FDA Approves Frontline Daratumumab/VMP Combo for Multiple Myeloma

Andrzej Jakubowiak, MD, PhD

The FDA has approved 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), based on findings from the ALCYONE study.

In the pivotal, open-label phase III study, 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 VMP 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.

“This approval is significant as we now have the first antibody-based regimen for treating newly diagnosed multiple myeloma patients who are not eligible for a stem cell transplant,” Andrzej Jakubowiak, MD, PhD, director of the Multiple Myeloma Program at University of Chicago Medical Center, said in a statement. “In clinical studies, patients who received treatment with daratumumab experienced a lower risk of disease progression and higher rates of response.”

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.

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.

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).

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.

"A patient's best chance at lasting remission often begins with a durable response to frontline therapy, because multiple myeloma can become more difficult to treat after relapse," ALCYONE lead investigator Maria-Victoria Mateos, MD, PhD, director of the Myeloma Unit at University Hospital of Salamanca-IBSAL, Salamanca, Spain, said in a statement. "Combi&shy;na&shy;tion therapy with daratumumab resulted in deep and durable responses in newly diagnosed patients with multiple myeloma who are transplant ineligible, supporting this regimen as an important new treatment option for these patients."

Daratumumab was first approved by the FDA in November 2015, with the combination of VMP and daratumumab marking the fifth indication for the medication. 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. In June 2017, the anti-CD38 antibody was approved with pomalidomide and dexamethasone for patients with multiple myeloma following 2 prior therapies.

References

1. 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.
2. 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.

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).

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.