A supplemental biologics license application has been submitted to the FDA for the approval of daratumumab in combination with lenalidomide and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.
Yusri Elsayed, MD, MHSc, PhD
A supplemental biologics license application (sBLA) has been submitted to the FDA for the approval of daratumumab (Darzalex) 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 transplant (ASCT).1
The application is based on findings from the phase III MAIA (MMY3008) trial, in which DRd led to a 44% reduction in the risk of disease progression or death in patients with newly diagnosed multiple myeloma who are transplant ineligible compared with Rd alone, at a median follow-up of 28 months (HR, 0.56; 95 CI, 0.43-0.73; P <.0001).2
"We are pleased to complete the latest Darzalex submission based upon the phase III MAIA study, which evaluated the efficacy and safety of this anti-CD38 monoclonal antibody as a combination regimen for newly diagnosed patients with multiple myeloma who are transplant ineligible," said Yusri Elsayed, MD, MHSc, PhD, vice president, Hematologic Malignancies Disease Area Leader, Janssen Research & Development, LLC, the manufacturer of daratumumab. "We look forward to closely collaborating with the agency throughout the expedited Real-Time Oncology Review process in support of this newly diagnosed, transplant ineligible multiple myeloma patient population for whom a combination treatment regimen with Darzalex may be useful."
The sBLA is also being reviewed by the FDA under the Real-Time Oncology Review pilot program, which, for certain applications, permits the FDA to review data before the applicant formally submits the complete application to potentially provide a more efficient review process and allow therapies to become available sooner to patients.
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.
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%).
The FDA previously approved daratumumab was previously approved in multiple myeloma for use in combination with bortezomib (Velcade), melphalan, and prednisone (VMP) for the treatment patients who are ineligible for ASCT, but the VMP regimen is mainly utilized in Europe.