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Circularly Permuted TRAIL, a Novel TRAIL Agonist, with Thalidomide and Dexamethasone in Patients with RRMM

Conference Correspondent  - ASH Highlights

Circularly permuted tumor necrosis factor–related apoptosis-inducing ligand (TRAIL; CPT) is a first-in-human antimyeloma drug targeting death receptor 4/5. A double-blind, placebo-controlled phase 3 study was conducted to investigate the safety and efficacy of CPT.

In this study, patients with relapsed/refractory multiple myeloma (RRMM) who were previously treated with ≥2 lines of therapy were randomly assigned in a 2:1 ratio to receive CPT + thalidomide and dexamethasone (TD; CPT group) or placebo plus TD (control group) from March 4, 2015, to July 3, 2019, across 36 centers in China. CPT or placebo (10 mg/kg) was administered intravenously on days 1 to 5. In addition, both groups were administered dexamethasone 40 mg orally on days 1 to 4 and thalidomide 150 mg daily in 28-day cycles until disease progression or unacceptable toxicity. The primary end point of this study 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 were randomized, with 415 patients receiving treatment with CPT+TD (n = 276) or placebo + TD (n = 139). Demographic, baseline disease, and clinical characteristics of the 2 groups were similar at baseline. The median age of the patients was 59 years. The median time from the initial multiple myeloma (MM) diagnosis to trial participation was 2.6 years, and the 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% with an immunomodulatory drug (IMiD).

At data cutoff, PFS was significantly longer for the CPT group than for the control group (median, 5.5 months vs 3.1 months; hazard ratio [HR], 0.619; P <.0001). The CPT group, when compared with the control group, also showed significantly improved ORR (30.4% vs 13.7%; P = .0002) and OS (median, 21.8 vs 17.0 months; HR, 0.723; P = .0166). Clinical benefit was seen in 45.3% of patients in the CPT group versus 29.5% in the control group. Subgroup analysis of PFS, OS, and ORR showed the superiority of CPT + TD over placebo + TD across nearly all subgroups. Among patients with a poor prognosis, including those with refractory MM with a history of previous PI and IMiD therapies, and those who had received >3 prior lines of therapy, CPT consistently exhibited excellent efficacy as measured by PFS, OS, and ORR. In the CPT group, PFS and ORR were also significantly improved among patients with PI and IMiD double-refractory MM. The CPT group also demonstrated superiority versus the control group with regard to TTP, DOR, and HRQOL.

Disease progression or death occurred in 73.6% of patients (n = 203) in the CPT group and 79.9% of patients (n = 111) in the control group. Serious adverse event (AE) rates were similar between the CPT group and the control group (40.6% vs 37.4%, respectively). Death rates were also similar between groups (7.6% vs 8.6%, respectively). Treatment-emergent AEs (TEAEs) occurring with ≥10% frequency in the CPT group than in the control group included elevated alanine transaminase, elevated aspartate transaminase, elevated lactate dehydrogenase, increased monocyte counts, hypocalcemia, and upper respiratory tract infections. Safety data suggested that CPT may induce hepatotoxicity; however, the majority of these events were grade 1/2 and were reversible. Grade 3/4 TEAEs reported in the CPT group and the control group were decreased neutrophil counts (26.8% vs 26.6%, respectively), pneumonia (25% vs 23.7%, respectively), and hyperglycemia (21% vs 12.2%, respectively).

The results of this study showed that CPT plus TD was an effective treatment for patients with RRMM, including patients who had received multiple lines of previous therapy and those who were PI- and/or IMiD-refractory. The combination of CPT and TD significantly prolonged PFS and OS, and increased the ORR. CPT + TD was also well tolerated. AEs found in this study were mild, transient, and reversible.


Reference

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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