Discussion
Pyrexia, death, tumor, nephrotoxicity, cancers, toxicity, cancer, hepatotoxicity, SD, anemia, hyperglycemia, TD, cardiotoxicity, hypertriglyceridemia, MR, hypocalcemia, diabetes
TUMOR, LYSIS, ADVERSE REACTION, EVENTS, HYPOCALCEMIA, ADVERSE REACTIONS, UPPER RESPIRATORY TRACT INFECTIONS, CANCER, SENSITIVITY, REMISSION, DIABETES, DECREASED LYMPHOCYTE, ADVERSE EVENTS, HYPOCALCEMIA, ANEMIA, HYPERTRIGLYCERIDEMIA, DISEASE, CANCERS, DISEASE, SECONDARY TUMORS, HYPERGLYCEMIA
In this study, aponermin was combined with TD regimens. In China, thalidomide was more widely used than lenalidomide and bortezomib because of its affordability. Although a few new drugs for RRMM have been approved in China in the last five years, they are expensive, and some patients are deterred. Therefore, thalidomide remains an indispensable anti-myeloma drug. The superiority of aponermin plus TD over placebo plus TD in RRMM was confirmed in this study. The PFS, OS, and ORR were significantly improved in the aponermin group compared to the placebo group. The OS benefit of aponermin group vs. placebo group was further improved in the updated analysis than that in the first analysis, from 4.8 months to 6.0 months. In the aponermin group, more patients achieved deep remission, with the much higher rate of VGPR or better response compared to the placebo group. For patients who had achieved PR or better responses, greater benefits in PFS and OS were observed in the aponermin group vs. the placebo group, suggesting that patients who received aponermin treatment were able to maintain longer periods of remission and longer overall survival.The benefits of the aponermin group regarding PFS and OS were observed in most prespecified subgroups, including those with poor prognosis, such as patients aged ≥ 65 years, previous exposure to TD/RD, refractory to PI and IMiD, or previous treated with more than three regimens. It is noteworthy that in patients with previous exposure to PI and IMiD, the risk of progression or death reduced by 45% and the risk of death reduced by 39% in the aponermin group compared to the placebo group. Of these, more than 50% patints had been treated with at least four regimens, and 38.3% had received lenalidomide. In the aponermin group, four patients had exposed to carfilzomib, bortezomib, and IMiD, one VGPR, one MR and two stable disease (SD) were observed; two patients had previously used monoclonal anti-CD38 antibody, bortezomib, and lenalidomide, one PR and one SD were obtained. The result suggests that aponermin combined with TD may be still an option even for patients with previous heavy treatment.Overall, the efficacy outcomes in this study were consistent with the results of the phase 2 trial, in which improvements in PFS and ORR were observed in patients of the aponermin plus TD group compared with those in the TD group [Treatment with aponermin may cause hepatotoxicity in some patients, as indicated by the elevated ALT and AST levels. The elevations of ALT and AST generally occurred after two days of treatment, reached a peak value after five days treatment of aponermin, and returned to normal or baseline levels before the next treatment cycle (the representative shown in Supplementary file: Figure SThe incidences of anemia and decreased lymphocyte count in the aponermin group were higher than that in the placebo group, but there was no statistical significance. After adjustment for drug exposure, rate of anemia was slightly lower in the aponermin group (132 vs. 140 events per 100 patient-years), and rates of decreased lymphocyte count were similar in the two groups (173 vs. 169 events per 100 patient-years). There was no decrease in leukocyte, platelet and neutrophil. The result suggests that aponermin has no hematological toxicity.Pyrexia (grade 1/2) is a confirmed adverse reaction of aponermin, which was reported by 20.7% and 12.2% patients in the aponermin group and the placebo group, respectively. More patients reported positive urine leukocyte (15.9% vs. 8.6%) and increased monocyte cell count (15.2% vs. 5.0%) in aponermin group compared to the placebo group, but there was no difference in the laboratory test results between the two groups. Hypocalcemia, upper respiratory tract infections, hypertriglyceridemia and hyperglycemia are the known adverse reactions of dexamethasone. Increased incidences of these adverse events were observed in the aponermin group compare to the placebo group, which mainly related to the longer drug exposure (5 vs. 3 cycles). More patients with a history of diabetes (14.9% vs. 10.8%) may be another reason for the higher incidence of hyperglycemia. The higher incidence of hypocalcemia in aponermin group may also be related to tumor lysis caused by aponermin. Hypocalcemia, upper respiratory tract infections, hypertriglyceridemia and hyperglycemia have not been observed eigher in the preclinical study, or in clinical studies of aponermin monotherapy. Further researches are needed to determine whether the added of aponermin to TD will increase the risks.There was no evidence that aponermin leads to nephrotoxicity, cardiotoxicity, or secondary tumors. The incidence of SAEs was similar between the two groups.The clinical benefit of aponermin was further supported by the results of HRQoL. In half of the domains of the QLQ-C30 and MY20, the LS mean changes of the aponermin group were significantly better compared to the placebo group. Disease symptoms and side effects of treatment of the QLQ-MY20 were stable across treatments in the aponermin group and were not worse than those in the placebo group. The result suggests that aponermin owned a good safety profile in clinic, and there is a broad space for its combined application with other antitumor drugs.In this study, efficacy analyses were based on a mITT population, with two patients excluded from the analysis for not receiving any study treatment. Sensitivity analysis of PFS for the mITT population was performed. The results of intention-to-treat population (417 patients) (median PFS 5.5 months for the aponermin group and 3.1 months for the placebo group, HR, 0.62; 95% CI, 0.49–0.78; The main limitation of this study is that the efficacy outcomes for both the aponermin group and the placebo groups were slightly weaker compared with the triplet regimens of novel drugs approved in recent years. In particular, the ORR of the placebo group was only 13.7%, which was lower than previously reported [Overall, the results of this study indicate that aponermin plus TD had a favourable benefit-risk profile compared with placebo plus TD in RRMM. The role of the TRAIL signalling pathway in inducing apoptosis has been explored for a long time. But, at present, no drug have been approved for anti-tumor therapy targeting death receptors 4/5. To our knowledge, this is the first phase 3 trial shows that activation of the TRAIL pathway is a feasible approach for the treatment of RRMM. This represents a genuine breakthrough in cancer treatment and brings a novel weapon to the arsenal for fighting cancers. Additionally, this opens the door to exploring the applications of TRAIL family members in other cancers.In conclusion, this phase 3 study demonstrated that aponermin plus TD has a favorable benefit-risk profile compared with placebo plus TD. Aponermin plus TD significantly improved PFS, OS, and ORR with manageable and reversible toxicity in RRMM patients with at least two prior therapies, and should be considered an effective treatment option for RRMM patients by targeting death receptors 4/5.