Supervisors info:
Ευάγγελος Τέρπος, Αιματολόγος, Καθηγητής Θεραπευτικής-Αιματολογίας, Μονάδα Πλασματοκυτταρικών Δυσκρασιών, Θεραπευτική Κλινική ΕΚΠΑ, Νοσοκομείο Αλεξάνδρα
Summary:
Multiple or plasma cell myeloma is one of the most common hematological malignancies,
resulting from the malignant plasma cells accumulate in bone marrow – crowding out the
normal plasma cells that help fight infection. Multiple myeloma, in 85% of cases, is found in the bone marrow, which is accompanied by uncontrolled proliferation of neoplastic clones within it, thus limiting normal hematopoiesization. Despite the significant progress made in recent years in its treatment, it continues to be an incurable disease with the appearance of relapses, even if after the initial treatment there is a complete remission of the disease. These relapses have been addressed by science in recent years with various types of treatments, one of which is the use of proteasoma inhibitors. The protease is involved in various cellular functions such as ridding cells of abnormal or incorrectly folded polypeptides. The proteins to be broken down are joined by a small protein called ubiquitin and the reaction of this binding is catalyzed by enzymes called ubiquitin ligases. Its main function is the degradation of intracellular proteins, thus regulating the transcription of various genes, the cell cycle, apoptosis, cell filtration, the progression of inflammation and angiogenesis . Thus, proteasoma inhibitors act primarily by activating the response pathway to unfolded proteins and leading to the apoptosis of mainly cells with increased content in unfolded proteins or proteins that are heading for degradation, a condition that occurs very strongly in cancer cells. All of the above make them suitable for administer to patients, as normal cells are affected to a much lesser extent than cancerous cells and can more quickly regain the activity of the protease. To date, 1st and 2nd generation inhibitors have been developed, as well as newer ones that can administered through the oral tract. This paper analyses a 2nd generation inhibitor, carfilzomib, from the preclinical stage all the way to clinical development. Carfilzomib is a non-reversible proteasoma inhibitor given to people who have received prior treatment, approved by both the American and European authorities. Preclinical studies of carfilzomib provided the basis for the next phases of the study in the treatment of hematological malignancies. In them, it appeared that carfilzomib has an anti-multi-triple and pre-declining effect on esmatological tumors. In animals, it inhibited the action of proteasoma in blood and tissues and delayed the development of tumors in multiple myeloma models. The main objective of the phase I studies was to assess product safety, the resistance limit and adverse reactions, while phase II studies investigated the efficacy of the drug, its safety towards patients and the dosing regimen both with exclusive administration of carfilzimib and in combination with other treatments. Finally, the
phase III studies were the last step in the planned evaluation of the new medicinal product prior to its final release and were primarily intended to investigate the efficacy of the drug and any side effects that occur. The two most important studies of this type were the randomized, open, multicenter Aspire study in which the combination of carfilzomib with lenalidomide and dexamethasone was assessed and the randomized, open, controlled Endeavor study in which the combination of carfilzomib and dexamethasone was assessed. The primary objective of both recent studies was survival without disease progression in the population. In conclusion, the administration of carfilzomib showed greater efficacy against multiple myeloma both as monotherapy and in combination with other drugs compared to other courses of treatment used for multiple or plasma cell myeloma.
Keywords:
relapsed, multiple, myeloma, plasma, cell, carfilzomib, bortezomib, proteasoma, inhibitor, clinical, trial, aspire, endeavor
