FDA Approves Treatment for Multiple Myeloma Patients Ineligible for ASCT

The U.S. Food and Drug Administration (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).

The approval comes on the heels of findings from the pivotal, open-label phase 3 ALCYONE study, in which daratumumab plus VMP exhibited a 50% reduction in the risk of progression or death compared to 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 (OS) 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,” said Andrzej Jakubowiak, M.D., Ph.D., Director of the Multiple Myeloma Program at University of Chicago Medical Center, Chicago, Illinois and a Darzalex clinical study investigator. “In clinical studies, patients who received treatment with daratumumab experienced a lower risk of disease progression and higher rates of response.”

The ALCYONE trial enrolled 706 individuals with newly diagnosed multiple myeloma and randomized them to receiver either 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.

Both cohorts of patients saw similar baseline characteristics. In the daratumumab arm, the median age was 71 years old and 30% were 75 years of age or older. The Easteron Cooperative Oncology Group (ECOG) performance status was 0 (22%), 1 (52%), and 2 (26%). Light chain melanoma was present in 10% of patients, and the others were Immunoglobulin (IgG) (64%) and Immunoglobuilin A (IgA) (21%). The most typical International Staging System (ISS) stages were III (41%) and II (40%) By cytogenetic profile, 17% of patients were considered high-risk.

At the 12-month assessment, 87% of patients in the daratumumab group endured as alive and progression-free compared to 76% of those administered 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.

A substantially greater number of 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 compared to 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 were peripheral sensory neuropathy (1% vs 4%), diarrhea (3% each), and pneumonia (11% vs 4%), respectively.

Infusion-related reactions occurred in 27.7% of patients in the daratumumab group.

“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,” said Maria-Victoria Mateos, M.D., Ph.D., Director of the Myeloma Unit at University Hospital of Salamanca-IBSAL, Salamanca, Spain and ALCYONE primary investigator. “Combination 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.”

Data from the study were published in the New England Journal of Medicine and presented at the 2017 ASH Annual Meeting.

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. The agent continues to be investigated across several clinical trials, including the phase 3 CASSIOPEIA study, which is evaluating 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).

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