Randomized, Open-Label Clinical Study in Patients with Previously Untreated Multiple Myeloma 

A prospective, international, randomized (1:1), open-label clinical study (NCT00111319) of 682 patients was conducted to determine whether VELCADE administered intravenously (1.3 mg/m2) in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) resulted in improvement in time to progression (TTP) when compared to melphalan (9 mg/m2) and prednisone (60 mg/m2) in patients with previously untreated multiple myeloma. Treatment was administered for a maximum of nine cycles (approximately 54 weeks) and was discontinued early for disease progression or unacceptable toxicity. Antiviral prophylaxis was recommended for patients on the VELCADE study arm.

The median age of the patients in the study was 71 years (48;91), 50% were male, 88% were Caucasian and the median Karnofsky performance status score for the patients was 80 (60;100). Patients had IgG/IgA/Light chain myeloma in 63%/25%/8% instances, a median hemoglobin of 105 g/L (64;165), and a median platelet count of 221,500/microliter (33,000;587,000). 

Efficacy results for the trial are presented in Table 14. At a prespecified interim analysis (with median follow-up of 16.3 months), the combination of VELCADE, melphalan and prednisone therapy resulted in significantly superior results for time to progression, progression-free survival, overall survival and response rate. Further enrollment was halted, and patients receiving melphalan and prednisone were offered VELCADE in addition. A later, prespecified analysis of overall survival (with median follow-up of 36.7 months with a hazard ratio of 0.65, 95% CI: 0.51, 0.84) resulted in a statistically significant survival benefit for the VELCADE, melphalan and prednisone treatment arm despite subsequent therapies including VELCADE based regimens. In an updated analysis of overall survival based on 387 deaths (median follow-up 60.1 months), the median overall survival for the VELCADE, melphalan and prednisone treatment arm was 56.4 months and for the melphalan and prednisone treatment arm was 43.1 months, with a hazard ratio of 0.695 (95% CI: 0.57, 0.85). 

TTP was statistically significantly longer on the VELCADE, melphalan and prednisone arm (see Figure 1). (median follow-up 16.3 months)

Figure 1: Time to Progression VELCADE, Melphalan and Prednisone vs Melphalan and Prednisone 

Overall survival was statistically significantly longer on the VELCADE, melphalan and prednisone arm (see Figure 2). (median follow-up 60.1 months)

Figure 2: Overall Survival VELCADE, Melphalan and Prednisone vs Melphalan and Prednisone

Randomized, Clinical Study in Relapsed Multiple Myeloma of VELCADE vs Dexamethasone

A prospective Phase 3, international, randomized (1:1), stratified, open-label clinical study (NCT00048230) 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 (one previous line vs more than one line of therapy), time of progression relative to prior treatment (progression during or within six months of stopping their most recent therapy vs relapse >6 months after receiving their most recent therapy), and screening beta2-microglobulin levels (≤2.5 mg/L vs >2.5 mg/L).

Baseline patient and disease characteristics are summarized in Table 15. 

Patients in the VELCADE treatment group were to receive 8, three week treatment cycles followed by 3, five week treatment cycles of VELCADE. Patients achieving a CR were treated for four cycles beyond first evidence of CR. Within each three week treatment cycle, VELCADE 1.3 mg/m2/dose alone was administered by intravenous bolus twice weekly for two weeks on Days 1, 4, 8, and 11 followed by a ten day rest period (Days 12 to 21). Within each five week treatment cycle, VELCADE 1.3 mg/m2/dose alone was administered by intravenous bolus once weekly for four weeks on Days 1, 8, 15, and 22 followed by a 13 day rest period (Days 23 to 35) [see Dosage and Administration (2.2)].

Patients in the dexamethasone treatment group were to receive 4, five week treatment cycles followed by 5, four week treatment cycles. Within each five 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 to 35). Within each four 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. 

In the VELCADE arm, 34% of patients received at least one VELCADE dose in all eight of the three 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 four of the five week treatment cycles of therapy, and 6% received at least one dose in all nine cycles.

The time to event analyses and response rates from the relapsed multiple myeloma study are presented in Table 16. Response and progression were assessed using the European Group for Blood and Marrow Transplantation (EBMT) criteria. 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 two occasions for a minimum of at least six 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+).

TTP was statistically significantly longer on the VELCADE arm (see Figure 3).

Figure 3: Time to Progression Bortezomib vs Dexamethasone (Relapsed Multiple Myeloma Study)

As shown in Figure 4, VELCADE had a significant survival advantage relative to dexamethasone (p <0.05). The median follow-up was 8.3 months.

Figure 4: Overall Survival Bortezomib vs Dexamethasone (Relapsed Multiple Myeloma Study)

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 beta2-microglobulin levels at baseline.

Randomized, Open-Label Clinical Study of VELCADE Subcutaneous vs Intravenous in Relapsed Multiple Myeloma 

An open-label, randomized, Phase 3 noninferiority study (NCT00722566) compared the efficacy and safety of the subcutaneous administration of VELCADE vs the intravenous administration. This study included 222 bortezomib naïve patients with relapsed multiple myeloma, who were randomized in a 2:1 ratio to receive 1.3 mg/m2 of VELCADE by either the subcutaneous (n=148) or intravenous (n=74) route for eight cycles. Patients who did not obtain an optimal response (less than Complete Response (CR)) to therapy with VELCADE alone after four cycles were allowed to receive oral dexamethasone 20 mg daily on the day of and after VELCADE administration (82 patients in subcutaneous treatment group and 39 patients in the intravenous treatment group). Patients with baseline Grade ≥2 peripheral neuropathy or neuropathic pain, or platelet counts <50,000/µL were excluded. A total of 218 patients were evaluable for response. 

Stratification factors were based on the number of lines of prior therapy the patient had received (one previous line vs more than one line of therapy), and international staging system (ISS) stage (incorporating beta2-microglobulin and albumin levels; Stages I, II, or III).

The baseline demographic and other characteristics of the two treatment groups are summarized as follows: the median age of the patient population was approximately 64 years of age (range: 38 to 88 years), primarily male (subcutaneous: 50%, intravenous: 64%); the primary type of myeloma is IgG (subcutaneous: 65% IgG, 26% IgA, 8% light chain; intravenous: 72% IgG, 19% IgA, 8% light chain), ISS staging I/II/III (%) was 27, 41, 32 for both subcutaneous and intravenous, Karnofsky performance status score was ≤70% in 22% of subcutaneous and 16% of intravenous, creatinine clearance was 67.5 mL/min in subcutaneous and 73 mL/min in intravenous, the median years from diagnosis was 2.68 and 2.93 in subcutaneous and intravenous respectively and the proportion of patients with more than one prior line of therapy was 38% in subcutaneous and 35% in intravenous.

This study met its primary (noninferiority) objective that single agent subcutaneous VELCADE retains at least 60% of the overall response rate after four cycles relative to single agent intravenous VELCADE. The results are provided in Table 17. 

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 mg/m2 or 1.3 mg/m2 intravenous bolus twice weekly for two weeks on Days 1, 4, 8, and 11 followed by a ten 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 two years, and patients had received a median of one prior line of treatment (median of three prior therapies). A single complete response was seen at each dose. The overall response rates (CR + PR) were 30% (8/27) at 1 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 seven 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 three week dosing schedule during the extension study. No new cumulative or new long-term toxicities were observed with prolonged VELCADE treatment [see Adverse Reactions (6.1)].

A Single-Arm Trial of Retreatment in Relapsed Multiple Myeloma

A single-arm, open-label trial (NCT00431769) was conducted to determine the efficacy and safety of retreatment with VELCADE. One hundred and thirty patients (≥18 years of age) with multiple myeloma who previously had at least partial response on a VELCADE-containing regimen (median of two prior lines of therapy [range: 1 to 7]) were retreated upon progression with VELCADE administered intravenously. Patients were excluded from trial participation if they had peripheral neuropathy or neuropathic pain of Grade ≥2. At least six months after prior VELCADE therapy, VELCADE was restarted at the last tolerated dose of 1.3 mg/m2 (n=93) or ≤1 mg/m2 (n=37) and given on Days 1, 4, 8 and 11 every three weeks for maximum of eight cycles either as single agent or in combination with dexamethasone in accordance with the standard of care. Dexamethasone was administered in combination with VELCADE to 83 patients in Cycle 1 with an additional 11 patients receiving dexamethasone during the course of VELCADE retreatment cycles.

The primary endpoint was best confirmed response to retreatment as assessed by European Group for Blood and Marrow Transplantation (EBMT) criteria. Fifty of the 130 patients achieved a best confirmed response of Partial Response or better for an overall response rate of 38.5% (95% CI: 30.1, 47.4). One patient achieved a Complete Response and 49 achieved Partial Response. In the 50 responding patients, the median duration of response was 6.5 months and the range was 0.6 to 19.3 months.