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In Patients with RRMM, Circularly Permuted TRAIL, a Novel TRAIL Agonist, Is Combined with Thalidomide and Dexamethasone

2020 Year in Review - Multiple Myeloma

Results from a phase 3 study of a circularly permuted tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) combined with thalidomide and dexamethasone showed this was a safe and effective treatment for patients with relapsed/refractory multiple myeloma (RRMM), including those with a poor prognosis.

Circularly permuted TRAIL (CPT), a recombinant permuted human TRAIL, is a first-in-human anti-myeloma drug targeting death receptor 4/5. This double-blind, placebo-controlled phase 3 study was conducted to investigate the safety and efficacy of CPT.

From March 4, 2015, to July 3, 2019, across 36 centers in China, patients with RRMM who were treated previously with ≥2 lines of therapy were randomly assigned in a 2:1 ratio to receive CPT plus thalidomide and dexamethasone (TD; CPT group) or placebo plus TD (control group). On days 1 to 5, CPT or placebo (10 mg/kg) was administered intravenously. In addition, on days 1 to 4, both groups were administered dexamethasone 40 mg orally and thalidomide 150 mg daily in 28-day cycles until disease progression or unacceptable toxicity. The study’s primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), overall response rate (ORR), time to progression (TTP), time to response, duration of response (DOR), health-related quality of life (HRQoL), and safety.

A total of 417 patients enrolled; 415 patients received treatment with CPT + TD (N = 276) or placebo + TD (N = 139). At baseline, demographic, baseline disease, and clinical characteristics of the 2 groups were similar. Median patient age was 59 years. Median time from the initial diagnosis of multiple myeloma to trial participation was 2.6 years, and median number of prior lines of therapy was 3. Seventy-four percent of patients were previously treated with a proteasome inhibitor (PI) and 86.5% of patients with an immunomodulatory drug (IMiD).

PFS was significantly longer for the CPT group than for the control group at data cutoff (median, 5.5 vs 3.1 months; hazard ratio [HR], 0.619; P <.0001). When compared with the control group, the CPT group also showed significantly improved ORR (30.4% vs 13.7%; P = .0002) and OS (median, 21.8 vs17.0 months; HR, 0.723; P = .0166). Subgroup analysis of PFS, OS, and ORR showed the superiority of CPT + TD over placebo + TD across nearly all subgroups. Patients with a poor prognosis, including those with refractory multiple myeloma, with a history of previous PI and IMiD therapies, and those who received >3 lines of prior therapies, exhibited excellent efficacy consistently with CPT as measured by PFS, OS, and ORR. Among patients with PI and IMiD double-refractory multiple myeloma in the CPT group, PFS and ORR rates were also significantly improved. The CPT group also showed superiority versus the control group regarding TTP, DOR, and HRQoL.

In 73.6% of patients (N = 203) in the CPT group and 79.9% of patients (N = 111) in the control group, disease progression or death occurred. Serious adverse event rates were similar between the CPT group and the control group (40.6% vs 37.4%, respectively). Also similar between groups were death rates (7.6% vs 8.6%, respectively). In the CPT group versus the control group, treatment-emergent adverse events (TEAEs) occurring with ≥10% frequency included elevated alanine transaminase, elevated aspartate transaminase, elevated lactate dehydrogenase, increased monocyte counts, hypocalcemia, and upper respiratory tract infections. Based on safety data, CPT may induce hepatotoxicity; however, most of these events were of grade 1 or 2 and reversible. Grade 3 or 4 TEAEs reported in the CPT and control groups were decreased neutrophil counts (26.8% vs 26.6%), pneumonia (25% vs 23.7%), and hyperglycemia (21% vs 12.2%).

In conclusion, study results showed that CPT + TD was an effective treatment for patients with RRMM, including among those patients with multiple lines of previous therapy and those who were PI- and/or IMiD-refractory. PFS and OS rates were significantly prolonged by the combination of CPT with TD, and the ORR rate was increased. CPT + TD was also well-tolerated. Adverse events found in this study were mild, transient, and reversible.

Abstract 416. ASH 2020. December 6, 2020. Circularly permuted TRAIL (CPT) combined with thalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma: a randomized, double-blind, placebo-controlled phase 3 study (CPT-MM301).

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