In the randomised MM5 German study,r 3 cycles of VCD was compared with PAD in 504 newly diagnosed, transplant eligible myeloma patients. VCD has non-inferior response rate (37% vs 34.3% having ≥ very good partial response (VGPR), p=0.0001), lower rates of progressive disease (0.4% vs 4.8%, p=0.003), lower neuropathy (8.4% vs 14.9%, p=0.03), severe adverse events (24.0% vs 32.7%, p=0.04) and thromboembolic events (0.4% vs 2.8%, p=0.04). The study favours the use of VCD over PAD as initial induction therapy for transplant-eligible myeloma patients.
In another randomised French IFM 2013-04 study,r 4 cycles of VCD was compared with VTD in 340 newly diagnosed, transplant eligible patients. VCD has lower VGPR or better response (66.3% vs 56.2%, p=0.05) and lower ORR (92.3% vs 83.4%, p=0.01), although no differences was noted in rate of CR. VCD had higher grade 3 to 4 cytopenias (33.1% vs 18.9%, p=0.003), but VTD had higher rate of grade 2-4 peripheral neuropathy (21.9% vs 12.9%, p=0.008). In contrast, an earlier integrated analysis comparing VTD to VCD trialsr found that VTD had significantly higher post-induction CR/nCR rates (34% vs 6%, OR 3.9, 95% CI 1.5-11.3; p= 0.002) and VGPR rates (62% vs 7%, OR = 4.3, 95% CI 2.5- 7.2, p<0.0001) but no significant difference in ORR (90% vs 88%, p= 0.74). It should be noted that under current PBS funding restrictions, concomitant bortezomib with thalidomide cannot be given.
© British Journal of Haematology 2014
Further evidence regarding the efficacy is present in the 2019 published VCAT Studyr which investigated the role of bortezomib, thalidomide and prednisone consolidation in newly diagnosed transplant eligible myeloma patients. In this study all patients received initial therapy with 3 cycles of bortezomib (1.3mg/m2 D1,4,8,11), cyclophosphamide (300mg/m2 D1,8,15), and dexamethasone (20mg D1,2,4,5,8,9,11,12). Of the 256 patients enrolled in the trial, 250 patients completed 3 cycles of VCD with an VGPR rate post induction of 18.1% and a PR rate of 53.5%. Peripheral neuropathy rates following 3 cycles of induction were reported at 39%, however >= grade 3 PN account for 3.5% of patients.
Primary refractory or relapsed disease
Several phase II trials utilised VCD in the relapsed-refractory setting. De Waal et alr administered 6 cycles of VCD with 50 mg daily cyclophosphamide, followed by 1 year of bortezomib and cyclophosphamide maintenance, and showed an ORR of 71%, and a median PFS and OS of 18.4 months and 28.1 months respectively. Earlier, Kropff et alr used VCD with twice weekly bortezomib for 8 cycles, followed by weekly bortezomib for another 5 cycles. An ORR of 90% was achieved, with a median EFS and OS of 12 months and 22 months respectively.
Following encouraging results of phase 2 trials, a randomized controlled trial comparing bortezomib and dexamethasone with or without cyclophosphamide in patients with primary refractory or relapsed myeloma was performed.r The trial was prematurely terminated, due to lack of recruitment. 96 patients were randomized into 2 groups. The updated results demonstrated a median time to progression of 9.9 months in the VCD arm, compared with 12.6 months in the VD arm. Overall response rates were similar (70% in VCD arm and 74% in VD arm).r