Proteasome Inhibitor Bortezomib

Bortezomib (N-pyrazine carbonyl-L-phenylalanine-L-leucine boronic acid, previously known as PS-341 or MLN-341), a boronic acid dipeptide, is a specific inhibitor of the proteasome pathway.23 24 Bortezomib inhibits the proteasome pathway in a rapid and reversible manner by binding directly with the 20S pro-teasome complex and blocking its enzymatic activity. The proteasome pathway regulates the degradation of the NF-kB inhibitor, I-kB.25 26 Several effects of borte-zomib, including the induction of apoptosis in the malignant plasma cell, appear to be mediated through inhibition of NF-KB. Bortezomib prevents the degradation of I-kB and thereby inhibits NF-kB activation.5

In view of encouraging in vitro data, a phase I study using bortezomib was initiated in patients with refractory hematologic malignancies (MM, lymphoma) to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacodynamics of the molecule.27 Bortezomib was administered at doses ranging from 0.4 to 1.38 mg/m2, twice weekly for 4 weeks, followed by a 2-week rest. DLTs, including grade III hyponatremia, fatigue and malaise, and hypokalemia, were observed at the highest dose levels (1.38 mg/m2 and 1.20 mg/m2); 1.04 mg/m2 was considered the MTD. Although grade IV events did occur, none was felt to be related to bortezomib. Evidence of antineoplastic activity was observed in patients with MM and non-Hodgkin's lymphoma. Of the nine evaluable patients with plasma cell dyscrasias, a complete response was observed in one patient, and the remaining eight showed evidence of decreased paraprotein levels or bone marrow plasmacytosis. In another phase I trial, DLTs were nonhematologic and included diarrhea and painful sensory neuropathy. Grade III sensory neuropathy was experienced by two of 12 patients treated at the highest dose level (1.56 mg/m2).28 Based on the pre-clinical and phase I activity in MM, a phase II study (SUMMIT) was initiated in patients with relapsed and refractory MM.24 The dose established for bortezomib in the treatment of relapsed/refractory myeloma was 1.3 mg/m2 given twice weekly on days 1, 4, 8, and 11 every 21 days.24 This schedule of at least 72 h between the dosages of bortezomib allows for the recovery of the inhibited proteasome, thus minimizing the incidence of significant and severe side effects. Dexamethasone (20 mg the day of and after each borte-zomib dose) was permitted if progressive disease was observed after two cycles, or in the presence of stable disease after four cycles. A total of 202 heavily pre-treated patients were enrolled. Of the 202 patients entered, 193 were evaluable for response. The overall response rate [complete remission (CR) + partial response (PR) + minimal response (MR)] was 35% (67 of

193 patients). Seven patients (4%) had a CR, and 12 (6%) had a near-CR (NCR) (myeloma protein undetectable by electrophoresis but immunofixation positive). An additional 34 patients (18%) achieved a PR, and 14 (7%) others an MR.24 The median time to disease progression for bortezomib as a single agent was 7 months, compared with 3 months that was reported for the patients' previous therapy (P = 0.01). In a landmark analysis, patients who achieved a CR or PR by the end of the second cycle survived significantly longer than those achieving other types of responses. Additional clinical benefits observed in these patients included increases in hemoglobin levels and platelet counts, resulting in a reduction in transfusion requirements. Moreover, levels of unaffected immunoglobu-lins improved. The factors that predicted poor response to bortezomib were older age (>65 years) and >50% plasma cells in the bone marrow. In this bortezomib trial, serum ^-microglobulin level, number or type of previous therapies, and chromosomal abnormalities, including chromosome 13 deletions, did not predict for poor response. This observation might be important for future development of bortezomib therapy in combination with other agents or strategies, especially in patients with poor prognosticators.242930

Drug-related adverse events of any grade occurring in >25% of patients included nausea (55%), diarrhea (44%), fatigue (41%), thrombocytopenia (40%), peripheral neuropathy (31%), vomiting (27%), and anorexia (25%). The most common grade III adverse events included thrombocytopenia (28%), fatigue (12%), peripheral neuropathy (12%), and neutropenia (11%). The most common grade IV events included thrombocytopenia (3%) and neutropenia (3%). Peripheral neuropathy was more likely to occur in patients who suffered from neuropathy at baseline (80%). Among the 33 patients who did not have evidence of peripheral neuropathy on study entrance, 17 developed peripheral neuropathy during the course of therapy. Most of the adverse events reported during the trial were manageable with standard supportive symptomatic therapy.

Bortezomib is an active agent in the management of relapsed/refractory MM, with responses occurring relatively quickly (within 6 weeks of the initiation of therapy). In view of its ability to sensitize myeloma cells to other biologics and chemotherapeutic agents,223132 further development using the agent in combination with other agents at low dosages is in progress. A maintenance strategy is being investigated as part of the phase III, APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial. Studies defining the dose and the frequency are urgently needed to maximize the benefits of this drug's mechanisms of action.

0 0

Post a comment