FDA Grants Priority Review to Daratumumab Triplets for Relapsed Myeloma

Jan van de Winkel, PhD

The FDA has granted a priority review designation to 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. The priority review was based on findings from the phase III POLLUX and CASTOR studies, which were published in The New England Journal of Medicine.^1,2

In the phase III POLLUX trial,¹ 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 phase III CASTOR trial,² 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 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 FDA is scheduled to make a final decision on the supplemental application for the triplet regimens by February 17, 2017.

“People suffering from multiple myeloma always ultimately relapse after receiving treatment with the therapies available today," Jan van de Winkel, PhD, chief executive officer of Genmab, which codevelops daratumumab with Janssen, said in a statement. "The application for daratumumab in combination with current backbone therapies for patients who have already received at least 1 type of treatment is a key step towards trying to bring new treatment options to patients with multiple myeloma."

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 study² 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.

In addition to the priority review, the FDA has also granted a standard review to the combination of daratumumab, pomalidomide (Pomalyst), and dexamethasone for patients with relapsed or refractory multiple myeloma following at least 2 prior therapies, with a proteasome inhibitor and an IMiD. This review will be based on data from the phase Ib MMY1001 study.³ A decision for this indication is anticipated by June 17, 2017.

In the MMY1001 study, 77 patients with relapsed/refractory myeloma received daratumumab, pomalidomide, and dexamethasone. The median age of patients was 64 years, and the median number of prior therapies was 3.5. Overall, 65% of patients were refractory to bortezomib, 30% to carfilzomib, 88% to lenalidomide, and 65% to both a proteasome inhibitor and IMiD.

In 75 evaluable patients, the ORR was 71% with the triplet (95% CI, 59.0-80.6). The stringent CR rate was 5%, the CR rate was 4%, and the VGPR rate was 33%. In patients with double-refractory disease, the ORR was 67%. The median time to best response was 2.8 months.

Serious AEs occurred in 42% of patients, and grade ≥3 events were seen in 91% of patients. Overall, 46% of patients required G-CSF and 25% needed blood transfusions. The most common grade ≥3 events were neutropenia (60%), anemia (25%), leukopenia (20%), and thrombocytopenia (15%).

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.
3. Chari A, Lonial S, Suvannasankha A, et al: Open-label multicenter phase 1b study of daratumumab in combination with pomalidomide and dexamethasone in patients with at least 2 lines of prior therapy and relapsed or relapsed and refractory multiple myeloma. Presented at the 2015 ASH Annual Meeting and Exposition. Abstract 508.

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.