Mechanism of Action
Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma.
Following intravenous administration of 1.0 mg/m2 and 1.3 mg/m2 doses to 24 patients with multiple myeloma (n=12, per each dose level), the mean maximum plasma concentrations of bortezomib (Cmax) after the first dose (Day 1) were 57 and 112 ng/mL, respectively. In subsequent doses, when administered twice weekly, the mean maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the 1.0 mg/m2 dose and 89 to 120 ng/mL for the 1.3 mg/m2 dose. The mean elimination half-life of bortezomib upon multiple dosing ranged from 40 to 193 hours after the 1.0 mg/m2 dose and 76 to 108 hours after the 1.3mg/m2 dose. The mean total body clearances was 102 and 112 L/h following the first dose for doses of 1.0 mg/m2 and 1.3 mg/m2, respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1.0 and 1.3 mg/m2, respectively.
The mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m2 following single- or repeat-dose administration of 1.0mg/m2 or 1.3mg/m2 to patients with multiple myeloma. This suggests bortezomib distributes widely to peripheral tissues. The binding of bortezomib to human plasma proteins averaged 83% over the concentration range of 100 to 1000 ng/mL.
In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 2C19, and 1A2. Bortezomib metabolism by CYP 2D6 and 2C9 enzymes is minor. The major metabolic pathway is deboronation to form 2 deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated bortezomib metabolites are inactive as 26S proteasome inhibitors. Pooled plasma data from 8 patients at 10 min and 30 min after dosing indicate that the plasma levels of metabolites are low compared to the parent drug.
The pathways of elimination of bortezomib have not been characterized in humans.
Age: Analyses of data after the first dose of Cycle 1 (Day 1) in 39 multiple myeloma patients who had received intravenous doses of 1.0 mg/m2 and 1.3 mg/m2 showed that both dose-normalized AUC and Cmax tend to be less in younger patients. Patients < 65 years of age (n=26) had about 25% lower mean dose-normalized AUC and Cmax than those ≥ 65 years of age (n=13).
Gender: Mean dose-normalized AUC and Cmax values were comparable between male (n=22) and female (n=17) patients after the first dose of Cycle 1 for the 1.0 and 1.3 mg/m2 doses.
Race: The effect of race on exposure to bortezomib could not be assessed as most of the patients were Caucasian.
Hepatic Impairment: No pharmacokinetic studies were conducted with bortezomib in patients with hepatic impairment (see PRECAUTIONS).
Renal Impairment: Clinical studies included patients with creatinine clearance values as low as 13.8 mL/min (see PRECAUTIONS).
Pediatric: There are no pharmacokinetic data in pediatric patients.
No formal drug interaction studies have been conducted with bortezomib.
In vitro studies with human liver microsomes indicate that bortezomib is primarily a substrate of cytochrome P450 3A4, 2C19, and 1A2 (see PRECAUTIONS).
Bortezomib is a poor inhibitor of human liver microsome cytochrome P450 1A2, 2C9, 2D6, and 3A4, with IC50 values of >30µM (>11.5µg/mL). Bortezomib may inhibit 2C19 activity (IC50 = 18 µM, 6.9 µg/mL) and increase exposure to drugs that are substrates for this enzyme.
Bortezomib did not induce the activities of cytochrome P450 3A4 and 1A2 in primary cultured human hepatocytes.
Following twice weekly administration of 1.0 mg/m2 and 1.3 mg/m2 bortezomib doses (n=12 per each dose level), the maximum inhibition of 20S proteasome activity (relative to baseline) in whole blood was observed 5 minutes after drug administration. Comparable maximum inhibition of 20S proteasome activity was observed between 1.0 and 1.3 mg/m2 doses. Maximal inhibition ranged from 70% to 84% and from 73% to 83% for the 1.0 mg/m2 and 1.3 mg/m2 dose regimens, respectively.
Randomized, Open-Label, Phase 3 Clinical Study in Relapsed Multiple Myeloma
A prospective phase 3, international, randomized (1:1), stratified, open-label clinical study enrolling 669 patients was designed to determine whether VELCADE resulted in improvement in time to progression (TTP) compared to high-dose dexamethasone in patients with progressive multiple myeloma following 1 to 3 prior therapies. Patients considered to be refractory to prior high-dose dexamethasone were excluded as were those with baseline grade ≥2 peripheral neuropathy or platelet counts <50,000/µL. A total of 627 patients were evaluable for response.
Stratification factors were based on the number of lines of prior therapy the patient had previously received (1 previous line versus more than 1 line of therapy), time of progression relative to prior treatment (progression during or within 6 months of stopping their most recent therapy versus relapse >6 months after receiving their most recent therapy), and screening β2-microglobulin levels (≤2.5 mg/L versus >2.5 mg/L).
Baseline patient and disease characteristics are summarized in Table 1.
Table 1: Summary of Baseline Patient and Disease Characteristics in the Phase 3 Multiple Myeloma Study
| Median age in years (range)||62.0 (33, 84)||61.0 (27, 86)|
| Gender: Male/female||56% / 44%||60% / 40%|
| Race: Caucasian/black/other||90% / 6% / 4%||88% / 7% / 5%|
| Karnofsky performance status score ≤70||13%||17%|
| Hemoglobin <100 g/L||32%||28%|
| Platelet count <75 x 109/L||6%||4%|
| Type of myeloma (%): IgG/IgA/Light chain||60% / 23% / 12%||59% / 24% / 13%|
| Median β2-microglobulin (mg/L)||3.7||3.6|
| Median albumin (g/L)||39.0||39.0|
| Creatinine clearance ≤30 mL/min [n (%)]||17 (5%)||11 (3%)|
|Median Duration of Multiple Myeloma Since Diagnosis (Years)||3.5||3.1|
|Number of Prior Therapeutic Lines of Treatment|
| 1 prior line||40%||35%|
| >1 prior line||60%||65%|
| Any prior steroids, e.g., dexamethasone, VAD||98%||99%|
| Any prior anthracyclines, e.g., VAD, mitoxantrone||77%||76%|
| Any prior alkylating agents, e.g., MP, VBMCP||91%||92%|
| Any prior thalidomide therapy||48%||50%|
| Vinca alkaloids||74%||72%|
| Prior stem cell transplant/other high-dose therapy||67%||68%|
| Prior experimental or other types of therapy||3%||2%|
Patients in the VELCADE treatment group were to receive eight 3-week treatment cycles followed by three 5-week treatment cycles of VELCADE. Within each 3-week treatment cycle, VELCADE 1.3 mg/m2/dose alone was administered by IV bolus twice weekly for 2 weeks on Days 1, 4, 8, and 11 followed by a 10-day rest period (Days 12 to 21). Within each 5-week treatment cycle, VELCADE 1.3 mg/m2/dose alone was administered by IV bolus once weekly for 4 weeks on Days 1, 8, 15, and 22 followed by a 13-day rest period (Days 23 to 35) (see DOSAGE AND ADMINISTRATION).
Patients in the dexamethasone treatment group were to receive four 5-week treatment cycles followed by five 4-week treatment cycles. Within each 5-week treatment cycle, dexamethasone 40 mg/day PO was administered once daily on Days 1 to 4, 9 to 12, and 17 to 20 followed by a 15-day rest period (Days 21-35). Within each 4-week treatment cycle, dexamethasone 40 mg/day PO was administered once daily on Days 1 to 4 followed by a 24-day rest period (Days 5 to 28). Patients with documented progressive disease on dexamethasone were offered VELCADE at a standard dose and schedule on a companion study.
Following a preplanned interim analysis of time to progression, the dexamethasone arm was halted and all patients randomized to dexamethasone were offered VELCADE, regardless of disease status. At this time of study termination, a final statistical analysis was performed. Due to this early termination of the study, the median duration of follow-up for surviving patients (n=534) is limited to 8.3 months.
In the VELCADE arm, 34% of patients received at least one VELCADE dose in all 8 of the 3-week cycles of therapy, and 13% received at least one dose in all 11 cycles. The average number of VELCADE doses during the study was 22, with a range of 1 to 44. In the dexamethasone arm, 40% of patients received at least one dose in all 4 of the 5-week treatment cycles of therapy, and 6% received at least one dose in all 9 cycles.
The time to event analyses and response rates from the phase 3 multiple myeloma study are presented in Table 2. Response and progression were assessed using the European Group for Blood and Marrow Transplantation (EBMT) criteria.1 Complete response (CR) required <5% plasma cells in the marrow, 100% reduction in M-protein, and a negative immunofixation test (IF-). Partial Response (PR) requires ≥50% reduction in serum myeloma protein and ≥90% reduction of urine myeloma protein on at least 2 occasions for a minimum of at least 6 weeks along with stable bone disease and normal calcium. Near complete response (nCR) was defined as meeting all the criteria for complete response including 100% reduction in M-protein by protein electrophoresis, however M-protein was still detectable by immunofixation (IF+).
Table 2: Summary of Efficacy Analyses in the Phase 3 Multiple Myeloma Study
|Efficacy Endpoint||All Patients||1 Prior Line of Therapy||> 1 Prior Line of Therapy|
|a Kaplan-Meier estimate.|
|b Hazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable. A hazard ratio less than 1 indicates an advantage for VELCADE.|
|c p-value based on the stratified log-rank test including randomization stratification factors.|
|d Precise p-value cannot be rendered.|
|e Response population includes patients who had measurable disease at baseline and received at least 1 dose of study drug.|
|f EBMT criteria1; nCR meets all EBMT criteria for CR but has positive IF. Under EBMT criteria. nCR is in the PR category.|
|g In 2 patients, the IF was unknown.|
|h p-value for Response Rate (CR + PR) from the Cochran-Mantel-Haenszel chi-square test adjusted for the stratification factors; |
|i Not Estimable.|
|j Not Applicable, no patients in category.|
| Time to Progression |
Events n (%)
|147 (44)||196 (58)||55 (42)||64 (54)||92 (46)||132 (61)|
|Hazard ratio b|
| Overall Survival |
Events (deaths) n (%)
|51 (15)||84 (25)||12 (9)||24 (20)||39 (20)||60 (28)|
|Hazard ratio b|
| Response Rate |
Population e n = 627
|CR f n (%)||20 (6)||2 (<1)||8 (6)||2 (2)||12 (6)||0 (0)|
|PR f n(%)||101 (32)||54 (17)||49 (38)||27 (25)||52 (28)||27 (13)|
|nCR f,g n(%)||21 (7)||3 (<1)||8 (6)||2 (2)||13 (7)||1 (<1)|
|CR + PR f n (%)||121 (38)||56 (18)||57 (45)||29 (26)||64 (34)||27 (13)|
|Median Response Duration|
|CR f||9.9 mo||NE i||9.9 mo||NE||6.3 mo||NA j|
|nCR f||11.5 mo||9.2 mo||NE||NE||11.5 mo||9.2 mo|
|CR + PR f||8.0 mo||5.6 mo||8.1 mo||6.2 mo||7.8 mo||4.1 mo|
TTP was statistically significantly longer on the VELCADE arm (see Figure 1).
As shown in Figure 2, VELCADE had a significant survival advantage relative to dexamethasone (p<0.05). The median follow-up was 8.3 months.
For the 121 patients achieving a response (CR or PR) on the VELCADE arm, the median duration was 8.0 months (95% CI: 6.9, 11.5 months) compared to 5.6 months (95% CI: 4.8, 9.2 months) for the 56 responders on the dexamethasone arm. The response rate was significantly higher on the VELCADE arm regardless of β2-microglobulin levels at baseline.
Phase 2 Single-arm Clinical Study in Relapsed Multiple Myeloma
The safety and efficacy of VELCADE in relapsed multiple myeloma were evaluated in an open-label, single-arm, multicenter study of 202 patients who had received at least 2 prior therapies and demonstrated disease progression on their most recent therapy. The median number of prior therapies was 6. Baseline patient and disease characteristics are summarized in Table 3.
An IV bolus injection of VELCADE 1.3 mg/m2/dose was administered twice weekly for 2 weeks on Days 1, 4, 8, and 11 followed by a 10-day rest period (Days 12 to 21) for a maximum of 8 treatment cycles. The study employed dose modifications for toxicity (see DOSAGE AND ADMINISTRATION). Patients who experienced a response to VELCADE were allowed to continue VELCADE treatment in an extension study.
Table 3: Summary of Baseline Patient and Disease Characteristics in a Phase 2 Multiple Myeloma Study*
|Patient Characteristics||N = 202|
|* Based on number of patients with baseline data available|
| Median age in years (range)||59 (34, 84)|
| Gender: Male/female||60% / 40%|
| Race: Caucasian/black/other||81% / 10% /8%|
| Karnofsky Performance Status score ≤70||20%|
| Hemoglobin <100 g/L||44%|
| Platelet count <75 x 109/L||21%|
| Type of myeloma (%): IgG/IgA/Light chain||60% / 24% / 14%|
| Median β2-microglobulin (mg/L)||3.5|
| Median creatinine clearance (mL/min)||73.9|
| Abnormal cytogenetics ||35%|
| Chromosome 13 deletion||15%|
|Median Duration of Multiple Myeloma Since Diagnosis in Years||4.0|
| Any prior steroids, e.g., dexamethasone, VAD||99%|
| Any prior alkylating agents, e.g., MP, VBMCP||92%|
| Any prior anthracyclines, e.g., VAD, mitoxantrone||81%|
| Any prior thalidomide therapy ||83%|
| Received at least 2 of the above||98%|
| Received at least 3 of the above||92%|
| Received all 4 of the above||66%|
| Any prior stem cell transplant/other high-dose therapy||64%|
| Prior experimental or other types of therapy||44%|
Responses to VELCADE alone are shown in Table 4. Response rates to VELCADE alone were determined by an independent review committee (IRC) based on EBMT criteria.1 Response rates using the Southwest Oncology Group (SWOG) criteria2 are also shown. SWOG response required a ≥75% reduction in serum myeloma protein and/or ≥90% urine protein. A total of 188 patients were evaluable for response; 9 patients with nonmeasurable disease could not be evaluated for response by the IRC, and 5 patients were excluded from the efficacy analyses because they had had minimal prior therapy. The mean number of cycles administered was 6. The median time to response was 38 days (range 30 to 127 days). The median survival of all patients enrolled was 17 months (range <1 to 36+ months).
Table 4: Summary of Response Outcomes in a Phase 2 Multiple Myeloma Study
|Response Analyses (VELCADE monotherapy) N = 188||N (%)||(95% CI)|
|a Clinical Remission (SWOG) required ≥75% reduction in serum myeloma protein and/or ≥90% reduction of urine myeloma protein on at least 2 occasions for a minimum of at least 6 weeks, stable bone disease and normal calcium.2|
|Overall Response Rate (EBMT) (CR + PR)||52 (28%)||(21, 35)|
| Complete Response (CR)||5 (3%)||(1, 6)|
| Partial Response (PR)||47 (25%)||(19, 32)|
|Clinical Remission (SWOG)a||33 (18%)||(12, 24)|
|Kaplan-Meier Estimated Median Duration of Response (95% CI)||385 Days||(245, 538)|
Of the 202 patients enrolled, 35% were 65 years of age or older. Nineteen percent (19%) of patients aged 65 years or older experienced CR or PR.
In this study, the response rate to VELCADE, based on a univariate analysis, was independent of the number and types of prior therapies. There was a decreased likelihood of response in patients with either >50% plasma cells or abnormal cytogenetics in the bone marrow. Responses were seen in patients with chromosome 13 abnormalities.
A Randomized Phase 2 Dose-Response Study in Relapsed Multiple Myeloma
An open-label, multicenter study randomized 54 patients with multiple myeloma who had progressed or relapsed on or after front-line therapy to receive VELCADE 1.0 mg/m2 or 1.3 mg/m2 IV bolus twice weekly for 2 weeks on Days 1, 4, 8, and 11 followed by a 10-day rest period (Days 12 to 21). The median duration of time between diagnosis of multiple myeloma and first dose of VELCADE on this trial was 2.0 years, and patients had received a median of 1 prior line of treatment (median of 3 prior therapies). A single complete response was seen at each dose. The overall response rates (CR + PR) were 30% (8/27) at 1.0 mg/m2 and 38% (10/26) at 1.3 mg/m2.
A Phase 2 Open-Label Extension Study in Relapsed Multiple Myeloma
Patients from the two phase 2 studies who in the investigators’ opinion would experience additional clinical benefit continued to receive VELCADE beyond 8 cycles on an extension study. Sixty-three (63) patients from the phase 2 multiple myeloma studies were enrolled and received a median of 7 additional cycles of VELCADE therapy for a total median of 14 cycles (range 7 to 32). The overall median dosing intensity was the same in both the parent protocol and extension study. Sixty-seven percent (67%) of patients initiated the extension study at the same or higher dose intensity at which they completed the parent protocol, and 89% of patients maintained the standard 3-week dosing schedule during the extension study. No new cumulative or new long-term toxicities were observed with prolonged VELCADE treatment (see ADVERSE REACTIONS).
A Phase 2 Single-arm Clinical Study in Relapsed Mantle Cell Lymphoma After Prior Therapy
The safety and efficacy of VELCADE in relapsed or refractory mantle cell lymphoma were evaluated in an open-label, single-arm, multicenter study of 155 patients with progressive disease who had received at least 1 prior therapy. The median age of the patients was 65 years (42, 89), 81% were male, and 92% were caucasian. Of the total, 75% had one or more extra-nodal sites of disease, and 77% were stage 4. In 91% of the patients, prior therapy included all of the following: an anthracycline or mitoxantrone, cyclophosphamide, and rituximab. A total of thirty seven percent (37%) of patients were refractory to their last prior therapy. An IV bolus injection of VELCADE 1.3 mg/m2/dose was administered twice weekly for 2 weeks on Days 1, 4, 8, and 11 followed by a 10-day rest period (Days 12 to 21) for a maximum of 17 treatment cycles. The study employed dose modifications for toxicity (see DOSAGE AND ADMINISTRATION).
Responses to VELCADE are shown in Table 5. Response rates to VELCADE were determined according to the International Workshop Criteria (IWRC)3 based on independent radiologic review of CT scans. The median number of cycles administered across all patients was 4; in responding patients the median number of cycles was 8. The median time to response was 40 days (range 31 to 204 days). The median duration of follow-up was more than 13 months.
Table 5: Response Outcomes in a Phase 2 Mantle Cell Lymphoma Study
|Response Analyses (N = 155)||N (%)||95% CI|
| Overall Response Rate (IWRC) (CR + CRu + PR)||48 (31)||(24, 39)|
| Complete Response (CR + CRu) ||12 (8)||(4, 13)|
| CR||10 (6)||(3, 12)|
| CRu||2 (1)||(0, 5)|
| Partial Response (PR)||36 (23)||(17, 31)|
|Duration of Response||Median||95% CI|
| CR + CRu + PR (N = 48)||9.3 months||(5.4, 13.8)|
| CR + CRu (N = 12)||15.4 months||(13.4, 15.4)|
| PR (N=36)||6.1 months||(4.2, 9.3)|