Bortezomib in multiple myeloma: treatment approach and outcomes

Abstract

Because multiple myeloma (MM) remains incurable, new therapeutic approaches are needed. Proteasome inhibition represents a new therapeutic strategy with the potential to inhibit multiple pathogenic pathways in MM. In phase I trials, the novel proteasome inhibitor bortezomib demonstrated encouraging activity in patients with advanced MM. In the SUMMIT phase II trial, 202 heavily pre-treated patients with relapsed and refractory MM received bortezomib 1.3 mg/m 2 twice weekly for 2 weeks, followed by a 1-week rest. The overall response rate, defined as complete + partial + minimal responses (CR + PR + MR), was 35%, with CR or near-CR in 10% of patients. Median duration of response was 12 months and median duration of survival 16 months for all patients. Adverse effects included manageable gastrointestinal symptoms, thrombocytopaenia, and peripheral neuropathy. Thrombocytopaenia and neuropathy were generally reversible and occurred mainly in patients who already had these toxicities at time of enrollment. In the CREST phase II trial, 54 patients with relapsed or refractory MM after first-line therapy were randomised to receive bortezomib 1.0 mg or 1.3 mg/m 2, twice weekly for 2 weeks, followed by a 1-week rest. Overall response rates were 33% at the 1.0 mg dose and 50% at the 1.3 mg dose. Toxicities were similar to those seen in SUMMIT, with nausea, diarrhoea and peripheral neuropathy occurring more frequently at the higher dose level. In conclusion, the results of the SUMMIT and CREST trials show that bortezomib is highly active in patients with relapsed and refractory MM. A large phase III trial comparing bortezomib with dexamethasone in relapsed MM patients was recently stopped after a pre-specified interim analysis showed a statistically significant improvement in time to disease progression for patients receiving bortezomib. Studies testing bortezomib as front-line therapy are ongoing.