The FDA approved the sBLA for the RANK ligand inhibitor denosumab, expanding its indication to include the prevention of skeletal-related events (SREs) in patients with multiple myeloma (MM).
The approval was based on results from the pivotal international, randomized, double-blind, multicenter, phase III ‘482 study that enrolled 1,718 patients with newly diagnosed MM and bone disease. Participants were randomized 1:1 to receive:
- denosumab 120 mg administered subcutaneously and intravenous (IV) placebo every 4 weeks (n=859)
- zoledronic acid (ZA) 4 mg IV (adjusted for renal function) and subcutaneous placebo every 4 weeks (n=859)
Denosumab was non-inferior to ZA in delaying time to first on-study SRE (including pathologic fracture, radiation to bone, surgery to bone, or spinal cord compression; primary endpoint). Median time to first on-study SRE was 22.83 months with denosumab and 23.98 months with ZA (HR=0.98, 95% CI 0.85-1.14; p value for non-inferiority =0.01). However, denosumab did not demonstrate superiority in delaying time to first SRE and delaying time to first-and-subsequent SREs (secondary endpoints).
Overall survival (OS) was comparable for denosumab and ZA (HR=0.90; 95% CI 0.70-1.16; p value for non-inferiority =0.41). Median PFS was 10.7 months longer in the denosumab group than the ZA group (46.1 months [range = 34.3 months to not estimable] and 35.4 months [range = 30.2 months to not estimable]; HR=0.82 [95% CI 0.68-0.99]; p=0.036).
The most common AEs (occurring in ≥10% of patients) associated with denosumab were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%), and headache (11%). Patients discontinued denosumab most commonly because of osteonecrosis of the jaw. This AE occurred more often in the denosumab group than in the ZA cohort (4.1% vs. 2.8%; p values not reported).
The median treatment exposure was 16 months (range = 1-50 months) with denosumab and 15 months (range = 1-45 months) with ZA.
Source: Amgen press release, January 5, 2018.