Daratumumab Combinations Get FDA Approval for Relapsed Myeloma

New Treatment for Relapsed Myeloma: Daratumumab Combination Therapy Gets FDA Approval

Following on findings from the phase III POLLUX and CASTOR studies, the FDA has granted approval to daratumumab (Darzalex) in combination with either lenalidomide (Revlimid) and dexamethasone or bortezomib (Velcade) and dexamethasone for patients with relapsed multiple myeloma who have had at least 1 prior therapy.

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.

“This is an exciting day for patients with multiple myeloma in the United States, who will now have the opportunity to receive Darzalex at an earlier point in treatment of their disease," Jan van de Winkel, PhD, CEO of Genmab, which codevelops daratumumab with Janssen, said in a statement. “We believe daratumumab has the potential to become a backbone therapy for multiple myeloma.”

The application was preceded by a breakthrough therapy designation for the same indication, which the CD38-targeted monoclonal antibody received in July 2016. The agent was given an initial accelerated approval as a monotherapy for myeloma after ≥3 prior therapies in November 2015.

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.

The FDA is also reviewing an application for the combination of daratumumab, pomalidomide (Pomalyst), and dexamethasone in patients with relapsed or refractory multiple myeloma following at least 2 prior therapies, with a proteasome inhibitor and an IMiD. A decision for this indication is anticipated by June 17, 2017.

References

• 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.