FDA Grants Daratumumab Combos Breakthrough Designation for Myeloma

Meletios A. Dimopoulos, MD

The FDA granted daratumumab (Darzalex) a breakthrough therapy designation for use in combination with lenalidomide/dexamethasone or bortezomib/dexamethasone as a treatment for patients with multiple myeloma following at least 1 prior therapy, according to Janssen, which is developing the CD38-targeted antibody with Genmab.

The designation, which will expedite the development and review of the daratumumab regimens, is based on 2 phase III trials. The phase III POLLUX trial demonstrated that combining daratumumab with lenalidomide (Revlimid) and dexamethasone reduced the risk of disease progression by 63% versus lenalidomide and dexamethasone alone in patients with relapsed/refractory multiple myeloma. In the phase III CASTOR trial, adding daratumumab to bortezomib (Velcade) and dexamethasone reduced the risk of progression or death by 61% in patients with recurrent or refractory multiple myeloma.

“Despite tremendous progress in the past 15 years, multiple myeloma remains a highly complex and difficult disease to treat, with most patients relapsing or becoming resistant to therapy,” POLLUX lead author Meletios A. Dimopoulos, MD, department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece, said in a statement. “Daratumumab has already shown pronounced activity as a monotherapy in heavily pretreated patients. This designation underscores the potential of daratumumab in combination with either a proteasome inhibitor or an immunomodulatory agent to provide much-needed benefit to patients with at least one prior therapy.”

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). Daratumumab was dosed at 16 mg/kg IV once weekly during cycles 1 and 2, every 2 weeks during cycles 3 to 6, and once only (on day 1) of cycles 7 onward. Oral lenalidomide was administered at 25 mg daily for the first 3 weeks of each cycle and dexamethasone was dosed at 40 mg weekly (20 mg weekly in patients older than 75 or with a BMI <8.5). Treatment cycles for both study arms were 28 days. Patients were treated until progression or unacceptable toxicity.

The median patient age was 65 years. The median number of of prior treatment lines was 1, with 19% of patients having received ≥3 lines of therapy. Eighty-six percent of patients had received a proteasome inhibitor; 55% had been treated with an immunomodulatory agent (IMiD), including 18% with lenalidomide; and 44% had previously receiving both a proteasome inhibitor and an IMiD. Across the study population, 27% of patients were refractory to their most recent treatment and 18% were refractory to a proteasome inhibitor; however, no patients were refractory to lenalidomide.

The primary endpoint of the study was progression-free survival (PFS), with secondary outcome measures including time to progression, overall response rate (ORR), overall survival, and very good partial response (VGPR). At a preplanned interim analysis in May 2016, the study was unblinded after an independent panel determined the trial met its primary endpoint of improved PFS. Patients in the control arm were allowed to receive daratumumab at progression.

At a median follow-up of 13.5 months, the median 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 <.0001). The ORR was 93% versus 76%, respectively, P <.0001. The VGPR or better rate was 76% with daratumumab versus 44% in the control arm (P <.0001) and the compete response rates were 43% and 19%, respectively (P <.0001).

The safety profile was consistent with previously report adverse events (AEs) for single-agent daratumumab and the combination of lenalidomide and dexamethasone. The most common all-grade AEs included neutropenia (59% with the daratumumab triplet vs 43% in the control arm), diarrhea (43% vs 25%), fatigue (35% vs 28%), upper respiratory tract infection (32% vs 21%), anemia (31% vs 35%), constipation (29% vs 25%), cough (29% vs 13%), thrombocytopenia (27% each), and muscle spasms (26% vs 19%).

Infusion reactions related to daratumumab were reported in 48% of patients and were mostly grade 1/2, with 5% experiencing grade 3. Ninety-two percent of these reactions occurred during the initial infusion.

The most common grade 3/4 AEs were neutropenia (52% in the daratumumab arm vs 37% in the control arm), thrombocytopenia (13% vs 14%), and anemia (12% vs 20%). Grade 3/4 infections occurred in 28% of patients receiving daratumumab compared with 23% of patients in the control arm. The most common grade 3/4 infection was pneumonia, which occurred in 8% of patients in each arm. Discontinuation rates due to AEs occurred in 7% and 8% of patients in the 2 arms, respectively.

The CASTOR trial included 498 patients were who were randomized 1:1 to receive 8 cycles of bortezomib/dexamethasone with or without 16 mg/kg of daratumumab. Bortezomib was administered subcutaneously at 1.3 mg/m² on days 1, 4, 8, and 11 of each 21-day cycle for a maximum of 8 cycles. Patients received 20 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles. Patients in the daratumumab group were administered an IV infusion of the antibody at 16 mg/kg weekly for the first 3 cycles, on day 1 of cycles 4 to 9, and then every 4 weeks. Treatment was administered until disease progression or unacceptable toxicity.

Patients in the trial had received a median of 2 prior lines of therapy (range, 1-10) and 66% had received prior bortezomib, 76% has received prior IMiDs, and 48% had received prior proteasome inhibitors and IMiDs. Thirty-three percent were IMiD-refractory and 32% were refractory to last line of prior therapy.

The primary endpoint was PFS and secondary endpoints include time-to-progression, ORR, overall survival, and safety.

Median PFS was 7.2 months in the standard treatment arm and was not yet reached in the daratumumab arm (HR, 0.39; 95% CI, 0.28-0.53; P <.0001). The ORR was 83% and 63% (P <.0001) in the experimental and control arms, respectively. Nineteen percent of patients in the daratumumab arm had a complete response (CR) or better and 59% of patients had a VGPR or better compared with 9% of patients experiencing a CR and 29% experiencing a VGPR in the control arm (P = .0012 and P <.0001, respectively).

The most common treatment-emergent AEs were thrombocytopenia, which occurred in 59% of patients in the daratumumab arm versus 44% in the bortezomib/dexamethasone arm; sensory peripheral neuropathy, which occurred in 47% and 38% of patients in the experimental and control arms, respectively; diarrhea, which occurred in 32% and 22% of patients in each arm respectively, and anemia, which occurred in 26% and 31% of patients in each arm, respectively.

Seven percent of patients in the daratumumab arm discontinued treatment due to AEs versus 9% of patients receiving bortezomib/dexamethasone alone. Infusion-related reactions (IRRs) were experienced by 45% of patients in the study overall. Nine percent were grade 3, there were no grade 4 IRRs, and 98% occurred during the first infusion.

Commenting on the breakthrough status, Craig L. Tendler, MD, vice president, Late-Stage Development and Global Medical Affairs for Oncology, Hematology, and Supportive Care at Janssen, said, “This is an important recognition of the transformative potential of daratumumab and its possible benefit as a backbone therapy in combination with 2 of the most widely used regimens for multiple myeloma. We look forward to working closely with the FDA throughout the review process and remain committed to exploring the full clinical benefit of this promising compound for multiple myeloma patients who are eagerly awaiting new treatment options.”

In November 2015, the FDA granted an accelerated approval to daratumumab as a monotherapy for patients who have relapsed after ≥3 prior lines including a proteasome inhibitor and an IMiD or who are double-refractory to those therapies. In May 2016, the European Commission granted conditional marketing approval to daratumumab for the treatment of patients with relapsed/refractory multiple myeloma previously treated with a proteasome inhibitor and an IMiD who progressed on their last therapy.

1. Dimopoulos MA , Oriol A, Nahi H, et al. An open-label, randomised phase 3 study of daratumumab, lenalidomide, and dexamethasone (DRd) versus lenalidomide and dexamethasone (Rd) in relapsed or refractory multiple myeloma (RRMM): POLLUX. Presented at: 2016 European Hematology Association Congress; June 9-12, 2016; Copenhagen, Denmark. Abstract LB2238.
2. Palumbo A, Chanan-Khan A, Weisel K et. al. Phase 3 randomized controlled study of daratumumab, bortezomib and dexamethasone (DVd) vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (RRMM): CASTOR. Presented at: ASCO 2016; June 3-7, 2016; Chicago abstract: LBA4.