Results of the phase III VCAT study: subcutaneous bortezomib, thalidomide and prednisolone consolidation

Consolidation therapy with thalidomide and prednisolone (TP) in patients with newly diagnosed multiple myeloma (NDMM), post-autologous stem cell transplant (ASCT) is the standard of care in Australia.¹ In other studies, consolidation with bortezomib (Velcade^®), a proteasome inhibitor (PI), has been shown to deepen responses and prolong progression free survival (PFS) in patients with NDMM following ASCT. Therefore, it was hypothesized that adding bortezomib to the TP consolidation regimen, may increase patient outcomes.

In this study by Noemi Horvath, Royal Adelaide Hospital, AUS, and colleagues, patients with NDMM were treated with an induction regimen of bortezomib, cyclophosphamide and dexamethasone, proceeded to ASCT, and then received consolidation therapy of bortezomib + TP (VTP), or TP alone. The results of their randomized, open-label, phase III study, VCAT (NCT01539083), were recently published in Leukemia and Lymphoma.²

Patient characteristics and study design

• The study recruited adult patients (N = 256) with NDMM who were eligible for transplant
• Participating centers were in Australia, Korea and China
• Primary endpoint: proportion of post-ASCT evaluable patients achieving complete response (CR) + very good partial response (VGPR) (≥VGPR) after 12 months of consolidation
• Secondary endpoints:
• CR rate and stringent CR rate (sCR) after 3, 6, 9 and 12 months of consolidation, PFS from randomization, disease free survival (DFS) in patients with CR, overall survival (OS), overall response rate (ORR) to induction and ASCT, safety and tolerability, health related quality of life (HRQoL), patient-related symptoms of peripheral neuropathy (PN)
• Median age in intent-to-treat (ITT) population (N = 256): 59 years (32–71)

Therapy pathway:

• Three, 21-day, cycles of induction with bortezomib, cyclophosphamide and dexamethasone (VCD)
• Subcutaneous bortezomib: 1.3 mg/m² on days 1, 4, 8 and 11
• Oral cyclophosphamide: 300 mg/m² on days 1, 8 and 15
• Oral dexamethasone: 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12
• Peripheral blood stem cell (PBSC) mobilization and collection
• High-dose therapy (HDT) of 200 mg/m² of intravenous melphalan and ASCT
•  Randomized 1:1 followed by consolidation with thalidomide and prednisolone (TP) or bortezomib + TP (VTP) (N = 203)
• TP (N = 100): thalidomide 100mg/d for ≤12 months or until progressive disease (PD) and prednisolone: 50 mg on alternate days, indefinitely or until PD
• VTP (N = 103): subcutaneous bortezomib: 1.3 mg/m² every 2 weeks for 32 weeks plus TP

Key Findings

All results are given as VTP versus TP

Efficacy

• Induction therapy (N = 254):
• Evaluable for response: N = 243
• ≥VGPR achieved in 18.1% of patients
• ORR: 71.6%
• Post-ASCT
• ≥VGPR: 35.8%
• ORR: 79%
• CR: 2.5%
• PD developed in 8 patients during induction/post-transplant
• At randomization:
• ≥VGPR: 42.9% vs 37.5%
• CR: 2% vs 4.2%
• After randomization:
• ≥VGPR at 3 months: 69% vs 65%
• ≥VGPR at 12 months: 85.7% vs 77.1% (primary endpoint)
  • Rate difference: 8.6% (95% CI, 2.3–19.5%, P = 0.122)
• Twelve months following consolidation, minimal residual disease (MRD) negativity was achieved in 20.4% vs 20.8%
• Median duration of response (DoR) in responders to consolidation was not reached in either treatment arm

Survival:

• Median follow-up post randomization: 22.3 months vs 23.2 months
• PFS
• Median: 31.7 vs 32.8 months
• Hazard ratio [HR] 1.12, 95% CI, 0.67–1.87, P = 0.6689)
• Twelve month: 89.7% vs 86.4%
• Twenty-four month: 65.5% vs 74.2%
• During consolidation, 11 patients developed PD
• OS: at data cut-off, OS data was not mature
• DFS
• Median (in responders): 11.2 (N = 39) vs 16.4 (N = 43) months
• Twelve month: 44.0% vs 61.9%
• Thirty month: 28.0% vs 33.6%

Safety

During VCD induction (N = 254):

• Median number of cycles: 3
• Drug-related TEAE: 85% (N = 216)
• Grade ≥3 TEAE: 42% (N = 107)
• Most common grade ≥3 TEAE: neutropenia (6%, N = 15)
• PN not elsewhere classified (NEC), grade 3: 3.5% (N = 9)

During consolidation:

• Median duration of treatment:
• Bortezomib (VTP cohort): 6.9 months (0–8.4)
• Thalidomide: 10.2 months (0–11.1) vs 10.1 months (0–13.8)
• Prednisolone: 10.2 months (0–13.2) vs 10.2 months (0–13.8)
• TEAE:
• Drug-related TEAE: 87% (N = 90) vs 91% (N = 90)
• Most common all-cause TEAEs: PN (62%) and upper respiratory tract infection (38%) vs PN (63%) and constipation (38%)
• Grade ≥3 TEAE: 28% vs 36%
• Most frequent grade ≥3 TEAE: pneumonia (5%) and neutropenia (4%) vs PN (8%) and pneumonia (6%)
• PN:
• Frequency of PN: 62% (N = 64) vs 63% (N = 62)
• Grade ≥3 PN: 2% vs 8%
• The rate of hematologic TEAEs was low in both groups
• Serious adverse events (SAEs): 27% (N = 28) vs 22% (N = 22)
• Drug-related SAEs: 15% (N = 15) vs 8% (N = 8)
• Discontinuations: 85 (53 prior to randomization and 32 post-randomization)
• Post-randomization discontinuations predominantly due to TEAEs and PD
• No deaths due to drug-related TEAEs during consolidation
• HRQoL: largely similar between patient groups

Patients in this study were treated with the same induction therapy; therefore, upon starting consolidation all patients were IMid-naïve but bortezomib-exposed. It is possible that the improvements in efficacy were due to the exposure to thalidomide (an IMiD), explaining the similarity in the increases of response. Investigators had hypothesized an improvement of 15%, which was not reached.

It is possible that the number of cycles of induction therapy or the route of administration of bortezomib may have influenced the ≥VGPR rate. Additionally, whilst patients were recruited from Australia, China and Korea, 79% were white, meaning the patient population was not representative of all patients with NDMM.

With regards to safety, the addition of bortezomib was well tolerated and no new safety concerns emerged; with both VTP and TP regimens well-tolerated. However, a higher proportion of patients discontinued treatment due to TEAEs in the VTP group. The rate of hematologic AEs was low.

During consolidation, the percentage of patients achieving a VGPR or better was improved in both treatment arms and despite an improvement trend in the ≥VGPR rate after 12 months in the VTP arm, statistical significance was not reached. No statistically significant differences were observed in the secondary endpoints (PFS, DFS and HRQoL). The VTP regimen investigated here is not recommended compared to TP alone for patients with NDMM who receive VCD induction and ASCT.