A Type II variation application has been submitted to the European Medicines Agency for the combination of daratumumab with lenalidomide and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation.
Jose Antonio Burun Vidal
A Type II variation application has been submitted to the European Medicines Agency for the combination of daratumumab (Darzalex) 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 application is based on results from the phase III MAIA (MMY3008) trial, which showed that the daratumumab regimen led to a 44% reduction in the risk of disease progression or death in transplant-ineligible patients with newly diagnosed multiple myeloma who are transplant ineligible compared with lenalidomide/dexamethasone alone (HR, 0.56; 95 CI, 0.43-0.73; P <.0001).2
“Today’s submission brings us one step closer to our goal of improving treatment outcomes for people newly diagnosed with multiple myeloma,” said José Antonio Burón Vidal, vice president of medical affairs, Europe, Middle East and Africa (EMEA), Janssen-Cilag Limited, the manufacturer of daratumumab. “We are incredibly grateful to the patients and investigators who participated in the MAIA clinical trial program and look forward to working closely with the regulatory authorities to secure approval of this new combination.”
In the open-label, multicenter, phase III MAIA trial, 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, results also demonstrated 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%).
In Europe, daratumumab is currently indicated in combination with bortezomib (Velcade), melphalan, and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for ASCT; as a single agent for the treatment of adult patients with relapsed/refractory multiple myeloma who previously received a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy; and in combination with either lenalidomide/dexamethasone or bortezomib/dexamethasone, for the treatment of adult patients with myeloma who have received at least 1 prior therapy.
The combination is also being reviewed by the FDA under the Real-Time Oncology Review pilot program.