The European Medicines Agency's Committee for Medicinal Products for Human Use has backed approval of daratumumab for use in combination with lenalidomide and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation.
Jan van de Winkel, PhD
The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has backed approval of daratumumab (Darzalex) for use in combination with lenalidomide (Revlimid) and dexamethasone (DRd) for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT).1
The CHMP based its positive opinion on findings from the phase III MAIA (MMY3008) trial, in which the daratumumab regimen led to a 44% reduction in the risk of disease progression or death versus lenalidomide/dexamethasone alone in transplant-ineligible patients with newly diagnosed multiple myeloma (HR, 0.56; 95 CI, 0.43-0.73; P <.0001).2,3
The EMA application was submitted in March 2019 by Janssen Pharmaceuticals. Genmab granted Janssen an exclusive global license in August 2012 to develop, manufacture, and commercialize daratumumab.
“We are encouraged that the CHMP are recommending a broadening of the current Darzalex marketing authorization in the European Union to include Darzalex in combination with lenalidomide and dexamethasone as a possible treatment for patients newly diagnosed with multiple myeloma. This would give patients another treatment option, in addition to the already approved combination of daratumumab plus bortezomib, melphalan and prednisone in this same setting,” Jan van de Winkel, PhD, chief executive officer of Genmab.
In the open-label, multicenter, phase III MAIA study, 737 newly diagnosed patients with multiple myeloma who were ineligible for high-dose chemotherapy and ASCT aged 45 to 90 years old. Patients were randomized to receive either DRd or Rd alone in 28-day cycles. In the DRd arm, patients received daratumumab intravenously at 16 mg/kg 16 weekly for cycles 1 to 2, every 2 weeks for cycles 3 to 6, and every 4 weeks for cycle 7 and thereafter; also in this arm, 25 mg of lenalidomide was administered on days 1 to 21 of each 28-day cycle, and dexamethasone at 40 mg once a week for each cycle. Treatment was administered in both arms until disease progression or unacceptable toxicity.
The median age was 73 (range, 45-90), and 52% of patients were male and 92% were white. The ECOG performance status was 0 or 1 for 83% of patients. Per the multiple myeloma international staging system, 27% of patients were stage I, 43% of patients were stage II, and 29% of patients were stage III. Of the total population, cytogenetic risk level could be determined for 642 patients. A total 86% of these patients were standard risk and 14% of these patients were high risk.
At a median follow-up of 28 months, findings showed that the median progression-free survival for DRd has not yet been reached compared with 31.9 months for patients who received Rd alone. Moreover, DRd led to deeper responses versus Rd alone, including higher rates of a complete response or better at 48% versus 25%. The overall response rate was also higher with the triplet regimen, at 93% versus 81%, respectively.
Regarding safety, the most common grade 3/4 treatment-emergent adverse events (TEAEs) for DRd (≥10%) included neutropenia (5%), lymphopenia (15%), pneumonia (14%) and anemia (12%). Infusion-related reactions occurred in 41% of patients, 3% of which were grade 3/4. The safety profile of daratumumab was consistent with what has been reported in prior studies.
The most common grade 3/4 hematologic TEAEs in the DRd arm were neutropenia (50% vs 35% with Rd), lymphopenia (15% vs 11%), anemia (12% vs 20%), and thrombocytopenia (7% vs 9%).
The most frequently occurring nonhematologic TEAEs in the DRd arm included pneumonia (14% vs 8% with Rd); fatigue (8% vs 4%); diarrhea (7% vs 4%); deep vein thrombosis, pulmonary embolism, or both (6% in each arm); asthenia (4% in each arm); back pain (3% in each arm); constipation (2% vs <1%); peripheral edema (2% vs <1%); and nausea (1% vs ≤1%).
The FDA approved the DRd regimen in June 2019 for use in this setting.