Jan van de Winkel, PhD
The EMA’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of daratumumab (Darzalex) in combination with lenalidomide (Revlimid) and dexamethasone or bortezomib (Velcade) and dexamethasone for patients with relapsed multiple myeloma following at least 1 prior therapy, based on findings from the phase III POLLUX and CASTOR studies.1,2
The positive opinion will now be reviewed by the European Commission and a final approval decision for use in the European Union is expected in about 2 months
In the POLLUX trial, adding daratumumab to lenalidomide and dexamethasone reduced the risk of progression or death by 63% versus lenalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma. In the CASTOR trial, the addition of daratumumab to bortezomib and dexamethasone reduced the risk of progression or death by 61% compared with the 2 drugs alone for patients with recurrent or refractory multiple myeloma.
“We are very pleased to receive this positive opinion from the CHMP which brings the potential for patients in Europe with relapsed or refractory multiple myeloma to have access to treatment with Darzalex a key step closer. We very much look forward to a final decision from the European Commission on the application to expand the product label,” Jan van de Winkel, PhD, CEO of Genmab, which codevelops daratumumab with Janssen, said in a statement.
The international, open-label POLLUX trial randomized 569 patients with relapsed/refractory multiple myeloma to daratumumab combined with lenalidomide/dexamethasone (n = 286) or lenalidomide plus dexamethasone alone (n = 283). Patient characteristics were well balanced between the study arms. The median age across the trial was 65 years and the median number of prior treatment lines for each cohort was 1.
At a median follow-up of 13.5 months, the median progression-free survival (PFS) was not yet reached in the daratumumab arm versus 18.4 months with lenalidomide/dexamethasone alone (HR, 0.37; 95% CI, 0.27-0.52; P
<.001). The overall response rate (ORR) was 92.9% versus 76.4%, respectively (P
<.001). The very good partial response (VGPR) or better rate was 75.8% with daratumumab versus 44.2% in the control arm (P
<.001). The complete response (CR) rates were 43.1% and 19.2%, respectively (P
The CASTOR study randomized 498 patients with relapsed or refractory multiple myeloma to bortezomib and dexamethasone alone (n = 247) or with daratumumab (n = 251). Patients had received a median of 2 prior lines of therapy. Overall, 66% had received prior bortezomib, 76% received a prior immunomodulatory drug (IMiD), and 48% had received prior proteasome inhibitors and IMiD.
The 12-month PFS rate was 60.7% with daratumumab, bortezomib, and dexamethasone versus 26.9% for bortezomib and dexamethasone alone. After a median follow-up of 7.4 months, the median PFS was not reached in the daratumumab arm compared with 7.2 months in the control group (HR, 0.39; 95% CI, 0.28-0.53; P
The ORR with the addition of daratumumab was 82.9% compared with 63.2% in the control group (P
<.001). The VGPR or better rate was 59.2% with daratumumab versus 29.1% in the control arm (P
<.001). The CR rate was 19.2% with daratumumab versus 9.0% with the doublet (P
In the POLLUX study, the safety profile was consistent with previously report adverse events (AEs) for single-agent daratumumab and the combination of lenalidomide and dexamethasone. The most common grade 3/4 AEs were neutropenia (51.9% in the daratumumab arm vs 37% in the control arm), thrombocytopenia (12.7% vs 13.5%), and anemia (12.4% vs 19.6%). Infusion-related reactions associated with daratumumab were reported for 47.7% of patients and for the most part, were grade 1/2.
In the CASTOR study, the most common grade 3/4 AEs were thrombocytopenia (45.3% in the daratumumab group vs 32.9% in the control), anemia (14.4% vs 16.0%), and neutropenia (12.8% vs 4.2%). Daratumumab-associated infusion-related reactions were reported in 45.3% of patients. These were mostly grade 1/2, and occurred predominantly during the first infusion.
- Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331.
- Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-766.