Post-Marketing Surveillance of Bortezomib Treatment for Multiple Myeloma (MM) in Japan: Results of Interim Analysis by the Velcade Japan Proper Use Guideline Committee (2008)

Abstract [Background] Bortezomib (VELCADE® for Injection 3 mg) was approved in Japan on October 10, 2006 for the treatment of relapsed or refractory MM. As required for most oncology drug approvals in Japan, a special post-marketing surveillance program was implemented on December 1, 2006, enrolling all patients treated with bortezomib to assess its safety and efficacy from actual medical practice experience in Japan. [Patients and Methods] This surveillance is a prospective program designed to enroll patients before starting treatment with bortezomib. It included 1048 consecutive patients treated with bortezomib in the first year after the drug approval in Japan. This report summarizes the results of an interim analysis of safety and preliminary efficacy of the first two cycles of bortezomib in 525 patients. Patients are to be observed for 3 years at maximum. Observational items include: gender, age, medical history, prior therapies, administration of bortezomib, concomitant drug/therapy, laboratory testing, physical examination, clinical symptoms, anti-tumor effects, and adverse event (AE) collection. In addition, for AEs of special interest, such as lung disorder/interstitial lung disorder (LD/ILD), cardiac dysfunction, tumor lysis syndrome (TLS), peripheral neuropathy, hematotoxicity, pyrexia, skin disorder, hypotension and gastrointestinal disorder, heightened surveillance was conducted to capture onset, clinical course and outcomes. [Results] Males outnumbered females (55.8% [293/525] vs. 44.2% [232/525]). Patients elder than 50 years old accounted for 92.6% (486/525). Most of the patients were in stage III by both the International Staging System and Durie & Salmon system. More than half of the patients (59.1% [310/525]) had a duration of illness ranged from 1 to 5 years. Coexisting medical conditions were present in 62.3% (327/525) of patients; the most common was hypertension (17.5%). 7.6% and 10.5% of patients had coexisting medical conditions related to lung disease or heart disease, respectively. Most of the patients had received prior treatment for MM, which included MP (melphalan, prednisolone), thalidomide, dexamethasone, VAD (vincristine, doxorubicin, dexamethasone), and stem cell transplantation. The most commonly observed adverse drug reactions (ADRs) were abnormal changes in hematological laboratory tests (74.3%). Incidence of serious ADRs was 21.1% (111/525). The most frequent serious ADRs were low platelet count (5.3% [28/525]) and peripheral neuropathy (2.1% (11/525). LD/ILD was seen in 4.2% (22/525). TLS was observed in 5.0% (26/525). With regard to the preliminary analysis of anti-tumor effect, the overall response rate as determined by the investigator-based clinical evaluations was 50.2% (257/512). The overall response rate based on M-protein concentration was 41.8% (214/512). 12 (2.3%) patients died within 30 days after the final administration of bortezomib. Progression of disease was the most common cause of death, and worse performance status prior to initiating bortezomib was associated with early mortality. [Conclusion] Based on the interim analysis, this post-marketing surveillance reveals no new safety signals in Japanese patients with relapsed/refractory MM treated with bortezomib. The incidence rates of AEs of special interest were comparable to those observed outside Japan except for LD/ILD which was less than those initially reported for the Japanese population.