TNF-related apoptosis-including ligand/Apo2 (TRAIL)-mediated immunotherapy is an attractive anti-tumor modality with high tumor specificity. In order to improve its therapeutic efficacy, we further need to implement a novel maneuver for sensitization of malignant cells to TRAIL. Bortezomib (BTZ), a novel anti-myeloma (MM) agent, potently induces endoplasmic reticulum (ER) stress to cause apoptosis. Here, we explored the roles of BTZ in the cytotoxicity of anti-TRAIL receptor agonistic antibodies against MM cells with special reference to ER stress. BTZ enhanced the expression of death receptor 5 (DR5) but not DR4 in MM cells at surface protein as well as mRNA levels. However, the DR5 expression was not affected by BTZ without ER stress induction in MM cells with a point mutation in a BTZ-binding proteasome β₅ subunit. Tunicamycin, an ER stress inducer, was able to enhance the DR5 expression even in the BTZ-resistant MM cells, suggesting the role of ER stress in up-regulation of DR5 expression. Interestingly, BTZ facilitated extrinsic caspase-mediated apoptosis by anti-DR5 agonistic antibody in MM cells along with reducing c-FLICE-like interleukin protein, a caspase 8 inhibitor. These results suggest that BTZ enhances DR5 expression and its downstream apoptotic signaling through ER stress to sensitize MM cells to TRAIL-mediated immunotherapy.

THALED® CAPSULE (thalidomide) was approved as a drug for relapsed/refractory multiple myeloma (MM) in October 2008 in Japan. Because the number of patients included in the domestic clinical study was small, the post-marketing surveillance was necessary and was conducted accordingly. This study included 1,548 patients during a period from February 2009 to February 2010. The mean age was 68.5 years, and the male/female ratio was 1.03. Mean disease duration was 3.8 years from the diagnosis of myeloma. Almost all patients (98.5%) were treated at a dosage below 200 mg/day. All grade and serious adverse events (AEs) were observed in 58.6% and 8.7%, respectively. The incidence of these AEs was lower than that observed in the previous domestic clinical study; however the monitoring and audit was not performed in this surveillance, so that the low grade AEs might have been missed. Main AEs were peripheral neuropathy, constipation, somnolence and leukopenia. Serious AEs were leukopenia, pneumonia, neutropenia and peripheral neuropathy. Venous thromboembolism (VTE) was observed only in 1.4%. Median overall survival was not reached, and median duration of treatment was 24.0 weeks. It is difficult to compare the present data with the other data because this is a post-marketing surveillance. However, the incidence of AEs, especially VTE, was obviously lower than that reported in western countries, so that THALED® CAPSULE can be used safely in clinical practice of Japanese MM patients.