Approval Summary for Bortezomib for Injection in the Treatment of Multiple Myeloma

Abstract

The dose finding study of 54 patients showed a higher response rate for patients given 1.3 mg/m 2 compared with 1.0 mg/m 2 twice weekly for two of the 3-week schedule, but the study was too small for statistical dose-response comparisons. The most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness) in 65%, nausea (64%), diarrhea (51%), appetite decreased (including anorexia; 43%), constipation (43%), thrombocytopenia (43%), peripheral neuropathy (37%, including peripheral sensory neuropathy and peripheral neuropathy aggravated), pyrexia (36%), vomiting (36%), and anemia (32%).Conclusions: The FDA granted marketing approval to Millennium Pharmaceuticals on May 13, 2003 for bortezomib for use as a single agent for the treatment of multiple myeloma in patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. Accelerated approval was based on a surrogate end point of response rate rather than clinical benefit, such as an improvement in survival. The recommended dose of bortezomib is 1.3 mg/m 2 administered twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21). Accelerated approval was based on the results of two Phase II studies in a total of 256 patients and additional Phase I safety information. Mandated Phase IV study commitments to characterize clinical efficacy and safety more precisely are discussed.

Bortezomib significantly impairs the immunostimulatory capacity of human myeloid blood dendritic cells

“…These concentrations were chosen according to the range of previously reported median maximum plasma levels of bortezomib in myeloma patients after administration. 35 Subsequently, and after additional 6 h of cultivation, expression levels of CD54, CD83, CD86 and HLA-DR were analyzed. Exposure to 500 ng/ml (Figure 1) or 50 ng/ml (data not shown) bortezomib …”

Selective Inhibition of Endoplasmic Reticulum-associated Degradation Rescues ΔF508-Cystic Fibrosis Transmembrane Regulator and Suppresses Interleukin-8 Levels

“…The recent approval of bortezomib as a drug for refractory multiple myeloma (37)(38)(39) marks the beginning of a new era of regulation of protein catabolism for therapeutics. Bortezomib (pyrazylcarbonyl-PheLeu-boronate) is an extremely potent, stable, reversible, and selective inhibitor of chymotryptic threonine protease activity (37).…”

Regulatory Role of Proteasome in Determination of Platelet Life Span

“…Proteasome Inhibition Induces Apoptosis-like Changes in Human Platelets Associated with Up-regulation of Bax-Bortezomib, a highly selective inhibitor of proteasomal peptidase activity, has been employed in cancer therapy for its ability to induce apoptosis in tumor cells (24). To determine whether proteasome inhibition regulates platelet life span through induction of apoptosis, we investigated the effect of different inhibitors of proteasome activity on ⌬ m and surface exposure of phosphatidylserine (PS) in mice platelets in vivo and human platelets in vitro.…”