across all weight subgroups examined. Notably, neutropenia was found to be well managed.

Overall incidences of grade 3/4, grade 5, and serious TEAEs that led to discontinuation of study treatment proved to be comparable across body weight subgroups for both formulations of daratumumab. The only serious TEAE to be reported in 5% or more of participants in a body weight subgroup was pneumonia. In the SC arm, 4% in the ≤65-kg group had it, 1% in the >65-85–kg group did, and 3% in the >85-kg group did; in the IV arm, the rates were 5%, 3%, and 5%, respectively. Lower overall rates of IRRs were reported with the SC formulation compared with the IV formulation, at 13% versus 35%, respectively (P < .0001).

“Subcutaneous daratumumab achieved adequate exposure consistent with the IV [formulation] and was well tolerated across all body weight subgroups, the authors concluded. “The higher concentrations of SC daratumumab in patients [who weighed more than] 65 kg did not have a clinically relevant effect on safety. Overall, these results suggest that no dose individualization of SC daratumumab is necessary on the basis of body weight.”

In May 2020, the FDA approved daratumumab and hyaluronidase-fihj for use in adult patients with newly diagnosed or relapsed/refractory multiple myeloma; this product allows for the SC administration of the drug.

The regulatory decision was based on data from COLUMBA; it was also supported by results from the ongoing phase 2 PLEIADES (MMY2040) trial (NCT03412565), which is evaluating SC daratumumab in combination with standard multiple myeloma treatment regimens.³

References

1. Mateos M-V, Usmani SZ, Grosicki S, et al. Phase 3, open-label, noninferiority study of subcutaneous versus intravenous daratumumab in patients with relapsed/refractory multiple myeloma (RRMM): body weight subgroup analysis of COLUMBA. Presented at: 2020 European Society for Blood and Marrow Transplantation Annual Meeting; August 30-September 2, 2020; Virtual. Poster #A355.
2. Mateos M-V, Nahi H, Leggier 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. J Clin Oncol. 2019;37(suppl 15):8005. doi:10.1200/JCO.2019.37.15_suppl.8005
3. A study to evaluate subcutaneous daratumumab in combination with standard multiple myeloma treatment regimens. ClinicalTrials.gov. Updated August 14, 2020. Accessed September 1, 2020. https://clinicaltrials.gov/ct2/show/NCT03412565.