New orally active proteasome inhibitors in multiple myeloma

• Published in: Leukemia research 2014-01, Vol.38 (1), p.1-9
• Main Authors: Allegra, Alessandro, Alonci, Andrea, Gerace, Demetrio, Russo, Sabina, Innao, Vanessa, Calabrò, Laura, Musolino, Caterina
• Format: Article
• Language: English
• Subjects: Administration, Oral; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; Bortezomib; Carfilzomib; Clinical Trials as Topic; Delanzomib; Hematology, Oncology and Palliative Medicine; Humans; Indexing in process; Ixazomib; Marizomib; Molecular Structure; Multiple myeloma; Multiple Myeloma - drug therapy; Oral administration; Proteasome inhibitor; Proteasome Inhibitors - administration & dosage; Proteasome Inhibitors - chemistry; Proteasome Inhibitors - therapeutic use; Therapy; Treatment Outcome
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/j.leukres.2013.10.018

Abstract Bortezomib is the first proteasome inhibitor approved for the therapy of multiple myeloma (MM). Although Bortezomib has renovated the treatment of MM, a considerable proportion of subjects fail to respond to Bortezomib treatment and almost all patients relapse from this drug either alone or when used in combination therapies. However, the good clinical outcome of Bortezomib treatment in MM patients gave impulsion for the development of second generation proteasome inhibitors with the ambition of improving efficacy of proteasome inhibition, enhancing antitumor activity, and decreasing toxicity, as well as providing flexible dosing schedules and patient convenience. This review provides an overview of the role of oral proteasome inhibitors including Marizomib, Oprozomib, Delanzomib, chemical proteasome inhibitors, and cinnabaramides, in the therapy of MM, focusing on developments over the past five years. These emerging drugs with different mechanisms of action have exhibited promising antitumor activity in patients with relapsed/refractory MM, and they are creating chances to target multiple pathways, overcome resistance, and improve clinical outcomes, mainly for those subjects who are refractory to approved agents. Future steps in the clinical development of oral inhibitors include the optimization of the schedule and the definition of their antitumor activity in MM.