Based on findings from the ALCYONE study, which were published in the <em>New England Journal of Medicine</em> and presented at the 2017 ASH Annual Meeting,<sup> </sup>the FDA has granted a priority review designation to daratumumab (Darzalex) in combination with bortezomib (Velcade), melphalan, and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.
Jan van de Winkel, PhD
Based on findings from the ALCYONE study, which were published in theNew England Journal of Medicineand presented at the 2017 ASH Annual Meeting,1,2the FDA has granted a priority review designation to daratumumab (Darzalex) in combination with bortezomib (Velcade), melphalan, and prednisone (VMP) for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT).
In findings from the phase III study, daratumumab plus VMP elicited an 18-month progression-free survival (PFS) rate of 71.6% (95% CI, 65.5%-76.8%) compared with 50.2% (95% CI, 65.5%-76.8%) for VMP alone, representing a 50% reduction in the risk of progression or death (HR, 0.50; 96% CI, 0.38-0.65;P<.001). At a median follow-up of 16.5 months, follow-up for long-term survival remained ongoing.
The FDA will decide on the application for the anti-CD38 antibody daratumumab plus VMP by May 21, 2018, as part of the Prescription Drug User Fee Act (PDUFA).
“The granting of priority review to the submission of daratumumab in front-line multiple myeloma is an important step forward towards potentially bringing this product to an even larger number of patients in need,” said Jan van de Winkel, PhD, chief executive officer of Genmab, which codevelops daratumumab with Janssen, said in a statement.
In the open-label ALCYONE trial, 706 with newly diagnosed multiple myeloma were randomized to receive VMP alone (n = 356) or in combination with daratumumab (n = 350). VMP was administered at standard doses and daratumumab was added at 16 mg/kg once weekly in cycle 1 and every 3 weeks in cycles 2 through 9. Beyond month 9 in the investigational arm, daratumumab was continued every 4 weeks until disease progression.
Baseline characteristics were similar between the two groups of patients. In the daratumumab arm, the median age was 71 years and 30% were ≥75 years of age. The ECOG performance status was 0 (22%), 1 (52%), and 2 (26%). Ten percent of patients had light chain myeloma, with the remainder being IgG (64%) and IgA (21%). The most common ISS stages were III (41%) and II (40%). Seventeen percent of patients were high-risk by cytogenetic profile.
The median PFS was 18.1 months in the VPM arm and was not yet reached for those treated with the daratumumab regimen. At the 12-month assessment, 87% of patients remained alive and progression-free in the daratumumab group versus 76% for VMP. PFS was improved with the addition of daratumumab across subgroups.
The objective response rate (ORR) with the daratumumab regimen was 90.9% compared with 73.9% in the control arm (P<.001), this included a complete response (CR) or better for 42.6% of patients in the daratumumab arm compared with 24.4% in the VMP alone group (P<.001). The very good partial response or better rate was 71% for daratumumab versus 50% for VMP alone. The median duration of response was 21.3 months for VMP and was not yet reached in the daratumumab group.
The most common hematologic adverse events (AEs) of grade 3/4 severity with the daratumumab combination versus VMP alone, respectively, were neutropenia (39.9% vs 38.7%), thrombocytopenia (37.6% vs 34.4%), and anemia (19.8% vs 15.9%). The most common grade 3/4 nonhematologic AEs for daratumumab versus VMP, respectively, were peripheral sensory neuropathy (1% vs 4%), diarrhea (3% each), and pneumonia (11% vs 4%). Infusion-related reactions occurred in 27.7% of patients in the daratumumab group.
The rate of grade 3/4 infection was 23.1% for daratumumab compared with 14.7% for VMP alone. Infections led to treatment discontinuation for 1.4% of patients in the VMP group and 0.9% in the daratumumab group. Serious AEs occurred in 41.6% of patients in the daratumumab arm and for 32.5% of patients in the VMP group. AEs led to discontinuation for 4.9% of patients in the daratumumab group versus 9.0% for the control arm.
"ALCYONE strongly supports daratumumab-VMP as a standard of care in transplant-ineligible newly diagnosed multiple myeloma," lead investigator Maria-Victoria Mateos, MD, PhD, director of the Myeloma Unit at University Hospital of Salamanca-IBSAL Salamanca, Spain, said during a presentation of the results at the 2017 ASH Annual Meeting. "Daratumumab plus VMP reduced the risk of progression or death and induced significantly deeper responses. There were no new safety signals observed except for higher infection events that resolved."
In November 2016, the FDA approved daratumumab in combination with lenalidomide (Revlimid) and dexamethasone or bortezomib and dexamethasone for patients with relapsed multiple myeloma following at least 1 prior therapy. This indication was based on a 61% to 63% reduction in the risk of progression or death in the phase III CASTOR and POLLUX trials.
The agent continues to be explored across several clinical trials, including the phase III CASSIOPEIA study, which is looking at the daratumumab in combination with bortezomib, thalidomide, and dexamethasone for untreated transplant-ineligible patients with multiple myeloma (NCT02541383). Additionally, a subcutaneous administration route of the intravenous medication is also being explored in a phase III trial (NCT03277105).
Significantly more patients tested negative for minimal residual disease (MRD) in the daratumumab group versus VMP alone. In the investigational arm, 22.3% were negative for MRD versus 6.2% in the VMP group (P<.001).