FDA Approves Split-Dosing Regimen of Daratumumab for Multiple Myeloma

The FDA has approved a split-dosing regimen of daratumumab (Darzalex) for patients with multiple myeloma, providing physicians the option to split the first infusion of the CD38-directed monoclonal antibody over 2 consecutive days or complete in a single session.¹

The approval is based on findings from the phase Ib EQUULEUS (MMY1001) trial, which demonstrated that the pharmacokinetic concentrations of daratumumab at 16 mg/kg were comparable at the end of weekly dosing, regardless of whether it was a split-dose or a single infusion.² Additionally, the safety profiles were similar across both dosing regimens.

“The first infusion of daratumumab is an important first step in a patient’s course of therapy, and this approval provides added flexibility for how patients may receive initial treatment,” Craig Tendler, MD, vice president, clinical development and global medical affairs, Janssen Research & Development, LLC, which codevelops daratumumab with Genmab, said in a press release. “We are committed to exploring options that may improve the overall treatment experience for patients.”

This decision follows approvals in both Canada and the European Union in December 2018 for the daratumumab initial infusion split-dosing regimen.

Daratumumab is currently indicated as a single agent for patients with myeloma who have received ≥3 prior lines of therapy; in combination with lenalidomide (Revlimid) and dexamethasone or bortezomib (Velcade) and dexamethasone for patients who have received ≥1 prior line of therapy; in combination with pomalidomide (Pomalyst) and dexamethasone for those with myeloma who have received at least 2 prior lines of therapy, including lenalidomide and a proteasome inhibitor; and in combination with bortezomib, melphalan, and prednisone for the treatment of newly diagnosed myeloma who are ineligible for autologous stem cell transplant.

In the international, multi-arm, open-label, nonrandomized EQUULEUS trial (NCT01998971), investigators evaluated daratumumab in combination with various backbone therapies in patients with relapsed/refractory multiple myeloma. In a subgroup analysis of the trial, findings of which were reported at the 2018 ASCO Annual Meeting, 85 patients with relapsed/refractory multiple myeloma were treated with daratumumab in combination with carfilzomib (Kyprolis) and dexamethasone.

Patients had received 1 to 3 prior lines of therapy, including bortezomib and an immunomodulatory (IMiD) agent. Per protocol, daratumumab was administered intravenously (IV) as a single first dose of 16 mg/kg (n = 10) or as a split first dose of 8 mg/kg on days 1 and 2 of cycle 1 (n = 75). Patients also received carfilzomib at 20 mg/m² IV on day 1 of cycle 1, and dexamethasone IV or orally at 40 mg weekly on days 1, 8, 15, and 22.

The baseline characteristics were similar in the lenalidomide-refractory cohort (n = 51) and the overall population (n = 85). The primary endpoints were safety and tolerability; secondary endpoints were overall response rate (ORR) and overall survival (OS).

At a median follow-up of 12.0 months for the overall and lenalidomide-refractory population, the treatment-emergent adverse event (TEAE) profiles were similar across both groups. In the overall population, the most common hematologic TEAEs were thrombocytopenia (67%), anemia (47%), neutropenia (29%), and lymphopenia (25%). Nonhematologic TEAEs were nausea (40%), upper respiratory tract infection (39%), asthenia (38%), vomiting (37%), dyspnea (34%), pyrexia (33%), insomnia (31%), diarrhea (31%), hypertension (25%), cough (25%), headache (22%), and back pain (22%). Grade 3/4 TEAEs in ≥20% of patients were thrombocytopenia (31%), anemia (21%), neutropenia (21%), and lymphopenia (22%).

Regarding the dosing regimens, infusion-related reactions (IRRs) were reported in 50% (n = 5) of patients on the single daratumumab infusion compared with 36% (n = 27) reported on the first split dose and 4% (n = 3) on the second split dose. The median infusion time was 7.1 hours (range, 6.5-8.9) compared with 4.3 hours (range, 3.9-10.6) on the first split dose and 4.2 hours (range, 3.9-8.6) on the second split dose. The IRRs rates and infusion times were consistent between single and split first dose regimens for subsequent infusions.

Findings also showed that the split and single daratumumab doses have similar pharmacokinetic profiles. Overall, the findings suggested that the split-dosing regimen is feasible and may improve patient convenience for initial dosing.

Regarding efficacy, the ORR in the overall population who were treated with the triplet regimen was 84% compared with 79% in the lenalidomide-refractory population and 90% in patients who were exposed to lenalidomide but not refractory. Minimal residual disease (MRD)-negative rates were 36%, 20%, and 50% in the overall, lenalidomide-refractory, and lenalidomide-exposed-but-not-refractory populations, respectively. The investigators noted that responses are anticipated to deepen over longer follow-up.

The median progression-free survival (PFS) in the overall and lenalidomide-exposed groups were not estimable compared with 14.1 months for the lenalidomide-refractory population. The 12-month PFS rates were 71%, 87%, and 62%, respectively. For patients who were refractory to a PI and an IMiD agent, the median PFS was not estimable and the 12-month PFS rate was 51%.

The median OS was not estimable in the overall and lenalidomide-exposed populations. In the lenalidomide-refractory group, the median OS was 21.1 months (95% CI, 18.8-NE) and 18.8 months (95% CI, 18.8-NE) in the PI/IMiD-refractory groups. The 12-month OS rates were 82%, 90%, 75%, and 75%, respectively. Follow-up for OS is ongoing.

Additionally, Janssen and Genmab have completed the first part of a supplemental biologics license application for daratumumab in combination with lenalidomide and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma. The agency is reviewing the sBLA under the Real-Time Oncology Review pilot program.

References

1. U.S. FDA Approves DARZALEX® (daratumumab) Split-Dosing Regimen. Janssen. Published February 12, 2019. https://prn.to/2tkVelH. Accessed February 12, 2019.
2. Chari AJ, Martinez-Lopez J, Mateos MV, et al. Daratumumab (DARA) in combination with carfilzomib and dexamethasone (D-Kd) in lenalidomide (Len)-refractory patients (Pts) with relapsed multiple myeloma (MM): Subgroup analysis of MMY1001. J Clin Oncol. 2018;36 (suppl; abstr 8002).