FDA Approves Third Daratumumab Triplet for Myeloma

Jan van de Winkel, PhD

The FDA has approved daratumumab (Darzalex) for use in combination with pomalidomide (Pomalyst) and dexamethasone for patients with multiple myeloma who have received at least 2 prior therapies, including a proteasome inhibitor and lenalidomide (Revlimid).

The approval is based on data from the phase I EQUULEUS (MMY1001) trial, in which the overall response rate (ORR) was 59% (95% CI, 49.1%-68.8%) with the daratumumab triplet in patients with relapsed/refractory myeloma.

The FDA previously approved daratumumab in combination with lenalidomide (Revlimid) and dexamethasone or bortezomib (Velcade) and dexamethasone for patients with relapsed multiple myeloma following at least 1 prior therapy.

“We are very pleased to receive the FDA’s decision to approve Darzalex in combination with pomalidomide and dexamethasone. This offers another alternative to patients with multiple myeloma who haven’t seen lasting effects from other types of treatment,” Jan van de Winkel, PhD, CEO of Genmab, the manufacturer of daratumumab, said in a statement.

The Pom-D arm of the open-label EQUULEUS trial included 103 patients with multiple myeloma who had received prior treatment with a proteasome inhibitor and an immunomodulatory agent. The median patient age was 64 years, and 8% of patients were aged ≥75 years.

The median number of prior therapy lines was 4, and three-fourths of patients had prior autologous stem cell transplant. Eighty-nine percent of patients were refractory to lenalidomide, 71% were refractory to bortezomib, and 64% were refractory to both agents.

Patients received daratumumab at 16 mg/kg combined with pomalidomide and dexamethasone.

The very good partial response rate was 28%, the complete response (CR) rate was 6%, and the stringent CR rate was 8%. The median time to response was 1 month (range, 0.9-2.8), and the median duration of response was 13.6 months (range, 0.9+ to 14.6+).

The most frequent adverse reactions (>20% of patients) in the study were infusion reactions (50%), diarrhea (38%), nausea (30%), vomiting (21%), fatigue (50%), pyrexia (25%), upper respiratory tract infection (50%), muscle spasms (26%), cough (43%) and dyspnea (33%). The most common treatment-emergent hematology laboratory abnormalities were lymphopenia (94%), neutropenia (95%), thrombocytopenia (75%), and anemia (57%).

Serious adverse reactions occurred in 49% of patients. The only grade 3/4 serious adverse reaction reported in more than 5% of patients was pneumonia at 7%. The most common grade 3/4 treatment-emergent hematology laboratory abnormalities were neutropenia (82%), lymphopenia (71%), anemia (30%), and thrombocytopenia (20%).

The previous daratumumab triplet approvals were based on the phase III POLLUX and CASTOR studies. In the POLLUX trial, adding daratumumab to lenalidomide and dexamethasone reduced the risk of progression or death by 63% versus lenalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma. In the CASTOR trial, the addition of daratumumab to bortezomib and dexamethasone reduced the risk of progression or death by 61% compared with the 2 drugs alone for patients with recurrent or refractory multiple myeloma.

The international, open-label POLLUX trial randomized 569 patients with relapsed/refractory multiple myeloma to daratumumab combined with lenalidomide/dexamethasone (n = 286) or lenalidomide plus dexamethasone alone (n = 283). Patient characteristics were well balanced between the study arms. The median age across the trial was 65 years and the median number of prior treatment lines for each cohort was 1.

At a median follow-up of 13.5 months, the median progression-free survival (PFS) was not yet reached in the daratumumab arm versus 18.4 months with lenalidomide/dexamethasone alone (HR, 0.37; 95% CI, 0.27-0.52; P <.001). The ORR was 92.9% versus 76.4%, respectively (P <.001). The very good partial response or better rate was 75.8% with daratumumab versus 44.2% in the control arm (P <.001). The CR rates were 43.1% and 19.2%, respectively (P <.001).

The CASTOR study randomized 498 patients with relapsed or refractory multiple myeloma to bortezomib and dexamethasone alone (n = 247) or with daratumumab (n = 251). Patients had received a median of 2 prior lines of therapy. Overall, 66% had received prior bortezomib, 76% received a prior immunomodulatory drug (IMiD), and 48% had received prior proteasome inhibitors and IMiD.

The 12-month PFS rate was 60.7% with daratumumab, bortezomib, and dexamethasone versus 26.9% for bortezomib and dexamethasone alone. After a median follow-up of 7.4 months, the median PFS was not reached in the daratumumab arm compared with 7.2 months in the control group (HR, 0.39; 95% CI, 0.28-0.53; P <.0001).