Bortezomib

Bortezomib (VELCADE®) is a proteasome inhibitor that not only targets the myeloma cell, but also acts in the bone marrow micro-environment, inhibiting the binding of myeloma cells to bone marrow stromal cells, as well as demonstrating anabolic effects on bone.

Intravenous bortezomib, with or without dexamethasone, is effective and well tolerated in patients with relapsed/refractory multiple myeloma, as demonstrated in the phase II CREST and SUMMIT trials, and the phase III APEX trial, and is a recommended treatment for this patient group. Based on the results of another phase III trial, the combination of bortezomib plus pegylated liposomal doxor-ubicin is also a recommended treatment for patients with relapsed/refractory multiple myeloma. Other bortezomib-combination regimens have demonstrated promising response data in phase II trials in patients with relapsed/refractory disease, although response and survival data for these combinations need to be confirmed in larger phase III trials.

Following multiple intravenous doses of bortezomib 1.3mg/m², mean maximum plasma concentrations (89–120 ng/mL) were reached quickly (≤0.20 hours). Bortezomib is distributed widely to peripheral tissues and is extensively bound to human plasma proteins (mean 83%). Bortezomib is primarily metabolized by the cytochrome P450 (CYP) enzymes CYP3A4, CYP2C19 and CYP1A2, with a minor amount of metabolism occurring via CYP2D6 and CYP2C9. Bortezomib 1.3 mg/m² was eliminated more rapidly after the first dose than after subsequent doses (elimination half-life 12 vs 76–108 hours).

Two open-label, phase II trials (SUMMIT [n = 202] and CREST [n = 54]) established the efficacy of bortezomib 1.3mg/m² (with or without dexa-methasone) administered by intravenous bolus on days 1, 4, 8 and 11 of a 21-day cycle for a maximum of eight cycles in heavily pretreated patients with relapsed/refractory multiple myeloma. With this regimen, the percentages of patients with at least a minimal response (≥MR; i.e. complete [CR] plus partial [PR] plus MR) was 50% in CREST and 35% in SUMMIT. The randomized, open-label, phase III APEX trial which randomized 669 patients with relapsed multiple myeloma after one to three previous therapies demonstrated the superiority of a bortezomib 1.3 mg/m² regimen over a high-dose dexa-methasone regimen. As a result, the high-dose dexamethasone arm was halted at a planned interim analysis and all dexamethasone recipients were offered bortezomib. The median time to disease progression (TTP) was longer (6.2 vs 3.5 months; p< 0.001) with bortezomib than dexamethasone. With the bortezomib regimen, more patients achieved ≥PR (38% vs 18%; p<0.001) and CR (6% vs <1%; p<0.001), and the overall 1-year survival rate was higher (80% vs 66%; p = 0.003).

The combination of bortezomib 1.3 mg/m² plus pegylated liposomal doxo-rubicin significantly prolonged the TTP compared with bortezomib alone in a phase III trial in 646 bortezomib-naive patients with relapsed or refractory multiple myeloma. Bortezomib plus pegylated liposomal doxorubicin versus bortezomib alone was associated with a 45% reduction in the risk of disease progression; median TTP was 6.5 months with bortezomib alone and increased to 9.3 months with the combination regimen (p = 0.000004). The ≥PR rates were not significantly different between the two treatment arms of the trial; however, the median duration of response was longer with the combination regimen (10.2 vs 7.0 months; p = 0.0008). When thalidomide was added to a regimen of bortezomib plus pegylated liposomal doxorubicin (using a 28-day cycle), the ≥PR rate was 65% and CR rate was 23%.

Phase I/II trials in patients with relapsed/refractory disease have demonstrated that various three- or four-drug combinations involving bortezomib and other agents (including melphalan, prednisone, cyclophosphamide, dexamethasone, thalidomide or lenalidomide) were associated with promising responses (≥PR rates of 66–92%) and survival data. These combinations have yet to be fully investigated in phase III trials.

A regimen of bortezomib plus melphalan plus prednisone was significantly more effective than a regimen of melphalan plus prednisone with respect to the TTP and response rates, according to data from the phase III VISTA trial in 682 elderly patients with newly diagnosed multiple myeloma who were ineligible for transplantation. The bortezomib-containing regimen was associated with a 52% reduction in the risk of disease progression; median TTP was 24.0 versus 16.6 months, respectively (p< 0.001). The ≥PR rates (71% vs 35%) and CR rates (30% vs 4%) were also significantly higher (both p< 0.001) with the bortezomib-containing regimen. After a median follow-up of 25.9 months, the bortezomib-containing regimen was associated with higher 3-year survival rates (72% vs 59%; p = 0.003). Preliminary data from a phase III trial in 354 patients aged >65 years with newly diagnosed disease indicated that the addition of thalidomide to the bortezomib-containing regimen used in the VISTA trial was associated with an improved response (at least a very good partial response [≥VGPR] 55% vs 45%; p = 0.02).

Preliminary data from phase III trials have demonstrated the efficacy of induction regimens of bortezomib plus dexamethasone (≥VGPR 39%), bortezomib plus dexamethasone plus thalidomide (≥VGPR 62%) and bortezomib plus doxorubicin plus dexamethasone (≥VGPR 42%) in patients with newly diagnosed multiple myeloma. Bortezomib-containing induction regimens were superior to the comparator regimens for overall response rates (≥PR) both before and after autologous stem cell transplantation. Preliminary data from phase I/II trials have indicated high activity (≥VGPR of 55–74%) with various other bortezomib-containing induction regimens.

The most frequently reported adverse events (incidence ≥30%) associated with the use of bortezomib are asthenic conditions (fatigue, weakness, malaise), gastrointestinal events (nausea, diarrhoea, constipation, vomiting), peripheral neuropathy, pyrexia, thrombocytopenia, neutropenia, psychiatric disorders and anorexia/decreased appetite, according to data from the phase III APEX trial in patients with refractory or relapsed multiple myeloma. In the APEX trial, grade 3 or 4 adverse events occurred in 61% and 14% of bortezomib recipients. Common grade 3 adverse events associated with bortezomib included thrombocytopenia and neutropenia (26% and 12%); these adverse events were also the most commonly reported grade 4 adverse events (4% and 2%). Peripheral neuropathy occurred in 36% of bortezomib recipients in the APEX trial (7% with grade 3 and 1% with grade 4). Improvement or resolution of at least grade 2 peripheral neuropathy occurred in 64% of bortezomib recipients, with a median time to resolution of 110 days from onset. A change in the dose or schedule of administration of bortezomib is recommended in patients who experience new or worsening peripheral neuropathy.

In general, the combination of bortezomib with other chemotherapeutic agents resulted in a tolerability profile that was consistent with the known tolerability profiles of the individual agents involved, and did not result in any unexpected adverse events, according to data from phase III trials. Drug-related adverse events could generally be managed by dosage modifications and supportive therapy.