FDA Approval Sought for Daratumumab Combos in Multiple Myeloma

A supplemental biologics license application has been submitted to the FDA for the use of daratumumab (Darzalex) in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone as a treatment for patients with multiple myeloma following at least 1 prior therapy.

Peter F. Lebowitz, MD, PhD

A supplemental biologics license application (sBLA) has been submitted to the FDA for the use of daratumumab (Darzalex) in combination with lenalidomide/dexamethasone or bortezomib/dexamethasone as a treatment for patients with multiple myeloma following at least 1 prior therapy, according to Janssen, which is developing the CD38-targeted antibody with Genmab.

The submission follows an FDA breakthrough therapy designation in this setting granted in July. The FDA will decide within 60 days on whether to award the sBLA a priority review, which would mean a final approval decision would be made within 6 months from today.

The application to expand daratumumab’s approval was based on 2 phase III trials. The phase III POLLUX trial demonstrated that combining daratumumab with lenalidomide (Revlimid) and dexamethasone reduced the risk of disease progression by 63% versus lenalidomide and dexamethasone alone in patients with relapsed/refractory multiple myeloma.1 In the phase III CASTOR trial, adding daratumumab to bortezomib (Velcade) and dexamethasone reduced the risk of progression or death by 61% in patients with recurrent or refractory multiple myeloma.2 The sBLA also included phase I data for treatment with daratumumab in combination with pomalidomide (Pomalyst) and dexamethasone following ≥2 lines of therapy.

“Daratumumab has been shown to provide clinically meaningful benefit as a backbone therapy in combination with two of the most widely used treatment regimens for multiple myeloma,” Peter F. Lebowitz, MD, PhD, global oncology head, Janssen, said in a statement. “Today's submission marks an important step forward in realizing the full potential of daratumumab earlier in the treatment pathway, and we look forward to working with the FDA during its review of our application.”

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). Daratumumab was dosed at 16 mg/kg IV once weekly during cycles 1 and 2, every 2 weeks during cycles 3 to 6, and once only (on day 1) of cycles 7 onward. Oral lenalidomide was administered at 25 mg daily for the first 3 weeks of each cycle and dexamethasone was dosed at 40 mg weekly (20 mg weekly in patients older than 75 or with a BMI <8.5). Treatment cycles for both study arms were 28 days. Patients were treated until progression or unacceptable toxicity.

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 <.0001). The overall response rate (ORR) was 93% versus 76%, respectively (P <.0001). The very good partial response (VGPR) or better rate was 76% with daratumumab versus 44% in the control arm (P <.0001) and the compete response (CR) rates were 43% and 19%, respectively (P <.0001).

The CASTOR trial included 498 patients were who were randomized 1:1 to receive 8 cycles of bortezomib/dexamethasone with or without 16 mg/kg of daratumumab. Bortezomib was administered subcutaneously at 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21-day cycle for a maximum of 8 cycles. Patients received 20 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles. Patients in the daratumumab group were administered an IV infusion of the antibody at 16 mg/kg weekly for the first 3 cycles, on day 1 of cycles 4 to 9, and then every 4 weeks. Treatment was administered until disease progression or unacceptable toxicity.

Median PFS was 7.2 months in the standard treatment arm and was not yet reached in the daratumumab arm (HR, 0.39; 95% CI, 0.28-0.53; P <.0001). The ORR was 83% and 63% (P <.0001) in the experimental and control arms, respectively. Nineteen percent of patients in the daratumumab arm had a CR or better and 59% of patients had a VGPR or better compared with 9% of patients experiencing a CR and 29% experiencing a VGPR in the control arm (P = .0012 and P <.0001, respectively).

The most common treatment-emergent AEs were thrombocytopenia, which occurred in 59% of patients in the daratumumab arm versus 44% in the bortezomib/dexamethasone arm; sensory peripheral neuropathy, which occurred in 47% and 38% of patients in the experimental and control arms, respectively; diarrhea, which occurred in 32% and 22% of patients in each arm respectively, and anemia, which occurred in 26% and 31% of patients in each arm, respectively.

  1. Dimopoulos MA , Oriol A, Nahi H, et al. An open-label, randomised phase 3 study of daratumumab, lenalidomide, and dexamethasone (DRd) versus lenalidomide and dexamethasone (Rd) in relapsed or refractory multiple myeloma (RRMM): POLLUX. Presented at: 2016 European Hematology Association Congress; June 9-12, 2016; Copenhagen, Denmark. Abstract LB2238.
  2. Palumbo A, Chanan-Khan A, Weisel K et. al. Phase 3 randomized controlled study of daratumumab, bortezomib and dexamethasone (DVd) vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (RRMM): CASTOR. Presented at: ASCO 2016; June 3-7, 2016; Chicago abstract: LBA4.

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 (52% in the daratumumab arm vs 37% in the control arm), thrombocytopenia (13% vs 14%), and anemia (12% vs 20%).

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