Consolidation with VTd significantly improves the complete remission rate and time to progression following VTd induction and single autologous stem cell transplantation in multiple myeloma
High-dose therapy plus autologous stem cell transplantation (ASCT) is considered the standard of care for the frontline treatment in younger patients with multiple myeloma (NDMM). The achievement of complete response (CR) or at least very good partial response (VGPR) at the end of the ASCT procedure has been one of the key markers associated with an improved outcome. In recent years, several strategies were paralleled to increase the CR plus VGPR rate in the ASCT paradigm that included improving the induction treatment, and more recently, the consolidation and the maintenance phases post ASCT. The high activity shown by immunomodulatory drugs and bortezomib-based regimens before ASCT has recently led to their use as consolidation and maintenance therapies. Several studies have demonstrated the impact of VTd on response rates and progression-free survival (PFS) either as induction or consolidation regimen in NDMM; however, no data are available regarding the role of VTd consolidation in the context of bortezomib-triple-based VTd induction regimen followed by a single ASCT. We aimed to assess the efficacy and safety of VTd as consolidation therapy in the context of VTd as induction regimen, followed by a single ASCT (VTd-auto-VTd regimen). Thus, we have performed a retrospective multicentre study that has included NDMM eligible for ASCT upfront in two cohorts from 2009 to 2011 across nine IFM (Intergroupe Francophone du Myélome) centers. We recruited all patients diagnosed in the selected period of time in these centers in order to minimize the bias of our series. The VTd-auto-VTd cohort included 121 NDMM, a regimen consisting of three induction and two consolidation cycles of VTd (bortezomib 1.3 mg/m intravenously on days 1, 4, 8 and 11, thalidomide 100 mg/day orally and dexamethasone 40 mg weekly orally). All patients underwent ASCT with high-dose melphalan 200 mg/m. The 96 NDMM of the second cohort (VTd-auto) completed the same VTd-auto regimen without consolidation. None of the patients received maintenance therapy across cohorts. The study was approved by the ethics committee of CHRU of Lille and was conducted in accordance with the principles of the Declaration of Helsinki. All response rates were determined according to the International Myeloma Working Group criteria. In the whole study, the median age was 56 years; the sex ratio was 1.49; 50% had ISS 2 and 3; 22% had adverse FISH [t(4;14); del17p]. There was no significant difference regarding the patients’ characteristics across the two groups. Overall, the ORR (overall response rate) was identical in the two cohorts at the completion of therapy, although the CR rate was significantly greater in patients who received a VTd consolidation (P1⁄4 0.001) (Table 1). In the two cohorts, the CR rate increased by B20% following ASCT (from 10 to 30%), and to a similar extent (from 33 to 52%) in the cohort of patients who received two additional cycles of consolidation. Of note, 28/116 (24%) patients improved the depth of response after completion of consolidation. Importantly, 23 (20%) improved the depth of response to CR among these 28 patients and 5 improved to VGPR (Table 1). Furthermore, the patients who reached VGPR following ASCT had a significantly greater chance to reach CR following consolidation as compared with patients who did not reach VGPR, 38% versus 11.5%, respectively (P1⁄4 0.018). With a median follow-up of 30 months, the relapse rate was significantly lower in the cohort VTd-auto-VTd, 25 (21%) versus 43 (45%) patients, respectively (P1⁄4 0.001). The lower relapse rate consequently improved the median time to progression (TTP) in the cohort VTd-auto-VTd (P1⁄4 0.005) (Figure 1a); the estimated 4-year TTP was 62% and 29%, respectively, in either cohort. We further observed that patients in CR after consolidation had a greater median TTP as compared with patients who did not reach CR (Po0.0001) (Figure 1b). In the study, nine (8%) and six patients (8%) had died in either cohort, and the expected 4-year survival was 91% and 84%, respectively (P1⁄4 nonsignificant (ns)). A longer follow-up might help to demonstrate greater survival end points benefit in favor of VTd consolidation. Moreau et al. have reported a 89% ORR, 74% VGPRþ CR rate, 29% CR rate after the first ASCT in the VTd arm as induction without consolidation of the phase 3 trial IFM2007-02. The relapse rate was 53% and the median PFS was 26 months (median follow-up 32 months). On the other hand, Cavo et al. reported 97.5% ORR, 92% VGPRþCR rate, 61% CR rate, 39% 3-year progression and 62% estimated 5-year PFS (follow-up 43 months), respectively, in the VTd arm of the GIMEMA (Gruppo Italiano Malattie EMatologiche dell’Adulto) phase 3 trial, in which VTd was given as induction (three cycles) before and consolidation (two cycles) after double ASCT upfront in myeloma. The efficacy of consolidation therapy was significantly enhanced with the addition of bortezomib to TD, as shown by the higher rates of CR (60.6% versus 46.6%) in this trial. Interestingly, we report herein a 52% CR rate with a single ASCT in our study, and the 9% difference on CR rate between the two studies may reflect the impact of the tandem ASCT. The role of tandem ASCT in the context of novel agent-based induction and consolidation is currently under evaluation both in Europe (EMN02 study—a study to compare bortezomib, melphalan and prednisone (VMP) with single or tandem ASCT followed by bortezomib, lenalidomide and dexamethasone (VRD) consolidation and lenalidomide maintenance in patients with NDMM (HO95)) and in the US (BMT CTN 0702 trial—a multicenter phase 3 trial of tandem ASCT versus the strategy of single ASCT plus consolidation therapy with lenalidomide, bortezomib and dexamethasone (RVD) or single ASCT without consolidation, lenalidomide is being used as maintenance therapy for 3 years in all arms) as part of upfront treatment of MM.