There are at least 4 phase III trials that demonstrate the efficacy of bortezomib and dexamethasone as induction therapy pre-transplantation. This combination has superior response rate post induction compared with other combinations Vincristine Doxorubicin and Dexamethasone (VAD) and Thalidomide and Dexamethasone (TD). These trials have also shown that stem cell mobilization is feasible after bortezomib/dexamethasone and yields satisfactory stem cells for double autologous stem cell transplantation (ASCT). Toxicity is comparable to VAD and TD. There is one phase III trial that demonstrates an improved PFS. Bortezomib is approved by TGA for treatment of newly diagnosed patients but not subsidized by PBS for this indication.
The administration schedule of bortezomib for induction pre-transplant is limited to 3-4 cycles whereas the bortezomib for relapsed disease is more prolonged usually 8-11 cycles if patients continue to respond. The dose of dexamethasone in the bortezomib/dexamethasone protocol for induction pre-transplant is higher per cycle than the doses used in relapsed disease.
IFM Phase II trial studied bortezomib plus dexamethasone as induction before autologous stem cell transplantation in 48 previously untreated myeloma patients.r They were treated with 4 cycles of 21 days. Bortezomib was given as 1.3mg/m2 on days 1,4,8,11; Dexamethasone 40mg was given on days 1 to 4 and 9 to 12 for the first 2 cycles and on days 1 to 4 for the following 2 cycles. Stem cells were harvested by G-CSF alone (10 µg/kg/day from days 17 to 23. 39 cases were collected after 3 cycles and 3 cases after the fourth cycle.
The IFM 2005-01 phase III trial compared VAD (A1), VAD plus DCEP consolidation (A2), bortezomib plus dexamethasone (B1), bortezomib plus dexamethasone (B2) plus DCEP consolidation, prior to autologous stem cell transplant.r
VAD is four 4-week cycles of vincristine 0.4 mg/day and doxorubicin 9 mg/m2/day by continuous infusion days 1 to 4 plus dexamethsone 40 mg orally days 1 to 4 (all cycles) and days 9 to 12 and days 17 to 20 (cycles 1 and 2). Bortezomib and dexamethasone comprised of four 3-week cycles of bortezomib 1.3 mg/m2 IVI on days 1,4,8,11 plus dexamethasone 40 mg days 1 to 4 (all cycles) and days 9 to 12 (cycles 1 to 2). DCEP comprised of two 4-week cycles of dexamethasone 40 mg days 1 to 4 plus cyclophosphamide 400 mg/m2, etoposide 40 mg/m2 and cisplatin 15 mg/m2/d by continuous infusion days 1-4. Recommended concomitant medications included bisphosphonates and antibiotics, antifungal and antiviral prophylaxis.
Stem cells were mobilized with GCSF 10 µg/kg/d from day 15, induction cycle 3. If collection was inadequate, cyclophosphamide 3 g/m2 plus G-CSF 5 µg/kg/d was undertaken after cycle 4. Conditioning for the first ASCT was melphalan 200 mg /m2. A second transplant was not given if the patient had at least VGPR.
Moreau et al reported a phase III trial comparing the post induction response rate of Bortezomib and Dexamethasone (VD) and reduced dose Bortezomib, thalidomide and dexamethasone (vtD).r 199 patients were randomized to each arm in 1:1 ratio. VD consisted four 3- week cycles of bortezomib 1.3 mg/m2 IVI on day 1,4,8,11 plus dexamethasone 40 mg days 1 to 4 (all cycles) and 9 to 12 (cycles 1 and 2). vTD consisted of four three weeks cycle of bortezomib 1 mg/m2 days 1,4,8 and 11, thalidomide 100 mg daily and same does of dexamethasone. In the case of less than a partial response after cycle 2 in vTD arm, the dose of bortezomib was increased to 1.3 mg/m2 and the dose of thalidomide to 200 mg/day. Stem cells were mobilized by G-CSF alone.
Cavo et al conducted a phase III, randomized study, comparing VTD vs TD as induction pre double autologous stem cell transplant and consolidation in newly diagnosed multiple myeloma (GIMEMA, Italian Myeloma Network).r There were 480 patients; 241 received VTD and 239 received TD. VTD consisted of three 21 cycles of bortezomib (1·3 mg/m2 on days 1, 4, 8, and 11), thalidomide (100 mg daily for the first 14 days and 200 mg daily thereafter) plus dexamethasone (40 mg daily on days 1,2,4,5,8,9,11,12). TD consisted of three 21 cycles of thalidomide (100 mg daily for the first 14 days and 200 mg daily thereafter) plus dexamethasone (40 mg daily on days 1 to 4 and 9 to 12).
Stem cells were mobilized with high dose cyclophosphamide 4 g/m2. Patients then had first ASCT, followed by thalidomide, dexamethasone, then second transplant and consolidation with either VTD or TD depending on the original randomization.
Rosinol et al performed a phase III trial, comparing VTD versus, TD versus VBMCP/VBAD/B) as induction therapy pre-ASCT (PETHEMA/GEM).r There were 386 patients.
TD consisted of thalidomide 200 mg daily (starting with escalating dose of 50 mg day 1 to 14 and 100 mg day 15 to 28 in cycle 1). Dexamethasone was 40 mg po day 1 to 4 and 9 to 12 at 4 weeks interval for 6 cycles. VTD was the same as TD plus bortezomib 1.3 mg/m2 on day 1,4,8,11 of each cycle.
VBMCP /VBAD/B consisted of 4 alternating cycles of VBMCP and VBAD followed by 2 cycles of bortezomib at 3 weeks interval (1.3 mg/m2 at day 1,4,8,11).
The IFM phase II trial showed the following response rates:
CR 21%; VGPR 10%; PR 35%. The median number of CD34+ stem cells collected was 6.7 10*6/kg (2.0 to 33.8 x 10*6/kg). Two patients were harvested after salvage chemotherapy (VAD or DCEP). Stem cells were not collected from 4 patients because three had progressive disease and one died. 27% of patients did not have enough stem cells for 2 transplants. 88% of patients (42 out of 48) proceeded with ASCT. After ASCT, there were 33% CR, 21% VGPR, 36% PR.r
© J Clin Oncol 2010
© J Clin Oncol 2010
There was no difference in PFS and OS after a median follow up of 31.2 months. Median PFS for VAD was 29.7 months and for bortezomib and dexamethasone was 36 months.
The use of DCEP consolidation did not have significant impact on response rate. Bortezomib and dexamethasone had better CR and at least VGPR than VAD plus DCEP. Bortezomib and dexamethasone’s CR and at least VGPR were 19.6% and 41.1% compared with 26% and 50% with bortezomib plus dex plus DCEP.
Moreau et al showed that the CR rate and the OR rate were the same in VD and vtD. However, CR+VGPR was higher in the vtD group (49% vs 36%, p=0.05). The VD group had higher median number of CD34+, lower number of apheresis and increased number of patients with target yield of 2 x 10*6/kg.r
Subsequent consolidation and maintenance treatment was at physicians’ discretion and there was increased consolidation and maintenance in the VD group.
The phase III study by Cavo et al showed that the rates of CR, VGPR and PR were significantly greater in the VTD compared with TD at all time points, after induction, first transplant and second transplant. The estimated 3-year rate of progression-free survival was 68% in the VTD group and 56% in the TD group (p=0·0057).r The CR rate was 35%, 14%, 21%, statistically significant. The median PFS was 56.2 months, 28.2, 35.5, p=0.01.
In the phase III IFM trial toxicity profile there were 7 deaths in the VAD group and no mortality in the bortezomib dexamethasone group (p=0.02). Grade 3 and 4 anaemia, neutropenia and thrombosis were significantly more common in the VAD group. There was significantly more peripheral neuropathy in the bortezomib dexamethasone group.
© J Clin Oncol 2010
Greater than or equal to grade 2 peripheral was higher in the VD group than the vtD group, 34% vs 14%.
Grade 3 and 4 peripheral neuropathy and skin rash occurred in a significantly higher proportion of patients on VTD (10% and 10%) than in those on TD (2% and 2%). There was no difference in the median number of CD34+ between VTD and TD.