The use of PAD as salvage therapy in relapsed/refractory myeloma patients was initially presented by Palumbo et al in 2008.r 64 consecutive, non-randomised patients were treated with bortezomib 1.3 mg/m2 on day 1, 4, 8, and 11; doxorubicin 20 mg/m2 (34 patients), or liposomal doxorubicin (30 patients) 30 mg/m2 on day 1 and 4 (depending on drug availability in the treating centre); and dexamethasone 40 mg days 1-4 in a 28-day cycle for up to six cycles. Previous treatment with bortezomib or anthracyclines was permitted in the study. The median number of prior therapies was 2 (range 1-7). 58% of patients had previously undergone ASCT, 70% had previous anthracycline exposure, 27% had prior bortezomib.
Lee et al has also reported the use of PAD (Bortezomib 1.3 mg/m2 days 1, 4, 8, 11; Doxorubicin 4.5 mg/m2 days 1-4; Dexamethasone 40 mg on days 1-4) followed by 12 months of Thalidomide (100 mg daily) and Dexamethasone (40 mg days 1-4 q28d) maintenance in relapsed/refractory patients.r This open-labelled phase II study recruited 37 evaluable, Bortezomib-naive patients whom have received a median of 2 prior therapy regimens. Of note, 58% had previously undergone ASCT, 83% had prior anthracyclines, and 33% had prior Thalidomide. 42% of patients had cytogenetic abnormalities, but the paper did not elaborate on the nature of the abnormalities.
Subsequently, it has also been evaluated in two large randomised studies in patients with newly diagnosed myeloma.
The HOVON-65/ GMMG-HD4r trial randomised 833 patients with newly diagnosed myeloma to receive either PAD (bortezomib 1.3 mg/m2 days 1, 4, 8, 11, doxorubicin 9 mg/m2 days 1-4, and dexamethasone 40 mg days 1-4, 9-12, 17-20), or VAD (vincristine 0.4 mg days 1-4, doxorubicin 9 mg/m2 days 1-4, and dexamethasone 40 mg days 1-4, 9-12, 17-20). Patients were then offered autologous stem cell transplant (ASCT) if fit enough and still on protocol. Following ASCT, patients in the VAD arm received 2 years maintenance with thalidomide 50 mg daily; those in the PAD are received 2 years maintenance with bortezomib 1.3 mg/m2 every 2 weeks. Patients with an HLA-identical sibling were given the option of proceeding to non-myeloblative allogeneic stem cell transplant, after which no maintenance was offered.
Mai et alr conducted a phase III randomised non-inferiority trial, comparing PAD with VCD (bortezomib, cyclophosphamide and dexamethasone) as induction in 504 newly diagnosed, transplant-eligible multiple myeloma patients. Response rates were evaluated after induction and prior to further therapies such as transplant.
In the Palumbo PAD trial,r CR or VGPR was achieved in 25% of patients, with median time to best response at 2 months. Overall, 1-year PFS was 34% with 1-year OS from the start of therapy being 66%. There was no significant difference in response (CR or PR) between patients with or without prior bortezomib exposure. Between patients whom received doxorubicin or liposomal doxorubicin, there was no significant difference in CR or VGPR rates.
With PAD salvage in bortezomib-naïve patients as reported by Lee et al, CR was 51%, VGPR 5% and PR 13% after a median follow-up period of 27 months. Median PFS was 18 months from the start of treatment. The 1-year PFS was 57% and 3-year PFS of 26%. 1-year OS was 75% and 3-year OS was 27% (median OS 35.1 months, 95% CI 18.5-51.7).r
In the HOVON-65/ GMMG-HD4 trial, CR (complete response) rates for PAD vs VAD were 36% vs 24% (P<0.001), and very good partial response (VGPR) rates were 76% vs 56% (P<0.001). Median PFS was 28 months for the VAD arm and 35 months for the PAD arm. Median overall survival was not reached in either arm at 66 months, but 5 year overall survival was 61% in the PAD arm, and 55% in the VAD arm. This only reached statistical significance in a multivariate analysis.r
In the Mai et alr trial, VCD was found to be non-inferior to PAD with respect to VGPR or better rates (34% vs 37%, P=0.001), but superior with respect to progressive disease rates 0.4% (VCD) versus 4.8% (PAD; P=0.003).
In the HOVON-65/ GMMG-HD4r trial, peripheral neuropathy was more common in the PAD arm (40% vs 18%).
In Mai et al,r leukocytopenia/neutropenia (> grade 3) occurred more frequently in the VCD arm (35.2% versus 11.3%, P<0.001). Neuropathy rates (> grade 2) were higher in the PAD group (14.9% versus 8.4%, P=0.03). Serious adverse events, both overall and those related to thromboembolic events, were higher in the PAD group (32.7% versus 24.0%, P=0.04 and 2.8% versus 0.4%, P=0.04).
The toxicity of PAD in the salvage setting (bortezomib naïve patients) is summarised below, both during PAD induction and the maintenance period with thalidomide and dexamethasone:r
© Ann Haematol 2010