FDA Accepts Application for Frontline Daratumumab for Myeloma

The U.S. Food and Drug Administration (FDA) received a supplemental biologics license application (sBLA) for daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) for patients with newly diagnosed multiple myeloma (MM) who are ineligible for autologous hematopoietic cell transplantation (AHCT).

The application was supported by results from the randomized, open-label, multicenter, phase III ALCYONE trial, which compared frontline D-VMP versus VMP alone in 706 patients (median age = 71 years; range = 40-93 years) with MM who were ineligible for AHCT.

Participants were randomized 1:1 to receive a maximum of nine, six-week cycles of VMP or D-VMP in the following dosing regimens:

  • VMP: bortezomib 1.3 mg/m2 subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle 1, and days 1, 8, 22, and 29 thereafter; melphalan 9 mg/m2 twice-daily; and prednisone 60 mg/m2 twice-daily on days 1-4
  • D-VMP: VMP regimen plus daratumumab 16 mg/kg intravenously once-weekly during cycle 1, every 3 weeks for cycles 2-9, and once-monthly thereafter

By June 12, 2017 (prespecified date of analysis), patients had received a median of 12 treatment cycles (range = 1-24 cycles) in the D-VMP group and nine cycles (range = 1-9 cycles) in the VMP group. At a median follow-up of 16.5 months (range not provided), patients who received the daratumumab combination had a 50 percent reduction in the risk of progression or death, compared with VMP (hazard ratio [HR] for progression-free survival [PFS] = 0.50; 95% CI 0.38-0.65; p<0.0001). The median PFS was not reached in the D-VMP group and was 18.1 months in the VMP group (ranges not provided).

More patients in the D-VMP group attained minimal residual disease-negative status, compared with patients in the control group (22.3% vs. 6.2%; HR=4.36; 95% CI 2.64-7.21; p<0.0001).

Toxicity profiles were similar between study cohorts, except for the high incidence of any-grade upper respiratory tract infection (26.3% vs. 13.8%) and grade 3/4 pneumonia (11.3% vs. 4.0%) in the D-VMP group. Other common any-grade treatment-related adverse events (AEs) occurring in the D-VMP and VMP groups included neutropenia (49.7% vs. 52.5%), thrombocytopenia (48.8% vs. 53.7%), anemia (28.0% vs. 37.6%), and peripheral sensory neuropathy (28.3% vs. 34.2%). Common grade 3/4 AEs included neutropenia (39.9% vs. 38.7%), thrombocytopenia (34.4% vs. 37.6%), and anemia (15.9% vs. 19.8%).

Sources: Janssen press release, November 21, 2017; Mateos MV, Dimopoulos MA, Cavo M, et al. Phase 3 randomized study of daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) in newly diagnosed multiple myeloma (NDMM) patients (Pts) ineligible for transplant (ALCYONE). Abstract LBA-4. Presented at the 2017 American Society of Hematology Annual Meeting, December 12, 2017; Atlanta, GA.