Regulatory Decision Summary for Darzalex

Authorization of Darzalex (daratumumab) was based on the results from a two part, open-label, randomized, active-control, parallel group study that was designed to assess the safety and efficacy of adding daratumumab to induction (4 cycles) and consolidation (2 cycles) treatment with bortezomib, thalidomide and dexamethasone (VTd) in newly diagnosed patients with multiple myeloma who are eligible for an autologous stem cell transplant (ASCT). A total of 1,074 patients were randomized 1:1 to receive induction and consolidation therapy with daratumumab, bortezomib, thalidomide and dexamethasone (DVTd) versus VTd alone.

The primary endpoint was stringent complete response (sCR) at Day 100 post ASCT. More patients achieved sCR with the use of DVTd treatment (28.9%) compared to VTd treatment (20.3%). Secondary endpoints included the rate of complete response (CR) or better at Day 100 post-ASCT, as well as progression free survival (PFS). The rate of CR or better (38.9% vs 26%) was higher in the DVTd treatment arm compared to VTd alone. Median PFS had not been reached.

Safety findings are consistent with previous observations for daratumumab. The most common treatment emergent adverse events (TEAEs) in either group were peripheral sensory neuropathy, constipation, asthenia, nausea, peripheral edema, neutropenia, pyrexia, paresthesia and thrombocytopenia. There was a higher frequency (>5%) of TEAEs reported in the DVTd arm for the following events: thrombocytopenia, nausea, neutropenia, lymphopenia and cough. Infusion related reactions occurred in 35.4% of patients treated with daratumumab. Known events of interest with daratumumab that were seen with a higher frequency in the DVTd arm compared to the VTd arm in this study included neutropenia, thrombocytopenia, infection and infestation, opportunistic infections and hypertension.

The recommended dose of daratumumab is 16 mg/kg weekly for induction cycle 1 and 2, and 16 mg/kg every 2 weeks for induction cycle 3 and 4 and for consolidation therapy. Refer to the Product Monograph for details.

Daratumumab in combination with VTd demonstrated a deeper response to therapy compared to VTd alone, with early data showing an improvement in PFS in newly diagnosed patients with multiple myeloma who are transplant eligible. The safety profile is consistent with the known adverse events associated with daratumumab and is acceptable. Overall, the benefit-risk profile is positive and a Notice of Compliance (NOC) was recommended for daratumumab in combination with bortezomib, thalidomide and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma who are eligible for ASCT.