EU Approves Daratumumab Triplets for Myeloma

Jan van de Winkel, PhD

The European Commission (EC) has approved daratumumab (Darzalex) for use in combination with lenalidomide (Revlimid) and dexamethasone or bortezomib (Velcade) and dexamethasone for the treatment of patients with multiple myeloma following at least 1 prior therapy, based primarily on findings from the phase III POLLUX and CASTOR studies.^1,2

In the POLLUX trial, adding the CD38-targeted antibody 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.

The approval follows a recommendation from the European Medicines Agency’s Committee for Medicinal Products for Human Use issued in February. The EC action also converts the previous conditional marketing authorization for single-agent daratumumab to a full approval.

“We are very pleased that Darzalex is now approved in Europe in combination with other standard multiple myeloma therapies and that a far greater number of patients suffering from this incurable disease will now have access to this first-in-class immunotherapy,” 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 <.001).

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 <.0001).

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 = .001).

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.

Daratumumab was previously approved by the EC as a monotherapy for the treatment of adult patients with relapsed/refractory multiple myeloma whose prior therapy included a proteasome inhibitor and an immunomodulatory agent.

References

1. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331.
2. 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.