Japan Approves Daratumumab for Relapsed/Refractory Myeloma

Jan van de Winkel, PhD

The Japanese Ministry of Health, Labor and Welfare has approved the use of daratumumab (Darzalex) for the treatment of adults with relapsed/refractory multiple myeloma.

Daratumumab, a human IgG1k monoclonal antibody that binds with high affinity to the CD38 molecule, is indicated for use in combination with lenalidomide (Revlimid) and dexamethasone or bortezomib (Velcade) and dexamethasone. The FDA approved these triplet regimens in November 2016.

“Multiple myeloma is one of the most common forms of blood cancer in Japan and we are very pleased that Darzalex will soon also become available for Japanese multiple myeloma patients who have failed other treatments,” Jan van de Winkel, PhD, Genmab CEO, said in a press release. Genmab co-develops daratumumab with Janssen.

The Japanese approval is primarily based on results from CASTOR and POLLUX, a pair of pivotal phase III trials published in 2016.^1,2

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.

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.

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.