Newly diagnosed patients with multiple myeloma who are not candidates for high-dose chemotherapy and autologous stem cell transplant saw a 45% reduction in the risk of disease progression or death with the addition of daratumumab (Darzalex) to lenalidomide (Revlimid) and dexamethasone compared with lenalidomide/dexamethasone alone.
Jan van de Winkel, PhD
Newly diagnosed patients with multiple myeloma who are not candidates for high-dose chemotherapy and autologous stem-cell transplant (ASCT) saw a 45% reduction in the risk of disease progression or death with the addition of daratumumab (Darzalex) to lenalidomide (Revlimid) and dexamethasone (DRd) compared with lenalidomide/dexamethasone (Rd) alone, according to topline findings from an interim analysis of the phase III MAIA study (MMY3008).1
Additional data from the trial will be submitted for presentation at a medical conference and publication in a peer-reviewed journal, the companies noted. Genmab and Janssen also intend to communicate with regulatory authorities regarding an indication for the triplet regimen in this setting.
“We are highly encouraged by this data as this is the fifth randomized study showing a profound benefit when adding daratumumab to standard of care treatments in multiple myeloma, and the second showing efficacy for patients with newly diagnosed multiple myeloma who are not eligible for ASCT. As such this data increases our hope that daratumumab may 1 day help even more patients at the outset of treatment of this disease,” Jan van de Winkel, PhD, chief executive officer, Genmab, said in a statement.
The open-label, multicenter phase III MAIA trial (NCT02252172) included 737 newly diagnosed patients with multiple myeloma who were not candidates for high-dose chemotherapy and ASCT. Patients were randomized to lenalidomide (25 mg orally on days 1-21 of each 28-day cycle) and dexamethasone (40 mg once a week) with or without daratumumab. Daratumumab was administered at 16 mg/kg weekly for the first 8 weeks (cycles 1 and 2), every other week for 16 weeks (cycles 3 to 6), and then every 4 weeks (cycle 7 and beyond) until disease progression or unacceptable toxicity. PFS was the primary endpoint.
Frontline daratumumab was previously approved in multiple myeloma for use in combination with bortezomib (Velcade), melphalan, and prednisone (VMP) for the treatment patients who are ineligible for ASCT. However, the VMP regimen is mostly utilized in Europe, not in the United States.
The frontline approval of daratumumab plus VMP was based on the phase III ALCYONE study, in which the 4-drug regimen 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 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.
Data from the study were published in theNew England Journal of Medicineand presented at the 2017 ASH Annual Meeting.2,3In the ALCYONE trial, 706 patient 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.
In addition to the VMP regimen, daratumumab has 3 other FDA-approved indications: in combination with lenalidomide and dexamethasone, or bortezomib (Velcade) and dexamethasone, for the treatment of patients with multiple myeloma who have received at least 1 prior therapy; in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor (PI); and as monotherapy, for the treatment of patients with multiple myeloma who have received at least 3 prior lines of therapy including a PI and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent.
The median progression-free survival (PFS) had not been reached for the daratumumab triplet compared with 31.9 months in the Rd group (HR, 0.55; 95% CI, 0.43-0.72;P<.0001). The safety data were comparable to those previously reported for single-agent daratumumab and the Rd regimen, according to a press release from Genmab A/S and Janssen Biotech, the developers of daratumumab.