A large phase 3 clinical trial has demonstrated that adding the novel drug aponermin to standard therapy significantly improves outcomes for patients with relapsed or refractory multiple myeloma. The randomized, double-blind, placebo-controlled study was conducted across 36 hospitals in China and published in BMC Cancer on October 16, 2023.
The trial, known as CPT-MM301, evaluated the efficacy and safety of aponermin, a circularly permuted tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), when added to thalidomide and dexamethasone in patients who had received at least two prior therapies for multiple myeloma. It was funded by the National Major Science and Technology Projects of China and Beijing Sunbio Biotech Co., Ltd.
Multiple myeloma remains an incurable blood cancer, with most patients eventually developing resistance to available treatments. New therapeutic options are urgently needed, particularly for those with relapsed or refractory disease. Aponermin represents a novel approach, targeting death receptors 4 and 5 to selectively induce apoptosis in cancer cells while sparing normal cells.
The study enrolled 417 patients with relapsed or refractory multiple myeloma between February 2015 and July 2019. Key eligibility criteria included age 18-75 years, having received at least two prior treatment regimens, and measurable disease based on serum or urine M-protein levels. Patients were excluded if they were refractory to thalidomide plus dexamethasone or lenalidomide plus dexamethasone as their most recent therapy.
Participants were randomized in a 2:1 ratio to receive either aponermin plus thalidomide and dexamethasone (278 patients) or placebo plus thalidomide and dexamethasone (139 patients). The median age was 59 years, and 42.2% were women. Patients had received a median of 3 prior treatment regimens, with 46% having received 4 or more regimens. The vast majority had prior exposure to proteasome inhibitors (73.6%) and immunomodulatory drugs (86.6%).
The primary endpoint was progression-free survival as assessed by an independent review committee. Key secondary endpoints included overall survival, overall response rate, and safety.
After a median follow-up of 17.2 months, the aponermin group demonstrated significantly improved progression-free survival compared to placebo, with a median of 5.5 months versus 3.1 months (hazard ratio 0.62, p<0.001). The overall response rate was also superior with aponermin (30.4% vs 13.7%, p<0.001).
Importantly, the survival advantage continued to increase over time. In an updated analysis with 48 months of follow-up, median overall survival was 22.4 months with aponermin versus 16.4 months with placebo (hazard ratio 0.70, p=0.003). This 6-month improvement in survival is clinically meaningful for this heavily pretreated patient population.
The progression-free and overall survival benefits were consistent across most prespecified subgroups, including those with high-risk cytogenetics. Notably, patients who had received both proteasome inhibitors and immunomodulatory drugs previously appeared to derive particular benefit from aponermin.
The safety profile was generally manageable, with similar rates of serious adverse events between groups (40.6% vs 37.4%). The most common grade 3-4 adverse events included neutropenia, pneumonia, and hyperglycemia. Aponermin was associated with higher rates of liver enzyme elevations, but these were mostly grade 1-2 and reversible. There was no evidence of increased hematologic toxicity, nephrotoxicity, or cardiotoxicity with aponermin.
Quality of life assessments showed that aponermin maintained or improved several domains compared to placebo, including global health status, emotional functioning, and disease-related symptoms. This suggests the survival benefit did not come at the cost of reduced quality of life.
The authors concluded that aponermin plus thalidomide and dexamethasone represents an effective new treatment option for patients with relapsed or refractory multiple myeloma, offering improved progression-free and overall survival with a manageable safety profile. They noted this is the first phase 3 trial to demonstrate a survival benefit by targeting the TRAIL pathway in multiple myeloma.
Several limitations of the study were acknowledged. The overall efficacy outcomes were somewhat modest compared to recent trials of other novel agents in relapsed/refractory multiple myeloma. However, cross-trial comparisons are challenging due to differences in study populations. The authors noted their trial included a heavily pretreated cohort, with nearly half having received 4 or more prior regimens.
Additionally, the control arm of thalidomide plus dexamethasone is no longer considered a standard treatment in many countries where newer agents are widely available. However, it remains commonly used in China and other resource-limited settings due to its affordability and accessibility. The authors suggest future studies should evaluate aponermin in combination with more potent antimyeloma drugs like proteasome inhibitors or monoclonal antibodies.
The potential clinical impact of these findings is significant. For patients with relapsed or refractory multiple myeloma who have exhausted standard options, aponermin offers a novel mechanism of action that can provide meaningful extensions in progression-free and overall survival. The oral administration of thalidomide and dexamethasone, combined with short infusions of aponermin, may be more convenient than some other regimens requiring frequent clinic visits.
The results also open new avenues for further research. As the first drug targeting death receptors 4/5 to demonstrate a survival benefit in a phase 3 cancer trial, aponermin validates this pathway as a therapeutic target. This could spur development of other TRAIL-based therapies across various cancer types.
Questions remain about how to optimally integrate aponermin into treatment algorithms for multiple myeloma. Biomarker studies to identify which patients are most likely to benefit would be valuable. Combination strategies with other novel agents also warrant investigation to potentially further improve outcomes.
In conclusion, this large phase 3 trial provides robust evidence that adding aponermin to thalidomide and dexamethasone significantly improves progression-free and overall survival in relapsed or refractory multiple myeloma. While not a cure, it represents an important new treatment option for patients with limited alternatives. Further research is needed to build upon these results and determine how to maximize the clinical benefit of this novel therapeutic approach.
References
Xia Z, Leng Y, Fang B, et al. Aponermin or placebo in combination with thalidomide and dexamethasone in the treatment of relapsed or refractory multiple myeloma (CPT-MM301): a randomised, double-blinded, placebo-controlled, phase 3 trial. BMC Cancer. 2023;23(1):980. Published 2023 Oct 14. doi:10.1186/s12885-023-11489-8
