DARZALEX Shows Overall Survival Benefit in Multiple Myeloma Patients

The Janssen Pharmaceutical Companies of Johnson & Johnson announced overall survival (OS) results from the Phase 3 ALCYONE study, which showed the addition of DARZALEX® (daratumumab) to bortezomib, melphalan and prednisone (D-VMP) improved OS in patients with newly diagnosed, transplant-ineligible multiple myeloma, with a 40 percent reduction in the risk of death compared to VMP alone. These updated data from the ALCYONE study also demonstrated that the addition of DARZALEX® to VMP resulted in higher rates of minimal residual disease (MRD) negativity.

"As a physician treating patients with multiple myeloma, I want to achieve the deepest response in the frontline setting to hopefully provide long-term benefit," said Maria-Victoria Mateos, M.D., Ph.D., Director of the Myeloma Unit at University Hospital of Salamanca-IBSAL, Salamanca, Spain, and a study investigator. "This longer follow-up from the ALCYONE study is encouraging because we see that adding daratumumab to VMP in the frontline setting can provide an important overall survival advantage compared with a current standard of care."

Results of a prespecified interim analysis, after a median duration of follow-up of more than three years, showed an estimated 42-month OS rate of 75 percent for DARZALEX®-VMP versus 62 percent for VMP, with a statistically significant improvement in OS observed for DARZALEX®-VMP versus VMP alone (hazard ratio [HR]=0.60; 95 percent confidence interval [CI], 0.46-0.80; P=0.0003). Of note, median OS was not assessed in either group and follow-up is ongoing. In addition, DARZALEX®-VMP resulted in a median progression-free survival (PFS) of 36.4 months versus 19.3 months with VMP alone after a median follow-up of 40.1 months (HR=0.42; 95 percent CI, 0.34-0.51; P<0.0001). The results also demonstrated that DARZALEX®-VMP achieved significantly higher rates of MRD-negativity compared to VMP alone (28 percent vs. 7 percent, respectively) at a threshold of one tumor cell per 10-5 white cells.

The most common Grade 3/4 treatment-emergent adverse events (TEAEs) occurring in ≥3 percent for DARZALEX®-VMP arm compared to the VMP arm included neutropenia (40.2 percent vs. 39 percent), thrombocytopenia (34.7 percent vs. 37.9 percent), anemia (17.3 percent vs. 19.8 percent) and pneumonia (13 percent vs. 4.2 percent).1 Grade 5 TEAEs were 6.9 percent in the DARZALEX®-VMP treatment arm compared with 5.6 percent in the VMP arm and discontinuation due to TEAEs was 6.9 percent in the DARZALEX®-VMP arm vs. 9.3 percent in the VMP arm, and the rate of invasive second primary malignancy in the DARZALEX®-VMP vs. VMP treatment arms were 4.9 percent vs. 4.5 percent, respectively.1 No new safety concerns were identified.

Common Grade 3/4 TEAEs occurring in ≥10 percent of patients in the DARZALEX®-Rd arm compared to the Rd arm were neutropenia (51 percent vs. 35 percent), lymphopenia (15 percent vs. 11 percent), pneumonia (15 percent vs. 9 percent), anemia (14 percent vs. 21 percent), leukopenia (11 percent vs. 6 percent) and hypokalemia (10 percent vs. 10 percent), respectively. The most common serious TEAE in the DARZALEX®-Rd arm compared to the Rd arm was pneumonia (14 percent vs. 9 percent, respectively). The most common Grade 3/4 infection rates were 36 percent in the DARZALEX®-Rd treatment arm compared with 27 percent in the Rd arm.2 In the DARZALEX®-Rd arm, 9 percent of patients discontinued treatment due to TEAEs, compared with 18 percent of patients in the Rd arm.

The randomized, open-label, multicenter Phase 3 ALCYONE (MMY3007) study enrolled 706 newly diagnosed patients with multiple myeloma who were ineligible for high-dose chemotherapy with autologous stem cell transplant (ASCT). The median age was 71 years (range: 40-93). Patients were randomized to receive up to nine cycles of either DARZALEX®-VMP or VMP alone. In the DARZALEX®-VMP arm, patients received 16 mg/kg of DARZALEX® once weekly for the first six weeks (Cycle 1), followed by once every three weeks for the next 48 weeks (Cycles 2–9). Following the nine cycles, patients in the DARZALEX®-VMP arm continued to receive 16 mg/kg of DARZALEX® once every four weeks until disease progression.

The randomized, open-label, multicenter Phase 3 study included 737 newly diagnosed patients aged 45-90 years old (median age of 73) with multiple myeloma ineligible for high-dose chemotherapy and ASCT. Patients were randomized to receive either DARZALEX®-Rd or Rd alone in 28-day cycles. In the DARZALEX®-Rd treatment arm, patients received DARZALEX® 16 mg/kg IV weekly for cycles 1–2, every two weeks for cycles 3–6 and every 4 weeks for cycle 7 and thereafter.

DARZALEX® (daratumumab), the first CD38-directed antibody approved anywhere in the world, is the only CD38-directed antibody approved to treat multiple myeloma. CD38 is a surface protein that is present in high numbers on multiple myeloma cells, regardless of the stage of disease. DARZALEX® binds to CD38 and inhibits tumor cell growth causing myeloma cell death. DARZALEX® may also have an effect on normal cells. DARZALEX® is being evaluated in a comprehensive clinical development program across a range of treatment settings in multiple myeloma, such as in frontline and relapsed settings. Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant hematologic diseases in which CD38 is expressed, such as smoldering myeloma.

In the U.S., DARZALEX® received initial FDA approval in November 2015 as a monotherapy for patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double refractory to a PI and an immunomodulatory agent. DARZALEX® received additional approvals in November 2016 in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. In June 2017, DARZALEX® received approval in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a PI. In May 2018, DARZALEX® received approval in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for ASCT, making it the first monoclonal antibody approved for newly diagnosed patients with this disease. In June 2019, DARZALEX® received approval in combination with lenalidomide and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma who are transplant ineligible. In September 2019, DARZALEX® received approval in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for ASCT.

Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow. When damaged, these plasma cells rapidly spread and replace normal cells with tumors in the bone marrow. In 2019, it is estimated that 32,110 people will be diagnosed and 12,960 will die from the disease in the U.S. While some patients with multiple myeloma have no symptoms, most patients are diagnosed due to symptoms, which can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.

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