Bortezomib, a novel proteasome inhibitor, in the treatment of hematologic malignancies.
Proteasome inhibition is a novel approach to treating malignancy, and bortezomib is the first proteasome inhibitor in this class to be approved for clinical use. In preclinical studies, bortezomib caused cell cycle arrest and apoptosis in myeloma and lymphoma cell lines as well as in other neoplastic cell types. Phase I clinical trials established an optimal dosing strategy and demonstrated a manageable toxicity profile. Cyclical thrombocytopenia and peripheral neuropathy, which generally abate after cessation of treatment, are the most clinically significant toxicities. Two phase II trials, SUMMIT and CREST, demonstrated impressive activity with bortezomib 1.3 mg/m2 monotherapy in relapsed and refractory myeloma, with an impressive 35% response rate (complete+partial+minimal responses) in SUMMIT and a 50% response rate in CREST, using the rigorous European Group for Blood and Marrow Transplantation criteria. A recently completed phase III trial showed the significant clinical benefits of bortezomib over high-dose dexamethasone in patients with relapsed myeloma. Results of ongoing trials with bortezomib in the first-line treatment of myeloma have been extremely encouraging and have demonstrated the benefit of using bortezomib as part of an induction regimen prior to stem cell transplantation. Importantly, two clinical trials with bortezomib as monotherapy in refractory non-Hodgkin's lymphoma have shown impressive response rates, particularly in aggressive mantle cell lymphoma.
Jackson
Graham
G
Department of Haematology, Royal Victoria Infirmary, Queen Victoria Road, Newcastle Upon Tyne NE1 4LP, United Kingdom. graham.jackson@newcastle.ac.uk
Einsele
Hermann
H
Moreau
Phillippe
P
Miguel
Jesus San
JS
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D002986:Clinical Trials as Topic; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D011719:Pyrazines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib