FDA Approves Daratumumab/VMP for First-Line Treatment of Multiple Myeloma

The FDA has approved the monoclonal antibody 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).

The approval is based on findings from the open-label phase III ALCYONE study, which showed that daratumumab plus VMP demonstrated a 50% reduction in the risk of progression or death compared with VMP alone (HR, 0.50; 95% CI, 0.38-0.65; P <.001). The median progression-free survival (PFS) was 18.1 months in the VPM arm and was not yet reached for those treated with the daratumumab regimen. Follow-up remained ongoing for overall survival at the 16.5-month assessment.

“With this label expansion, Darzalex becomes the first antibody therapeutic to be approved for patients with newly diagnosed multiple myeloma,” Jan van de Winkel, PhD, chief executive officer of Genmab, which codevelops daratumumab with Janssen, said in a statement. “This is an important step forward as it provides an additional treatment option to patients who are newly diagnosed with multiple myeloma.”

The ALCYONE Trial

In the 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.

At the 12-month assessment, 87% of patients remained alive and progression-free in the daratumumab group versus 76% for VMP. The 18-month PFS rate was 71.6% (95% CI, 65.5%-76.8%) with daratumumab plus VMP compared with 50.2% (95% CI, 43.2%-56.7%) for VMP alone. 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.

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).

Adverse Effects

The most common hematologic adverse effects (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.

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.

Data from the study were published in the New England Journal of Medicine and presented at the 2017 ASH Annual Meeting.^1,2 A marketing authorization application (MAA) for daratumumab plus VMP is pending in the European Union, where the VMP regimen is more commonly used. The MAA was submitted to the European Medicines Agency in November 2017.

Future Applications

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).

References

• Mateos M-V, DA Meletios, Cavo M, et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2017. DOI:10.1056/NEJMoa1714678.
• Mateos M-V, DA Meletios, 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). Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta, Georgia. Abstract LBA-4.